Ian & Stuart's Australian Mac: Not for Sale/Another.not.for.sale (Australia).iso/hold me in your arms/ravers/pihkal

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Subject: PiHKAL: The Chemical Story.  File 1 of 6


This is part 1 of 6 of the second half of PiHKAL: A Chemical Love
Story, by Alexander Shulgin and Ann Shulgin.  Please forgive any typos
or misprints in this file; further, because of ASCII limitations,
many of the typographical symbols in the original book could not be
properly represented in these files.

If you are seriously interested in the chemistry contained in these
files, you should order a copy of the book PiHKAL.  The book may be
purchased for $22.95 ($18.95 + $4.00 postage and handling) from
Transform Press, Box 13675, Berkeley, CA 94701.  California residents
please add $1.38 State sales tax.

At the present time, restrictive laws are in force in the United
States and it is very difficult for researchers to abide by the
regulations which govern efforts to obtain legal approval to do work
with these compounds in human beings....  No one who is lacking legal
authorization should attempt the synthesis of any of the compounds
described in these files, with the intent to give them to man.  To do
so is to risk legal action which might lead to the tragic ruination of
a life.  It should also be noted that any person anywhere who
experiments on himself, or on another human being, with any of the
drugs described herin, without being familiar with that drug's action
and aware of the physical and/or mental disturbance or harm it might
cause, is acting irresponsibly and immorally, whether or not he is
doing so within the bounds of the law.






    A SHORT INDEX TO THE PHENETHYLAMINES




This short index to the phenethylamines lists the 179 entries that
follow in alphebetical order.  The abbreviation PEA is for
phenethylamine, and A is for amphetamine.  The long index includes all
synonyms and is in Appendix A.

    Code    Compact         chemical name

    1    AEM        a-Ethyl-3,4,5-trimethoxy-PEA
    2    AL        4-Allyloxy-3,5-dimethoxy-PEA
    3     ALEPH        4-Methylthio-2,5-dimethoxy-A
    4     ALEPH-2        4-Ethylthio-2,5-dimethoxy-A
    5     ALEPH-4        4-Isopropylthio-2,5-dimethoxy-A
    6    ALEPH-6        4-Phenylthio-2,5-dimethoxy-A
    7    ALEPH-7        4-Propylthio-2,5-dimethoxy-A
    8    ARIADNE        2,5-Dimethoxy-a-ethyl-4-methyl-PEA
    9     ASB        3,4-Diethoxy-5-methoxy-PEA
    10     B        4-Butoxy-3,5-dimethoxy-PEA
    11    BEATRICE    2,5-Dimethoxy-4,N-dimethyl-A
    12     BIS-TOM        2,5-Bismethylthio-4-methyl-A
    13     BOB        4-Bromo-2,5,'-trimethoxy-PEA
    14     BOD        2,5,'-Trimethoxy-4-methyl-PEA
    15     BOH        '-Methoxy-3,4-methylenedioxy-PEA
    16     BOHD        2,5-Dimethoxy-'-hydroxy-4-methyl-PEA
    17    BOM        3,4,5,'-Tetramethoxy-PEA
    18     4-Br-3,5-DMA    4-Bromo-3,5-dimethoxy-A
    19     2-Br-4,5-MDA    2-Bromo-4,5-methylenedioxy-A
    20     2C-B         4-Bromo-2,5-dimethoxy-PEA
    21    3C-BZ         4-Benzyloxy-3,5-dimethoxy-A
    22     2C-C        4-Chloro-2,5-dimethoxy-PEA
    23     2C-D         4-Methyl-2,5-dimethoxy-PEA
    24     2C-E        4-Ethyl-2,5-dimethoxy-PEA
    25     3C-E        4-Ethoxy-3,5-dimethoxy-A
    26     2C-F        4-Fluoro-2,5-dimethoxy-PEA
    27     2C-G        3,4-Dimethyl-2,5-dimethoxy-PEA
    28     2C-G-3        3,4-Trimethylene-2,5-dimethoxy-PEA
    29     2C-G-4        3,4-Tetramethylene-2,5-dimethoxy-PEA
    30     2C-G-5        3,4-Norbornyl-2,5-dimethoxy-PEA
    31     2C-G-N        1,4-Dimethoxynaphthyl-2-ethylamine
    32     2C-H        2,5-Dimethoxy-PEA
    33     2C-I         4-Iodo-2,5-dimethoxy-PEA
    34     2C-N        4-Nitro-2,5-dimethoxy-PEA
    35     2C-O-4        4-Isopropoxy-2,5-dimethoxy-PEA
    36     2C-P        4-Propyl-2,5-dimethoxy-PEA
    37     CPM        4-Cyclopropylmethoxy-3,5-dimethoxy-PEA
    38     2C-SE        4-Methylseleno-2,5-dimethoxy-PEA
    39     2C-T        4-Methylthio-2,5-dimethoxy-PEA
    40     2C-T-2        4-Ethylthio-2,5-dimethoxy-PEA
    41    2C-T-4        4-Isopropylthio-2,5-dimethoxy-PEA
    42     Y-2C-T-4     4-Isopropylthio-2,6-dimethoxy-PEA
    43     2C-T-7        4-Propylthio-2,5-dimethoxy-PEA
    44     2C-T-8        4-Cyclopropylmethylthio-2,5-dimethoxy-PEA
    45     2C-T-9        4-(t)-Butylthio-2,5-dimethoxy-PEA
    46     2C-T-13        4-(2-Methoxyethylthio-2,5-dimethoxy-PEA
    47     2C-T-15     4-Cyclopropylthio-2,5-dimethoxy-PEA
    48     2C-T-17        4-(s)-Butylthio-2,5-dimethoxy-PEA
    49     2C-T-21        4-(2-Fluoroethylthio)-2,5-dimethoxy-PEA
    50     4-D        4-Trideuteromethyl-3,5-dimethoxy-PEA
    51    '-D         ','-Dideutero-3,4,5-trimethoxy-PEA
    52     DESOXY        4-Me-3,5-Dimethoxy-PEA
    53     2,4-DMA        2,4-Dimethoxy-A
    54     2,5-DMA        2,5-Dimethoxy-A
    55     3,4-DMA     3,4-Dimethoxy-A
    56      DMCPA         2-(2,5-Dimethoxy-4-methylphenyl)-
                         cyclopropylamine
    57     DME        3,4-Dimethoxy-'-hydroxy-PEA
    58     DMMDA        2,5-Dimethoxy-3,4-methylenedioxy-A
    59     DMMDA-2     2,3-Dimethoxy-4,5-methylenedioxy-A
    60     DMPEA        3,4-Dimethoxy-PEA
    61     DOAM        4-Amyl-2,5-dimethoxy-A
    62     DOB        4-Bromo-2,5-dimethoxy-A
    63    DOBU        4-Butyl-2,5-dimethoxy-A
    64     DOC        4-Chloro-2,5-dimethoxy-A
    65     DOEF        4-(2-Fluoroethyl)-2,5-dimethoxy-A
    66     DOET        4-Ethyl-2,5-dimethoxy-A
    67     DOI        4-Iodo-2,5-dimethoxy-A
    68     DOM        4-Methyl-2,5-dimethoxy-A
    69    Y-DOM         4-Methyl-2,6-dimethoxy-A
    70     DON         4-Nitro-2,5-dimethoxy-A
    71     DOPR        4-Propyl-2,5-dimethoxy-A
    72     E        4-Ethoxy-3,5-dimethoxy-PEA
    73     EEE         2,4,5-Triethoxy-A
    74    EEM        2,4-Diethoxy-5-methoxy-A
    75     EME        2,5-Diethoxy-4-methoxy-A
    76    EMM        2-Ethoxy-4,5-dimethoxy-A
    77    ETHYL-J        N,a-diethyl-3,4-methylenedioxy-PEA
    78     ETHYL-K        N-Ethyl-a-propyl-3,4-methylenedioxy-PEA
    79     F-2        Benzofuran-2-methyl-5-methoxy-6-
                         (2-aminopropane)
    80     F-22        Benzofuran-2,2-dimethyl-5-methoxy-6-
                         (2-aminopropane)
    81    FLEA         N-Hydroxy-N-methyl-3,4-methylenedioxy-A
    82     G-3        3,4-Trimethylene-2,5-dimethoxy-A
    83    G-4         3,4-Tetramethylene-2,5-dimethoxy-A
    84     G-5        3,4-Norbornyl-2,5-dimethoxy-A
    85     GANESHA        3,4-Dimethyl-2,5-dimethoxy-A
    86     G-N        1,4-Dimethoxynaphthyl-2-isopropylamine
    87    HOT-2         2,5-Dimethoxy-N-hydroxy-4-ethylthio-PEA
    88      HOT-7        2,5-Dimethoxy-N-hydroxy-4-(n)-propylthio-PEA
    89     HOT-17        2,5-Dimethoxy-N-hydroxy-4-(s)-butylthio-PEA
    90     IDNNA        2,5-Dimethoxy-N,N-dimethyl-4-iodo-A
    91    IM        2,3,4-Trimethoxy-PEA
    92     IP         3,5-Dimethoxy-4-isopropoxy-PEA
    93      IRIS        5-Ethoxy-2-methoxy-4-methyl-A
    94     J        a-Ethyl-3,4-methylenedioxy-PEA
    95     LOPHOPHINE    3-Methoxy-4,5-methylenedioxy-PEA
    96     M        3,4,5-Trimethoxy-PEA
    97    4-MA        4-Methoxy-A
    98     MADAM-6     2,N-Dimethyl-4,5-methylenedioxy-A
    99     MAL        3,5-Dimethoxy-4-methallyloxy-PEA
    100     MDA         3,4-Methylenedioxy-A
    101     MDAL        N-Allyl-3,4-methylenedioxy-A
    102     MDBU        N-Butyl-3,4-methylenedioxy-A
    103    MDBZ        N-Benzyl-3,4-methylenedioxy-A
    104    MDCPM        N-Cyclopropylmethyl-3,4-methylenedioxy-A
    105     MDDM         N,N-Dimethyl-3,4-methylenedioxy-A
    106     MDE        N-Ethyl-3,4-methylenedioxy-A
    107     MDHOET        N-(2-Hydroxyethyl)-3,4-methylenedioxy-A
    108     MDIP         N-Isopropyl-3,4-methylenedioxy-A
    109     MDMA         N-Methyl-3,4-methylenedioxy-A
    110     MDMC         N-Methyl-3,4-ethylenedioxy-A
    111     MDMEO        N-Methoxy-3,4-methylenedioxy-A
    112     MDMEOET     N-(2-Methoxyethyl)-3,4-methylenedioxy-A
    113     MDMP        a,a,N-Trimethyl-3,4-methylenedioxy-PEA
    114     MDOH        N-Hydroxy-3,4-methylenedioxy-A
    115     MDPEA        3,4-Methylenedioxy-PEA
    116     MDPH        a,a-Dimethyl-3,4-methylenedioxy-PEA
    117    MDPL        N-Propargyl-3,4-methylenedioxy-A
    118     MDPR        N-Propyl-3,4-methylenedioxy-A
    119     ME         3,4-Dimethoxy-5-ethoxy-PEA
    120     MEDA        3,4-Ethylenedioxy-5-methoxy-A
    121     MEE         2-Methoxy-4,5-diethoxy-A
    122     MEM         2,5-Dimethoxy-4-ethoxy-A
    123     MEPEA         3-Methoxy-4-ethoxy-PEA
    124     META-DOB    5-Bromo-2,4-dimethoxy-A
    125     META-DOT    5-Methylthio-2,4-dimethoxy-A
    126     METHYL-DMA    N-Methyl-2,5-dimethoxy-A
    127     METHYL-DOB     4-Bromo-2,5-dimethoxy-N-methyl-A
    128     METHYL-J    N-Methyl-a-ethyl-3,4-methylenedioxy-PEA
    129     METHYL-K    N-Methyl-a-propyl-3,4-methylenedioxy-PEA
    130     METHYL-MA     N-Methyl-4-methoxy-A
    131     METHYL-MMDA-2    N-Methyl-2-methoxy-4,5-
                    methylenedioxy-A
    132     MMDA        3-Methoxy-4,5-methylenedioxy-A
    133     MMDA-2        2-Methoxy-4,5-methylenedioxy-A
    134     MMDA-3a     2-Methoxy-3,4-methylenedioxy-A
    135     MMDA-3b        4-Methoxy-2,3-methylenedioxy-A
    136     MME         2,4-Dimethoxy-5-ethoxy-A
    137     MP        3,4-Dimethoxy-5-propoxy-PEA
    138     MPM        2,5-Dimethoxy-4-propoxy-A
    139     ORTHO-DOT    2-Methylthio-4,5-dimethoxy-A
    140     P        3,5-Dimethoxy-4-propoxy-PEA
    141      PE         3,5-Dimethoxy-4-phenethyloxy-PEA
    142     PEA PEA
    143    PROPYNYL    4-Propynyloxy-3,5-dimethoxy-PEA
    144     SB        3,5-Diethoxy-4-methoxy-PEA
    145     TA        2,3,4,5-Tetramethoxy-A
    146    3-TASB        4-Ethoxy-3-ethylthio-5-methoxy-PEA
    147     4-TASB        3-Ethoxy-4-ethylthio-5-methoxy-PEA
    148     5-TASB         3,4-Diethoxy-5-methylthio-PEA
    149     TB         4-Thiobutoxy-3,5-dimethoxy-PEA
    150     3-TE          4-Ethoxy-5-methoxy-3-methylthio-PEA
    151     4-TE        3,5-Dimethoxy-4-ethylthio-PEA
    152     2-TIM        2-Methylthio-3,4-dimethoxy-PEA
    153     3-TIM         3-Methylthio-2,4-dimethoxy-PEA
    154     4-TIM        4-Methylthio-2,3-dimethoxy-PEA
    155    3-TM        3-Methylthio-4,5-dimethoxy-PEA
    156    4-TM        4-Methylthio-3,5-dimethoxy-PEA
    157     TMA         3,4,5-Trimethoxy-A
    158     TMA-2        2,4,5-Trimethoxy-A
    159     TMA-3        2,3,4-Trimethoxy-A
    160     TMA-4        2,3,5-Trimethoxy-A
    161     TMA-5         2,3,6-Trimethoxy-A
    162     TMA-6        2,4,6-Trimethoxy-A
    163     3-TME        4,5-Dimethoxy-3-ethylthio-PEA
    164    4-TME        3-Ethoxy-5-methoxy-4-methylthio-PEA
    165     5-TME        3-Ethoxy-4-methoxy-5-methylthio-PEA
    166     2T-MMDA-3a     2-Methylthio-3,4-methylenedioxy-A
    167     4T-MMDA-2     4,5-Thiomethyleneoxy-2-methoxy-A
    168     TMPEA         2,4,5-Trimethoxy-PEA
    169     2-TOET        4-Ethyl-5-methoxy-2-methylthio-A
    170    5-TOET        4-Ethyl-2-methoxy-5-methylthio-A
    171     2-TOM         5-Methoxy-4-methyl-2-methylthio-A
    172     5-TOM        2-Methoxy-4-methyl-5-methylthio-A
    173     TOMSO        2-Methoxy-4-methyl-5-methylsulfinyl-A
    174     TP        4-Propylthio-3,5-dimethoxy-PEA
    175     TRIS        3,4,5-Triethoxy-PEA
    176     3-TSB        3-Ethoxy-5-ethylthio-4-methoxy-PEA
    177     4-TSB        3,5-Diethoxy-4-methylthio-PEA
    178     3-T-TRIS    4,5-Diethoxy-3-ethylthio-PEA
    179     4-T-TRIS     3,5-Diethoxy-4-ethylthio-PEA


PHENETHYLAMINES



#1     AEM;     a-ETHYLMESCALINE;     2-AMINO-1-(3,4,5-TRIMETHOXYPHENYL)BUTANE;     1-(3,4,5-TRIMETHOXYPHENYL)-2-AMINOBUTANE

SYNTHESIS: To a solution of 45 g 3,4,5-trimethoxybenzaldehyde in 1.2 L
IPA, there was added 125 g nitropropane and 67.5 g t-butylammonium
acetate and the reaction mixture was held at reflux for 16 h.  This
was poured into 6 L H2O, and extracted with 2x250 mL hexane.  The
pooled extracts were stripped of solvent under vacuum giving a residue
that slowly set to a crystalline mass.  On filtering, there was
obtained 9.4 g of a crude yellow product which, on recrystallization
from hexane provided 8.7 g of slightly sticky bright yellow crystals
of 2-nitro-1-(3,4,5-trimethoxyphenyl)butene-1, with a mp of 71-73 !C.
A second recrystallization from hexane gave fine yellow crystals with
a mp of 72-73 !C.  Attempts at the preparation of this nitrostyrene by
the more conventional methods with ammonium acetate in acetic acid led
either to the formation of a white product C23H30N2O8 which was
composed of a molecule of the nitrostyrene, one of the benzaldehyde
itself, and a molecule of ammonia, or to 3,4,5-trimethoxybenzonitrile,
from reaction with the decomposition products of nitropropane.

A stirred suspension of 5.9 g LAH in 310 mL anhydrous Et2O was held at
a gentle reflux in an inert atmosphere.  A solution of 8.5 g
2-nitro-1-(3,4,5-trimethoxyphenyl)butene-1 in 125 mL Et2O is added
drop-wise over the course of 0.5 h.  The reaction was maintained at
reflux for 6 h, then cooled, and the excess hydride destroyed by the
cautious addition of 300 mL 1.8 N H2SO4.  The phases were separated,
and the aqueous phase brought to a pH of 6 by the addition of a
saturated Na2CO3 solution.  The neutral solution was brought to a
boil, and clarified by filtration through paper.  To the hot filtrate
there was added a solution of 8.9 g picric acid in 100 mL boiling
EtOH.  The mixture was stirred and cooled, with the formation of a
heavy yellow crystalline mass.  After standing in the ice tub for
several hours the mixture was filtered, providing 8.0 g of the picrate
salt with a mp of 176-181 !C from H2O.  A solution of this salt in 300
mL boiling H2O was treated with 60 mL concentrated HCl.  On cooling,
there was a deposition of picric acid, which was removed by
filtration.  The aqueous filtrate was washed with 3x50 mL
nitrobenzene, then with 3x50 mL Et2O.  The pH was brought above 9 by
the addition of aqueous NaOH, and the filtrate was extracted with
3x100 mL CH2Cl2.  Removal of the solvent from the pooled extracts gave
a nearly colorless oil, which was dissolved in 300 mL anhydrous Et2O
and saturated with hydrogen chloride gas.  The white crystals of
2-amino-1-(3,4,5-trimethoxyphenyl)butane hydrochloride (AEM) were
removed by filtration, Et2Owashed, and air dried.  They weighed 4.72
g.

DOSAGE: greater than 220 mg.

DURATION: unknown.

EXTENSIONS AND COMMENTARY: The extension of the two-carbon chain of
mescaline by alpha-methylation to the three carbon chain of TMA
approximately doubled the potency of the compound.  And it was felt to
be a completely logical possibility that, by extending it one more
carbon atom, to the four carbon chain of alpha-ethyl-mescaline, it
might double again.  And following that logical progression, the
doubling of potency with each additional carbon atom, the factor would
be 2 to the 7th power by the alpha-octyl (or 256x that of mescaline,
or a milligram as active dose) and with a side chain of a 70-carbon
alkyl group (alpha-heptacontylmescaline) it would take just a single
molecule to be intoxicating.  This was rich fantasy stuff.  As an
active compound, just where would it go in the brain?  With an
80-carbon side-chain, would one-thousandth of a single molecule be
enough for a person?  Or might a single molecule intoxicate a thousand
people?  And how long a chain on the alpha-position might be
sufficient that, by merely writing down the structure on a piece of
paper, you would get high?  Maybe just conceiving the structure in
your mind would do it.  That is, after all, the way of homeopathy.

Maybe it was just as well that this added two-carbon side-chain with
lowered activity was already enough to disprove the doubling pattern.
But by the time this non-activity had been learned, the alpha series
had already been pushed out quite aways.  The machinery of making the
appropriate nitroalkane was straightforward, by reaction of the alkyl
halide with nitrous acid, and separating the unwanted nitrite ester
from the wanted nitroalkane by fractional distillation.  The
nitrostyrenes all formed reasonably although often in terrible yields,
and reduced reasonably, and all formed crystalline picrates for
isolation and crystalline hydrochloride salts for pharmacological
manipulation.  But since the first of these, AEM, was not active,
there was no enthusiasm for tasting anything higher.  This family was
never published; why publish presumably inactive and thus
uninteresting material?  The Table presents the properties of the
precursor nitrostyrenes, and the product picrate and hydrochloride
salts, at least whatever information I can still find after thirty
years:

TABLE.  Physical Properties of the a-Alkylmescaline Homologues and
their Precursor Nitrostyrenes

Code     Name            NS mp !C    picrate mp !C    HCl mp !C

APM      Alpha-propylmescaline     82-83         214-218

ABM     Alpha-butylmescaline     73-74         169-174     182-184

AAM     Alpha-amylmescaline     54-55         162-163     155-158

AHM     Alpha-hexylmescaline     51-52

ASM*    Alpha-heptylmescaline     43-44

AOM     Alpha-octylmescaline     **

ANM     Alpha-nonylmescaline     46-47    ***

AUM     Alpha-undecylmescaline         ***

    * S is for septyl, to distinguish heptyl from hexyl.  **Never
made, as no nonylbromide could be located to make the needed
nitrononane.  ***The synthesis got as far as the nitrostyrene stage
when the inactivity of AEM was determined, and the project was
dropped.



#2 AL; 4-ALLYLOXY-3,5-DIMETHOXYPHENETHYLAMINE;
3,5-DIMETHOXY-4-ALLYLOXYPHENETHYLAMINE

SYNTHESIS: A solution of 5.8 g of homosyringonitrile (see under E for
its preparation), 100 mg decyltriethylammonium iodide, and 13.6 g
allyl iodide in 50 mL anhydrous acetone was treated with 6.9 g finely
powdered anhydrous K2CO3 and held at reflux for 16 h.  The color
changed from a near-black to a light yellow.  The mixture was
filtered, the solids washed with acetone, and the solvent from the
combined filtrate and washes removed under vacuum.  The residue was
suspended in acidified H2O, and extracted with 3x100 mL CH2Cl2.  The
pooled extracts were washed with 2x50 mL 5% NaOH, once with dilute HCl
(which lightened the color of the extract) and then stripped of
solvent under vacuum giving 12.4 g of an amber-colored oil.  This was
distilled at 125-137 !C at 0.1 mm/Hg to yield 5.7 g of
3,5-dimethoxy-4-allyloxyphenylacetonitrile as a yellow oil.  Anal.
(C13H15NO3S) C,H.

A suspension of 4.0 g LAH in 150 mL anhydrous THF under N2 was cooled
to 0 !C and vigorously stirred.  There was added, dropwise, 2.8 mL
100% H2SO4, followed by 5.5 g
3,5-dimethoxy-4-allyloxyphenylacetonitrile in 10 mL anhydrous THF.
The reaction mixture was stirred at 0 !C for a few min, then brought
to a reflux on the steam bath for 30 min.  After cooling back to room
temperature, there was added sufficient IPA to destroy the excess
hydride, followed by sufficient 10% NaOH to form granular solids.
These were removed by filtration, and washed with 20 mL IPA.  The
filtrate and washes were stripped of solvent under vacuum andthe
residue added to 100 mL dilute H2SO4.  This was washed with 2x50 mL
CH2Cl2, made basic with aqueous NaOH, and extracted with 2x75 mL
CH2Cl2.  These extracts were pooled, the solvent removed under vacuum,
and the residue distilled at 110-120 !C at 0.4 mm/Hg to give 4.9 g of
a colorless oil.  This was dissolved in 15 mL IPA, neutralized with
concentrated HCl (55 drops required), and diluted with 50 mL Et2O.
The product was removed by filtration, washed with Et2O, and air dried
to give 4.9 g of 3,5-dimethoxy-4-allyloxyphenethylamine hydrochloride
(AL) as white crystals.

DOSAGE: 20 - 35 mg.

DURATION: 8 - 12 h.

QUALITATIVE COMMENTS: (with 24 mg) I first became aware of something
in about 10 minutes, a pleasant increase in energy.  By 20 minutes it
was getting pronounced and was a nice, smooth development.  During the
next hour positive and negative feelings developed simultaneously.
Following a suggestion, I ate a bit of food even though I had not been
hungry, and to my surprise all the negative feelings dropped away.  I
felt free to join the others wherever they were at.  I moved into the
creative, free-flowing kind of repertoire which I dearly love, and
found everything enormously funny.  Much of the laughter was so deep
that I felt it working through buried depressions inside me and
freeing me.  From this point on, the experience was most enjoyable.
The experience was characterized by clear-headedness and an abundance
of energy which kept on throughout the day and evening.  At one point
I went out back and strolled along to find a place to worship.  I had
a profound sense of the Presence and great love and gratitude for the
place, the people, and the activities taking place.  The come-down
from the experience was very gradual and smooth.  Food tasted
wonderful.  I went to bed late, and quite ready for bed, although the
energy was still running.  However, sleep was not long in coming.

(with 24 mg) The onset was extremely gradual and graceful, with the
first alert that one could really sense at about 50 minutes.  This was
succeeded by a slow gentle climb to the peak at one hour and fifteen
minutes.  The experience itself left all of the sensory modalities
functional; speech was cogent and rather fluid.  In fact, there was an
unusual ease of free association.  All throughout the session, the
talk was high in spirits and somehow indicative of an inner
excitement.  Affect was entirely pleasant, but not exalting nor
conducive to insight or to problem solving.  There were no
requirements for withdrawal into the self.  The material seemed wholly
social in nature.  No visual, auditory or olfactory sharpening was in
evidence.  The plateau for this material seemed unusually long.  I was
unable to sleep for several hours, and took 25 mg Librium before sleep
arrived.  The next day was a lethargic and slow one, with the inner
feeling that the effects had not worn off until the middle of the day
following ingestion.

(with 35 mg) I was a distinct +1 in 35 minutes and a +2 by the end of
the hour.  My head congestion in no way cleared up, absolving the
material from having that particular virtue.  The entire experience
was somewhat dissociated Q I could not connect with my feelings.
Although my mind remained clear, there was a hangover feeling at the
end of the experiment.

EXTENSIONS AND COMMENTARY: This compound was first explored in Prague
by Leminger.  He provided only the synthetic details and the statement
that it was the most active compound that he had studied, with
activity at 20 milligrams, with perceptual changes, color enhancement,
and difficult dreams during sleep that night.  Some effects persisted
for more than 12 hours.  Dosages above 35 milligrams remain
unexplored.

As AL is one of the most potent 3,4,5-trisubstituted phenethylamines
yet described, and since the corresponding amphetamines are of yet
greater potency, it would be a good guess that
4-allyloxy-3,5-dimethoxyamphetamine (3C-AL) would be an interesting
compound to explore.  It could be made from syringaldehyde in reaction
with allyl iodide, followed by the formation of a nitrostyrene with
nitroethane, followed by reduction with aluminum hydride.  It is, as
of the present time, both unsynthesized and unexplored.



#3 ALEPH; DOT; PARA-DOT; 2,5-DIMETHOXY-4-METHYLTHIOAMPHETAMINE

SYNTHESIS: A solution of 2.3 g
2,5-dimethoxy-4-(methylthio)benzaldehyde (see under 2C-T for its
synthesis) in 7.5 mL nitroethane was treated with 0.45 g anhydrous
ammonium acetate and heated on the steam bath for 6 h.  The excess
solvent/reagent was removed under vacuum leaving a mass of orange
crystals as residue.  These were ground up under 10 mL MeOH,
col-lected by filtration, washed with a little MeOH, and air dried to
provide 2.6 g crude
1-(2,5-dimethoxy-4-methylthiophenyl)-2-nitropropene.  After
recrystallization from 140 mL boiling MeOH, filtering and drying there
was in hand 1.8 g of bright orange crystals with a mp of 137-138 !C.
Anal. (C12H15NO4S) C,H,N,S.

A suspension of 1.4 g LAH in 10 mL anhydrous Et2O and 40 mL anhydrous
THF was put under an inert atmosphere and, with good stirring, brought
up to a gentle reflux.  A solution of 1.8 g
1-(2,5-dimethoxy-4-methylthiophenyl)-2-nitropropene in 30 mL anhydrous
THF was added dropwise at a rate that maintained the reflux.  Heating
and stirring were maintained for an additional 7 h, then the reaction
mixture was allowed to return to room temperature.  There was added
1.6 mL H2O (dissolved in a little THF), followed by 1.6 mL 15% NaOH,
and finally another 4.8 mL H2O.  Stirring was continued until all the
curdy solids had turned white.  The reaction mixture was filtered, and
the filter cake washed with THF.  The filtrate and the washings were
combined, and the solvent removed under vacuum.  The residue was 1.3 g
of a colorless oil that solidified.  Its mp of 90-93 !C was improved
slightly to 91-93 !C with recrystallization from hexane.  The product
was dissolved in 25 mL warm IPA, neutralized with concentrated HCl
(0.57 mL required) and then diluted with 100 mL anhydrous Et2O.  After
a moment's delay, the white crystalline product appeared.  It was
removed by filtration, washed with Et2O, and air dried to provide 1.2
g 2,5-dimethoxy-4-methylthioamphetamine hydrochloride (ALEPH) with a
mp of 200-201 !C.  Recrystallization from IPA gave an analytical
sample with a mp of 204-205 !C.  Anal. (C12H20ClNO2S) C,H; N: calcd,
5.04; found, 5.52.

DOSAGE: 5 - 10 mg.

DURATION: 6 - 8 h.

QUALITATIVE COMMENTS: (with 5 mg) The initial hints of action were
physical Q warming of first the legs, and then a comfortable warmth
spread over the entire body.  Intense intellectual stimulation, one
that inspired the scribbling of some 14 pages of handwritten notes.
Which is a pretty good record for an experience that is almost
entirely non-verbal.  The afterglow was benign and rich in empathy for
everything.  And by the sixth hour I was quite hungry.

(with 10 mg) There was a rapid shift of frame of reference that made
simple tasks such as reading and tuning the radio quite alien.  I
happened to catch the eyes of Pretty Baby, the cat, at the same moment
she looked at me, and she turned and fled.  I am able to interact with
people on the telephone quite well but mechanical things, such as
arranging flowers or alphabetizing names, are beyond me.  Driving
would be impossible.

EXTENSIONS AND COMMENTARY: This specific compound is probably the
first sulfur-containing phenethylamine to have been evaluated as a
potentially active CNS stimulant or psychedelic.  It was a complete,
total, absolute unknown.  The first trials were made at the
sub-microgram level, specifically at 0.25 micrograms, at 11:30 AM on
September 3, 1975.  Part of this extreme precaution was due to the
uniqueness of a new heteroatom in a phenethylamine system.  But part
was due to the strange manic excitement that occurred at the time of
the isolation and characterizing of the final product in the
laboratory.  Although it was certainly all placebo response, I was
jumpy and unable to stay in the lab for more than a few minutes at a
time.  Maybe dust in the air?  Maybe some skin contact with the free
base?  Now, I know there was nothing, but the possibility of
extraordinary potency was real, and I did indeed wash everything down
anyway.  In fact, it took a total of 18 trials to work the
experimental dosage up to as much as a single milligram.  In
retrospect, overly cautious.  But retrospection, as they say, is
cheap.

The 5 milligram experiment, briefly quoted from above, is the stuff of
Chapter 14 of this book, important in that it gives an interesting
example of some thought processes associated with psychedelic
intoxication, ego-inflation, and what might be thought of as bits of
mania.  As is always the case with peak experiences that happen to be
catalyzed by drugs, this extraordinary event could not be duplicated.
At 7 milligrams there was an uneventful +1, and some 10 milligrams was
needed to generate a full +3 experience.  The first clue of the
erratic nature of the Aleph family came from an independent assay by a
colleague of mine, one who was very familiar with such states of
consciousness, but for whom this was not a time for peak experiences.
At 10 milligrams he told me that he had had only mild effects which he
found relatively uninteresting.

As it stands, ALEPH remains relatively unexplored.  Its two positional
isomers are entered here as ORTHO-DOT and META-DOT.  Three higher
homologues have been more thoroughly looked at, and the generic name
ALEPH (the first letter of the Hebrew alphabet) was given this group
on the basis that they might have extraordinary properties in common.
But the real treasure came in the exploring of the 2-carbon
homologues, the compounds that make up the 2C-T family.  Here, there
proved to be much less uncertainty as to reasonable dosages, and much
more richness in the subjective nature of the experience.



#4 ALEPH-2; 2,5-DIMETHOXY-4-ETHYLTHIOAMPHETAMINE

SYNTHESIS: A solution of 2.0 g 2,5-dimethoxy-4-(ethylthio)benzaldehyde
(see under 2C-T-2 for its synthesis) in 12 mL nitroethane was treated
with 0.4 g anhydrous ammonium acetate and heated on the steam bath for
3 h.  All volatiles were removed under vacuum, leaving a residue that
set up as brilliant red crystals.  These were mechanically removed
from the evaporation flask, blown free of nitroethane vapor, and
recrystallized from boiling EtOH, producing 1.8 g pale orange
crystals, with a mp of 110-112 !C.  Recrystallization from 20 mL
boiling IPA gave, after filtering and air drying, 1.70 g light orange
crystals of 1-(2,5-dimethoxy-4-ethylthiophenyl)-2-nitropropene with a
mp of 112-113 !C.

A suspension of 1.2 g LAH in 75 mL anhydrous THF was put under an
inert atmosphere and, with good stirring, brought up to a gentle
reflux.  A solution of 1.5 g
1-(2,5-dimethoxy-4-ethylthiophenyl)-2-nitropropene in 20 mL anhydrous
THF was added dropwise.  Heating and stirring were maintained for an
additional 24 h, and then the reaction mixture was allowed to come
back to room temperature with stirring.  There was added 1.4 mL H2O
(dissolved in a little THF), followed by 1.4 mL 15% NaOH and finally
another 4.2 mL H2O.  Stirring was continued until all the curdy solids
had turned white.  The reaction mixture was filtered, and the filter
cake washed with THF.  The filtrate and the washings were combined,
and the solvent removed under vacuum.  The residue was 1.1 g of a pale
amber oil.  This was dissolved in 6 mL IPA, neutralized with
concentrated HCl (about 8 drops were required) and then diluted with
150 mL anhydrous Et2O.  The slightly cloudy solution was stirred for a
couple of min, then there was the formation of a heavy white
crystalline mass.  This was removed by filtration, washed with Et2O,
and air dried to provide 1.1 g 2,5-dimethoxy-4-ethylthioamphetamine
hydrochloride (ALEPH-2) with a mp of 128-130 !C with decomposition.

DOSAGE: 4 - 8 mg

DURATION: 8 - 16 h.

QUALITATIVE COMMENTS: (with 4 mg) There was a warm feeling in the
total body and a light pressure in the head that changed with time
into the feeling of a balloon without any anatomical definition.  The
usual color perception was not very much increased, and my vision was
not sharpened as it was with DOM.  Rather, I noticed waves of
movement, very smooth and not too busy.  Both my tactile perception
and auditory acuity were enhanced.  The main effect for me was,
paradoxically, an easier handling of the outer world.  None of the
jitters of amphetamine.  The body feeling is good, healthy, and I am
at peace with the body-mind dualism.  These are pretty much personal
comments Q I will write up the pharmacological points later.

(with 5 mg) This turned out to be a day of extraordinary visuals and
interpretations.  About two hours into it, I felt that the effects
were still climbing, but there was a marvelous onset of visual
distortions and illusions, right at the edge of hallucination.  The
logs in the fireplace were in continuous motion.  The notepaper I was
writing on seemed to scrunch and deform under the pressure of the pen.
Nothing would stay still; everything was always moving.  There was a
phase of unabated inflation.  The intensity was noticeably dropping at
the five hour point and I observed considerable residual shakes and a
muscular tremor.  Even towards midnight there was some
tooth-rubbiness, but I was able to get a somewhat fretful though
adequate sleep.

(with 5 mg) I was exposed to a number of new environments and it was
difficult to completely separate the experience into what was seen
differently and what was seen for the first time.  The Santa Cruz
Mystery Spot should have been bizarre but it was simply hokey.  And
yet the boardwalk that should have been depressing was totally
magical.  The day was unworldly and I ended up with considerable
muscular weakness.  All in all, I handled it well, but I probably
wonUt do it again.

(with 7 mg) An amazing unification of visual hallucination seen only
in the very fine detail of something, and what must be considered
retinal hallucination.  There is no one-to-one correspondence between
the many retinal cells of the high-resolution part of the eye.  Thus,
the mind can pick and choose, sometimes from the right eye, and
sometimes from the left.  And so a small curve or bump can become
whatever you wish.  For a moment.  And then it chooses again, but
differently.  Is all of our perceived world as subjective as this?S

(with 8 mg) Extreme intoxication, but almost no visual phenomena.
Even well into the evening, I know I absolutely could not drive.  Why?
I donUt know, since this experiment, at least, seemed to be quite free
of strange colors and wiggly lines and streaks of light.  It's that I
donUt trust that the reality I see is the same reality that the other
driver might see.  I am very much the center of the world about me,
and I donUt think I could trust anyone else to fully respect my
reality.

EXTENSIONS AND COMMENTARY: As with ALEPH itself, and in most ways with
the entire ALEPH family, there is no predictability of the
dose/response relationship.  One person had expressed his psychic
isolation by taking and maintaining a fetal position in relative
hibernation for several hours and with substantial amnesia; this at a
four milligram dose.  Yet another person, at fully twice this amount,
was aware of a slight light-headedness that could in no way be
measured as more than a bare threshold.  But by the time this erratic
nature had become apparent, the ALEPHS had been assigned and made, up
to and including ALEPH-7.

ALEPH-3 was intended to be the methallylthio compound,
2,5-dimethoxy-4-('-methallylthio)amphetamine.  The thioether
(2,5-dimethoxyphenyl '-methallyl sulfide) was easily made from
2,5-dimethoxythiophenol (see 2C-T-2 for its preparation) with 3.4 g
dissolved in a solution of 1.7 g KOH in 25 mL boiling EtOH, and 2.72 g
methallyl chloride, heated 1 h on the steam bath, poured into 250 mL
H2O, extracted with 3x100 mL CH2Cl2, and solvent removal yielding 4.4
g of the sulfide as an amber oil.  An effort to convert this to
2,5-dimethoxy-4-('-methallylthio)benzaldehyde (7.2 g POCl3, 6.7 g
N-methylformanilide, 4.2 g of the crude sulfide from above, 15 min
heating on the steam bath, H2O hydrolysis, hexane extraction of the
residues from a CH2Cl2 extraction) produced 3.1 g of a
peppermint-smelling oil that distilled at 140-160 !C at 0.3 mm/Hg and
which did indeed have an aldehyde group present (by proton NMR) but
the rest of the spectrum was a mess, and the project was abandoned.

Several years later, this entire project was reinitiated, and the
aldehyde was obtained as a yellow crystal, but again it was not
pursued.  At that time, the earlier try had been totally forgotten,
and a brand new ALEPH- (or 2C-T-) number had been assigned; i.e., 20.
Thus, the corresponding phenethylamine
(2,5-dimethoxy-4-('-methallylthio)phenethylamine), had it ever been
made, which it was not, would have been called either 2C-T-3 or
2C-T-20, and the amphetamine homologue would probably have been
ALEPH-20.

A closely related 2C-T-X compound was also started quite a while later
Q this was the allylthio homologue of the methallyl material 2C-T-3 or
2C-T-20.  Its place in the flow of things is evident from its
numbering, 2C-T-16.  A mixture of 2,5-dimethoxythiophenol and KOH and
allyl chloride in MeOH gave 2,5-dimethoxyphenyl allyl sulfide as a
white oil which boiled at 110-125 !C at 0.25 mm/Hg.  This, with POCl3
and N-methylformanilide provided
2,5-dimethoxy-4-(allylthio)benzaldehyde which distilled at 140-160 !C
at 0.4 mm/Hg and could be recrystallized from MeOH as a pale yellow
solid.  Reaction of this aldehyde in nitroethane in the presence of
ammonium acetate (steam bath for 2.5 h) provided
2,5-dimethoxy-4-allylthio-'-nitrostyrene as red crystals from
acetonitrile.  Its mp was 114-115 !C.  Anal. (C13H15NO4S) C,H. This
has not yet been reduced to the final amine,
2,5-dimethoxy-4-allylthiophenethylamine, 2C-T-16.  The corresponding
amphetamine would be, of course, ALEPH-16.

ALEPH-5 was to be the cyclohexylthio analogue
(2,5-dimethoxy-4-cyclohexylthioamphetamine).  The thioether
(2,5-dimethoxyphenyl cyclohexyl sulfide) was successfully made from
1.7 g 85% KOH pellets in 25 mL hot EtOH, 3.4 g 2,5-dimethoxythiophenol
(again, see under 2C-T-2 for its preparation), and 4.9 g cyclohexyl
bromide, 3 h on the steam bath, into 500 mL H2O, extraction with 3x100
mL CH2Cl2, washing the extracts with 5% NaOH, and evaporation to yield
5.2 g of an amber oil.  The aldehyde, (made from 6.1 g POCl3 and 5.4 g
N-methylformanilide, heated until claret colored, then treated with
5.0 g of the above crude thioether, heating for 20 min on the steam
bath, into 300 mL H2O, and over-night stirring) was obtained as 3.1 g
of a flesh-colored solid that was clearly neither pure nor completely
correct.  Repeated partitioning with organic solvents and cooling and
scratching the residues finally provided a pale orange crystal (1.3 g,
mp 88-93 !C) which, after twice recrystallizing from MeOH, gave 0.4 g
of pale yellow crystals with a mp 95-96 !C and a textbook perfect NMR
in CDCl3 (CHO, 1H (s) 10.41; ArH 2H (s) 6.93, 7.31; OCH3, 6H, (2s) at
3.88 and 3.92; CH, 1H br. at 3.34; and (CH2)5 10H br. at 1.20-2.34).
The nitrostyrene was prepared from 200 mg of the above aldehyde in 1.2
mL nitroethane and 0.1 g ammonium acetate overnight on the steam bath,
the solvent removed to give an orange oil that spontaneously
crystallized after a few monthsU standing.  This was never
characterized, but sits there on the shelf to be reduced to ALEPH-5
some inspired day.  The two-carbon homo-logue of this
(2,5-dimethoxy-4-cyclohexylthiophenethylamine) will someday be called
2C-T-5 (if it is ever made).

The remaining members of this family, ALEPH-4, ALEPH-6, and ALEPH-7
have actually been prepared and they have all been entered here in
Book II, under their own names.



#5 ALEPH-4; 2,5-DIMETHOXY-4-(i)-PROPYLTHIOAMPHETAMINE

SYNTHESIS: A solution of 2.0 g
2,5-dimethoxy-4-((i)-propylthio)benzaldehyde (see under 2C-T-4 for its
synthesis) in 12 mL nitroethane was treated with 0.4 g anhydrous
ammonium acetate and heated on the steam bath for 12 h, then allowed
to stir for another 12 h at room temperature.  The excess
solvent/reagent was removed under vacuum leaving a residue as a heavy
deep orange two-phase oily mass.  This was brought into one phase with
2 mL MeOH and then, with continued stirring, everything spontaneously
crystallized.  This product was removed by filtration and, after
washing sparingly with cold MeOH and air drying, yielded 2.0 g of
1-(2,5-dimethoxy-4-(i)-propylthiophenyl)-2-nitropropene as orange
crystals with a mp of 96-98 !C.  After recrystallization from 15 mL
boiling 95% EtOH, filtering and air drying to constant weight, there
was obtained 1.6 g of orange crystals with a mp of 99-100 !C.

A suspension of 1.0 g LAH in 100 mL warm THF was stirred under a N2
atmosphere and heated to a gentle reflux.  To this there was added,
dropwise, a solution of 1.2 g
1-(2,5-dimethoxy-4-(i)-propylthiophenyl)-2-nitropropene in 20 mL
anhydrous THF.  This mixture was held at reflux for 1 day, then
stirred at room temperature for 2 days.  There was then added, slowly
and with caution, 1 mL of H2O, followed by 1 mL of 15% NaOH, and
finally by another 3 mL of H2O.  Stirring was continued until the
reaction mixture became white and granular, then all solids were
removed by filtration and the filter cake was washed with additional
THF.  The filtrate and washings were combined, and the solvent removed
under vacuum to give 1.1 g of residue which was an almost white oil.
This was dissolved in 6 mL IPA, neutralized with concentrated HCl (10
drops were required) and then diluted with 200 mL anhydrous Et2O.  The
resulting slightly turbid solution was clarified by filtration through
a sintered glass filter, and the clear and slightly yellow filtrate
was allowed to stand.  A fine white crystalline product slowly
separated over the next few h.  This product,
2,5-dimethoxy-4-(i)-propylthioamphetamine hydrochloride (ALEPH-4) was
removed by filtration, and after washing with Et2O and air drying,
weighed 0.5 g and had a mp of 146-147 !C, with prior sintering at 144
!C.

DOSAGE: 7 - 12 mg.

DURATION: 12 - 20 h

QUALITATIVE COMMENTS: (with 7 mg) Things started off going downhill,
initially negative with tension and depression, but as the momentum
developed, so did the positive effect.  My discomfort continued to
develop, but I was struck by the visual beauty of the trees and the
small stream that flowed off the mountain.  My experience continued to
grow, simultaneously, in both the negative and the positive direction.
Physically I was uncomfortable and found my breathing difficult, but I
acknowledged a rapture in the very act of breathing.  All moved over
to the plus side with time, and the evening was gorgeous.  I have
never seen the sky so beautiful.  The only flaw was when I choked on
some lemonade and it seemed to me I almost drowned.  I have been
extremely conscious of eating, drinking and swallowing ever since.  I
barely slept the whole night and awoke extremely tired.  I felt that
the experience continued for many days, and I feel that it is one of
the most profound and deep learning experiences I have had.  I will
try it again, but will block out more time for it.

(with 8 mg) There was without question a plus two, but none of the
edges of unreality that are part of LSD.  The sounds that are just
outside of my hearing are intriguing, and distract me from the
eyes-closed imagery that is just barely possible with music while
lying down.  But, going outside, there were no obvious sources of the
sounds that I heard.  Could I drive?  I suspect so.  I took a shower
and did just that Q I drove to San Francisco without incident, and
walked amongst the many strange faces on the downtown streets.

(with 12 mg) The experience was very intense but completely under
control except for a twenty minute period right in the middle of it.
I had to get away from everything, from everyone.  There was a sense
of being surrounded and moved in upon that was suffocating.  I was
weighed down with everything Q physical, psychic, emotional.  My
clothes had to come off, my hair had to be released, my shoes went, I
needed to move away from where I was, to somewhere else, to some new
place, any new place, with the hope that my other old place wouldnUt
follow me.  Pretty soon I found I was myself, I could breathe again,
and I was OK.  Rather sheepishly, I dressed and rejoined the group.
The rest of the day was spectacular, but those few minutes were scary.
What if I couldnUt have escaped?S

EXTENSIONS AND COMMENTARY: Again, there are hints and suggestions of
complexities.  These, and several other reports, suggest some sensory
confusion, and interpretive aspects that are to some extent
threatening.  There is an underlying suggestion of body toxicity.  I
know of no experiment that exceeded 12 milligrams and I would not be
able to predict what might come forth at higher dosages.  I personally
choose not to try them.



#6 ALEPH-6 2,5-DIMETHOXY-4-PHENYLTHIOAMPHETAMINE

SYNTHESIS: To a 300 mL three-neck round-bottom flask set up with a
magnetic stirrer and protected with a N2 atmosphere, there was added
75 mL hexane, 3.5 g tetramethylethylenediamine, and 4.2 g
p-dimethoxybenzene.  The reaction mixture was cooled to 0 !C with an
external ice bath, and there was then added 19 mL of 1.6 M
butyllithium in hexane.  With stirring, the reaction was brought up to
room temperature, and there were produced loose, creamy solids.  There
was then added, as a solid and portionwise, 6.6 g diphenyldisulfide
which resulted in an exothermic reaction and the production of a
nearly clear solution.  After stirring an additional 10 min, the
reaction was quenched in 500 mL of dilute NaOH.  The hexane phase was
separated, and the aqueous phase extracted with 4x100 mL CH2Cl2 The
organic extracts were combined, washed with dilute HCl and the
solvents were removed under vacuum to provide 6.0 g of
2,5-dimethoxyphenyl phenyl sulfide as an impure amber oil.  A small
sample was saved for microanalysis and NMR, and the re-mainder
converted to the corresponding benzaldehyde.

A mixture of 6.1 g POCl3 and 5.4 g N-methylformanilide was heated for
3 min on the steam bath, and then added to the remainder of the
above-described 2,5-dimethoxyphenyl phenyl sulfide.  The reaction
became immediately a deep red and, after heating on the steam bath for
0.5 h, was dumped into a large quantity of H2O, producing a granular
brown solid.  This was removed by filtration, and washed sparingly
with cold MeOH (the washes were saved).  The resulting pale yellow
solids were recrystallized from 20 mL boiling absolute EtOH providing,
after cooling, filtration and air drying, 4.4 g of extremely pale
yellow crystals of 2,5-dimethoxy-4-(phenylthio)benzaldehyde.  This had
a mp of 119-119.5 !C.  All washes and mother liquors were combined,
flooded with H2O and extracted with CH2Cl2.  This solvent was removed
under vacuum, and the residue (a viscous oil) was dissolved in a
little EtOH which, on cooling in dry ice, gave 1.2 g of a second crop
of the aldehyde, mp 117-119 !C.  Recrystallization from 5 mL 95% EtOH
gave an additional 0.4 g product with a mp of 118-119 !C.  This mp was
not improved by recry-stallization from cyclohexane.  The NMR specrum
was excellent, with OCH3 singlets (3H) at 3.45 and 3.80 ppm; ArH
singlets at 6.28 and 7.26 ppm, the C6H5 as a broad peak centered at
7.50, and the CHO proton at 10.37 ppm.

A solution of 4.4 g 2,5-dimethoxy-4-(phenylthio)benzaldehyde in 32 mL
nitroethane was treated with 0.8 g anhydrous ammonium acetate and
heated on the steam bath for 21 h.  The excess solvent/reagent was
removed under vacuum, leaving a dark red oil as residue.  After much
diddling and fiddling around, this set up as a crystalline mass.
These solids were ground under 20 mL cold MeOH and filtered, providing
5.3 g of the crude nitrostyrene as an orange crystalline residue
product after air-drying.  This was ground up under 10 mL MeOH, the
insolubles collected by filtration, washed with a little MeOH, and air
dried to provide 5.3 g crude
1-(2,5-dimethoxy-4-phenylthiophenyl)-2-nitropropene as yellow
crystals, with a mp of 100-102 !C (with prior sintering at about 98
!C).  This was recrystallized from 50 mL boiling 95% EtOH.  After
cooling in an ice bath, it was filtered, washed with EtOH, and air
drying provided gold-yellow crystals with a mp of 105-106 !C.  The
proton NMR was excellent (in CDCl3).

A suspension of 2.0 g LAH in 100 mL refluxing THF, under an inert
atmosphere and with good stirring, was treated with a solution of 3.5
g 1-(2,5-dimethoxy-4-phenylthiophenyl)-2-nitropropene in 20 mL
anhydrous THF added dropwise at a rate that maintained the reflux.
Heating and stirring were maintained for an additional 36 h, and then
the reaction mixture was stirred at room temperature for an additional
24 h.  There was added 2.0 mL H2O (dissolved in a little THF),
followed by 2.0 mL 15% NaOH, and finally another 6.0 mL H2O.  Stirring
was continued until all formed solids had turned white.  The reaction
mixture was filtered, and the filter cake washed with THF.  The
filtrate and the washings were combined and the solvent removed under
vacuum.  The residue was 2.8 g of an oil that quite obviously
contained some H2O.  This was dissolved in 400 mL CH2Cl2, washed first
with dilute NaOH and then with 4x150 mL 1N HCl.  The organic phase was
stripped of solvent under vacuum, yielding a pale amber oil that
crystallized.  This was ground first under Et2O, giving 3.4 g of a
yellow solid.  This was then ground under 10 mL of acetone, yielding
2.4 g of a white crystalline solid that darkened at 170 !C, sintered
at 187 !C and had a mp of 191-193 !C.  This was dissolved in 20 mL hot
95% EtOH, and diluted with 40 mL Et2O to provide a clear solution
which, after a minute's scratching with a glass rod, deposited
2,5-dimethoxy-4-phenylthioamphetamine hydrochloride (ALEPH-6) as white
solids.  After filtration and air drying, the weight was 1.8 g, with a
mp of 194-195 !C.  The dilute HCl washes, after being made basic with
aqueous NaOH and extraction with CH2Cl2 gave a trivial quantity of
additional product.

DOSAGE: greater than 40 mg.

DURATION: probably long.

QUALITATIVE COMMENTS: (with 30 mg) I had an alert at the one hour
point, and in another hour there was a clear 1+.  There was a not well
defined, gentle un-worldliness.  And it was still there quite
unchanged twelve hours later.  In a group I find that all voices about
me are of equal intensity and equal importance.  But this is not at
all distracting.  This will be a long lived thing for sure.

(with 40 mg) I am into a subtle but real effect, no more than one
plus, but real.  I feel primed, but nothing more.  It is not
interfering with work, maybe even helping with it.  After another hour
of static one-plusness I decided to use it as a primer to LSD, using
the usual 60 microgram quantity that is standard for primer studies.
The combination showed definite synergism, with a rapid show of the
LSD effects (within fifteen minutes) and an almost three plus effect.
This is most unusual for the usual 60 microgram challenge amount.  An
absolutely delightful intoxication that had sufficiently descended
towards baseline that I accepted a ride to a party that evening in
Marin County to attend a poetry reading.  There I felt myself at
baseline and accepted (unusual for me) a little marijuana.  And with
the utmost quiet and delicacy, a rather incredible change of state
took place.  The most memorable event was the awareness of a clarinet
playing somewhere, and the sneaky sounds from it actually coming along
the carpet out of the dining room and into the hallway and through the
door and into the room where I was, and all of them gathering at my
feet like docile kittens waiting for me to acknowledge them.  I did,
non-verbally, and I was amazed at the many additional follow-up sounds
that came from the same clarinet along the same twisty path along the
floor and through the door and into my space, over what seemed to be
the next million hours.  I ended up with a marvelous collection of
notes and phrases at my feet, and I felt somehow honored.  My speech
sounded OK to me, but I knew that it would be odd to the ears of
others, so I kept quiet.  A final measure of the weirdness of the
ALEPH-6/LSD/Pot combination was the viewing of the Larkspur ferry at
its dock, abandoned for the evening and with no one aboard it, and
with all that clean, dry sleeping space going to waste with so many
people sleeping on the streets these days.  Once home, I slept soundly
and for a long while.  Incredible experience.

EXTENSIONS AND COMMENTARY: In a sense, this compound was a
disappointment.  The beauty of putting a whole new ring into an active
structure is that it provides a marvelous vehicle for introducing new
substituents in new arrangements.  Had Aleph-6 been a cleanly active
and potent compound, then the new phenyl group could have been made
electronegative to varying degrees (with methoxy substitution for
example) or electropositive to varying degrees (with trifluoromethyls
or nitros) and this fine-tuning could have been extremely rewarding.

But this material had the earmarks of one of those forever threshold
things.  The 40 milligram experiment was hopelessly compromised, and
nothing higher was ever scheduled or tried.  The two-carbon homologue,
2,5-dimethoxy-4-phenylthiophenethylamine, or 2C-T-6, has never even
been synthesized, let alone assayed.



#7 ALEPH-7; 2,5-DIMETHOXY-4-(n)-PROPYLTHIOAMPHETAMINE

SYNTHESIS: A solution of 2.6 g
2,5-dimethoxy-4-((n)-propylthio)benzaldehyde (see under 2C-T-7 for its
synthesis) in 20 mL nitroethane and 0.5 g anhydrous ammonium acetate
was heated on the steam bath overnight.  The excess solvent/reagent
was removed under vacuum leaving an orange oil as a residue that
cry-stallized spontaneously.  This crude product was recrystallized
from 20 mL boiling MeOH to give, after cooling, filtering, and air
drying, 2.4 g of
1-(2,5-dimethoxy-4-(n)-propylthiophenyl)-2-nitropropene as orange
crystals.  Its mp was 83-84 !C with prior sintering at 81 !C.

A suspension of 1.5 g LAH in 150 mL of warm anhydrous THF was stirred
under an inert atmosphere and brought up to a gentle reflux.  A
solution of 2.3 g
1-(2,5-dimethoxy-4-(n)-propylthiophenyl)-2-nitropropene in 25 mL
anhydrous THF was added dropwise at a rate that maintained the reflux.
Heating and stirring were continued for 2 days, and then the reaction
mixture was allowed to stir at room temperature for an additional 2
days.  There was added 1.5 mL H2O (dissolved in 10 mL THF), followed
by 1.5 mL 15% NaOH, and finally another 4.5 mL H2O.  Stirring was
continued until all the curdy solids had turned white.  The reaction
mixture was filtered, and the filter cake washed with slightly wet
THF.  The filtrate and the washings were combined, and the solvent
removed under vacuum.  The residue was about 2 mL of an amber colored
oil that was dissolved in 200 mL CH2Cl2.  This solution was washed
with first dilute NaOH, and then with saturated brine.  Removal of the
solvent gave a pale amber oil that was dissolved in 10 mL IPA,
neutralized with about 14 drops of concentrated HCl, and diluted with
200 mL anhydrous Et2O.  The clear solution was decanted from a little
gritty material, and then set aside to allow the formation of
2,5-dimethoxy-4-(n)-propylthioamphetamine hydrochloride (ALEPH-7) as
fine white crystals.  After filtration and air drying, there was
obtained 1.8 g of an off-white powder.

DOSAGE: 4 - 7 mg.

DURATION: 15 - 30 h.

QUALITATIVE COMMENTS: (with 4 mg) At the second hour I had a
paraesthetic twinge or two (all pins and needles), and then felt quite
relaxed, quite willing to let this play itself out.  In the evening my
ears still feel 'popped' and there is a little bit of physical
awareness.  There is not much fun with this.  The night following, I
was unable to sleep and only dozed slightly, but I seemed to be OK the
next day.

(with 6 mg) The alert was felt within a half hour, and then nothing
more.  Then, over the next two hours, there was the evolution of an
extremely neutral state.  I danced wildly to a record of Keith
Jarrett, but somehow didnUt care for his style.  I fell apart
emotionally, with tears and a feeling of total loss of everything.
Everything was visible to me only in some strange wide-angle lens
viewing.  I went for a walk, a waste of time.  I tried classical
music, but only jazz was acceptable.  It was a couple of days before I
lost the residual strangeness feeling.  Never again.

(with 7 mg) I did this alone, and in retrospect I wish I had not.
Somewhere between the hours 2 and 3, I got to a full +++, and I was
concerned that I saw the effects still developing.  Where would it go
now?  There was no reality loss as with LSD, no shakes or shimmers,
but an intense and profound +++ of something characterized only by the
absence of extremes. And I am frightened because this is still
deepening.  A couple of calls to friends were not successful, but I
found an ally in the Palo Alto area, and I told him I was coming to
visit.  My greater than one hour drive there was okay only because I
had programmed every move ahead of time.  In retrospect, to drive was
completely stupid, and I certainly will never do it again, under any
circumstances.  But, there I was.  I knew which lane I would be on, on
the S.F. Bay Bridge, at every moment of my travels.  The middle lane
through the tunnel.  The second from the left when descending into San
Francisco.  The white lane-marker stripes were zipping up past my
lateral field of vision as I drove, those that were to my right zipped
past my right eye, those to the left past my left eye.  Like disturbed
fruit flies leaving an over-ripe peach.  But, as everything had been
preprogrammed, there were no surprises.  I made it successfully, and
my baby-sitting friend probed, with a blend of curiosity, love, and
envy, my uncaring state.  And in the course of the next couple of
hours, this state evolved into a friendly, familiar place.  I was
still fully +++, but now for the first time I was at peace with it.  A
fruit salad tasted heavenly.  By midnight I was able to doze lightly,
and the next day I was sure that there were some residual effects.
The second evening's sleep repaired everything.  The neutralness was
something new to me.  I donUt like not caring.  Was this the RBethS
state of the strange twenty minutes seen by SL in the ALEPH-4
experience?S

(with 7 mg) Strange, pleasant, unexciting, long-lasting.  The induced
state was characterized by: clear unintoxicated central field of
vision, concentration but with the periphery sensed as being filled
with a kind of strangeness, and also something sensed inside, at the
back of the head.  A feeling of something waiting to erupt, which
never does.  I had a faint touch of amusement, yet no part of the
experience had the depth or richness of other compounds.  No tremors.
Slight visuals, but only when looked for.  Hunger not present, but
food tasted fine when eaten.  Mildly pleasant but one would not take
it again unless bored stiff.

EXTENSIONS AND COMMENTARY: This drug was the first definition of the
term, Beth state.

There is something of the Fournier Transform in any and all drug
experiments.  A psychedelic drug experience is a complex combination
of many signals going all at the same time.  Something like the sound
of an oboe playing the notes of the A-major scale.  There are events
that occur in sequence, such as the initial A, followed by B, followed
by C-sharp and on and on.  That is the chronology of the experience,
and it can be written down as a series of perceived phenomena.  The
notes of the scale.  Black quarter notes, with flags at the tops of
their staffs, going up the page of music.

But within each of these single events, during the sounding of the
note RA,S for example, there is a complex combination of harmonics
being produced at the same time, including all components from the
fundamental oscillation on up through all harmonics into the
inaudible.  This mixture defines the played instrument as being an
oboe.  Each component may be shared by many instruments, but the
particular combination is the unique signature of the oboe.

This analogy applies precisely to the study of psychedelic drugs and
their actions.  Each drug has a chronology of effect, like the notes
of the A-major scale.  But there are many components of a drugUs
action, like the harmonics from the fundamental to the inaudible
which, taken in concert, defines the drug.  With musical instruments,
these components can be shown as sine waves on an oscilloscope.  One
component, 22%, was a sine wave at a frequency of 1205 cycles, and a
phase angle of +55!.  But in psychopharmacology?  There is no psychic
oscillo-scope.  There are no easily defined and measured harmonics or
phase angles.  Certainly, any eventual definition of a drug will
require some such dissection into components each of which makes some
contribution to the complex whole.  The mental process may some day be
defined by a particular combination of these components.  And one of
them is this Beth state.  It is a state of uncaring, of anhe-donia,
and of emotionlessness.

Many drugs have a touch of this Beth state, ALEPH-7 more than most.
If a sufficient alphabet of effects (I am using the Alephs, Beths,
Gimels, and Daleths of the Hebrew as token starters only) were to be
accumulated and defined, the actions of new materials might someday be
more exactly documented.  Could depression, euphoria, and
disinhibition for example, all be eventually seen as being made up of
their component parts, each contributing in some measured way to the
sum, to the human experience?  The psychologists of the world would be
ecstatic.  And drugs such as ALEPH-7 might be useful in helping to
define one of these parts.



#8 ARIADNE; 4C-DOM; BL-3912; DIMOXAMINE;
1-(2,5-DIMETHOXY-4-METHYLPHENYL)-2-AMINOBUTANE;
2,5-DIMETHOXY-a-ETHYL-4-METHYLPHENETHYLAMINE

SYNTHESIS: In 50 mL of benzene there was dissolved 31.6 g
2,5-dimethoxy-4-methylbenzaldehyde (see recipe for 2C-D for its
preparation), 20.2 mL 1-nitropropane, and 6 mL cyclohexylamine.  This
solution was held at reflux in a Dean Stark apparatus for 24 h,
effectively removing the water of reaction.  Upon cooling, there was
deposited 19.6 g of 1-(2,5-dimethoxy-4-methylphenyl)-2-nitro-1-butene
as brilliant orange crystals.  The mp, after recrystallization from
MeOH, was 114-115 !C and a second recrystallization increased the mp
another 2 !C.  Anal. (C13H17NO4) C,H,N.

A suspension of 12.5 g LAH in 600 mL anhydrous THF was stirred
magnetically, and brought up to a reflux.  To this there was added,
dropwise, 15.0 g 1-(2,5-dimethoxy-4-methylphenyl)-2-nitro-1-butene
dissolved in 150 mL THF.  Refluxing was continued for 15 h and, after
cooling, the excess hydride was decomposed by the addition of 12.5 mL
H2O.  The inorganic salts were made loose and granular by the addition
of 12.5 mL 15% NaOH followed by an additional 37.5 mL H2O.  These
solids were removed by filtration, and the filter cake was washed with
THF.  The combined filtrate and washings were stripped of solvent
under vacuum.  The residue was dissolved in anhydrous Et2O, and
treated with hydrogen chloride gas, yielding
1-(2,5-dimethoxy-4-methylphenyl)-2-aminobutane hydrochloride (ARIADNE)
as white crystals which, after recrystallization from IPA, weighed
11.4 g and had a mp of 232.5-234.5 !C.  Anal. (C13H22ClNO2) C,H,N,Cl.
The racemic mixture was resolved into its optical isomers by the
formation of salts with (+)-2'-nitrotartranilic acid (to give the RSS
isomer) or with (+)-2'-chlorotartranilic acid (to give the RRS
isomer).  The RRS isomer can also be prepared by the reductive
amination of 1-(2,5-dimethoxy-4-methylphenyl)-2-butanone (from the
above nitrostyrene and elemental iron) with (+)-a-methyl benzylamine
followed by the hydrogenolysis of the benzyl group.

DOSAGE: as psychedelic, unknown.

DURATION: short.

QUALITATIVE COMMENTS: (with 12 mg) I believe that my mood has
distinctly improved, and my sleep that evening was excellent.  This is
physically benign.

(with 32 mg) There was some sort of threshold that lasted for a
couple of hours.

(with 25 mg of the RRS isomer) There is the alert of a psychedelic,
with none of the rest of the package.  Perhaps a bit of paranoia.  And
by the fifth hour everything is largely gone.

EXTENSIONS AND COMMENTARY: How does one discover a new drug for a
malady that does not exist in experimental animals?  Drugs that
interfere with sleep, or with appetite, or with some infecting
bacterium, are naturals for animal screening, in that animals sleep,
eat, and can be easily infected.  But there are lots of syndromes that
involve a state of mind, and these are uniquely human.  Many of the
psychopharmacological anti-this or anti-that agents address ailments
such as anxiety, psychosis, paranoia, or depression, which are only
known in man.  So how does one discover a new drug in areas such as
these?  If one has in hand a drug that is known to be effective in one
of these human ailments, an animal assay can be set up to give some
measurable response to that specific drug, or a biochemical property
can be rationalized as being related to a mechanism of action.  And
with the known drug as a calibration, and restricting your search to
structurally related compounds, you can find structural relatives that
give the same responses.

But how does one find a new class?  One way is to kind of stumble into
it as a side-line of human experimentation with new psychedelics.  But
it is really difficult to pick up the clues as to what will be a good
anti-depressant if you are not depressed.  This compound, to which I
had given the name of ARIADNE as the first of my ten Rclassic ladiesS
(IUll say more about them later), was not really a stimulant of any
kind, certainly it was not a psychedelic, and yet there was something
there.  It had been explored rather extensively as a potential
psychotherapeutic ally by a friend of mine.  He said that there seemed
to be some value in a few of his patients who had some underlying
depression, but not much of anything with the others.  So, I decided
to call it an anti-depressant.  I had mentioned some of this history
one time when I was giving an address at a conference on the East
Coast, and my host (who happened to be the research director at a
large pharmaceutical house) asked if I would send him a sample.  His
company did many animal tests, one of which showed that it was not
hallucinogenic (a cat whose tail erected dramatically with DOM did
nothing with ARIADNE) and another that showed re-motivation (some old
maze-running monkeys who had decided not to run any more mazes changed
their minds with ARIADNE).

So patents were obtained for the RRS isomer, the more effective
isomer, covering its use for such things as the restoring of
motivation in senile geriatric patients.  And a tradename of
Dimoxamine was assigned it, despite several voices that held out for
Ariadnamine.  But it didnUt have what was needed to make it all the
way to the commercial market

Many, many analogues of ARIADNE have been made, and for a variety of
reasons.  In the industrial world there is research backup carried
out, not only for the discovery of new things, but also for patent
protection of old things.  Several dozen analogues of ARIADNE have
been made and pharmacologically evaluated, and some of them have been
put into the published literature.  The major points of variation have
been two: keep the 4-position methyl group intact, and make the
variations on the alpha-carbon (propyl, butyl, dimethyl, phenyl,
benzyl, phenethyl, etc. Q an extensive etc.) or: keep the
alpha-position ethyl group intact and make the variations on the
4-position (chloro, iodo, methylthio, carboxy, etc. Q again, an
extensive etc.).

Some of these analogues I had made, and sent in for animal screening.
The high potency of DOB suggested the bromo-counterpart of ARIADNE.
The making of this entailed the proteo counterpart,
1-(2,5-dimethoxyphenyl)-2-aminobutane.  Reaction of
2,5-dimethoxybenzaldehyde with nitropropane in benzene in a Dean Stark
apparatus with cyclohexylamine as a catalyst produced
1-(2,5-dimethoxyphenyl)-2-nitrobutene, which crystallized as orange
crystals from MeOH with a mp of 47-47.5 !C.  Anal. (C12H15NO4) C,H,N.
This was reduced to the amine 1-(2,5-dimethoxyphenyl)-2-aminobutane
with LAH in ether, and this gave a hydrochloride salt with a mp of
172-174 !C after recrystallization from acetonitrile.  The free base
of this compound was brominated in acetic acid to give
1-(2,5-dimethoxy-4-bromophenyl)-2-aminobutane which yielded a white
hydrochloride salt with a mp of 204-206 !C following recrystallization
from IPA.  The isomeric non-brominated analogue,
1-(3,4-dimethoxyphenyl)-2-aminobutane was made and explored by the
Chemical Warfare group at Edgewood Arsenal; its code number is
EA-1322.

Several of the alpha-ethyl analogues of ARIADNE were N,N-dialkylated,
and were target compounds for halogenation with radio-iodine or
radio-fluorine, for evaluation as potential brain blood-flow
indicators.  In these studies. all examples followed a common flow
diagram.  The reaction of the appropriate benzaldehyde and
nitropropane, using N,N-dimethylethylenediamine as a catalyst and
following recrystallization from MeOH, gave the corresponding
1-aromatic-2-nitro-1-butene (the nitrostyrene) which, by reduction
with elemental iron, gave the corresponding 2-butanone (which was
distilled at about 0.3 mm/Hg).  This led, by reductive amination with
dimethylamine hydrochloride and sodium cyanoborohydride, to the
corresponding N,N-dimethyl product which was distilled at about 0.3
mm/Hg and which, in no case, either formed a solid HCl salt or reacted
with carbon dioxide from the air.  From 2,4-dimethoxybenzaldehyde, the
nitrostyrene appeared as yellow crystals, the ketone as a white oil,
and the product N,N-dimethyl-1-(2,4-dimethoxyphenyl)-2-aminobutane as
a white oil.  From 2,5-dimethoxybenzaldehyde, the nitrostyrene formed
bright yellow crystal, the ketone was an off-white oil, and the
product N,N-dimethyl-1-(2,5-dimethoxyphenyl)-2-aminobutane was a white
oil.  From 3,5-dimethoxybenzaldehyde, the nitrostyrene formed pale
yellow crystals that discolored on exposure to the light, the ketone
was an off-white clear oil, and the product
N,N-dimethyl-1-(3,5-dimethoxyphenyl)-2-aminobutane was a white oil.
From 2,6-dimethoxybenzaldehyde, the nitrostyrene was obtained as
orange crystals, and was not pursued further.

A number of ARIADNE analogues have been made, or at least started,
purely to serve as probes into whatever new areas of
psychopharmacological activity might be uncovered.  One of these is a
HOT compound, and one is a TOM compound, and a couple of them are the
pseudo (or near-pseudo) orientations.  The HOT analogue was made from
the nitrostyrene precursor to ARIADNE itself, reduced not with LAH or
AH (which would give the primary amine), but rather with sodium
borohydride and borane dimethylsulfide.  The product,
1-(2,5-dimethoxy-4-methylphenyl)-N-hydroxy-2-aminobutane
hydrochloride, was a white crystalline material. The 5-TOM analogue
got as far as the nitrostyrene.  This was made from
2-methoxy-4-methyl-5-(methylthio)benzaldehyde (see under the 5-TOM
recipe for its preparation) and nitropropane in acetic acid, and gave
bright yellow crystals.  The true pseudo-analogue is the
2,4,6-trimethoxy material based on TMA-6, which is the RrealS
pseudo-TMA-2.  The nitrostyrene from 2,4,6-trimethoxybenzaldehyde and
nitropropane crystallized from MeOH/CH3CN as fine yellow crystals, and
this was reduced with AH in cold THF to
1-(2,4,6-trimethoxyphenyl)-2-aminobutane which was a bright, white
powder.

And the near-pseudo analogue?

First, what is near-pseudo?  I have explained already that the
RnormalS world of substitution patterns is the 2,4,5.  Everyone knows
that that is the most potent pattern.  But, the 2,4,6 is in many ways
equipotent, and has been named the pseudo-stuff.  The Rreal,S or
RtrueS pseudo-stuff.  So what is the RnearS pseudo-stuff?  I am
willing to bet that the rather easily obtained 2,3,6-trisubstitution
pattern, and the much more difficult to obtain 2,3,5-substitution
pattern, will produce treasures every bit as unexpected and remarkable
as either the 2,4,5- or the 2,4,6- counterparts.  These are neither
RrealS nor Rpseudo,S but something else, and I will find a name for
them when the time comes, something weird from the Greek alphabet.
And this will double again the range of possible exploration.  The
TMA-5 analogue mentioned came from 2,3,6-trimethoxybenzaldehyde and
nitropropane using cyclohexylamine as a catalyst (yellow-orange
solids) which was reduced to the amine with AH.  This hydrochloride
salt is an air-stable white powder.  All of these materials remain
unexplored.

Somewhere in the wealth of compounds implicit in the many structural
variables possible (the normal versus the pseudo versus the
near-pseudo patterns, coupled with the wide variety of promising
substituents that can be placed on the 4-position, together with the
availability of the the unexplored members of the Ten Classic Ladies
harem), it would seem inescapable that interesting compounds will
emerge.

Just what is this all about the ten RClassic Ladies?S In the chemical
struc-ture of DOM, there is a total of nineteen hydrogen atoms.  Some
of these are indis-tinguishable from others, such as the three
hydrogen atoms on a methyl group.  But there are exactly ten RtypesS
of hydrogen atoms present.  And, not having much, if any, intuition as
to just why DOM was so powerful a psychedelic, I decided to
systematically replace each of the ten unique hydrogens, one at a time
of course, with a methyl group.  And I planned to give the resulting
materials the names of famous ladies, alphabetically, as you walk
around the molecule.

ARIADNE was the first of these, the methyl for a hydrogen atom on the
methyl group of the amphetamine chain.  It was Ariadne who gave the
long piece of thread to Theseus to guide him through the mazes of the
Labyrinth so he could escape after killing the Minotaur.  The record
is fuzzy as to whether, after the successful killing, she went with
him, or let him go on alone.  A methyl group on the nitrogen atom
produced BEATRICE.  There is the legendary Beatrijs of the Dutch
religious literature of the 14th century, and there is the Beatrice
from Beatrice and Benedict (of Berlioz fame).  But the one I had in
mind was the lady from Florence whom Dante immortalized in the Divina
Commedia, and she is entered under her own name in this footnote.
Replacing the alpha-hydrogen of DOM with a methyl group would give the
phentermine analogue which is named CHARMIAN.  You may be thinking of
Cleopatra's favorite attendant, but I was thinking of the sweet wife
of a very dear friend of mine, a lady who has been in a state of
gentle schizophrenia for some forty years now.  The MDA analogue of
CHARMIAN has been described in this foornote under the code name of
MDPH.  CHARMIAN, herself, has been synthesized and is of very much
reduced potency in animals, as compared to DOM.  It has not been tried
in man as far as I know.

The two beta-hydrogen atoms of DOM are distinct in that, upon being
replaced with methyl groups, one would produce a threo-isomer, and the
other an erythro-isomer.  I have named them DAPHNE (who escaped from
Apollo by becoming a laurel tree which was, incidentally, named for
her) and ELVIRA (who might not be too well known classically, but
whose name has been attached to Mozart's 21st piano concerto as its
slow movement was used as theme music for the movie Elvira Madigan).
I donUt know if either of this pair has been made Q I started and got
as far as the cis-trans mixture of adducts betweeen nitroethane and
2,5-dimethoxy-4-methylacetophenone.  Whoever finally makes them gets
to assign the names.  I had made and tested the corresponding
homologues of DMMDA that correspond to these two ladies.

And there are five positions (2,3,4,5 and 6) around the aromatic ring,
each of which either carries a hydrogen atom or a methyl group that
has a hydrogen atom.  There is the 2-methoxy group which can become a
2-ethoxy group to produce a compound called FLORENCE.  Her name is the
English translation of the Italian Firenze, a city that, although
having a female name, has always seemed thoroughly masculine to me.
There is the 3-hydrogen atom which can become a 3-methyl group to
produce a compound called GANESHA.  This is a fine elephant-headed
Indian God who is the symbol of worldly wisdom and also has been seen
as the creator of obstacles.  Here I really blew it; the Classic Lady
turned out to be a Classic Gentle-man; not even the name is feminine.
There is the 4-methyl group which can become a 4-ethyl group to
produce a compound called HECATE who presided over magic arts and
spells.  There is the 5-methoxy group which can become a 5-ethoxy
group to produce a compound called IRIS, who is the Goddess of the
rainbow.  And there is the 6-hydrogen atom which can become a 6-methyl
group to produce a compound called JUNO, who is pretty much a ladyUs
lady, or should I say a woman's woman.

GANESHA, 2,5-dimethoxy-3,4-dimethylamphetamine has been made, and has
proven to be an extraordinary starting point for a large series of
potent phenethylamines and amphetamines which are described in this
book.  HECATE was given a synonym early in this process, and is now
known as DOET (2,5-dimethoxy-4-ethylamphetamine).  IRIS has also been
entered under her name, and the other ethoxy homologue, FLORENCE,
would be easily made based on the preparation of the phenethylamine
analogue, 2CD-2ETO.  Perhaps it has already been made somehow,
somewhere, as I have noted that I have claimed its citrate salt as a
new compound in a British patent.  And, finally, JUNO
(3,6-dimethoxy-2,4-dimethylamphetamine) has been made (from
2,5-dimethoxy-m-xylene, which was reacted with POCl3 and
N-methylformanilide to the benzaldehyde, mp 53-54 !C, and to the
nitrostyrene with nitroethane, mp 73-74 !C from cyclohexane, and to
the final amine hydrochloride with LAH in THF).  Rather amazingly, I
have had JUNO on the shelf for almost 14 years and have not yet gotten
around to tasting it.



#9 ASB; ASYMBESCALINE; 3,4-DIETHOXY-5-METHOXYPHENETHYLAMINE

SYNTHESIS: To a solution of 32 g of 5-bromobourbonal in 150 mL DMF
there was added 31 g ethyl iodide and 32 g of finely ground 85% KOH
pellets.  There was the formation of a purple color and a heavy
precipitate.  On gradual heating to reflux, the color faded to a pale
yellow and the precipitate dissolved over the course of 1 h.  The
heating was continued for an additional 1 h.  The reaction mixture was
added to 1 L H2O, and extracted with 2x150 mL of petroleum ether.  The
extracts were pooled, washed with 2x200 mL 5% NaOH and finally with
H2O.  After drying over anhydrous K2CO3 the solvents were removed
under vacuum to yield 36 g of crude 3-bromo-4,5-diethoxybenzaldehyde
as an amber liquid.  This was used without purification for the
following step.  Distillation at 105-115 !C at 0.3 mm/Hg provided a
white sample which did not crystallize.  Anal. (C11H13BrO3 ) C,H.

A mixture of 36 g 3-bromo-4,5-diethoxybenzaldehyde and 17 mL
cyclohexylamine was heated with an open flame until it appeared to be
free of H2O.  The residue was put under a vacuum (0.4 mm/Hg) and
distilled at 135-145 !C, yielding 42 g
3-bromo-N-cyclohexyl-4,5-diethoxybenzylidenimine as a viscous light
greenish oil.  This slowly set to a crystalline glass with a mp of
60-61 !C.  Recrystallization from hexane gave a white crystalline
product without any improvement in the mp.  Anal. (C17H24BrNO2) C,H.
This is a chemical intermediate to a number of active bases, taking
advantage of the available bromine atom.  This can be exchanged with a
sulfur atom (leading to 5-TASB and 3-T-TRIS) or with an oxygen atom as
described below.

A solution of 18 g 3-bromo-N-cyclohexyl-4,5-diethoxybenzylidenimine in
250 mL anhydrous Et2O was placed in an atmosphere of He, stirred
magnetically, and cooled with an external dry ice/acetone bath.  Then
36 mL of a 1.5 M solution of butyllithium in hexane was added over 2
min, producing a clear yellow solution.  This was stirred for 10 min.
There was then added 30 mL of butyl borate at one time, the stirring
continued for 5 min.  The stirred solution was allowed to return to
room temperature.  There was added 150 mL of saturated aqueous
ammonium sulfate.  The Et2O layer was separated, and the aqueous phase
extracted with another 75 mL Et2O.  The combined organic phases were
evaporated under vacuum.  The residue was dissolved in 100 mL MeOH,
diluted with 20 mL H2O, and then treated with 15 mL 35% H2O2 added
over the course of 2 min.  This mildly exothermic reaction was allowed
to stir for 15 min, then added to 500 mL H2O.  This was extracted with
2x100 mL CH2Cl2 and the solvent removed under vacuum.  The residue was
suspended in 150 mL dilute HCl and heated on the steam bath for 0.5 h.
Stirring was continued until the reaction was again at room
temperature, then it was extracted with 2x75 mL CH2Cl2.  These
extracts were pooled and extracted with 3x100 mL dilute aqueous KOH.
The aqueous extracts were washed with CH2Cl2, reacidified with HCl,
and reextracted with 2x75 mL CH2Cl2.  These extracts were pooled, and
the solvent removed under vacuum to yield a brown residue.  This was
distilled at 107-127 !C at 0.4 mm/Hg to yield 8.3 g of
3,4-diethoxy-5-hydroxybenzaldehyde as an oil that set to a tan solid.
Recrystallization from cyclohexane gave a white product with a mp of
70.5-71.5 !C.  Anal. (C11H14O4) C,H.

A solution of 8.3 g of 3,4-diethoxy-5-hydroxybenzaldehyde and 3.0 g
KOH in 75 mL EtOH was treated with 5 mL methyl iodide and stirred at
room temperature for 5 days.  The reaction mixture was added to 400 mL
H2O and extracted with 2x50 mL CH2Cl2.  The extracts were pooled,
washed with 2x150 mL dilute NaOH, and the solvent removed under
vacuum.  The residual oil was distilled at 95-110 !C at 0.3 mm/Hg to
yield 8.2 g of 3,4-diethoxy-5-methoxybenzaldehyde as a pale yellow
liquid.  This product was a crystalline solid below 20 !C but melted
upon coming to room temperature.  It was analyzed, and used in further
reactions as an oil.  Anal. (C12H16O4) C,H.

To a solution of 6.4 g 3,4-diethoxy-5-methoxybenzaldehyde in 40 mL
nitromethane there was added about 0.5 g anhydrous ammonium acetate,
and this was held at reflux for 1 h.  The excess solvent/reagent was
removed under vacuum, producing a red oil which set up to crystals.
These were recrystallized from 40 mL boiling MeOH to yield 3.0 g of
3,4-diethoxy-5-methoxy-'-nitrostyrene as yellow plates, with a mp of
89-90 !C.  Anal. (C13H17NO5) C,H.

A solution of 3.0 g LAH in 150 mL anhydrous THF under He was cooled to
0 !C and vigorously stirred.  There was added, dropwise, 2.1 mL of
100% H2SO4, followed by the dropwise addition of a solution of 3.5 g
3,4-diethoxy-5-methoxy-'-nitrostyrene in 30 mL anhydrous THF, over the
course of 10 min.  The addition was exothermic.  The mixture was held
at reflux on the steam bath for 30 min.  After cooling again, the
excess hydride was destroyed with IPA, followed by the addition of 10%
NaOH sufficient to covert the aluminum oxide to a white, granular
form.  This was removed by filtration, the filter cake washed with
IPA, the mother liquor and filtrates combined, and the solvents
removed under vacuum to provide a yellow oil.  This residue was added
to 100 mL dilute H2SO4 producing a cloudy suspension and some yellow
insoluble gum.  This was washed with 2x75 mL CH2Cl2.  The aqueous
phase was made basic with 25% NaOH, and extracted with 2x75 mL CH2Cl2.
The solvent was removed from these pooled extracts and the residue
distilled at 110-135 !C at 0.4 mm/Hg to provide 2.0 g of a colorless
liquid.  This was dissolved in 7 mL IPA, neutralized with about 40
drops of concentrated HCl, followed by 50 mL anhydrous Et2O with
stirring.  The initially clear solution spontaneously deposited a
white crystalline solid.  This was diluted with an additional 30 mL
Et2O, let stand for 1 h, and the solids removed by filtration.  After
Et2O washing, the product was air-dried to yield 1.25 g of
3,4-diethoxy-5-methoxyphenethylamine hydrochloride (ASB) with a mp of
142-143 !C.  Anal. (C13H22ClNO3) C,H.

DOSAGE: 200 - 280 mg.

DURATION: 10 - 15 h.

QUALITATIVE COMMENTS: (with 240 mg) There was a pleasant and easy
flow of day-dreaming thoughts, quite friendly and somewhat erotic.
There was a gentle down-drift to my starting baseline mental status by
about midnight (I started at 9:00 AM).  I never quite made it to a
+++, and rather regretted it.

(with 280 mg) The plateau of effect was evident by hour two, but I
found the experience lacking the visual and interpretive richness that
I had hoped for.  Sleep was very fitful after the effects had largely
dropped Q it was hard to simply lie back and relax my guard Q and even
while being up and about the next day I felt a residual plus one.
Over all, there were few if any of the open interactions of 2C-B or
LSD.  Some negative side seemed to be present.

(with 280 mg) The entire session was, in a sort of way, like being in
a corridor outside the lighted halls where a beautiful mescaline
experience is taking place, sensing the light from behind a grey door,
and not being able to find my way in from the dusky underside
passageways.  This is sort of a gentle sister of mescaline, but with a
tendency to emphasize (for me, at this time) the negative, the sad,
the struggling.  Sleep was impossible before the fifteenth hour.  When
I tried, I got visions of moonlight in the desert, with figures around
me which were the vampire-werewolf aspect of the soul, green colored
and evil.  I had to sit quietly in the living room and wait patiently
until they settled back to wherever they belonged and stopped trying
to take over the scene.  During the peak of the experience, my pulse
was thready, somewhat slowed, and uneven.  There was a faint feeling
of physical weirdness.

EXTENSIONS AND COMMENTARY: This specific amine was a target for a
single study in cats many years ago, in Holland, using material
obtained from Hoffman La Roche in Basel.  Their findings are hard to
evaluate, in that 200 milligrams was injected into a 3.75 kilogram cat
(53 mg/Kg), or about twice the dosage that they used in their studies
with metaescaline.  Within 5 minutes there were indications of
catatonia, and within a half hour the animal was unable to walk.  This
condition persisted for two days, at which time the animal died.
Although this dose was many times that used in man, perhaps hints of
the physical unease and long action are there to be gleaned.  The
consensus from over a half dozen experiments is that there is not
enough value to be had to offset the body load experienced.

A comment is needed on the strange name asymbescaline!  In the
marvelous world of chemical nomenclature, bi- (or di-) usually means
two of something, and tri- and tetra- quite reasonably mean three and
four of something.  But occasionally there can be an ambiguity with bi
(or tri or tetra) in that bi some-thing-or-other might be two
something-or-others hooked together or it might be two things hooked
onto a something-or-other.  So, the former is called bi- and the
latter is called bis-.  This compound is not two escalines hooked
together (bi-escaline) but is only one of them with two ethyl groups
attached (bis-escaline or bescaline).  And since there are two ways
that this can be done (either symmetrically or asymmetrically) the
symmetric one is called symbescaline (or SB for short) and this one is
called asymbescaline (or ASB for short).  To complete the terminology
lecture, the term tri- becomes tris- (the name given for the drug with
all three ethoxy groups present in place of the methoxys of mescaline)
and the term tetra- mutates into the rather incredible tetrakis-!



#10 B; BUSCALINE; 4-(n)-BUTOXY-3,5-DIMETHOXYPHENETHYLAMINE

SYNTHESIS: A solution of 5.8 g of homosyringonitrile (see under E for
preparation), 100 mg decyltriethylammonium iodide, and 11 g n-butyl
bromide in 50 mL anhydrous acetone was treated with 6.9 g finely
powdered anhydrous K2CO3 and held at reflux for 10 h.  An additional 6
g of n-butyl bromide was added to the mixture, and the refluxing
continued for another 48 h.  The mixture was filtered, the solids
washed with acetone, and the solvent from the combined filtrate and
washes removed under vacuum.  The residue was suspended in acidified
H2O, and extracted with 3x175 mL CH2Cl2.  The pooled extracts were
washed with 2x50 mL 5% NaOH, once with dilute HCl, and then stripped
of solvent under vacuum giving 13.2 g of a deep yellow oil.  This was
distilled at 132-145 !C at 0.2 mm/Hg to yield 5.0 g of
4-(n)-butyloxy-3,5-dimethoxyphenylacetonitrile as a pale yellow oil
which set up to crystals spontaneously.  The mp was 42-43 !C.  Anal.
(C14H19NO3) C H N.

A solution of AH was prepared by the cautious addition of 0.67 mL of
100% H2SO4 to 25 mL of 1.0 M LAH in THF, which was being vigorously
stirred under He at ice bath temperature.  A total of 4.9 g of
4-(n)-butyloxy-3,5-dimethoxyphenylacetonitrile was added as a solid
over the course of 10 min.  Stirring was continued for another 5 min,
then the reaction mixture was brought to reflux on the steam bath for
another 45 min.  After cooling again to room temperature, IPA was
added to destroy the excess hydride (about 5 mL) followed by 10 mL of
15% NaOH which was sufficient to make the aluminum salts loose, white,
and filterable.  The reaction mixture was filtered, the filter cake
washed with IPA, and the mother liquor and washes combined and the
solvent removed under vacuum to yield an amber oil.  This residue was
treated with dilute H2SO4 which generated copious solids.  Heating
this suspension effected solution, and after cooling, all was washed
with 3x50 mL CH2Cl2.  The aqueous phase was made basic with aqueous
NaOH, and the product extracted with 2x100 mL CH2Cl2.  The extracts
were evaporated to a residue under vacuum, and this was distilled at
128-138 !C at 0.5 mm/Hg yielding 3.8 g of a colorless oil.  This was
dissolved in 40 mL IPA, neutralized with concentrated HCl (about 55
drops required) and, with vigorous stirring, 80 mL of anhydrous Et2O
was added which produced fine white plates.  After standing for
several h, the product was filtered, washed with 20% IPA in Et2O, and
finally with Et2O.  Air drying yielded 3.9 g of
4-(n)-butyloxy-3,5-dimethoxyphenethylamine hydrochloride (B) with a mp
of 152-153 !C.  An analytical sample melted at 155-157 !C.  Anal.
(C14H24ClNO3) C,H,N.

DOSAGE: greater than 150 mg.

DURATION: several hours.

QUALITATIVE COMMENTS: (with 120 mg) There is a strange taste, not
really bitter, it does not linger.  The slight change of baseline has
certainly disappeared by the eighth hour.  No noticeable changes in
either the visual or the auditory area.

(with 150 mg) Throughout the experiment it was my impression that
whatever effects were being felt, they were more in body than mind.
The body load never mellowed out, as it would have with mescaline,
after the first hour or two.  Mental effects didnUt develop in any
interesting way.  I was aware of brief heart arrhythmia.  Tummy was
uncomfortable, off and on, and there was light diarrhea.  Even as late
as the fifth hour, my feet were cold, and the whole thing left me with
a slightly uncomfortable, 'Why did I bother?' feeling.

EXTENSIONS AND COMMENTARY: There is a jingle heard occasionally in
chemical circles, concerning the homologues of methyl.  It goes,
RThere's ethyl and propyl, but butyl is futile.S And to a large
measure this is true with the 4-position homologues of mescaline.
This butyl compound, B or Buscaline, had originally been patented in
England in 1930 without any physical or pharmacological description,
and the few physical studies that had involved it (lipophilic this and
serotonin that) suggested that it was less active than mescaline.

In principle, the 5-, the 6-, the 7- and the on-up homologues might be
called amylescaline (possibly pentescaline?), hexescaline,
heptescaline (possibly septescaline), and God-knows-what-scaline.
They would certainly be easily makeable, but there would be little
value that could be anticipated from nibbling them.  In keeping with
the name B (for butoxy), these would be known as A (for amyloxy, as
the use of a P could confuse pentoxy with propoxy), as H (for
hexyloxy, but careful; this letter has been used occasionally for
DMPEA, which is Homopiperonylamine), and as S (the H for heptyloxy has
been consumed by the hexyloxy, so let's shift from the Greek hepta to
the Latin septum for the number seven).  It seems most likely that the
toxic symptoms that might well come along with these phenethylamines
would discourage the use of the dosage needed to affect the higher
centers of the brain.  The same generally negative feeling applies to
the amphetamine counterparts 3C-B, 3C-A, 3C-H and 3C-S.

A brief reiteration of the 2C-3C nomenclature, to avoid a possible
misunderstanding.  The drug 2C-B is so named in that it is the
two-carbon chain analogue of the three-carbon chain compound DOB.  The
drug 3C-B is so named because it is the three-carbon chain analogue of
the two-carbon chain compound Buscaline, or more simply, B.  There is
no logical connection whatsoever, either structural or
pharmacological, between 2C-B and 3C-B.



#11 BEATRICE; N-METHYL-DOM; 2,5-DIMETHOXY-4,N-DIMETHYLAMPHETAMINE

SYNTHESIS: A fused sample of 5.0 g of white, crystalline free base
2,5-dimethoxy-4-methylamphetamine, DOM, was treated with 10 mL ethyl
formate, and held at reflux on the steam bath for several h.  Removal
of the solvent gave 5.5 g of a white solid, which could be
recrystallized from 15 mL MeOH to give 3.8 g of fine white crystals of
2,5-dimethoxy-N-formyl-4-methylamphetamine.  An analytical sample from
ethyl formate gave granular white crystals.

To a stirred suspension of 4.0 g LAH in 250 mL anhydrous Et2O at
reflux and under an inert atmosphere, there was added, by the shunted
Soxhlet technique, 4.2 g of 2,5-dimethoxy-N-formyl-4-methylamphetamine
as rapidly as its solubility in hot Et2O would allow.  The mixture was
held at reflux for 24 h and then stirred at room temperature for
several additional days.  The excess hydride was destroyed with the
addition of dilute H2SO4 (20 g in 500 mL water) followed by the
additional dilute H2SO4 needed to effect a clear solution.  The Et2O
was separated, and the aqueous phase extracted with 100 mL Et2O and
then with 2x250 mL CH2Cl2.  Following the addition of 100 g potassium
sodium tartrate, the mixture was made basic with 25% NaOH.  The clear
aqueous phase was extracted with 3x250 mL CH2Cl2 These extracts were
pooled, and the solvent removed under vacuum.  The residual amber oil
was dissolved in 400 mL anhydrous Et2O, and saturated with hydrogen
chloride gas.  The white crystals that formed were removed by
filtration, washed with Et2O, and air dried to constant weight.  There
was obtained 4.2 g of product with a mp of 131.5-133.5 !C.  This
product was recrys-tallized from 175 mL boiling ethyl acetate to give
3.5 g 2,5-dimethoxy-4,N-di-methylamphetamine hydrochloride (BEATRICE)
as pale pink crystals with a mp of 136-137 !C.  A sample obtained from
a preparation that employed the methyl sulfate methylation of the
benzaldehyde adduct of DOM had a mp of 125-126 !C and presented a
different infra-red spectrum.  It was, following recrystallization
from ethyl acetate, identical to the higher melting form in all
respects.

DOSAGE: above 30 mg.

DURATION: 6 - 10 h.

QUALITATIVE COMMENTS: (with 20 mg) There was a gentle and demanding
rise from the one to the three hour point that put me into an
extremely open, erotic, and responsive place.  I had to find a
familiar spot to orient myself, and the kitchen served that need.  As
the experience went on, it showed more and more of a stimulant
response, with tremor, restlessness, and a bit of trouble sleeping.
But there was no anorexia!  An OK experience.

(with 30 mg) There is a real physical aspect to this, and I am not
completely happy with it.  There is diarrhea, and I am restless, and
continuously aware of the fact that my body has had an impact from
something.  The last few hours were spent in talking, and I found
myself still awake some 24 hours after the start of the experiment.
The mental was not up there to a +++, and yet the physical disruption
was all that I might care to weather, and exceeds any mental reward.
When I did sleep, my dreams were OK, but not rich.  Why go higher?S

EXTENSIONS AND COMMENTARY: This is another example of the N-methyl
homologues of the psychedelics.  None of them seem to produce stuff of
elegance.  It is clear that the adding of an N-methyl group onto DOM
certainly cuts down the activity by a factor of ten-fold, and even
then results in something that is not completely good.  Three
milligrams of DOM is a winner, but even ten times this, thirty
milligrams of N-methyl-DOM, is somewhat fuzzy.  In the rabbit
hyperthermia studies, this compound was some 25 times less active than
DOM, so even animal tests say this is way down there in value.  This
particular measure suggests that the active level in man might be 75
milligrams.  Well, maybe, but I am not at all comfortable in trying it
at that level.  In fact I do not intend to explore this any further
whatsoever, unless there is a compelling reason, and I see no such
reason.  For the moment, let us leave this one to others, who might be
more adventurous but less discriminating.

In browsing through my notes I discovered that I had made another
N-substitution product of DOM.  Efforts to fuse free-base DOM with the
ethyl cyclopropane carboxylate failed, but the reaction between it and
the acid chloride in pyridine gave the corresponding amide, with a mp
of 156-157 !C from MeOH.  Anal. (C16H23NO3) C,H,N.  This reduced
smoothly to the corresponding amine,
N-cyclopropyl-2,5-dimethoxy-4-methylamphetamine which formed a
hydrochloride salt melting at 153-156 !C.  I canUt remember the
reasoning that led to this line of synthesis, but it must not have
been too exciting, as I never tasted the stuff.



#12 BIS-TOM; 4-METHYL-2,5-bis-(METHYLTHIO)AMPHETAMINE

SYNTHESIS: A solution of 9.0 g 2,5-dibromotoluene in 50 mL petroleum
ether was magnetically stirred under a He atmosphere.  To this there
was added 50 mL of a 1.6 M hexane solution of butyllithium, and the
exothermic reaction, which produced a granular precipitate, was
allowed to stir for 12 h.  The mixture was cooled to 0 !C and there
was then added 7.5 g dimethyldisulfide.  There was a heavy precipitate
formed, which tended to become lighter as the addition of the
disulfide neared completion.  After 20 min additional stirring, the
reaction mixture was poured into H2O that contained some HCl.  The
phases were separated and the aqueous phase extracted with 50 mL Et2O.
The organic phase and extract were combined, washed with dilute NaOH,
and then with H2O.  After drying over anhydrous K2CO3, the solvent was
removed under vacuum and the residue distilled to give a fraction that
boiled at 75-85 !C at 0.3 mm/Hg and weighed 5.3 g.  This was about 80%
pure 2,5-bis-(methylthio)toluene, with the remainder appearing to be
the monothiomethyl analogues.  A completely pure product was best
obtained by a different, but considerably longer, procedure.  This is
given here only in outline.  The phenolic OH group of
3-methyl-4-(methylthio)phenol was converted to an SH group by the
thermal rearrangement of the N,N-dimethylthioncarbamate.  The impure
thiophenol was liberated from the product N,N-dimethylthiolcarbamate
with NaOH treatment.  The separation of the phenol/thiophenol mixture
was achieved by a H2O2 oxidation to produce the intermediate
3-methyl-4-methylthiophenyldisulfide.  This was isolated as a white
crystalline solid from MeOH, with a mp of 78-79 !C.  Anal. (C16H18S4)
C,H.  It was reduced with zinc in acetic acid, and the resulting
thiophenol (a water-white liquid which was both spectroscopically and
microanalytically correct) was methylated with methyl iodide and KOH
in MeOH to give the desired product, 2,5-bis-(methylthio)toluene, free
of any contaminating mono-sulfur analogues.

A solution of 3.9 g of 2,5-bis-(methylthio)toluene in 20 mL acetic
acid was treated with a crystal of iodine followed by the addition of
3.5 g elemental bromine.  This mixture was heated on the steam bath
for 1 h, which largely discharged the color and produced a copious
evolution of HBr.  Cooling in an ice bath produced solids that were
removed by filtration.  Recrystallization from IPA gave 1.9 g of
2,5-bis-(methylthio)-4-bromotoluene as a white crystalline solid with
a mp of 133-134 !C.  Anal. (C9H11BrS2) C,H.  An alternate synthesis of
this intermediate was achieved from 1,4-dibromobenzene which was
converted to the 1,4-bis-(methylthio)benzene (white crystals with a mp
of 83.5-84.5 !C) with sodium methylmercaptide in
hexamethylphosphoramide.  This was dibrominated to
2,5-dibromo-1,4-bis-(methylthio)benzene in acetic acid (white
platelets from hexane melting at 195-199 !C).  This, in Et2O solution,
reacted with BuLi to replace one of the bromine atoms with lithium,
and subsequent treatment with methyl iodide gave
2,5-bis-(methylthio)-4-bromotoluene as an off-white solid identical to
the above material (by TLC and IR) but with a broader mp range.

A solution of 2.4 g 2,5-bis-(methylthio)-4-bromotoluene in 100 mL
anhydrous Et2O, stirred magnetically and under a He atmosphere, was
treated with 10 mL of a 1.6 M solution of butyllithium in hexane.
After stirring for 10 min there was added 2.5 mL N-methylformanilide
which led to an exothermic reaction.  After another 10 min stirring,
the reaction mixture was added to 100 mL dilute HCl, the phases were
separated, and the aqueous phase extracted with 2x50 mL Et2O.  The
combined organic phase and extracts were dried over anhydrous K2CO3,
and the solvent removed under vacuum.  The partially solid residue was
distilled at 140-150 !C at 0.2 mm/Hg to give a crystalline fraction
that, after recrystallization from 15 mL boiling IPA gave
2,5-bis-(methylthio)-4-methylbenzaldehyde as a yellow-brown solid
which weighed 1.1 g and had a mp of 107-109 !C.  An analytical sample
from MeOH melted at 110-111 !C with an excellent IR and NMR.  Anal.
(C10H12OS2) C,H.  An alternate synthesis of this aldehyde employs the
2,5-bis-(methylthio)toluene described above.  A CH2Cl2 solution of
this substituted toluene containing dichloromethyl methyl ether was
treated with anhydrous AlCl3, and the usual workup gave a distilled
fraction that spontaneously crystallized to the desired aldehyde but
in an overall yield of only 11% of theory.

To a solution of 0.5 g 2,5-bis-(methylthio)-4-methylbenzaldehyde in 15
mL nitroethane there was added 0.15 g anhydrous ammonium acetate and
the mixture was heated on the steam bath for 1 h.  The excess solvent
was removed under vacuum and the residue was dissolved in 10 mL
boiling MeOH.  This solution was decanted from a little insoluble
residue, and allowed to cool to ice bath temperature yielding, after
filtering and drying to constant weight, 0.55 g of
1-[2,5-bis-(thiomethyl)-4-methylphenyl]-2-nitropropene as
pumpkin-colored crystals with a mp of 90-91 !C.  This was not improved
by recrystallization from EtOH.  Anal. (C12H15NO2S2) C,H.

A cooled, stirred solution of 0.5 g LAH in 40 mL THF was put under an
inert atmosphere, cooled to 0 !C with an external ice bath, and
treated with 0.42 mL 100% H2SO4, added dropwise.  A solution of 0.5 g
1-[2,5-bis-(thiomethyl)-4-methylphenyl]-2-nitropropene in 20 mL
anhydrous THF was added over the course of 5 min, and the reaction
mixture held at reflux for 30 min on the steam bath.  After cooling
again to ice temperature, the excess hydride was destroyed by the
addition of IPA and the inorganics were converted to a loose, white
filterable form by the addition of 1.5 mL 5% NaOH.  These solids were
removed by filtration and the filter cake was washed with 2x50 mL IPA.
The combined filtrate and washings were stripped of solvent under
vacuum to give a residue that was a flocculant solid.  This was
suspended in dilute H2SO4 and extracted with 2x50 mL CH2Cl2, and the
combined organics extracted with 2x50 mL dilute H3PO4.  The aqueous
extracts were made basic, and the product removed by extraction with
2x75 mL CH2Cl2.  After removal of the solvent under vacuum, the
residue was distilled at 126-142 !C at 0.2 mm/Hg to give 0.2 g of
product which crystallized in the receiver.  This was dissolved in 1.5
mL hot IPA, neutralized with 4 drops of concentrated HCl, and diluted
with 3 mL anhydrous Et2O to give, after filtering and air drying, 0.2
g. of 2,5-bis-(methylthio)-4-methylamphetamine hydrochloride (BIS-TOM)
as white crystals with a mp of 228-229 !C.  Anal. (C12H20ClNS2) C,H.

DOSAGE: greater than 160 mg.

DURATION: unknown.

QUALITATIVE COMMENTS: (with 160 mg) I was vaguely aware of something
in the latter part of the afternoon.  A suggestion of darting,
physically (when going to sleep), but nothing at the mental level.
This is as high as I will go.

EXTENSIONS AND COMMENTARY: It is reasonable, in retrospect, to accept
that BIS-TOM is not an active compound.  The replacement of the
2-position oxygen of DOM with a sulfur atom (to give 2-TOM) dropped
the potency by a factor of 15x, and the replacement of the 5-position
oxygen with a sulfur atom (to give 5-TOM) dropped the potency by a
factor of about 10x.  It would be a logical calculation that the
replacement of both oxygen atoms with sulfur might drop the potency by
a factor of 150x.  So, with DOM being active at maybe 5 milligrams, a
logical prediction of the active level of BIS-TOM would be 750
milligrams.  And maybe this would be the right level, but with the
hints of neurological disturbance that seemed to be there at 160 mg,
there was no desire to go up by a factor of five again.  The rewards
would simply not be worth the risks.

The 2-carbon analogue, 2C-BIS-TOM, was prepared from the intermediate
aldehyde above, first by reaction with nitromethane to give the
nitrostyrene as tomato-colored crystals from EtOAc, mp 145-146 !C.
Anal. (C11H13NO2S2) C,H.  This was reduced with AH to give
2,5-bis-(methylthio)-4-methylphenethylamine hydrochloride as
ivory-colored crystals with a mp of 273-277 !C.

Although there are many interesting psychedelic drugs with sulfur
atoms in them (the TOMUs, the TOETUs, the ALEPH's and all of the
2C-TUs), there just arenUt many that contain two sulfur atoms.
BIS-TOM bombed out, and 2C-BIS-TOM remains untried, but will probably
also fail, as the phenethylamines are rarely more potent than the
corresponding amphetamines.  This leaves 2C-T-14 as the remaining
hope, and its synthesis is still underway.



#13 BOB; '-METHOXY-2C-B; 4-BROMO-2,5-'-TRIMETHOXYPHENETHYLAMINE

SYNTHESIS: To a vigorously stirred suspension of 2.1 g
4-bromo-2,5-dimethoxy-'-nitrostyrene [from
4-bromo-2,5-dimethoxybenzaldehyde and nitromethane in acetic acid with
ammonium acetate as a catalyst, mp 157-158 !C, anal.  (C10H10BrNO4)
C,H] in 20 mL anhydrous MeOH, there was added a solution of sodium
methoxide in MeOH (generated from 0.5 g metallic sodium in 20 mL
anhydrous MeOH).  After a few min there was added 10 mL acetic acid
(no solids formed) followed by the slow addition of 50 mL of H2O.  A
cream-colored solid was produced, which was removed by filtration and
washed well with H2O.  After air drying the product,
1-(4-bromo-2,5-dimethoxyphenyl)-1-methoxy-2-nitroethane, weighed 2.0
g.  An analytical sample from MeOH was off-white in color and had a mp
of 119-120 !C.  Anal. (C11H14BrNO5) C,H.

A solution of LAH (15 mL of 1 M solution in THF) was diluted with an
equal volume of anhydrous THF, and cooled (under He) to 0 !C with an
external ice bath.  With good stirring there was added 0.38 mL 100%
H2SO4 dropwise, to minimize charring.  This was followed by the
addition of 1.0 g
1-(4-bromo-2,5-dimethoxyphenyl)-1-methoxy-2-nitroethane as a solid
over the course of 5 min.  After an hour of stirring at 0 !C, the
temperature was brought up to a gentle reflux on the steam bath for 30
min.  There was no vigorous exothermic reaction seen, unlike that with
the syntheses of BOD, BOH and BOM.  The reaction mixture was cooled
again to 0 !C, and the excess hydride was destroyed by the cautious
addition of IPA.  This was followed by sufficent dilute aqueous NaOH
to give a white granular character to the oxides, and to assure that
the reaction mixture was basic.  The reaction mixture was filtered,
and the filter cake washed first with THF fol-lowed by IPA.  The
combined filtrate and washings were stripped of solvent under vacuum
and dissolved in dilute H2SO4, with the apparent generation of yellow
solids.  This was washed with 2x50 mL CH2Cl2, and the aqueous phase
made basic with NaOH.  This was extracted with 2x50 mL CH2Cl2, and the
pooled extracts were stripped of solvent under vacuum.  The residue
was distilled at 130-150 !C at 0.2 mm/Hg to give 0.2 g of product as a
clear white oil.  This fraction was dissolved in 10 mL IPA, and
neutralized with 4 drops concentrated HCl.  The addition of 30 mL
anhydrous Et2O allowed the formation of
4-bromo-2,5,'-trimethoxyphenethylamine hydrochloride (BOB) as a fine
white crystalline product.  This was removed by filtration, washed
with Et2O, and air dried.  There was obtained 0.1 g white crystals
with a mp of 187-188 !C.  Anal. (C11H17BrClNO3) C,H.

DOSAGE: 10 - 20 mg.

DURATION: 10 - 20 h.

QUALITATIVE COMMENTS: (with 10 mg) I donUt know if it was me this
day, or if it was the chemical, but I got into a granddaddy of a
paranoid, sociopathic snit, without feeling and without emotion.  I
was indifferent to everything.  Later on, there was some improvement,
with body tingling (good, IUm pretty sure) and a sense of awareness
(good, I guess) but I still canceled my evening dinner company.  All
in all, pretty negative.

(with 10 mg) I had to get away and into myself, so I weeded in the
vegetable garden for almost an hour.  Then I lay down in the bedroom,
and enjoyed a magnificent vegetable garden, in Southern France, in my
mind's eye.  An extraordinary zucchini.  And the weeds had all been
magically pulled.  In another couple of hours a neurological
over-stimulation became apparent, and I spent the rest of the day
defending myself.  In the evening, I took 100 milligrams phenobarbital
which seemed to smooth things just enough.  Too bad.  Nice material,
otherwise.

(with 15 mg) The erotic was lustful, but at the critical moment of
orgasm, the question of neurological stability became quite apparent.
Does one really let go?  Everything seemed a bit irritable.  The
tinnitus was quite bad, but the excitement of the rich altered place I
was in was certainly worth it all.  Through the rest of the day, I
became aware of how tired I was, and how much I wanted to sleep, and
yet how scared I was to give myself over to sleep.  Could I trust the
body to its own devices without me as an overseeing caretaker?  LetUs
risk it.  I slept.  The next day there was a memory of this turmoil.
Clearly the first part of the experience might have been hard to
define, but it was quite positive.  But the last part makes it not
really worth while.

EXTENSIONS AND COMMENTARY: This compound, BOB, is the most potent of
the BOX series.  And yet, as with all of the members of this family,
there are overtones of physical concern, and of some worry as to the
integrity of the body.  There may well be a separation of activity
with the two optical isomers, but there is not a tremendous push to
explore this particular family much further.  They canUt all be
winners, I guess.  What would be the activities of compounds with a
sulfur instead of an oxygen at the beta-oxygen position?  What would
be the nature of action if there were an alpha-methyl group, making
all of these into amphetamine derivatives?  Or what about both a
sulfur and a methyl group?  And what about the isomers that are
intrinsic to all of this, the threo- and the erythro- and the RDUsS
and the RLUsS?  All this is terra incognita, and must someday be
looked into.  It is chemically simple, and pharmacologically
provocative.  Someone, somewhere, someday, answer these questions!



#14 BOD; '-METHOXY-2C-D; 4-METHYL-2,5,'-TRIMETHOXYPHENETHYLAMINE

SYNTHESIS: A solution of 39.6 g
1-(2,5-dimethoxy-4-methylphenyl)-2-nitrostyrene (see recipe for 2C-D
for its preparation) in 300 mL warm MeOH was prepared.  Separately, a
solution of 9 g elemental sodium in 150 mL MeOH was also prepared.
This sodium methoxide solution was added to the well-stirred
nitrostyrene solution, which resulted in a dramatic loss of color.
There was then added 75 mL acetic acid, and all was poured into 2 L
H2O.  This was extracted with 3x100 mL CH2Cl2.  The pooled extracts
were stripped of solvent, and the 35 g of residue was treated with 5
mL MeOH, allowed to stand for a short while, decanted from some
insoluble residue, and the separated clear solution kept at 0 !C
overnight.  There was the deposition of a yellow crystalline product
which, after removal by filtration and air drying, weighed 9.7 g.
Recrystallization from 25 mL MeOH gave, after filtering and drying,
8.4 g of canary-yellow crystals of
1-(2,5-dimethoxy-4-methylphenyl)-1-methoxy-2-nitroethane with a mp of
78-79 !C.  Evaporation of the mother liquors from the filtration of
the first crop yielded 3.8 g of additional product which, upon
recrystallization from 11 mL MeOH, provided another 2.7 g with a mp of
77-78 !C.  Further workup of the mother liquors yielded only impure
starting nitrostyrene.

A solution of LAH (96 mL of 1 M solution in THF) was cooled, under He,
to 0 !C with an external ice bath.  With good stirring there was added
2.4 mL 100% H2SO4 dropwise, to minimize charring.  This was followed
by the addition of 10.8 g
1-(2,5-dimethoxy-4-methylphenyl)-1-methoxy-2-nitroethane.  There was
immediate discoloration.  After the addition was complete, the
reaction mixture was held at reflux on the steam bath for 2 h.  After
cooling again, the excess hydride was destroyed with 4 mL IPA and the
reaction mixture made basic with 15% NaOH.  The insoluble inorganic
salts were removed by filtration, and the filter cake was washed first
with THF, and then with IPA.  The bright yellow filtrate and washes
were pooled and stripped of solvent under vacuum, yielding 14 g of a
yellow oil.  This was suspended in 1 L dilute H2SO4 to give an ugly,
cloudy, yellow-orange mess.  Extraction with 3x75 mL CH2Cl2 removed
much of the color, and the remaining aqueous phase was made basic with
25% NaOH, and extracted with 3x75 mL CH2Cl2.  Evaporation of the
solvent under vacuum gave 9 g of a pale amber oil which was distilled
at 115-130 !C at 0.4 mm/Hg.  The water-white distillate was dissolved
in 15 mL IPA, neutralized with concentrated HCl, and then diluted with
70 mL anhydrous Et2O.  After a few min, white crystals formed, and
these were removed by filtration and Et2O washed.  When air-dried to
constant weight, 4.49 g brilliant white crystals of
4-methyl-2,5,'-trimethoxyphenethylamine hydrochloride (BOD) with a mp
of 171-172 !C with decomposition, were obtained.  The mother liquors
on standing deposited 0.66 g additional crystals which were impure and
were discarded.  Anal. (C12H20ClNO3) C,H.

DOSAGE: 15 - 25 mg.

DURATION: 8 - 16 h.

QUALITATIVE COMMENTS: (with 20 mg) There were some very pleasant
visuals starting at 2-2.5 hours and continuing to 4-5 hours after the
beginning of the experiment.  Open eye visuals seem to come on after
staring at particular areas, such as the living room ceiling or at
trees.  The surroundings tended to move slightly.  There was no
flowing of the images at all.  When looking at the pine trees, the
needles appeared crystal clear and sharply defined, with strong
contrasts.  Though the mental effect is difficult to define, I am not
sure it was all that great.  I did become tired of the effect (along
with the confusion) after 8 hours, and was quite happy to note that it
did taper off in the early evening.  I am not particularly sure I
would want to try this material again.

(with 20 mg) For the first three or so hours, the beauty of the
experience was marred by a strange discomfort.  There was some
queasiness, and I felt a sluggishness of mind.  Then I began moving in
and out of a pleasant place, and finally the discomfort completely
dissolved and the experience turned full on.  Height of beauty, visual
perception.  Lights below are amazing.  Outside, marvelous sense of
Presence.  There is not an elation, as often with other materials, but
a strong, even powerful sense of goodness, inner strength, solidity.

(with 25 mg) This was quite quick.  The onset of the experience was
apparent within a half hour, and we were both at +++ within the hour.
Body load minimal.  There was very little visual, compared with some
materials.  Very interesting eyes-closed, but not continually Q just
now and then an intense vision might flash.  Very benign and friendly
and pleasant and good-humored feeling.  Superb for conversation and
conceptualization.

(with 25 mg) The body load was quite noticeable for everyone.  But
the general state of mind was excellent; everyone was extremely
relaxed and funny.  Puns, insults, delightful amusement.  Not very
much insight work possible.  Juices were needed and tolerated well,
but no one was particularly hungry.  Sleep was difficult for most
people, not deep and not too refreshing.  Excellent material, but body
price a bit too much for the mental effects.  Pleasant, and I wouldnUt
hesitate to take it again, but nothing very memorable except the
tremendous humor and laughter, which was truly delightful.

EXTENSIONS AND COMMENTARY: This compound, BOD, was the first
exploratory member of a new family of phenethylamines.  This family is
called the BOX series because an oxygen atom has been put on the
benzylic carbon (the Rbenzyl-oxyS or RBOS) of each of several well
studied drugs with recognized substituent patterns on the aromatic
ring.  The RXS would be RD,S as used here with BOD, making reference
to 2C-D, it would be a RBS in BOB making reference to 2C-B, etc.
Actually the original thought was to make the ROS into an ROMS for
methoxy, as this would allow more versatility in the naming of things
such as ethoxys (ROES) or hydroxys (ROHS), but the methoxylated 2C-B
analogue would have come out as BOMB, so the idea was dropped.

Actually, the concept of naming of drugs with some acronym that is
pronounceable has led into some interesting byways.  Some examples
have been unintended.  I have heard DOM pronounced RdomeS and DOET
pronounced as Rdo it.S And elsewhere I have mentioned the embarrassing
occasions where the TOM and TOET families were pronounced Rthe toms
and twats.S Some examples have had names that have been contractions
of popular names, such as XTC for ecstasy.  And there are instances
where a name might be proposed simply to irritate the newspaper
people.  An early street suggestion for PCP was FUK, and a current
name for free-base methamphetamine is SNOT.  And marijuana is fondly
called SHIT by its aficionados.  The final RAS on government groups
such as the CIA or the DEA or the FDA is strongly reminscent of the
final RAS which stands for amphetamine in things such as TMA and MDMA.
Might there someday be a drug such as
4-cyclopropylmethyl-N-isopropylamphetamine (CIA), or
3,5-dimethoxy-4-ethylamphetamine (DEA)?  It has just occurred to me
that there is already a 4-fluoro-2,5-dimethoxyamphetamine (FDA), but I
have already named it DOF.  If all drugs were known only by publicly
embarrassing names, there might be less publicity given them by the
press.

Back to the commentary on BOD.  The rationale for this inclusion of a
beta-oxygen atom into the structure of a phenethylamine is based
directly on the chemistry that occurs naturally in the brain.  The
phenethylamine neurotransmitter, dopamine, is converted both in the
brain and in the body to the equally important transmitter
norepinephrine by just this sort of transformation.  There is the
enzymatic addition of an oxygen atom to the RbenzylicS position of
dopamine.  And identical chemistry goes on with tyramine in a number
of plants and animals, with a similar addition of oxygen to form
octopamine, so-named for its discovered presence in the salivary
glands of Octopus vulgaris.  In the first explorations in the BOX
series, this oxygen was intentionally blocked with a methyl group, to
ease its entry into the brain, and increase the possibilities of its
being active as a psychedelic.  As mentioned above, the RDS in BOD
follows from its ring orientation pattern being the same as that of
2C-D (and this, originally from the mimicking of the pattern of DOM).
All of these D- compounds have the 2,5-dimethoxy-4-methyl
ring-substitution pattern.

An interesting complication is also part of this structure package.
The added methoxy group (or hydroxy group, see recipe for BOHD) also
adds a new asymmetric center, allowing for the eventual separation of
the material into two optical isomers.  And at such time as the
corresponding amphetamine homologues might be made and studied, the
presence of yet another chiral center (under the alpha-methyl group)
will demand that there be actually two racemic compounds synthesized,
and a total of four isomers to contend with, if really careful and
thorough work is to be done.

A parallel chemistry to all of this follows the addition of sodium
ethoxide (rather than sodium methoxide) to the nitrostyrene.  The
final product, then, is the ethoxy homologue
2,5-dimethoxy-'-ethoxy-4-methylphenethylamine, or BOED.  It is down in
human potency by a factor of three, with a normal dosage being 70-75
milligrams.  It has a ten hour duration, and is both anorexic and
diuretic.  There have been no visual effects or insights reported, but
rather simply a highly intoxicated state.

Two synonyms, two definitions, and an expression of admiration.  The
word norepinephrine is synonymous with noradrenalin, and the word
epinephrine is synonymous with adrenalin.  The distinctions are that
the first in each case is American and the second British.  And the
term RchiralS indicates a potential asymmetry in a molecule that would
allow eventual separation into two optical isomers.  The term
RracemicS refers to a mixture of these two isomers which has not yet
been separated into the individual components.  A racemic mixture is
called a racemate and, from the point of view of the human animal
(which is completely asymmetric), must be considered as a mixture of
two structurally identical but optically mirror-image isomers, which
can be potentially separated and which will certainly have different
pharmacologies.  And the admiration?  This is directed to the explorer
who ventured close enough to an octopus to locate its salivary glands
and to discover a phenethylamine there!



#15 BOH; '-METHOXY-3,4-METHYLENEDIOXYPHENETHYLAMINE

SYNTHESIS: To a solution of 30 g piperonal in 100 mL acetic acid there
was added 20 mL nitromethane and 10 mL cyclohexylamine.  After heating
on the steam bath for 1.5 h, the reaction mixture started to
crystallize.  The mixture was cooled in an ice bath, and the heavy
mass of deposited crystals removed by filtration and washed with 20 mL
acetic acid.  All was supended in 100 mL warm MeOH, cooled again, and
filtered to give 24.5 g of 3,4-methylenedioxy-'-nitrostyrene as
canary-yellow crystals, with a mp of 158-160 !C.  Reduction of this
compound with LAH gives rise to MDPEA, which is a separate entry with
a recipe of its own.

To a vigorously stirred suspension of 20 g 3,4-methylenedioxy-'-nitro
-styrene in 100 mL anhydrous MeOH there was added a freshly prepared
solution of 5.5 g elemental sodium in 100 mL MeOH.  The nitrostyrene
goes into solution over the course of 5 min.  There was then added,
first, 50 mL acetic acid with the stirring continued for an additional
1 min.  There was then added 300 mL H2O.  An oil separated and was
extracted into 200 mL CH2Cl2.  The organic extract was washed with 500
mL dilute aqueous NaHCO3, followed by 500 mL H2O.  Removal of the
solvent gave a residue that was distilled at 128-145 !C at 0.4 mm/Hg,
providing 16.6 g of a yellow viscous liquid which slowly crystallized.
An analytical sample was recrystallized from four volumes of MeOH to
give 1-methoxy-1-(3,4-methylenedioxyphenyl)-2-nitroethane as bright
yellow crystals with a mp of 58-59 !C.  Anal. (C10H11NO5) C,H.

A solution of LAH (100 mL of 1 M solution in THF) was cooled, under
He, to 0 !C with an external ice bath.  With good stirring there was
added 2.5 mL 100% H2SO4 dropwise, to minimize charring.  This was
followed by the addition of 12 g
1-methoxy-1-(3,4-methylenedioxyphenyl)-2-nitroethane over the course
of 2 min.  There was an immediate loss of color.  After a few minutes
further stirring, the temperature was brought up to a reflux with a
heating mantle.  There was a gentle gas evolution for a few min,
followed by an exothermic reaction that exceeded the capacity of the
condenser.  Once the reaction had subsided, the unreacted hydride was
destroyed with a minimum of IPA, and 15% NaOH was added to convert the
inorganics to a loose white filterable mass.  The reaction mixture was
filtered, and the filter cake washed thoroughly with THF.  The
combined filtrate and washes were stripped of solvent under vacuum,
providing an orange oil.  This was dissolved in 400 mL dilute H2SO4,
which was washed with 3x75 mL CH2Cl2.  After making the aqueous phase
basic, it was extracted with 2x100 mL CH2Cl2.  The pooled extracts
were stripped of solvent under vacuum, and the residue distilled at
103-112 !C at 0.5 mm/Hg.  There was obtained 2.5 g of a colorless,
viscous oil which was dissolved in 25 mL IPA, neutralized with 45
drops of concentrated HCl, and finally diluted with 30 mL anhydrous
Et2O.  There was thus formed
'-methoxy-3,4-methylenedioxyphenethylamine hydrochloride (BOH) as a
fine white crystalline product.  The mp was 105-106.5 !C, with
bubbling and darkening.  The mp properties proved to be inconsistent,
as the salt was a hydrate.  Recrystallization from CH3CN, or simply
heating to 100 !C in toluene, converted the salt to an anhydrous form,
with mp of 152-153 !C.  Anal. (C10H14ClNO3) C,H.

DOSAGE: 80 - 120 mg.

DURATION: 6 - 8 h.

QUALITATIVE COMMENTS: (with 90 mg) Distinct body awareness in an
hour.  The threshold is mostly physical.  Faint sense of inside
warmth, skin prickling, cold feet, loose bowels, anorexia.  By the
fifth hour, I was on the downslope, and in retrospect I found it good
humored but not insightful.

(with 100 mg) There was a vague nausea, and a chilling of the feet.
It reached a real plus two, with dilated pupils and quite a thirst.
How can one describe the state?  There were no visuals, and I was not
even stoned.  I was just very turned on.  And I was completely back to
baseline by hour number six.

EXTENSIONS AND COMMENTARY: There are several reports of a nice, mild
mood enhancement in the 20-40 milligram dosage area, but searches for
psychedelic effects at higher levels gave a strange mix of some sort
of an altered state along with bodily discomfort.  The BOH name for
this member of the BOX family follows the convention discussed in the
BOD recipe Q with RHS for homopiperonylamine, the simplest of the
muni-metro family, q.v.  The demethylated homologue of BOH is BOHH,
and is the methylenedioxy analogue of norepinephrine.  It might well
hydrolytically open up in the body to provide this neurotransmitter,
and serve as some sort of transmitter in its own right.  It is
discussed under DME.

Maybe there is something to the concept that when you imitate a
neurotransmitter too closely, you get a hybrid gemisch of activity.
The term Rpro-drugS is used to identify a compound that may not be
intrinsically active, but one which metabolizes in the body to provide
an active drug.  I feel the term should have been pre-drug, but
pro-drug was the word that caught on.  BOH may well act in the body as
a pro-drug to norepinephrine, but with the temporary blocking of the
polar functions with ether groups, it can gain access to the brain.
And once there, it can be stripped of these shields and play a direct
neurological role.  I uncovered a very similar analogy in the
tryptamine world some years ago.  Just as norepinephrine is a
neurotransmitter, so is serotonin.  And I found that by putting an
O-ether on the indolic phenol (to hide its polarity) and an
alpha-methyl group next to the primary amine (to protect it from
metabolic deaminase), it became an extremely potent, and most complex,
psychedelic.  This was the compound alpha,O-dimethylserotonin, or
a,O-DMS.  There is an uncanny analogy between this tryptamine and the
phenethylamine BOH.

Somehow the quiet voice deep inside me says, donUt use too much, too
quickly.  Maybe one of the optical isomers is the body thing, and the
other isomer is the mind thing.  So far, only the racemic mixture has
been tasted, to the best of my knowledge.



#16 BOHD; 2,5-DIMETHOXY-'-HYDROXY-4-METHYLPHENETHYLAMINE

SYNTHESIS: A solution of 0.4 g
1-(2,5-dimethoxy-4-methylphenyl)-1-methoxy-2-nitroethane (see
preparation in the recipe for BOD) in 3.0 mL acetic acid was heated to
100 !C on a steam bath.  There was added 1.0 g powdered zinc, followed
by additional acetic acid as needed to maintain smooth stirring.
After 0.5 h there was added 1.0 mL concentrated HCl and, following an
additional few minutes heating, the reaction mixture was poured into
300 mL H2O.  After washing the aqueous phase with 3x75 mL CH2Cl2, the
mixture was made basic with 25% NaOH, and extracted with 3x50 mL
CH2Cl2.  Removal of the solvent and distillation of the residue at
130-140 !C 0.25 mm/Hg gave an oil that, on dissolving in IPA,
neutralization with concentrated HCl, and the addition of anhydrous
Et2O, gave beautiful white crystals of
2,5-dimethoxy-'-hydroxy-4-methylphenethylamine hydrochloride (BOHD).
The yield was 0.2 g, and the mp was 180-181 !C.  The infrared spectrum
was that of an amine salt with a strong OH group present.  Anal.
(C11H18ClNO3) C,H.

DOSAGE: greater than 50 mg.

DURATION: unknown.

QUALITATIVE COMMENTS: (with 50 mg) At about the two hour point, there
was a precipitous drop of blood pressure (from 120/72 to 84/68)
although the pulse stayed steady at 60.  This trend had been apparent
in earlier trials, and was being watched carefully.  No further tests
are planned.

EXTENSIONS AND COMMENTARY: The usual method of making
beta-ethanolamine such as this is through the reduction of the
cyanohydrin of the corresponding benzaldehyde and, in fact, that
method is described in the recipe for DME.  This above procedure was
actually part of an exploration of different agents that might be used
in the reduction of the intermediate nitroalkane.  This product was
the unexpected result of trying zinc.

Why the potent cardiovascular effect seen by this compound?  There are
a couple of points that might argue for some adrenolytic toxicity.
This material is a beta-ethanolamine and, with maybe one or two
exceptions, clinically used beta-receptor blockers are
beta-ethanolamines.  In fact, a few of these so-called beta-blockers
actually have two methoxy groups on the aromatic rings, also a
property of BOHD.  The antidiabetic drug Butaxamine (BW 64-9 in the
code of Burroughs Wellcome) is identical to BOHD except that the
4-methyl group is on the alpha-carbon instead, and there is a tertiary
butyl group on the nitrogen atom.  Another point involves the
proximity of the beta-hydroxy group and the methoxyl oxygen atom in
the 2-position of the ring.  There is going to be a strong
hydrogen-bonding with this orientation, with the formation of a stable
six-membered ring.  This might help obscure the hydrophilic nature of
the free hydroxyl group and allow the compound to pass into the brain
easily.  If this group is masked by an easily removed group such as an
acetate ester, one gets the compound
beta-acetoxy-3,4-dimethoxy-4-methylphenethylamine (BOAD) which is
similar to BOHD as a hypotensive.

The code-naming procedure used here (and elsewhere here in Book II)
is: (1) to use RBOS as the alert to there being an oxygen on the
benzyl carbon of a phenethylamine (it is a benzyl alcohol); (2) if
there is just one more letter (a third and last letter) it will
identify the 2C-X parent from which it has been derived [RBS comes
from 2C-B, RDS comes from 2C-D, RHS comes from homopiperonylamine
(MDPEA) rather than from 2C-H, RMS comes from mescaline, and in every
case the beta-substituent is a methoxy group]; and (3) if there are
four letters, then the fourth letter is as above, and the third letter
(the next to last letter) is the substituent on that benzylic oxygen.
With a three letter code, the substituent is a methyl group, an RHS
for a third letter of four makes it a hydroxyl group, and an RAS for
the third letter is an acetyl group, and an RES is for an ethyl group.
A similar sort of cryptographic music was composed by Du Pont in their
three-number codes for the Freons.  The first number was one less than
the number of carbons in the molecule, the second number was one more
than the number of hydrogens in the molecule, the third number was the
exact number of fluorines in the molecule, and the rest of the bonds
were filled with chlorines, Thus Freon 11 (really Freon 011) was
trichlorofluoromethane and Freon 116 was hexafluoroethane.

Complex, yes.  But both systems are completely straightforward, and
flexible for future creations.  A few additional examples of similar
beta-ethanolamines are scattered throughout Book II and they have, in
general, proved to be uninteresting, at least as potential psychedelic
compounds.



#17 BOM; '-METHOXYMESCALINE; 3,4,5,'-TETRAMETHOXYPHENETHYLAMINE

SYNTHESIS: To a vigorously stirred suspension of 9.0 g
'-nitro-3,4,5-trimethoxystyrene (see under the recipe for M for the
preparation of this intermediate) in 50 mL anhydrous MeOH there was
added a solution obtained from the addition of 2.0 g metallic sodium
to 50 mL anhydrous MeOH.  The bright orange color faded to a light
cream as the nitrostyrene went into solution.  After 3 min there was
added 30 mL acetic acid, which produced white solids, and this was
followed by further dilution with 150 mL H2O.  The formed solids were
removed by filtration, washed well with H2O, and recrystallized from
150 mL boiling MeOH.  After removal of the product by filtration and
air drying to constant weight, there was obtained 6.9 g of
1-methoxy-2-nitro-1-(3,4,5-trimethoxyphenyl)ethane as fine,
cream-colored crystals.  The mp was 143-144 !C, and the Rf by TLC
(silica-gel plates and CH2Cl2 as moving phase) was identical to that
of the starting aldehyde.  Anal. (C12H17NO6) C,H.

A solution of LAH (50 mL of 1 M solution in THF) was cooled, under He,
to 0 !C with an external ice bath.  With good stirring there was added
1.25 mL 100% H2SO4 dropwise, to minimize charring.  This was followed
by the addition of 6 g of solid
1-methoxy-2-nitro-1-(3,4,5-trimethoxyphenyl)ethane over the course of
2 min.  There was some gas evolution.  After 5 min additional
stirring, the temperature was brought up to a reflux with a heating
mantle.  There was a gentle gas evolution for a few minutes, followed
by an exothermic reaction with vigorous gas evolution.  Once
everything had settled down, the reaction mixture was held at reflux
temperature for an additional 2 h.  The excess hydride was destroyed
by the addition of IPA and 15% NaOH was added to convert the inorganic
salts to a loose white filterable mass.  The reaction mixture was
filtered, and the filter cake washed thoroughly with THF.  The
combined filtrate and washes were stripped of solvent under vacuum
which provided a red-brown liquid.  This was dissolved in dilute H2SO4
and washed with 3x75 mL CH2Cl2.  After making the aqueous phase basic
with NaOH, it was extracted with 2x100 mL CH2Cl2.  The pooled extracts
were stripped of solvent under vacuum, and the colorless residue
distilled at 120-150 !C at 0.3 mm/Hg.  There was obtained 2.8 g of a
colorless oil which was dissolved in 30 mL IPA and neutralized with
concentrated HCl, allowing the spontaneous formation of the
hydrochloride salt.  This was diluted with 75 mL anhydrous Et2O,
yielding 2.8 g 3,4,5,'-tetramethoxyphenethylamine hydrochloride (BOM)
as a white crystalline product.  This had a mp of 198.5-199.5 !C.
Anal. (C12H20ClNO4) C,H.

DOSAGE: greater than 200 mg.

DURATION: unknown.

EXTENSIONS AND COMMENTARY: There are some indicators of central
activity with assays involving both the 120 milligram and the 180
milligram levels, but nothing that can be rated as over a plus one.
It can be seen with the two active members of the BOX series (BOD and
BOB) that the potency is about equal to, or a little more (up to a
factor of maybe x2), than the analogue without the methoxyl group on
the aliphatic chain.  If this formula were to hold in the relationship
between mescaline and BOM, the active level might well be in the
200-400 milligram range.  But at the moment, it remains unknown.

Again, the name of the compound (BOM) is from the RBO-S prefix of this
family (from benzyl + oxy), plus the RMS of mescaline (which has
provided the ring substitution pattern).



#18 4-BR-3,5-DMA; 3,5-DIMETHOXY-4-BROMOAMPHETAMINE

SYNTHESIS: The starting material 3,5-dimethoxy-4-bromobenzoic acid
(made from the commercially available resorcinol by the action of
methyl sulfate) was a white crystalline solid from aqueous EtOH with a
mp of 248-250 !C.  Reaction with thionyl chloride produced
3,5-dimethoxy-4-bromobenzoyl chloride which was used as the crude
solid product, mp 124-128 !C.  This was reduced with tri-O-(t)-butoxy
lithium aluminum hydride to produce 3,5-dimethoxy-4-bromobenzaldehyde
which was recrystallized from aqueous MeOH and had a mp of 112-114 !C.
Anal. (C9H9BrO3) C,H.  This aldehyde, with nitroethane and anhydrous
ammonium acetate in acetic acid, was converted to the nitrostyrene
1-(3,5-dimethoxy-4-bromophenyl)-2-nitropropene, with a mp of 121-121.5
!C.  Anal. (C11H12BrNO4) C,H,N.  This was reduced at low temperature
with just one equivalent of LAH, to minimize reductive removal of the
bromine atom.  The product 3,5-dimethoxy-4-bromoamphetamine
hydrochloride (4-BR-3,5-DMA) was isolated in a 37% yield and had a mp
of 221-222 !C.  Anal. (C11H17BrClNO2) C,H,N.

DOSAGE: 4 - 10 mg.

DURATION: 8 - 12 h.

QUALITATIVE COMMENTS: (with 3 mg) This is certainly no placebo.  At
about 2 hours I felt some analgesia and numbing in my extremities, but
if there were any sensory distortions, they were barely perceptible.

(with 6 mg) There is a very shallow threshold, no more.

(with 10 mg) I can certainly confirm the indications of anesthesia
that were hinted at.  It was for me central in nature, however.  I
could (this at three hours) pierce a skin pinch on my left arm with no
bother except for the emerging of the needle due to skin resistance.
There was little bleeding.  And multiple needle prickings into the
thumb abductor were not felt.  A quick plunge of the tip of my little
finger into boiling water elicited reflex response, but no residual
pain.  Judgment was OK, so I stayed out of physical trouble, luckily!
The perhaps ++ was dropping in the fourth or fifth hour, and by the
tenth hour there were few effects still noted, except for some
teeth-rubbiness and a burning irritation at the pin-prick area, so
feeling is back.  No sleep problems at just past midnight.

EXTENSIONS AND COMMENTARY: Here is a complex and, at the moment,
totally undefined drug.  There were two independent reports of
analgesia, yet a thorough screen in experimental animals, conducted by
a major pharmaceutical house, failed to confirm any of it.  A ++
report does not necessarily reflect a psychedelic effect, since this
quantitative measure of the level of activity represents the extent of
impairment of function, regardless of the nature of the drug producing
it.  In other words, if you were experiencing the effects of a drug
that would in your judgment interfere with safe and good driving, this
would be a ++ whether your performance was being limited by a
psychedelic, a stimulant, a hypnotic or a narcotic.  None of the
quantitative reports ever mentioned any sensory distortion (analgesia
is a loss, not a distortion) or visual effect.  Perhaps 4-BR-3,5-DMA
showed its ++ as a narcotic.  But then, the rats had said no.



#19 2-BR-4,5-MDA; 6-BR-MDA; 2-BROMO-4,5-METHYLENEDIOXYAMPHETAMINE

SYNTHESIS: A solution of 3,4-methylenedioxyamphetamine (MDA) in acetic
acid was treated with elemental bromine, generating the hydrobromide
salt of 2-bromo-4,5-methylenedioxyamphetamine in a yield of 61% of
theory.  The mp was 221-222 !C.  Anal. (C10H13Br2NO2) C,H,Br.

DOSAGE: 350 mg.

DURATION: unknown.

EXTENSIONS AND COMMENTARY: Both the synthetic and the pharmacological
details for this compound are sparse.  There has been only a single
report of the human activity of this drug in the literature, and the
statement has been offered that the effects are amphetamine-like.  No
other qualitative comments have been made available, and neither I nor
anyone in my circle has tried it, personally.  Someday, perhaps.  But
at that high level, perhaps not.



#20 2C-B; 4-BROMO-2,5-DIMETHOXYPHENETHYLAMINE

SYNTHESIS: A solution of 100 g of 2,5-dimethoxybenzaldehyde in 220 g
nitromethane was treated with 10 g anhydrous ammonium acetate, and
heated on a steam bath for 2.5 h with occasional swirling.  The
deep-red reaction mixture was stripped of the excess nitromethane
under vacuum, and the residue crystallized spontaneously.  This crude
nitrostyrene was purified by grinding under IPA, filtering, and
air-drying, to yield 85 g of 2,5-dimethoxy-'-nitrostyrene as a
yellow-orange product of adequate purity for the next step.  Further
purification can be achieved by recrystallization from boiling IPA.

In a round-bottomed 2 L flask equipped with a magnetic stirrer and
placed under an inert atmosphere, there was added 750 mL anhydrous
THF, containing 30 g LAH.  There was then added, in THF solution, 60 g
2,5-dimethoxy-'-nitrostyrene.  The final solution was a dirty
yellow-brown color, and it was kept at reflux temperature for 24 h.
After cooling, the excess hydride was destroyed by the dropwise
addition of IPA.  Then 30 mL 15% NaOH was added to convert the
inorganic solids to a filterable mass.  The reaction mixture was
filtered and the filter cake washed first with THF and then with MeOH.
The combined mother liquors and washings were freed of solvent under
vacuum and the residue suspended in 1.5 L H2O.  This was acidified
with HCl, washed with with 3x100 mL CH2Cl2, made strongly basic with
25% NaOH, and reextracted with 4x100 mL CH2Cl2.  The pooled extracts
were stripped of solvent under vacuum, yielding 26 g of oily residue,
which was distilled at 120-130 !C at 0.5 mm/Hg to give 21 g of a white
oil, 2,5-dimethoxy-phenethylamine (2C-H) which picks up carbon dioxide
from the air very quickly.

To a well-stirred solution of 24.8 g 2,5-dimethoxyphenethylamine in 40
mL glacial acetic acid, there was added 22 g elemental bromine
dissolved in 40 mL acetic acid.  After a couple of min, there was the
formation of solids and the simultaneous evolution of considerable
heat.  The reaction mixture was allowed to return to room temperature,
filtered, and the solids washed sparingly with cold acetic acid.  This
was the hydrobromide salt.  There are many complicated salt forms,
both polymorphs and hydrates, that can make the isolation and
characterization of 2C-B treacherous.  The happiest route is to form
the insoluble hydrochloride salt by way of the free base.  The entire
mass of acetic acid-wet salt was dissolved in warm H2O, made basic to
at least pH 11 with 25% NaOH, and extracted with 3x100 mL CH2Cl2.
Removal of the solvent gave 33.7 g of residue which was distilled at
115-130 !C at 0.4 mm/Hg.  The white oil, 27.6 g, was dissolved in 50
mL H2O containing 7.0 g acetic acid.  This clear solution was vigorous
stirred, and treated with 20 mL concentrated HCl.  There was an
immediate formation of the anhydrous salt of
2,5-dimethoxy-4-bromophenethylamine hydrochloride (2C-B).  This mass
of crystals was removed by filtration (it can be loosened considerably
by the addition of another 60 mL H2O), washed with a little H2O, and
then with several 50 mL portions of Et2O.  When completely air-dry,
there was obtained 31.05 g of fine white needles, with a mp of 237-239
!C with decomposition.  When there is too much H2O present at the time
of adding the final concentrated HCl, a hydrated form of 2C-B is
obtained.  The hydrobromide salt melts at 214.5-215 !C.  The acetate
salt was reported to have a mp of 208-209 !C.

DOSAGE: 12 - 24 mg.

DURATION: 4 - 8 h.

QUALITATIVE COMMENTS: (with 16 mg) A day at the Stanford museum.
Things were visually rich, yet I felt that I was reasonably
inconspicuous.  The Rodin sculptures were very personal and not
terribly subtle.  I saw Escher things in the ceiling design, when I
decided to sit in a foyer somewhere and simply pretend to rest.
Walking back, the displays seen in the bark of the eucalyptus trees,
and the torment and fear (of others? of themselves?) in the faces of
those who were walking towards us, were as dramatic as anything I had
seen in the art galleries.  Our appetites were enormous, and we went
to a smorgasbord that evening.  A rich experience in every possible
way.

(with 20 mg) The drug effect first became known to me as a shift of
colors toward golden and rose tones.  Pigments in the room became
intensified.  Shapes became rounder, more organic.  A sensation of
lightness and rivulets of warmth began seeping through my body.
Bright lights began pulsing and flashing behind my closed lids.  I
began to perceive waves of energy flowing through all of us in unison.
I saw all of us as a gridwork of electrical energy beings, nodes on a
bright, pulsating network of light.  Then the interior landscape
shifted into broader scenes.  Daliesque vistas were patterned with
eyes of Horus, brocades of geometric design began shifting and
changing through radiant patterns of light.  It was an artistUs
paradise Q representing virtually the full pantheon of the history of
art.

(with 20 mg) The room was cool, and for the first hour I felt cold
and chilled.  That was the only mildly unpleasant part.  We had been
hanging crystals earlier that day, and the visions I had were
dominated by prismatic light patterns.  It was almost as if I became
the light.  I saw kaleidoscopic forms Q similar to, but less intense
than, when on acid Q and organic forms like Georgia OUKeefe flowers,
blossoming and undulating.  My body was flooded with orgasms Q
practically from just breathing.  The lovemaking was phenomenal,
passionate, ecstatic, lyric, animal, loving, tender, sublime.  The
music was voluptuous, almost three-dimensional.  Sometimes the sound
seemed distorted to me, underwater like.  This was especially so for
the less good recordings Q but I could choose to concentrate on the
beauty of the music or the inadequacy of the sound's quality, and
mostly chose to concentrate on the beauty.

(with 24 mg) I am totally into my body.  I am aware of every muscle
and nerve in my body.  The night is extraordinary Q moon full.
Unbelievably erotic, quiet and exquisite, almost unbearable.  I cannot
begin to unravel the imagery that imposes itself during the finding of
an orgasm.  Trying to understand physical/spiritual merging in nature
Q .

EXTENSIONS AND COMMENTARY: Four quotations were chosen arbitrarily
from literally hundreds that have worked their ways into the files.
The vast majority are positive, ranging from the colorful to the
ecstatic.  But not all are.  There are people who choose not to go
into the corporeal but, rather, prefer the out-of-body experience.
They express discomfort with 2C-B, and seem to lean more to the
Ketamine form of altered state, one which dissociates body from mind.

There have been reports of several overdoses that prove the intrinsic
safety of this compound.  Prove is used here in the classic British
sense; i.e., to challenge.  RThe proof of the pudding is in the
eating,S is not a verification of quality, but an inquiry into the
quality itself.  (The French simplify all this by using two separate
verbs for prove.)  One overdose was intentional, the other accidental.

(with 64 mg) I found only mild visual and emotional effects at the 20
milligram dose, so I took the remaining 44 milligrams.  I was
propelled into something not of my choosing.  Everything that was
alive was completely fearsome.  I could look at a picture of a bush,
and it was just that, a picture, and it posed no threat to me.  Then
my gaze moved to the right, and caught a bush growing outside the
window, and I was petrified.  A life-form I could not understand, and
thus could not control.  And I felt that my own life-form was not a
bit more controllable.S This was from the comments of a physician who
assured me that he saw no neurological concerns during this dramatic
and frightening experience.

(with 100 mg) I had weighed correctly.  I had simply picked up the
wrong vial.  And my death was to be a consequence of a totally stupid
mistake.  I wanted to walk outside, but there was a swimming pool
there and I didnUt dare fall into it.  A person may believe that he
has prepared himself for his own death, but when the moment comes, he
is completely alone, and totally unprepared.  Why now?  Why me?  Two
hours later, I knew that I would live after all, and the experience
became really marvelous.  But the moment of facing death is a unique
experience.  In my case, I will some day meet it again, and I fear
that I will be no more comfortable with it then than I was just now.
This was from the comments of a psychologist who will, without doubt,
use psychedelics again in the future, as a probe into the unknown.

Many of the reports that have come in over the years have mentioned
the combination of MDMA and 2C-B.  The most successful reports have
followed a program in which the two drugs are not used at the same
time, nor even too closely spaced.  It appears that the optimum time
for the 2C-B is at, or just before, the final baseline recovery of the
MDMA.  It is as if the mental and emotional discoveries can be
mobilized, and something done about them.  This combination has
several enthusiastic advocates in the psychotherapy world, and should
be the basis of careful research when these materials become legal,
and accepted by the medical community.

A generalized spectrum of 2C-B action can be gleaned from the many
reports that have been written describing its effects.  (1) There is a
steep dose response curve.  Over the 12 to 24 milligram range, every 2
milligrams can make a profound increase or change of response.
Initially, one should go lightly, and increase the dosage in
subsequent trials by small increments.  A commonly used term for a
level that produces a just perceptible effect is Rmuseum level.S This
is a slightly-over-threshold level which allows public activities
(such as viewing paintings in a museum or scenery watching as a
passenger in a car) to be entered into without attracting attention.
There can be considerable discomfort associated with being in the
public eye, with higher doses.  (2) The 2C-B experience is one of the
shortest of any major psychedelic drug.  Wherever you might be, hang
on.  In an hour or so you will be approaching familiar territory
again.  (3) If there is anything ever found to be an effective
aphrodisiac, it will probably be patterned after 2C-B in structure.

There are two RTweetiosS known that are related to 2C-B.  (See recipe
#23 for the origin of this phrase.)  The 2-EtO- homologue of 2C-B is
4-bromo-2-ethoxy-5-methoxyphenethylamine, or 2CB-2ETO.  The
unbrominated benzaldehyde (2-ethoxy-5-methoxybenzaldehyde) had a
melting point of 47.5-48.5 !C, the unbrominated nitrostyrene
intermediate a melting point of 76-77 !C, and the final hydrochloride
a melting point of 185-186 !C.  The hydrobromide salt had a melting
point of 168.5-169.5 !C.  It seems that one gets about as much effect
as can be had, with a dosage of about 15 milligrams, and increases
above this, to 30 and to 50 milligrams merely prolong the activity
(from about 3 hours to perhaps 6 hours).  At no dose was there an
intensity that in any way resembled that of 2C-B.

The 2,5-DiEtO- homologue of 2C-B is
4-bromo-2,5-diethoxyphenethylamine, or 2CB-2,5-DIETO.  The
unbrominated impure benzaldehyde (2,5-diethoxybenzaldehyde) had a
melting point of about 57 !C, the unbrominated impure nitrostyrene
intermediate a melting point of about 60 !C, and the final
hydrochloride a melting point of 230-231 !C.  The hydrobromide salt
had a melting point of 192-193 !C.  At levels of 55 milligrams, there
was only a restless sleep, and strange dreams.  The active level is
not yet known.

I have been told of some studies that have involved a positional
rearrangement analogue of 2C-B.  This is
2-bromo-4,5-dimethoxyphenethylamine (or 6-BR-DMPEA).  This would be
the product of the elemental bromination of DMPEA, and it has been
assayed as the hydrobromide salt.  Apparently, the intravenous
injection of 60 milligrams gave a rapid rush, with intense visual
effects reported, largely yellow and black.  Orally, there may be some
activity at the 400 to 500 milligram area, but the reports described
mainly sleep disturbance.  This would suggest a stimulant component.
The N-methyl homologue of this rearranged compound was even less
active.



#21 3C-BZ; 4-BENZYLOXY-3,5-DIMETHOXYAMPHETAMINE

SYNTHESIS: A solution of 268 g 2,6-dimethoxyphenol and 212 g allyl
bromide in 700 mL dry acetone was treated with 315 g anhydrous K2CO3
and held at reflux for 16 h.  The solvent was removed under vacuum,
and the residue dissolved in H2O and extracted with 3x100 mL CH2Cl2.
The pooled extracts were washed with 5% NaOH, then with H2O, and the
solvent removed under vacuum.  The residue, which weighed 245 g, was
stirred and heated in an oil bath to 230 !C at which point an
exothermic reaction set in.  The heating was maintained at 230 !C for
0.5 h, and then the reaction mixture distilled.  There was obtained a
total of 127 g of 5-allyl-1,3-dimethoxy-2-hydroxybenzene as a
colorless distillate, that was identical in all respects to natural
5-methoxyeugenol obtained from Oil of Nutmeg.

A solution containing 40.4 g 5-methoxyeugenol and 26.6 g benzyl
chloride in 65 mL EtOH was added, all at once, to a hot and well
stirred solution of 11.7 g KOH in 500 mL EtOH.  The potassium salt of
the phenol crystallized out immediately.  By maintaining reflux
conditions, this slowly redissolved, and was replaced by the steady
deposition of KCl.  After 6 h, the reaction mixture was cooled, and
the solids removed by filtration.  The filtrate was stripped of
solvent under vacuum to give 57 g of crude
5-allyl-2-benzyloxy-1,3-dimethoxybenzene.  This was dissolved in a
solution of 60 g KOH in 80 mL EtOH and heated on the steam bath for 16
h.  The reaction mixture was quenched in 500 mL H2O, and extracted
with 2x200 mL CH2Cl2.  Removal of the solvent under vacuum gave 35.6 g
of crude 2-benzyloxy-1,3-dimethoxy-5-propenylbenzene.

To a stirred, ice-cold solution of 33.6 g of the above impure
2-benzyloxy-1,3-dimethoxy-5-propenylbenzene and 13.6 g pyridine in 142
mL acetone, there was added 24.6 g tetranitromethane.  After stirring
for 3 min, there was added a solution of 7.9 g KOH in 132 mL H2O,
followed by additional H2O.  The oily phase that remained was H2O
washed, and then diluted with an equal volume of MeOH.  This slowly
set up to yellow crystals, which were removed by filtration and washed
sparingly with MeOH.  There was obtained 9.2 g
1-(4-benzyloxy-3,5-dimethoxyphenyl)-2-nitropropene with a mp of 84-85
!C.  An analytical sample, from EtOH, had a mp of 86-87 !C.

    To a refluxing suspension of 5.5 g LAH in 360 mL anhydrous
Et2O under an inert atmosphere, there was added 8.6 g
1-(4-benzyloxy-3,5-dimethoxyphenyl)-2-nitropropene by letting the
condensing Et2O leach out a saturated solution from a modified Soxhlet
condenser.  The addition took 1.5 h and the refluxing was maintained
for an additional 4 h.  After cooling, the excess hydride was
destroyed by the cautious addition of 330 mL of 1.5 N H2SO4.  The
aqueous phase was heated up to 80 !C, filtered through paper to remove
a small amount of insoluble material, and treated with a solution of 8
g picric acid in 150 mL boiling EtOH.  Cooling in the ice chest
overnight gave globs of the amine picrate, but no clear signs of
crystallization.  These were washed with cold H2O, then dissolved in
5% NaOH to give a bright yellow solution.  This was extracted with
3x150 mL CH2Cl2, the solvent removed under vacuum, the residue
dissolved in 300 mL anhydrous Et2O, freed from a little particulate
material by filtration through paper, and then saturated with hydrogen
chloride gas.  There was thus obtained, after filtering, Et2O washing
and air drying, 2.5 g 4-benzyloxy-3,5-dimethoxyamphetamine
hydrochloride (3C-BZ) as a white solid with a mp of 161-164 !C.

DOSAGE: 25 - 200 mg.

DURATION: 18 - 24 h.

QUANTITATIVE COMMENTS: (with 25 mg) I went into an emotionally
brittle place, and for a while I was uncomfortable with childhood
reminiscences.  The seeing of my family's Christmas tree in my mind
was almost too much.  I cried.

(with 50 mg) The action is distinct Q wakeful Q alerting and wound
up.  Hypnogogic imagery, and I could not sleep at night with my mind
doing many uncontrolled, tangential, busy things.  I had fleeting
nausea early in the process.

(with 100 mg) I took this in two portions.  Following 50 milligrams I
was aware of a slight light-headedness at a half-hour, but there was
little else.  At 1 1/2 hours, I took the second 50 milligrams and the
augmentation of effects was noted in another half hour.  The
experience quietly built up to about the fifth hour, with some erotic
fantasy and suggestions of changes in the visual field.  I could not
sleep until the twelfth hour, and my dreams were wild and not too
friendly.  There was no body threat from this, but I was not
completely baseline until the next day.  I am not too keen to do this
again Q it lasts too long.

(with 100 mg) No effects.

(with 150 mg) This is in every way identical to 100 micrograms of
LSD.

(with 180 mg) I can compare this directly to TMA which was the
material I took last week.  Many similarities, but this is
unquestionably more intense than the TMA was at 200 milligrams.  It is
hard to separate the degree of impact that this drug has, from the
simple fact that it lasts forever, and I was getting physically tired
but I couldnUt sleep.  There is some amphetamine-like component, more
than with TMA.

EXTENSIONS AND COMMENTARY: Two points are worthy of commentary; the
potency and the promise of 3C-BZ.

As to potency, there is such uncertainty as to the effective dose,
that it is for all intents and purposes impossible to predict just
what dose should be considered for a person's first time with this.
The choice of quotations was made with the intention of giving a
picture of this scatter.  A total of ten subjects have explored this
compound, and the very broad range given above, 25 to 200 milligrams,
reflects the degree of variation that has been encountered.

Which is a shame, because the concept of a new ring such as is found
here on the 4-position would have allowed an extremely wide array of
substituents.  Electron-rich things, electron-poor things, heavy
things, light things, and on and on.  This could have been a location
of much variation, but it is a possibility that the uncertainties of
dosage might extrapolate to these novel ring substitutions as well.
Only a single variation was made, the 4-fluorobenzyl analogue.  This
was prepared following exactly the procedure given here for 3C-BZ,
except for the replacement of benzyl chloride with 4-fluorobenzyl
chloride.  The allyl intermediate was an oil, but the propenyl isomer
gave solids with a melting point of 59-60 !C from hexane.  The
nitrostyrene was a yellow crystalline solid from methanol with a
melting point of 98-99 !C.  The end product,
3,5-dimethoxy-4-(4-fluorobenzyloxy)amphetamine hydrochloride (3C-FBZ)
was a white solid with a melting point of 149-150 !C.  It has been
assayed only up to 4 milligrams and there was absolutely no activity
of any kind observed at that level.



#22 2C-C; 2,5-DIMETHOXY-4-CHLOROPHENETHYLAMINE

SYNTHESIS: (from 2C-H) The free base of 2,5-dimethoxyphenethylamine
was generated from its salt (see recipe for 2C-H for the preparation
of this compound) by treating a solution of 16.2 g of the
hydrochloride salt in 300 mL H2O with aqueous NaOH, extraction with
3x75 mL CH2Cl2, and removal of the solvent from the pooled extracts
under vacuum.  The colorless residue was dissolved in 75 mL glacial
acetic acid (the solids that initially formed redissolved completely)
and this was cooled to 0 !C with an external ice bath.  With vigorous
stirring, there was added 4.0 mL of liquid chlorine, a little bit at a
time with a Pasteur pipette.  The theoretical volume was 3.4 mL, but
some was lost in pipetting, some on contact with the 0 !C acetic acid,
and some was lost by chlorination of the acetic acid.  The reaction
turned a dark amber color, was allowed to stir for an additional 10
min, then quenched with 400 mL H2O.  This was washed with 3x100 mL
CH2Cl2 (which removed some of the color) then brought to neutrality
with dilute aqueous NaOH and treated with a small amount of sodium
dithionite which discharged most of the color (from deep brown to pale
yellow).  The reaction was made strongly basic with aqueous KOH, and
extracted with 3x75 mL CH2Cl2.  The pooled extracts were washed once
with H2O and the solvent was removed under vacuum leaving about 10 mL
of a deep amber oil as residue.  This was dissolved in 75 mL IPA and
neutralized with concentrated HCl which allowed spontaneous
crystallization.  These crystals were removed by filtration, washed
with an additional 20 mL IPA, and air-dried to constant weight.  There
was thus obtained 4.2 g 2,5-dimethoxy-4-chlorophenethylamine
hydrochloride (2C-C) with a mp of 218-221 !C.  Recrystallization from
IPA increased this to 220-222 !C.  The position of chlorination on the
aromatic ring was verified by the presence of two para-protons in the
NMR, at 7.12 and 7.20 ppm from external TMS, in a D2O solution of the
hydrochloride salt.

    Synthesis from 2C-B.  To a solution of 7.24 g
2,5-dimethoxy-4-bromophenethylamine (2C-B) and 4.5 g phthalic
anhydride in 100 mL anhydrous DMF there was added molecular sieves.
After 16 h reflux, the reaction mixture was cooled and the sieves
removed by filtration.  The addition of a little CH2Cl2 prompted the
deposition of yellow crystals which were recrystallized from EtOH.
The resulting 1-(2,5-dimethoxy-4-bromophenyl)-2-(phthalimido)ethane
weighed 7.57 g and had a mp of 141-142 !C.  Anal. (C18H16BrNO4)
C,H,N,Br.

A solution of 14.94 g of
1-(2,5-dimethoxy-4-bromophenyl)-2-(phthalimido)ethane and 4.5 g
cuprous chloride in 300 mL anhydrous DMF was heated for 5 h at reflux.
The cooled mixture was poured into 20 mL H2O that contained 13 g
hydrated ferric chloride and 3 mL concentrated HCl.  The mixture was
maintained at about 70 !C for 20 min, and then extracted with CH2Cl2.
After washing the pooled organic extracts with dilute HCl and drying
with anhydrous MgSO4, the volatiles were removed under vacuum to
provide a solid residue.  This was recrystallized from EtOH to provide
12.18 g of 1-(2,5-dimethoxy-4-chlorophenyl)-2-(phthalimido)ethane as
yellow needles that had a mp of 138-140 !C.  Anal. (C18H16ClNO4)
C,H,N,Cl.

To 60 mL absolute EtOH there was added 12.2 g
1-(2,5-dimethoxy-4-chlorophenyl)-2-(phthalimido)ethane and 2.9 mL of
100% hydrazine.  The solution was held at reflux for 15 min.  After
cooling, the cyclic hydrazone by-product was removed by filtration,
and the alcoholic mother liquors taken to dryness under vacuum.  The
residue was distilled at 145-155 !C at 0.05 mm/Hg to give 5.16 g of a
clear, colorless oil.  This was dissolved in anhydrous Et2O and
treated with hydrogen chloride gas, producing
2,5-dimethoxy-4-chlorophenethylamine hydrochloride (2C-C) as white
crystals with a mp of 220-221 !C.  Anal. (C10H15Cl2NO2) C,H,N.

DOSAGE: 20 - 40 mg.

DURATION: 4 - 8 h.

QUALITATIVE COMMENTS: (with 20 mg) This is longer lived than 2C-B,
and there is a longer latency in coming on.  It took an hour and a
half, or even two hours to get there.  It had a slight metallic
overtone.

(with 24 mg) I was at a moderately high and thoroughly favorable
place, for several hours.  It seemed to be a very sensual place, but
without too much in the way of visual distraction.

(with 40 mg) There were a lot of visuals Q something that I had noted
at lower levels. There seems to be less stimulation than with 2C-B,
and in some ways it is actually sedating.  And yet I was up all night.
It was like a very intense form of relaxation.

EXTENSIONS AND COMMENTARY: Other reports mention usage of up to 50
milligrams which seems to increase yet further the intensity and the
duration.  I have one report of an intravenous administration of 20
milligrams, and the response was described as overwhelming.  The
effects peaked at about 5 minutes and lasted for perhaps 15 minutes.

The halogens represent a small group of atoms that are unique for a
couple of reasons.  They are all located in a single column of the
periodic table, being monovalent and negative.  That means that they
can be reasonably stable things when attached to an aromatic nucleus.
But, being monovalent, they cannot be modified or extended in any way.
Thus, they are kind of a dead end, at least as far as the 2C-X series
is considered.  The heaviest, iodine, was explored as the
phen-ethylamine, as 2C-I, and as the amphetamine as DOI.  These are
the most potent.  The next lighter is bromine, where the
phenethylamine is 2C-B and the amphetamine is DOB.  These two are a
bit less potent, and are by far the most broadly explored of all the
halides.  Here, in the above recipe, we have the chlorine counterpart,
2C-C.  There is also the corresponding amphetamine DOC.  These are
less potent still, and much less explored.  Why?  Perhaps because
chlorine is a gas and troublesome to handle (bromine is a liquid, and
iodine is a solid).  The fluorine analogue is yet harder to make, and
requires procedures that are indirect, because fluorine (the lightest
of all the halides) is not only a gas, but is dangerous to handle and
does not react in the usual halogen way.  There will be mention made
of 2C-F, but DOF is still unexplored.

The treatment of the 2C-B phthalimide described above, with cuprous
cyanide rather than cuprous chloride, gave rise to the cyano analog
which, on hydrolysis with hydrazine, yielded
2,5-dimethoxy-4-cyanophenethylamine (2C-CN).  Hydrolysis of this with
hot, strong base gave the corresponding acid,
2,5-dimethoxy-4-carboxyphenethylamine, 2C-COOH.  No evaluation of
either of these compounds has been made in the human animal, as far as
I know.



#23 2C-D; LE-25; 2,5-DIMETHOXY-4-METHYLPHENETHYLAMINE

SYNTHESIS: Into 1 L H2O that was being stirred magnetically, there was
added, in sequence, 62 g toluhydroquinone, 160 mL 25% NaOH, and 126 g
dimethyl sulfate.  After about 2 h, the reaction mixture was no longer
basic, and another 40 mL of the 25% NaOH was added.  Even with
stirring for a few additional days, the reaction mixture remained
basic.  It was quenched in 2.5 L H2O, extracted with 3x100 mL CH2Cl2
and the pooled extracts stripped of solvent under vacuum.  The
remaining 56.4 g of amber oil was distilled at about 70 !C at 0.5
mm/Hg to yield 49.0 g of 2,5-dimethoxytoluene as a white liquid.  The
aqueous residues, on acidification, provided a phenolic fraction that
distilled at 75-100 !C at 0.4 mm/Hg to give 5.8 g of a pale yellow
distillate that partially crystallized.  These solids (with mp of
54-62 !C) were removed by filtration, and yielded 3.1 g of a solid
which was recrystallized from 50 mL hexane containing 5 mL toluene.
This gave 2.53 g of a white crystalline product with a mp of 66-68 !C.
A second recrystallization (from hexane) raised this mp to 71-72 !C.
The literature value given for the mp of 2-methyl-4-methoxyphenol is
70-71 !C. The literature value given for the mp of the isomeric
3-methyl-4-methoxyphenol is 44-46 !C.  This phenol, on ethylation,
gives 2-ethoxy-5-methoxytoluene, which leads directly to the 2-carbon
2CD-5ETO (one of the Tweetios) and the 3-carbon Classic Lady IRIS.

A mixture of 34.5 g POCl3 and 31.1 g N-methylformanilide was heated
for 10 min on the steam bath, and then there was added 30.4 g of
2,5-dimethoxytoluene.  Heating was continued for 2.5 h, and the
viscous, black, ugly mess was poured into 600 mL of warm H2O and
stirred overnight.  The resulting rubbery miniature-rabbit-droppings
product was removed by filtration and sucked as free of H2O as
possible.  The 37.2 g of wet product was extracted on the steam-bath
with 4x100 mL portions of boiling hexane which, after decantation and
cooling, yielded a total of 15.3 g of yellow crystalline product.
This, upon recrystallization from 150 mL boiling hexane, gave pale
yellow crystals which, when air dried to constant weight, represented
8.7 g of 2,5-dimethoxy-4-methylbenzaldehyde, and had a mp of 83-84 !C.
Anal. (C8H12O3) C,H,N.  The Gattermann aldehyde synthesis gave a
better yield (60% of theory) but required the use of hydrogen cyanide
gas.  The malononitrile derivative, from 5.7 g of the aldehyde and 2.3
g malononitrile in absolute EtOH, treated with a drop of
triethylamine, was an orange crystalline product.  A sample
recrystallized from EtOH gave a mp of 138.5-139 !C.

A solution of 8.65 g 2,5-dimethoxy-4-methylbenzaldehyde in 30 g
nitromethane was treated with 1.1 g anhydrous ammonium acetate and
heated for 50 min on the steam bath.  Stripping off the excess
nitromethane under vacuum yielded orange crystals which weighed 12.2
g.  These were recrystallized from 100 mL IPA providing yellow
crystals of 2,5-dimethoxy-4-methyl-'-nitrostyrene which weighed, when
dry, 7.70 g.  The mp was 117-118 !C, and this was increased to 118-119
!C upon recrystallization from benzene/heptane 1:2.

To a well stirred suspension of 7.0 g LAH in 300 mL of warm THF under
an inert atmosphere, there was added 7.7 g
2,5-dimethoxy-4-methyl-'-nitrostyrene in 35 mL THF over the course of
0.5 h.  This reaction mixture was held at reflux for 24 h, cooled to
room temperature, and the excess hydride destroyed with 25 mL IPA.
There was then added 7 mL 15% NaOH, followed by 21 mL H2O.  The
granular gray mass was filtered, and the filter cake washed with 2x50
mL THF.  The combined filtrate and washes were stripped of their
volatiles under vacuum to give a residue weighing 7.7 g which was
distilled at 90-115 !C at 0.3 mm/Hg to provide 4.90 g of a clear,
white oil, which crystallized in the receiver.  This was dissolved in
25 mL IPA, and neutralized with concentrated HCl which produced
immediate crystals of the salt.  These were dispersed with 80 mL
anhydrous Et2O, filtered, and washed with Et2O to give, after air
drying to constant weight, 4.9 g of fluffy white crystals of
2,5-dimethoxy-4-methylphenethylamine hydrochloride (2C-D).  The mp was
213-214 !C which was not improved by recrystallization from CH3CN/IPA
mixture, or from EtOH.  The hydrobromide salt had a mp of 183-184 !C.
The acetamide, from the free base in pyridine treated with acetic
anhydride, was a white crystalline solid which, when recrystallized
from aqueous MeOH, had a mp of 116-117 !C.

DOSAGE: 20 - 60 mg.

DURATION: 4 - 6 h.

QUALITATIVE COMMENTS: (with 10 mg) There is something going on, but
it is subtle.  I find that I can just slightly redirect my attention
so that it applies more exactly to what I am doing.  I feel that I can
learn faster.  This is a TsmartU pill!S

(with 20 mg) Butterflies in stomach whole time.  OK.  This is about
the right level.  In retrospect, not too interesting.  Primarily a
stimulant, not entirely physically pleasant.  The visual is not too
exciting.  I am easily distracted.  One line of thought to another.  I
feel that more would be too stimulating.

(with 30 mg) I was into it quite quickly (not much over
three-quarters of an hour) and got up to a ++ by the end of an hour.
There is something unsatisfactory about trying to classify this level.
I had said that I was willing to increase the dose to a higher level,
to break out of this not-quite-defined level into something
psychedelic.  But I may not want to go higher.  Under different
circumstances I would not mind trying it at a considerably lower
dosage, perhaps at the 10 or 15 milligrams.  I do not have a
comfortable label on this material, yet.

(with 45 mg) There was a rocket from the half-hour to the one and a
half hour, from nothing up to a +++.  Somehow the intimacy and the
erotic never quite knit, and I feel that I am always waiting for the
experience to come home.  Talking is extremely easy, but something is
missing.  Appetite is good.  I am down by the fifth hour, and sleep is
comfortable.  This compound will take some learning.

(with 75 mg) This is a +++, but the emphasis is on talking, not on
personal interacting.  I am putting out, but my boundaries are intact.
I was able to sleep at the sixth hour.  Communication was excellent.
This is fast on, but not too long lived.  Maybe a therapy tool?S

(with 150 mg) A truly remarkable psychedelic, one which could compare
favorably with 2C-B.  There are intense colors, and I feel that more
would be too much.

EXTENSIONS AND COMMENTARY: Wow!  This particular compound is what I
call a pharmacological tofu.  It doesnUt seem to do too much by
itself, always teasing, until you get to heroic levels.  But a goodly
number of experimental therapists have said that it is excellent in
extending the action of some other materials.  It seems to boost the
waning action of another drug, without adding its own color to the
experience.  Yet, the comment above, on the high level of 150
milligrams, is a direct quote from the use of this compound in Germany
(where it is called LE-25) in therapeutic research.

This is probably the most dramatic example of the loss of potency from
an amphetamine (DOM, active at maybe 3 milligrams) to a phenethylamine
(only one tenth as active).  It is so often the case that the first of
a series is not the most interesting nor the most potent member.  As
intriguing and as difficult-to-define as the 2C-D story might be, the
next higher homologue of this set, 2C-E, is maximally active at the 15
to 20 milligram level, and is, without any question, a complete
psychedelic.

The N-monomethyl and the N,N-dimethyl homologues of 2C-D have been
synthesized from 2C-D.  The N-monomethyl compound was obtained by the
quaternization of the Schiff's base formed between 2C-D and
benzaldehyde with methyl sulfate, followed by hydrolysis; the
hydrochloride salt had a melting point of 150-151 !C, from EtOH.  The
N,N-dimethyl compound resulted from the action of formaldehyde-formic
acid on 2C-D; the hydrochloride salt had a melting point of 168-169 !C
from EtOH/ether.  These two compounds were some ten times less
effective in interfering with conditioned responses in experimental
rats.  There is no report of their having been explored in man.

I have learned of an extensive study of ethoxy homologues of a number
of the phenethylamines in the 2C-X series; they have been collectively
called the RTweetios.S This Sylvester and Tweety-bird allusion came
directly from the compulsive habit of trying to alleviate the boredom
of driving long distances (not under the influence of anything) by the
attempt to pronounce the license plates of cars as they passed.  The
first of this series of compounds had a name that indicated that there
was an ethoxy group at the 2-position, or 2-EtO, or Tweetio, and the
rest is history.  In every compound to be found in the 2C-X family,
there are two methoxy groups, one at the 2-position and one at the
5-position.  There are thus three possible tweetio compounds, a
2-EtO-, a 5-EtO- and a 2,5-di-EtO-.  Those that have been evaluated in
man are included after each of the 2C-X's that has served as the
prototype.  In general, the 2-EtO- compounds have a shorter duration
and a lower potency, the 5-EtO- compounds have a relatively unchanged
potency and a longer time duration; the 2,5-di-EtO- homologues are
very weak, if active at all.

The 2-EtO-homologue of 2C-D is
2-ethoxy-5-methoxy-4-methylphenethylamine, or 2CD-2ETO.  The
benzaldehyde (2-ethoxy-5-methoxy-4-tolualdehyde) had a melting point
of 60.5-61 !C, the nitrostyrene intermediate a melting point of
110.5-111.5 !C, and the final hydrochloride a melting point of 207-208
!C.  The hydrobromide salt had a melting point of 171-173 !C.  At
levels of 60 milli-grams, there was the feeling of closeness between
couples, without an appreciable state of intoxication.  The duration
was about 4 hours.

The 5-EtO- homologue of 2C-D is
5-ethoxy-2-methoxy-4-methylphenethylamine, or 2CD-5ETO.  The
benzaldehyde (5-ethoxy-2-ethoxy-4-tolualdehyde) had a melting point of
81-82 !C, and the details of this synthesis are given in the recipe
for IRIS.  The nitrostyrene intermediate had a melting point of
112.5-113.5 !C and the final hydrochloride salt had a melting point of
197-198 !C.  The hydro-bromide salt had a melting point of 158-159 !C.
At dosage levels of 40 to 50 milli-grams, there was a slow, gradual
climb to the full effects that were noted in about 2 hours.  The
experience was largely free from excitement, but with a friendly
openness and outgoingness that allowed easy talk, interaction, humor,
and a healthy appetite.  The duration of effects was 12 hours.

The 2,5-di-EtO- homologue of 2C-D is
2,5-diethoxy-4-methylphenethylamine, or 2CD-2,5-DIETO.  The
benzaldehyde (2,5-diethoxy-4-tolualdehyde) had a melting point of
102-103 !C, the nitrostyrene intermediate a melting point of 108-109
!C, and the final hydrochloride salt a melting point of 251-252 !C.
At a level of 55 milligrams, a plus one was reached, and what effects
there were, were gone after four hours.



#24 2C-E; 2,5-DIMETHOXY-4-ETHYLPHENETHYLAMINE

SYNTHESIS: A suspension of 140 g anhydrous AlCl3 in 400 mL CH2Cl2 was
treated with 100 g acetyl chloride.  This slurry was added to a
vigorously stirred solution of 110 g p-dimethoxybenzene in 300 mL
CH2Cl2.  Stirring was continued at ambient temperature for an
additional 40 min, then all was poured into 1 L water and the phases
separated.  The aqueous phase was extracted with 2x100 mL CH2Cl2 and
the combined organic phases washed with 3x150 mL 5% NaOH.  These
washes, after combination and acidification, were extracted with 3x75
mL CH2Cl2 and the extracts washed once with saturated NaHCO3.
Re-moval of the solvent under vacuum provided 28.3 g of
2-hydroxy-5-methoxyaceto-phenone as yellow crystals which, on
recrystallization from 2 volumes of boiling MeOH and air drying,
provided 21.3 g of product with a mp of 49-49.5 !C.  Ethyl-ation of
this material serves as the starting point for the synthesis of
2CE-5ETO.  The CH2Cl2 fraction from the base wash, above, was stripped
of solvent on the rotary evaporator to give a residual oil that, on
distillation at 147-150 !C at the water pump, provided 111.6 g of
2,5-dimethoxyacetophenone as an almost white oil.

In a round bottom flask equipped with a reflux condenser, a take-off
adapter, an immersion thermometer, and a magnetic stirrer, there was
placed 100 g 2,5-dimethoxyacetophenone, 71 g 85% KOH pellets, 500 mL
of triethylene glycol, and 125 mL 65% hydrazine.  The mixture was
brought up to a boil by heating with an electric mantle, and the
distillate was removed, allowing the temperature of the pot contents
to continuously increase.  When the pot temperature had reached 210
!C, reflux was established and maintained for an additional 3 h.
After cooling, the reaction mixture and the distillate were combined,
poured into 3 L water, and extracted with 3x100 mL hexane.  After
washing the pooled extracts with water, the solvent was removed
yielding 22.0 g of a pale straw-colored liquid that was free of both
hydroxy and carbonyl groups by infrared.  This was distilled at
120-140 !C at the water pump to give 2,5-dimethoxy-1-ethylbenzene as a
white fluid product.  Acidification of the spent aqueous phase with
concentrated HCl produced a heavy black oil which was extracted with
3x100 mL CH2Cl2.  Removal of the solvent on the rotary evaporator
yielded 78 g.of a black residue that was distilled at 90-105 !C at 0.5
mm/Hg to provide 67.4 g of an orange-amber oil that was largely
2-ethyl-4-methoxyphenol.  This material could eventually be used as a
starting material for ethoxy homologues.  However, remethylation (with
CH3I and KOH in methanol) provided some 28 g additional
2,5-dimethoxyethylbenzene.

A solution of 8.16 g of 2,5-dimethoxy-1-ethylbenzene in 30 mL CH2Cl2
was cooled to 0 !C with good stirring and under an inert atmosphere of
He.  There was then added 11.7 mL anhydrous stannic chloride, followed
by 3.95 mL dichloromethyl methyl ether dropwise over the course of 0.5
h.  The stirred reaction mixture was allowed to come up to room
temperature, then held on the steam bath for 1 h.  The reaction
mixture was poured into 1 L water, extracted with 3x75 mL CH2Cl2, and
the pooled extracts washed with dilute HCl.  The organic phase was
stripped under vacuum yielding 10.8 g of a dark viscous oil.  This was
distilled at 90-110 !C at 0.2 mm/Hg to yield a colorless oil that, on
cooling, set to white crystals.  The yield of
2,5-dimethoxy-4-ethylbenzaldehyde was 5.9 g of material that had a mp
of 46-47 !C.  After purification through the bisulfite complex, the mp
increased to 47-48 !C.  The use of the Vilsmeier aldehyde synthesis
(with POCl3 and N-methylformanilide) gave results that were totally
unpredictable.  The malononitrile derivative (from 0.3 g of this
aldehyde and 0.3 g malononitrile in 5 mL EtOH and a drop of
triethylamine) formed red crystals which, on recrystallization from
toluene, had a mp of 123-124 !C.

A solution of 21.0 g of the unrecrystallized
2,5-dimethoxy-4-ethylbenzaldehyde in 75 g nitromethane was treated
with 4 g of anhydrous ammonium acetate and heated on the steam bath
for about 2 h.  The progress of the reaction was best followed by TLC
analysis of the crude reaction mixture on silica gel plates with
CH2Cl2 as the developing solvent.  The excess solvent/reagent was
removed under vacuum yielding granular orange solids that were
recrystallized from seven volumes of boiling MeOH.  After cooling in
external ice-water for 1 h, the yellow crystalline product was removed
by filtration, washed with cold MeOH and air dried to give 13.4 g of
2,5-dimethoxy-4-ethyl-'-nitrostyrene.  The mp was 96-98 !C which
improved to 99-100 !C after a second recrystallization from MeOH.

A total of 120 mL of 1.0 M solution of LAH in THF (120 mL of 1.0 M)
was transferred to a 3 neck 500 mL flask, under an inert atmosphere
with good magnetic stirring.  This solution was cooled to !C with an
external ice-water bath, and there was then added 3.0 mL of 100% H2SO4
over the course of 0.5 h.  This was followed by a solution of 5.85 g
of 2,5-dimethoxy-4-ethyl-'-nitrostyrene, in 40 mL of warm THF.  The
reaction mixture was stirred for 0.5 h, brought to room temperature,
heated on the steam bath for 0.5 h, and then returned to room
temperature.  The addition of IPA dropwise destroyed the excess
hydride, and some 4.5 mL of 5% NaOH produce a white cottage cheese, in
a basic organic medium.  This mixture was filtered, washed with THF,
and the filtrate evaporated to produce 2.8 g of an almost white oil.
The filter cake was resuspended in THF, made more basic with
additional 15 mL of 5% NaOH, again filtered, and the filtrate removed
to provide an additional 2.8 g of crude product.  These residues were
combined and distilled at 90-100 !C at 0.25 mm/Hg to give a colorless
oil.  This was dissolved in 30 mL IPA, neutralized with concentrated
HCl, and diluted with 50 mL anhydrous Et2O to provide, after
spontaneous crystallization, filtration, washing with Et2O, and air
drying, 3.87 g of 2,5-dimethoxy-4-ethylphenethylamine hydrochloride
(2C-E) as magnificent white crystals.  A similar yield can be obtained
from the reduction of the nitrostyrene in a suspension of LAH in THF,
without the use of H2SO4.  With 11.3 g of LAH in 300 mL dry THF, there
was added, dropwise, a solution of 13.4 g of
2,5-dimethoxy-4-ethyl-'-nitrostyrene in 75 mL THF over the course of 2
h.  The mixture was kept at reflux for an additional 8 h, and killed
by the careful addition of 11 mL H2O, followed with 11 mL 15% NaOH,
and finally another 33 mL of H2O.  This mass was filtered, washed with
THF, and the combined filtrates and washes evaporated to a residue
under vacuum The approximately 15 mL of residue was dissolved in 300
mL CH2Cl2 and treated with 200 mL H2O containing 20 mL concentrated
HCl.  On shaking the mixture, there was deposited a mass of the
hydrochloride salt which was diluted with a quantity of additional
H2O.  The organic phase was extracted with additional dilute HCL, and
these aqueous phases were combined.  After being made basic with 25%
NaOH, this phase was again extracted with 3x75 mL CH2Cl2 and after the
removal of the solvent, yielded 12.6 g of a colorless oil.  This was
dissolved in 75 mL of IPA and neutralized with concentrated HCl.  The
solidified mass that formed was loosened with another 50 mL IPA, and
then filtered.  After Et2O washing and air drying there was obtained
7.7 g of 2,5-dimethoxy-4-ethylphenethylamine hydrochloride (2C-E) as
lustrous white crystals.  Anal. (C12H20ClNO2) C,H.

DOSAGE: 10 - 25 mg.

DURATION: 8 - 12 h.

QUALITATIVE COMMENTS: (with 16 mg) There was a strange devil-angel
pairing.  As I was being told of the ecstatic white-light ascent of my
partner into the God-space of an out-of-body experience, I was
fighting my way out of a brown ooze.  She saw the young Jesus at the
bottom of a ladder drifting upwards step by step to some taking-off
place, and I saw all the funny gargoyles around the base of the ladder
surrounded by picnic bunting.  For me it was the 4th of July, rather
than Easter!S

(with 20 mg) The view out of the window was unreal.  The garden was
painted on the window, and every petal of flower and tuft of grass and
leaf of tree was carefully sculptured in fine strokes of oil paint on
the surface of the glass.  It was not out there; it was right here in
front of me.  The woman who was watering the plants was completely
frozen, immobilized by Vermeer.  And when I looked again, she was in a
different place, but again frozen.  I was destined to become the
eternal museum viewer.

(with 25 mg) I have a picture in my living room that is a stylized
German scene with a man on horseback riding through the woods, and a
young girl coming out to meet him from the nearby trees.  But she was
not just 'coming out.'  He was not just riding through the woods.  The
wind was blowing, and his horse was at full gallop, and his cape was
flapping in the storm, and she was bearing down upon him at full bore.
The action never ceased.  I became exhausted.

(with 25 mg) Within minutes I was anxious and sweaty.  Each person
has his own brand of toxic psychosis Q mine always starts with the
voices in my head talking to me, about all my worst fears, a jumble of
warnings and deep fears spinning faster.  Twenty minutes later this
complex chaos passed as quickly as it had come.  At lower dosages 2C-E
has been a truly enjoyable esthetic enhancer.  But it really has a
steep dose/response curve.

EXTENSIONS AND COMMENTARY: Here is another of the magical half-dozen.
The range is purposefully broad.  At 10 milligrams there have been
some pretty rich +++ experiences, and yet I have had the report from
one young lady of a 30 milligram trial that was very frightening.  My
first experience with 2C-E was really profound, and it is the
substance of a chapter within the story.  The amphet-amine homologue
is DOET, which is not only much longer in action, but considerably
more potent.  Several people have said, about 2C-E, RI donUt think I
like it, since it isnUt that much fun.  But I intend to explore it
again.S There is something here that will reward the experimenter.
Someday, the full character of 2C-E will be understood, but for the
moment, let it rest as being a difficult and worth-while material.  A
very much worth-while material.  One Tweetio of 2C-E is known.  The
5-EtO-homologue of 2C-E is 5-ethoxy-4-ethyl-2-methoxyphenethylamine,
or 2CE-5ETO.  The nitrostyrene intermediate had a melting point of
110-110.5 !C, and the final hydrochloride a melting point of 184-185
!C.  The effective level of 2CE-5ETO is in the 10 to 15 milligram
range.  It is gentle, forgiving, and extremely long lived.  Some 3 to
4 hours were needed to achieve plateau, and on occasion experi-ments
were interrupted with Valium or Halcion at the 16 hour point.  After a
night's sleep, there were still some effects evident the next day.
Thus, the dose is comparable to the parent compound 2C-E, but the
duration is 2 to 3 times longer.  It was given the nickname REternityS
by one subject.



#25 3C-E; 3,5-DIMETHOXY-4-ETHOXYAMPHETAMINE

SYNTHESIS: A solution of 3.6 g syringaldehyde (3,5-dimethoxy-4-
hydroxybenzaldehyde) in 50 mL MeOH was combined with a solution of 3.7
g 85% KOH in 75 mL warm MeOH.  This clear solution suddenly set up to
crystals of the potassium salt, too thick to stir satisfactorily.  To
this suspension there was added 7.4 g ethyl iodide (a large excess)
and the mixture was held at reflux temperature with a heating mantle.
The solids eventually loosened and redissolved, giving a clear
amber-colored smooth-boiling solution.  Refluxing was maintained for 2
days, then all volatiles were removed under vacuum.  The residue was
dissolved in 400 mL H2O, made strongly basic with 25% NaOH, and
extracted with 4x100 mL CH2Cl2.  The pooled extracts were washed with
saturated brine, and the solvent removed under vacuum to give 3.3 g of
a pale amber oil which set up as crystals of
3,5-dimethoxy-4-ethoxybenzaldehyde with a mp of 47-48 !C.  A small
sample recrystallized from methanol had a mp of 48-49 !C.

A solution of 3.3 g 3,5-dimethoxy-4-ethoxybenzaldehyde in 25 mL
nitroethane was treated with 0.5 g anhydrous ammonium acetate and
heated on the steam bath for 36 h.  The solvent/reagent was removed
under vacuum giving a thick yellow-orange oil that was dissolved in
two volumes hot MeOH.  As this cooled, crystals appeared
spontaneously, and after cooling in ice for a short time, these were
removed by filtration and washed sparingly with cold MeOH, Air drying
to constant weight provided 2.2 g
1-(3,5-dimethoxy-4-ethoxyphenyl)-2-nitropropene with a mp of 84-85 !C.
The mother liquors, on standing overnight, deposited large chunks of
crystalline material which was isolated by decantation, ground up
under a small amount of methanol, then recrystallized from 60% EtOH.
A second crop of 0.7 g of the nitrostyrene was thus obtained, as
canary-yellow crystals with a mp of 83-85 !C.

A solution of 2.7 g 1-(3,5-dimethoxy-4-ethoxyphenyl)-2-nitropropene in
20 mL anhydrous THF was added to a suspension of 2.0 g LAH in 150 mL
warm THF.  The mixture was held at reflux for 48 h.  After stirring at
room temperature for another 48 h, the excess hydride was destroyed by
the addition of 2.0 mL H2O in 10 mL THF, followed by 2.0 mL 15% NaOH
and then an additional 6.0 mL H2O.  The inorganic salts were removed
by filtration, and the filter cake washed with THF.  The combined
mother liquor and washings were stripped of solvent under vacuum
leaving a yellow oil with some inorganic salts still in it.  This was
dissolved in 300 mL CH2Cl2, washed with dilute NaOH, and extracted
with 3x150 mL 1 N HCl.  The pooled extracts were washed once with
CH2Cl2 made basic with 25% NaOH, and extracted with 3x100 mL CH2Cl2.
The combined organics were washed with saturated brine, and the
solvent removed under vacuum to yield about 2 mL of a colorless oil.
This was dissolved in 10 mL IPA, neutralized with concentrated HCl (10
drops were required), and diluted with 125 mL anhydrous Et2O.  The
slight cloudiness gradually became the formation of fine white
crystals.  After standing at room temperature for 2 h, these were
removed, Et2O washed, and air dried.  There was thus obtained 1.9 g of
3,5-dimethoxy-4-ethoxyamphetamine hydrochloride (3C-E) as brilliant
white crystals.

DOSAGE: 30 - 60 mg.

DURATION: 8 - 12 h.

QUALITATIVE COMMENTS: (with 40 mg) It developed into a strange and
indefinable something.  It is unworldly.  I am very much in control,
but with an undertone of unreality that is a little reminiscent of
high doses of LSD.  If there were a great deal of sensory input, I
might not see it.  And if I were in complete sensory quiet I would
miss it, too.  But just where I am, I can see it.  Eerie state of
awareness.  And by the 8th hour I am sober, with no residue except for
some slight teeth clenching, and pretty much disbelieving the whole
thing.

(with 60 mg) Visuals very strong, insistent.  Body discomfort
remained very heavy for first hour.  Sense of implacable imposition of
something toxic for a while.  I felt at the mercy of uncomfortable
physical effects Q faint or pre-nausea, heavy feeling of tremor
(although tremor actually relatively light) and general dis-ease,
un-ease, non-ease.  Kept lying down so as to be as comfortable as
possible.  Fantasy began to be quite strong.  At first, no eyes closed
images, and certainly anti-erotic.  2nd hour on, bright colors,
distinct shapes Q jewel-like Q with eyes closed.  Suddenly it became
clearly not anti-erotic.  That was the end of my bad place, and I shot
immediately up to a +++.  Complex fantasy which takes over Q hard to
know what is real, what is fantasy.  Continual erotic.  Image of
glass-walled apartment building in mid-desert.  Exquisite sensitivity.
Down by ? midnight.  Next morning, faint flickering lights on looking
out windows.

EXTENSIONS AND COMMENTARY: This is an interesting closing of the
circle.  Although mescaline launched the entire show, the first half
could be called the amphetamine period, with variations made on all
aspects of the molecule except for that three-carbon chain.  And it
was found that the 4-substitution position was of paramount importance
in both the potency and the quality of action of a compound.  Then,
looking at the long-ignored chain, lengthening it by the addition of a
carbon atom eliminated all psychedelic effects and gave materials with
reduced action.  The action present was that of an antidepressant.
But removing a carbon atom?  This returned the search to the world of
mescaline, but with the knowledge of the strong influence of the
4-position substituent.  The two-carbon side-chain world was
rediscovered, principally with 2C-B and 2C-D, and the
4-ethoxy-analogue of mescaline, E.  This second half of the show could
be called the phenethylamine period.  And with compounds such as 3C-E
which is, quite simply, Escaline (or E) reextended again to a 3-carbon
chain amphetamine, there is a kind of satisfying closure.  A
fascinating compound, but for most subjects a little too heavy on the
body.



#26 2C-F; 2,5-DIMETHOXY-4-FLUOROPHENETHYLAMINE

SYNTHESIS: A solution of 76.6 g 2,5-dimethoxyaniline in 210 mL H2O
containing 205 mL fluoroboric acid was cooled to 0 !C. with an
external ice bath.  There was then added, slowly, a solution of 35 g
sodium nitrite in 70 mL H2O.  After an additional 0.5 h stirring, the
precipitated solids were removed by filtration, washed first with cold
H2O, then with MeOH and finally Et2O.  Air drying yielded about 100 g
of the fluoroborate salt of the aniline as dark purple-brown solids.
This salt was pyrolyzed with the cautious application of a flame, with
the needed attention paid to both an explosion risk, and the evolution
of the very corrosive boron trifluoride.  The liquid that accumulated
in the receiver was distilled at about 120 !C at 20 mm/Hg, and was
subsequently washed with dilute NaOH to remove dissolved boron
trifluoride.  The product, 2,5-dimethoxyfluorobenzene, was a fluid,
straw-colored oil that weighed 7.0 g.

To a vigorously stirred solution of 40.7 g 2,5-dimethoxyfluorobenzene
in 215 mL CH2Cl2 cooled with an external ice bath, there was added 135
g of anhydrous stannic chloride.  There was then added, dropwise, 26 g
of dichloromethyl methyl ether at a rate that precluded excessive
heating.  The reaction mixture was allowed to come to room temperature
over the course of 0.5 h, and then quenched by dumping into 500 g
shaved ice containing 75 mL concentrated HCl.  This mixture was
stirred for an additional 1.5 h.  The separated organic layer was
washed with 2x100 mL dilute HCl, then with dilute NaOH, then with H2O
and finally with saturated brine.  Removal of the solvent under vacuum
yielded a solid residue that was recrystallized from aqueous EtOH
yielding 41.8 g 2,5-dimethoxy-4-fluorobenzaldehyde with a mp of 99-100
!C.

A solution of 2.5 g 2,5-dimethoxy-4-fluorobenzaldehyde in 15 mL acetic
acid containing 1 g nitromethane was treated with 0.2 g anhydrous
ammonium acetate, and heated on the steam bath for 4 h.  After
cooling, and following the judicious addition of H2O, crystals
separated, and additional H2O was added with good stirring until the
first signs of oiling out appeared.  The solids were removed by
filtration, and recrystallized from acetone to give 2.0 g of
2,5-dimethoxy-4-fluoro-'-nitrostyrene with a mp of 159-162 !C.

To a suspension of 2.0 g LAH in 200 mL cool anhydrous Et2O under an
inert atmosphere, there was added a THF solution of 2.0 g
2,5-dimethoxy-4-fluoro-'-nitrostyrene.  The reaction mixture was
stirred at room temperature for 2 h and then heated briefly at reflux.
After cooling, the excess hydride was destroyed by the cautious
addition of H2O, and when the reaction was finally quiet, there was
added 2 mL of 15% NaOH, followed by another 6 mL of H2O.  The basic
insolubles were removed by filtration, and washed with THF.  The
combined filtrate and washes were stripped of solvent, yielding a
residual oil that was taken up in 10 mL of IPA, neutralized with
concentrated HCl, and the generated solids diluted with anhydrous
Et2O.  The white crystalline 2,5-dimethoxy-4-fluorophenethylamine
hydrochloride (2C-F) was recrystallized from IPA to give an air-dried
product of 0.5 g with a mp of 182-185 !C.

DOSAGE: greater than 250 mg.

DURATION: unknown

QUALITATIVE COMMENTS: (with 250 mg) Even at 250 milligrams, the
effects were slight and uncertain.  There may have been some
eyes-closed imagery above normal, but certainly not profound.  At
several hours there was a pleasant lethargy; sleep was completely
normal that night.

EXTENSIONS AND COMMENTARY: A number of graded acute dosages were
tried, and it was only with amounts in excess of 100 milligrams that
there were any baseline disturbances at all.  And at no dose that was
tried was there any convincing indication of believable central
effects.

The three-carbon amphetamine analogue of 2C-F would quite logically be
called DOF (2,5-dimethoxy-4-fluoroamphetamine).  It has been prepared
by reaction of the above benzaldehyde with nitroethane (giving
1-(2,5-dimethoxy-4-fluorophenyl)-2-nitropropene, with a melting point
of 128-129 !C from ethanol) followed by LAH reduction to DOF (the
hydrochloride salt has a melting point of 166-167 !C, after
recrystallization from ether/ethyl acetate/ethanol).  Animal studies
that have compared DOF to the highly potent DOI and DOB imply that the
human activity will be some four to six times less than these two
heavier halide analogues.  As of the present time, no human trials of
DOF have been made.





#27 2C-G; 2,5-DIMETHOXY-3,4-DIMETHYLPHENETHYLAMINE

SYNTHESIS: To a clear solution of 40.4 g flake KOH in 400 mL warm EtOH
there was added 86.5 g 2,3-xylenol followed by 51.4 g methyl iodide.
This mixture was held at reflux for 2 days, stripped of volatiles
under vacuum, the residues dissolved in 1 L of H2O, and extracted with
4x200 mL CH2Cl2.  The pooled extracts were washed with 5% NaOH until
the washes remained basic.  Following a single washing with dilute
HCl, the solvent was removed under vacuum, and the residue, 41.5 g of
a pungent smelling amber oil, spontaneously crystallized.  The mp of
2,3-dimethylanisole was 25-26 !C and it was used without further
purification in the next step.  From the aqueous basic washes,
following acidification, extraction, and solvent removal, there was
obtained 46.5 g crude unreacted xylenol which could be recycled.

A mixture of 205 g POCl3 and 228 g N-methylformanilide was allowed to
incubate at room temperature until there was the development of a deep
claret color with some spontaneous heating.  To this, there was added
70.8 g 2,3-dimethylanisole, and the dark reaction mixture heated on
the steam bath for 2.5 h.  The product was then poured into 1.7 L H2O,
and stirred until there was a spontaneous crystallization.  These
solids were removed by filtration, H2O washed and air dried to give
77.7 g of crude benzaldehyde as brown crystals.  This was distilled at
70-90 !C at 0.4 mm/Hg to give 64.8 g of
2,3-dimethyl-4-methoxybenzaldehyde as a white crystalline product with
a mp of 51-52 !C.  Recrystallization from MeOH produced an analytical
sample with a mp of 55-55.5 !C.  Anal. (C10H12O2) C,H.  The
malononitrile derivative (from the aldehyde and malononitrile in EtOH
with a drop of triethylamine) had a mp of 133-133.5 !C from EtOH.
Anal. (C13H12N2O) C,H,N.  Recently, this aldehyde has become
commercially available.

A solution of 32.4 g 2,3-dimethyl-4-methoxybenzaldehyde in 800 mL
CH2Cl2 was treated with 58.6 g 85% m-chloroperoxybenzoic acid and held
at reflux for 3 days.  After cooling to room temperature, the white
solids (m-chlorobenzoic acid) were removed by filtration (about 40 g
when dry).  The filtrate was extracted with several portions of
saturated NaHCO3 (on acidification, this aqueous wash yielded
additional m-chlorobenzoic acid) and the organic solvent removed under
vacuum.  The crystalline residue (weighing 32 g and deeply colored)
was dissolved in 150 mL boiling MeOH to which there was added 18 g of
solid NaOH and the solution heated on the steam bath for a few min.
The mixture was added to 800 mL H2O, and a little surface scum
mechanically removed with a piece of filter paper.  The solution was
acidified with concentrated HCl, depositing 30.9 g of a tan solid.
Recrystallization from H2O gave 2,3-dimethyl-4-methoxyphenol as white
needles, with a mp of 95-96 !C.  Anal. (C9H12O2) H; C: calcd, 71.06;
found 70.20.  The N-methyl carbamate was made by the treatment of a
solution of the phenol (1 g in 75 mL hexane with 5 mL CH2Cl2 added)
with 2 g methyl isocyanate and a few drops of triethyl amine.  The
pale pink solids that separated were recrystallized from MeOH to give
a product that had a mp of 141-142 !C.  Anal. (C11H15NO3) C,H,N.

To a solution of 23.1 g flake KOH in 250 mL hot EtOH there was added
61.8 g 2,3-dimethyl-4-methoxyphenol followed by 60 g methyl iodide.
This was held under reflux for 12 h, then stripped of solvent under
vacuum.  The residue was dissolved in 1.2 L H2O, acidified with HCl,
and extracted with 3x200 mL CH2Cl2.  The combined extracts were washed
with 3x100 mL 5% NaOH, and the solvent was removed under vacuum.  The
residue set up as an off-white mass of leaflets weighing 37.7 g after
filtering and air drying.  Recrystallization from MeOH gave
2,3-dimethyl-1,4-dimethoxybenzene as white solids, with a mp of 78-79
!C.  Anal. (C10H14O2) C,H.  An alternate route leading from
2,3-xylenol to this diether via nitrogen-containing intermediates was
explored.  The sequence involved the reaction of 2,3-xylenol with
nitrous acid (4-nitroso product, mp 184 !C dec.), reduction with
sodium dithionite (4-amino product, mp about 175 !C), oxidation with
nitric acid (benzoquinone, mp 58 !C), reduction with sodium dithionite
(hydro-quinone) and final methylation with methyl iodide.  The yields
were inferior with this process.

A mixture of 88 g POCl3 and 99 g N-methylformanilide was allowed to
incubate until a deep claret color had formed, then it was treated
with 36.5 g 2,3-dimethyl-1,4-dimethoxybenzene and heated on the steam
bath for 3 h.  It was then poured into 1 L H2O, and stirred until the
formation of a loose, crumbly, dark crystalline mass was complete.
This was removed by filtration, and dissolved in 300 mL CH2Cl2.  After
washing first with H2O, then with 5% NaOH, and finally with dilute
HCl, the solvent was removed under vacuum yielding 39.5 g of a black
oil that solidified.  This was extracted with 2x300 mL boiling hexane,
the extracts were pooled, and the solvent removed under vacuum.  The
yellowish residue crystallized to give 32.7 g
2,5-dimethoxy-3,4-dimethylbenzaldehyde with a mp of 46-47 !C.
Repeated recrystallization from MeOH raised the mp to 59-60 !C.  The
malononitrile derivative was prepared (aldehyde and malononitrile in
EtOH with a few drops triethyl amine) as yellow crystals from EtOH,
with a mp of 190-191 !C.  Anal. (C14H14N2O2) C,H; N: calcd, 11.56;
found, 11.06, 11.04.

To a solution of 16.3 g 2,5-dimethoxy-3,4-dimethylbenzaldehyde in 50
mL nitromethane there was added 3.0 g anhydrous ammonium acetate, and
the mixture was heated on the steam bath overnight.  There was then
added an equal volume of MeOH, and with cooling there was obtained a
fine crop of yellow crystals.  These were removed by filtration,
washed with MeOH, and air dried to provide 4.4 g of
2,5-dimethoxy-3,4-dimethyl-'-nitrostyrene with a mp of 120-121 !C
which was not improved by recrystallization from MeOH (50 mL/g).  The
mother liquors of the above filtration were diluted with H2O to the
point of permanent turbidity, then set aside in a cold box.  There was
a chunky, granular, tomato-red crystal deposited which weighed 2.5 g
when dry.  It had a mp of 118-119.5 !C, which was undepressed in mixed
mp with the yellow sample.  Both forms had identical NMR spectra
(2.20, 2.25 CH3; 3.72, 3.84 OCH3; 6.80 ArH; 7.76, 8.28 CH=CH, with 14
cycle splitting), infrared spectra, ultra violet spectra (max. 324 nm
with shoulder at 366 nm in EtOH, two peaks at 309 and 355 nm in
hexane), and microanalyses.  Anal. (C12H15NO4) C,H,N.

A solution of LAH (56 mL of a 1 M solution in THF) was cooled, under
He, to 0 !C with an external ice bath.  With good stirring there was
added 1.52 mL 100% H2SO4 dropwise, to minimize charring.  This was
followed by the addition of 3.63 g
2,5-dimethoxy-3,4-dimethyl-'-nitrostyrene in 36 mL anhydrous THF over
the course of 1 h.  After a few minutes further stirring, the
temperature was brought up to a gentle reflux on the steam bath for
about 5 min, then all was cooled again to 0 !C.  The excess hydride
was destroyed by the cautious addition of 9 mL IPA followed by 2.5 mL
15% NaOH and finally 7.5 mL H2O.  The reaction mixture was filtered,
and the filter cake washed first with THF and then with IPA.  The
filtrate was stripped of solvent under vacuum and the residue was
distilled at 110-120 !C at 0.2 mm/Hg to give 2.07 g of
2,5-dimethoxy-3,4-dimethylphenethylamine as a clear white oil.  This
was dissolved in 10 mL IPA, neutralized with concentrated HCl, and
then diluted with 25 mL anhydrous Et2O.  The crystals that formed were
filtered, Et2O washed, and air dried to constant weight.  There was
obtained 2.13 g of beautiful white crystals of
2,5-dimethoxy-3,4-dimethylphenethylamine hydrochloride (2C-G) with a
mp of 232-233 !C.  Anal.  (C12H20ClNO2) C,H.

DOSAGE: 20 - 35 mg.

DURATION: 18 - 30 h.

QUALITATIVE COMMENTS: (with 22 mg) I am completely functional, with
writing and answering the telephone, but the coffee really tastes most
strange.  While the mental effects (to a ++ only) were dispersing, the
body still had quite a bit of memory of the day.  Sleep was fine, and
desirable, in the early evening.

(with 32 mg) Superb material, to be classified as a 'true
psychedelic' unless one is publishing, in which case it could be best
described as an 'insight-enhancer' and obviously of potential value in
psychotherapy (if one would wish to spend 30 hours in a therapy
session!).  I suppose it would be best to simply stick with the
insight-enhancing and skip the psychotherapy.  Just too, too long.
There was not any particular visual impact, at least for me.  The
non-sexual and the anorexic aspects might indeed change, with
increasing familiarity.  Remains to be seen.  The length of the
experience is against its frequent use, of course, which is a pity,
since this one is well worth investigating as often as possible.

(with 32 mg) There was, at the very beginning, a certain feeling of
non-physical heat in the upper back which reminded me of the onset of
various indoles, which this ainUt.  The energy tremor was quite strong
throughout, but somehow the body was generally at ease.

(with 32 mg) At a plateau at two hours, with just a bit of tummy
queasi-ness.  And I am still at the plateau several hours later.
Sleep finally at the 18th hour, but even after getting up and doing
all kinds of things the next day, I was not completely baseline until
that evening.  And a couple of days more for what is certainly
complete repair.  That is a lot of mileage for a small amount of
material.

EXTENSIONS AND COMMENTARY: Here is the first example, ever, of a
phen-ethylamine that is of about the same potency as therelated
three-carbon amphetamine.  At first approximation, one is hard put to
distinguish, from the recorded notes, any major differences either in
potency, in duration, or in the nature of activity, between 2C-G and
GANESHA itself.

I had always thought of the phenethylamines as being somewhat weaker
than the corresponding amphetamines.  Sometimes a little weaker and
sometimes a lot weaker.  But that is a totally prejudiced point of
view, an outgrowth of my earliest comparisons of mescaline and TMA.
That's the kind of thing that can color oneUs thinking and obscure
what may be valuable observations.  It is equally valid to think of
the phenethylamines as the prototypes, and that the amphetamines are
somewhat stronger than the corresponding phenethylamines.  Sometimes a
little stronger and sometimes a lot stronger.  Then the question
suddenly shifts from asking what is different about the
phenethylamines, to what is different about the amphetamines?  It is
simply a historic fact, that in most of my exploring, the amphetamine
was made and evaluated first, and so tended to slip into the role of
the prototype.  In any case, here the two potencies converge.



#28 2C-G-3; 2,5-DIMETHOXY-3,4-(TRIMETHYLENE)PHENETHYLAMINE;
5-(2-AMINOETHYL)-4,7-DIMETHOXYINDANE)

SYNTHESIS: To a solution of 22 g of KOH in 250 mL of hot EtOH, there
was added 50 g of 4-indanol and 75 g methyl iodide.  The mixture was
held at reflux for 12 h.  There was then added an additional 22 g KOH
followed by an additional 50 g of methyl iodide.  Refluxing was
continued for an additional 12 h.  The mixture was poured into 1 L
H2O, acidified with HCl, and extracted with 3x75 mL CH2Cl2. The pooled
extracts were washed with 5% NaOH, then with dilute HCl, and the
solvent was removed under vacuum.  The residue of crude
2,3-(trimethylene)anisole weighed 56.5 g and was used without further
purification in the following reaction.

A mixture of 327 g N-methylformanilide and 295 g POCl3 was allowed to
incubate until a deep claret color had formed.  To this there was then
added 110 g of crude 2,3-(trimethylene)anisole, and the mixture heated
on the steam bath.  There was a vigorous evolution of gases, which
largely quieted down after some 4 h of heating.  The reaction mixture
was added to 4 L H2O and stirred overnight.  The oily aqueous phase
was extracted with 3x200 mL CH2Cl2, and after combining the extracts
and removal of the solvent there was obtained 147 g of a black,
sweet-smelling oil.  This was distilled at 182-194 !C at the water
pump to yield 109.1 g of a pale yellow oil.  At low temperature, this
crystallized, but the solids melted again at room temperature.  Gas
chromatography of this product on OV-17 at 185 !C showed detectable
starting anisole and N-methylformanilide (combined, perhaps 5% of the
product) and a small but real isomeric peak, (about 5%, slightly
faster moving than the title aldehyde, again about 5% of the product)
of what was tentatively identified as the ortho-aldehyde
(2-methoxy-3,4-(trimethylene)-benzaldehyde).  The bulk of this crude
product (74 g) was redistilled at 110-130 !C at 0.3 mm/Hg to give 66 g
of 4-methoxy-2,3-(trimethylene)benzaldehyde as a nearly colorless oil
which set up as a crystalline solid.  A portion on porous plate showed
a mp of 28-29 C.  A gram of this aldehyde and a gram of malononitrile
in 25 mL of EtOH was treated with a few drops of triethylamine and
gave pale yellow crystals of the malononitrile derivative.  This, upon
recrystallization from 50 mL boiling EtOH, had a mp of 176-176.5 !C.
Anal. (C14H12N2O) C,H,N.  A side path, other than towards the intended
targets 2C-G-3 and G-3, was explored.  Reaction with nitroethane and
anhydrous ammonium acetate gave the 2-nitropropene analogue which was
obtained in a pure state (mp 74-75 !C from MeOH) only after repeated
extraction of the crude isolate with boiling hexane.  Reduction with
elemental iron gave the phenylacetone analogue which was reductively
aminated with dimethylamine and sodium cyanoborohydride to give
N,N-dimethyl-4-methoxy-2,3-(trimethylene)amphetamine.  This was
designed for brain blood-flow volume studies after iodination at the
5-position, a concept that has been discussed under IDNNA.  It has
never been tasted by anyone.  The corresponding primary amine,
4-methoxy-2,3-(trimethylene)amphetamine has not yet even been
synthesized.

A solution of 34.8 g 4-methoxy-2,3-(trimethylene)benzaldehyde in 800
mL CH2Cl2 was treated with 58.6 g of 85% m-chloroperoxybenzoic acid
and held at reflux for 3 days.  After cooling and standing for a few
days, the solids were removed by filtration and washed sparingly with
CH2Cl2.  The combined filtrate and washings were washed with 200 mL
saturated NaHCO3, and the solvent removed, yielding 43.5 g of a deeply
colored oil.  This was dissolved in 150 mL MeOH to which was added 9 g
NaOH and all heated to reflux on the steam bath.  After 1 h, a
solution of 9 g NaOH in 20 mL H2O was added, heated further, then
followed by yet another treatment with 9 g NaOH in 20 mL H2O followed
by additional heating.  All was added to 800 mL H2O, washed once with
CH2Cl2 (which removed a trivial amount of material) and then acidified
with HCl.  The dark crystals that were generated were filtered and air
dried to constant weight, yielding 27.5 g dark but nice-looking
crystals with a mp of 89-91 !C.  By all counts, this should have been
the product phenol, 4-methoxy-2,3-(trimethylene)phenol, but the
microanalysis indicated that the formate ester was still there.  Anal.
(C10H12O2) requires C = 73.08, H = 7.37.  (C11H12O3) requires C =
68.73, H = 6.29.  Found: C = 69.04, 68.84; H = 6.64, 6.58.  Whatever
the exact chemical status of the phenolic hydroxyl group might have
been, it reacted successfully in the following methylation step.

To a solution of 10 g KOH in 100 g EtOH (containing 5% IPA) there was
added 27.5 g of the above 89-91 !C melting material, followed by 25 g
methyl iodide.  The mixture was held at reflux overnight.  All was
added to 800 mL H2O, acidified with HCl, and extracted with 3x100 mL
CH2Cl2.  The combined extracts were washed with 3x100 mL 5% NaOH, then
once with dilute HCl, and the solvent removed under vacuum yielding
20.4 g of a fragrant crystalline residue.  This was recrystallized
from 60 mL boiling MeOH to give, after filtering and air drying, 16.0
g of 1,4-dimethoxy-2,3-(trimethylene)benzene (4,7-dimethoxyindane)
with a mp of 86-88 !C.  Anal. (C11H14O2) C,H.

To a mixture of 39.0 g of N-methylformanilide and 35.9 g POCl3 that
had been allowed to stand at ambient temperature until deeply claret
(about 45 min) there was added 15.8 g of
1,4-dimethoxy-2,3-(trimethylene)benzene.  The mixture was heated on
the steam bath for 4 h and then poured into 600 mL H2O.  After
stirring overnight there was produced a heavy crystalline mass.  This
was removed by filtration and, after air drying, was extracted with
3x100 mL boiling hexane.  Pooling and cooling these extracts yielded
9.7 g of salmon-colored crystals with a mp of 67-68 !C.  This was
recrystallized from 25 mL boiling EtOH to give, after filtration, EtOH
washing, and air drying to constant weight, 7.4 g of
2,5-dimethoxy-3,4-(trimethylene)benzaldehyde, with a mp of 71-72 !C.
The mother liquors on cautious treatment with H2O, yielded, after EtOH
recrystallization, 1 g additional product.  Anal. (C12H14O3) C,H.  A
solution of 150 mg aldehyde and an equal weight of malononitrile in
2.3 mL EtOH treated with 3 drops triethylamine gave immediate yellow
crystals of the malononitrile derivative, with a mp of 161-162 !C.
Anal. (C15H14N2O2) C,H,N.

A solution 3.7 g 2,5-dimethoxy-3,4-(trimethylene)benzaldehyde in 15 g
nitromethane was treated with 0.7 g anhydrous ammonium acetate and
heated on the steam bath for 14 h.  The volatiles were removed under
vacuum, and the residue set up to 3.5 g dark crystals, which melted
broadly between 126-138 !C.  Recrystallization of the entire mass from
70 mL boiling EtOH gave 3.2 g burnished gold crystals with a mp of
129-137 !C.  A further recrystallization of an analytical sample from
MeOH gave 2,5-dimethoxy-3,4-(trimethylene)-'-nitrostyrene as yellow
crystals with a mp of 146-147 !C.  Anal. (C13H15NO4) C,H.

To a cold solution of LAH in THF (40 mL of a 1 M solution) well
stirred and under an inert atmosphere, there was added dropwise 1.05
mL freshly prepared 100% H2SO4.  There was then added, dropwise, a
solution of 2.39 g 2,5-dimethoxy-3,4-(trimethylene)-'-nitrostyrene in
25 mL THF.  The bright yellow color was discharged immediately.  After
the addition was complete, stirring was continued for an additional 20
min, and the reaction mixture brought to a reflux on the steam bath
for another 0.5 h.  After cooling, the excess hydride was destroyed
with IPA (8 mL required) followed by sufficient 15% NaOH to convert
the inorganics into a loose, filterable mass.  This was removed by
filtration, and the filter cake washed with THF.  The combined
filtrate and washes were stripped of solvent under vacuum, and the
residue dissolved in dilute H2SO4.  After washing with CH2Cl2, the
aqueous phase was made basic with 25% NaOH and extracted with 3x75 mL
CH2Cl2.  After removal of the solvent under vacuum, the residue was
distilled at 125-160 !C at 0.45 mm/Hg to yield 0.80 g of a white oil.
This was dissolved in 8 mL IPA, neutralized with 20 drops of
concentrated HCl (the salt crystals started to form before this was
completed) followed with the addition of 65 mL anhydrous Et2O.  The
white crystalline mass was filtered, washed with Et2O, and air dried
to provide 1.16 g of 2,5-dimethoxy-3,4-(trimethylene)phenethylamine
hydrochloride (2C-G-3) with a mp of 214-216 !C with decomposition.
Anal. (C13H20ClNO2) C,H.

DOSAGE: 16 - 25 mg.

DURATION: 12 - 24 h.

QUALITATIVE COMMENTS: (with 16 mg) It came on in little leaps and
bounds.  All settled, and then it would take another little jump
upwards.  I am totally centered, and writing is easy.  My appetite is
modest.  Would I drive to town to return a book to the library?  No
ever-loving way!  I am very content to be right here where I am safe,
and stay with the writing.  It does take so much time to say what
wants to be said, but there is no quick way.  A word at a time.

(with 22 mg) I walked out for the mail at just about twilight.  That
was the most courageous thing that I could possibly have done, just
for one lousy postcard and a journal.  What if I had met someone who
had wanted to talk?  Towards evening I got a call from Peg who said
her bean soup was bubbling in a scary way and what should she do, and
I said maybe better make soap.  It was that kind of an experience!
Way up there, lots of LSD-like sparkles, and nothing quite really
making sense.  Marvelous.

(with 25 mg) There was easy talking, and no hint of any body concern.
Sleep that evening was easy, and the next day was with good energy.

EXTENSIONS AND COMMENTARY: The positives of a completely intriguing
altered state free from apparent physical threats, are here coupled
with the negative of having to invest such a long period of time.
There is a merry nuttiness which can give a joyous intoxication, but
with the underlying paranoia of how it looks to others.  There is an
ease of communication, but only within surroundings that are
well-known and friendly.  This might be a truly frightening experience
if it were in an unfamiliar or unstructured environment.

The numbering of this compound, and all the extensions of GANESHA,
have been made on the basis of the nature of the stuff at the
3,4-position.  Here there are three atoms (the trimethylene bridge)
and so 2C-G-3 seems reasonable.  With this logic, the dimethylene
bridge would be 2C-G-2 (and the corresponding amphetamine would be
G-2, of course).  But these compounds call upon a common intermediate
which is a benzocyclobutene, OK in principle but not yet OK in
practice.  The right benzyne reaction will be there someday, and the
dimethylene analogues will be made and assayed.  But, in the meantime,
at least the names have been assigned.



#29 2C-G-4; 2,5-DIMETHOXY-3,4-(TETRAMETHYLENE)PHENETHYLAMINE;
6-(2-AMINOETHYL)-5,8-DIMETHOXY-TETRALIN

SYNTHESIS: To a solution of 49.2 g 5,6,7,8-tetrahydronaphthol
(5-hydroxytetralin) in 100 mL MeOH, there was added 56 g methyl iodide
followed by a solution of 24.8 g KOH pellets (85% purity) in 100 mL
boiling MeOH.  The mixture was heated in a 55 !C bath for 3 h (the
first white solids of potassium iodide appeared in about 10 min).  The
solvent was stripped under vacuum, and the residues dissolved in 2 L
H2O.  This was acidified with HCl, and extracted with 4x75 mL CH2Cl2.
After washing the organic phase with 3x75 mL 5% NaOH, the solvent was
removed under vacuum to give 48.2 g of a black residue.  This was
distilled at 80-100 !C at 0.25 mm/Hg to provide 33.9 g
5-methoxy-1,2,3,4-tetrahydronaphthalene as a white oil.  The NaOH
washes, upon acidification and extraction with CH2Cl2 gave, after
removal of the solvent under vacuum and distillation of the residue at
0.35 mm/Hg, 11.4 g of recovered starting phenol.

A mixture of 61.7 g POCl3 and 54.3 g N-methylformanilide was heated on
the steam bath for 15 min which produced a deep red color.  This was
added to 54.3 g of 5-methoxy-1,2,3,4-tetrahydronaphthalene, and the
mixture was heated on the steam bath for 2 h.  The reaction mixture
was quenched in 1.2 L H2O with very good stirring.  The oils generated
quickly turned to brown granular solids, which were removed by
filtration.  The 79 g of wet product was finely triturated under an
equal weight of MeOH, filtered, washed with 20 mL ice-cold MeOH, and
air dried to yield 32.0 g of
4-methoxy-5,6,7,8-tetrahydronaphthaldehyde as an ivory-colored solid.
The filtrate, on standing, deposited another 4.5 g of product which
was added to the above first crop.  An analytical sample was obtained
by recrystallization from EtOH, and had a mp of 57-58 !C.  Anal.
(C12H14O2) C,H.

To a solution of 25.1 g 4-methoxy-5,6,7,8-tetrahydronaphthaldehyde in
300 mL CH2Cl2 there was added 25 g 85% m-chloroperoxybenzoic acid at a
rate that was commensurate with the exothermic reaction.  Solids were
apparent within a few min.  The stirred reaction mixture was heated at
reflux for 8 h.  After cooling to room temperature, the solids were
removed by filtration and washed lightly with CH2Cl2.  The pooled
filtrate and washes were stripped of solvent under vacuum and the
residue dissolved in 100 mL MeOH and treated with 40 mL 25% NaOH.
This was heated on the steam bath for an hour, added to 1 L H2O, and
acidified with HCl, producing a heavy crystalline mass.  This was
removed by filtration, air dried, and distilled at up to 170 !C at 0.2
mm/Hg.  There was thus obtained 21.4 g of
4-methoxy-5,6,7,8-tetrahydronaphthol as an off-white solid with a mp
of 107-114 !C.  An analytical sample was obtained by recrystallization
from 70% EtOH, and melted at 119-120 !C.  Hexane is also an excellent
recrystallization solvent.  Anal. (C11H14O2) C,H.  As an alternate
method, the oxidation of the naphthaldehyde to the naphthol can be
achieved through heating the aldehyde in acetic acid solution
containing hydrogen peroxide.  The yields using this route are
consistently less than 40% of theory.

A solution of 21.0 g of 4-methoxy-5,6,7,8-tetrahydronaphthol in 100 mL
acetone in a 1 L round-bottomed flask, was treated with 25 g finely
ground anhydrous K2CO3 and 26 g methyl iodide.  The mixture was held
at reflux on the steam bath for 2 h, cooled, and quenched in 1 L H2O.
Trial extraction evaluations have shown that the starting phenol, as
well as the product ether, are extractable into CH2Cl2 from aqueous
base.  The aqueous reaction mixture was extracted with 3x60 mL CH2Cl2,
the solvent removed under vacuum, and the residue (19.6 g) was
distilled at 90-130 !C at 0.3 mm/Hg to give 14.1 g of an oily white
solid mixture of starting material and product.  This was finely
ground under an equal weight of hexane, and the residual crystalline
solids removed by filtration.  These proved to be quite rich in the
desired ether.  This was dissolved in a hexane/CH2Cl2 mixture (3:1 by
volume) and chromatographed on a silica gel preparative column, with
the eluent continuously monitored by TLC (with this solvent system,
the Rf of the ether product was 0.5, of the starting phenol 0.1).  The
fractions containing the desired ether were pooled, the solvent
removed under vacuum and the residue, which weighed 3.86 g, was
dissolved in 1.0 mL hexane and cooled with dry ice.  Glistening white
crystals were obtained by filtration at low temperature.  The weight
of 5,8-dimethoxytetralin isolated was 2.40 g and the mp was 44-45 !C.
GCMS analysis showed it to be largely one product (m/s 192 parent peak
and major peak), but the underivitized starting phenol has abysmal GC
properties and TLC remains the best measure of chemical purity.

A well-stirred solution of 3.69 g 5,8-dimethoxytetralin in 35 mL
CH2Cl2 was placed in an inert atmosphere and cooled to 0 !C with an
external ice bath.  There was then added, at a slow rate, 4.5 mL
anhydrous stannic chloride, which produced a transient color that
quickly faded to a residual yellow.  There was then added 2.0 mL
dichloromethyl methyl ether, which caused immediate darkening.  After
a few min stirring, the reaction mixture was allowed to come to room
temperature, and finally to a gentle reflux on the steam bath.  The
evolution of HCl was continuous.  The reaction was then poured into
200 mL H2O, the phases separated, and the aqueous phase extracted with
2x50 mL CH2Cl2.  The organic phase and extracts were pooled, washed
with 3x50 mL 5% NaOH, and the solvent removed under vacuum.  The
residue was distilled at 120-140 !C at 0.3 mm/Hg to give 3.19 g of a
white oil that spontaneously crystallized.  The crude mp of
1,4-dimethoxy-5,6,7,8-tetrahydro-2-naphthaldehyde was 70-72 !C.  An
analytical sample from hexane had the mp 74-75 !C.  The GCMS analysis
showed only a single material (m/s 220, 100%) with no apparent
starting dimethoxytetralin present.  Attempts to synthesize this
aldehyde by the Vilsmeier procedure (POCl3 and N-methylformanilide)
gave complex mixtures of products.  Synthetic efforts employing
butyllithium and DMF gave only recovered starting material.

To a solution of 1.5 g
1,4-dimethoxy-5,6,7,8-tetrahydro-2-naphthaldehyde in 20 g nitromethane
there was added 0.14 g anhydrous ammonium acetate and the mixture
heated on the steam bath for 50 min.  The rate of the reaction was
determined by TLC monitoring, on silica gel with CH2Cl2 as the moving
solvent; the Rf of the aldehyde was 0.70, and of the product
nitrostyrene, 0.95.  Removal of the volatiles under vacuum gave a
residue that spontaneously crystallized.  The fine yellow crystals
that were obtained were suspended in 1.0 mL of MeOH, filtered, and air
dried to yield 1.67 g
2,5-dimethoxy-'-nitro-3,4-(tetramethylene)styrene with a mp of
151.5-152.5 !C. Anal. (C14H17NO4) C,H.

DOSAGE: unknown.

DURATION: unknown

EXTENSIONS AND COMMENTARY: The road getting to this final product
reminded me of the reasons why, during the first few billion years of
the universe following the big bang, there was only hydrogen and
helium.  Nothing heavier.  When everything had expanded enough to cool
things sufficiently for the first actual matter to form, all was
simply very energetic protons and neutrons.  These were banging into
one-another, making deuterium nuclei, and some of these got banged up
even all the way to helium, but every time a helium nucleus collided
with a particle of mass one, to try for something with mass five, the
products simply couldnUt exist.  Both Lithium-5 and Helium-5 have the
impossible half-lives of 10 to the minus 21 seconds.  Hence, in the
primordial soup, the only way to get into something heavier than
helium was to have a collision between a couple of the relatively
scarcer heavy nuclei, or to have a three body collision.  Both of
these would be extremely rare events, statistically.  And if a few got
through, there was another forbidden barrier at mass 8, since
Beryllium-8 has a half life of 10 to the minus 16 seconds.  So
everything had to wait for a few suns to burn down so that they could
process enough helium into heavy atoms, to achieve some nuclear
chemistry that was not allowed in the early history of the universe.

And in the same way, there were two nearly insurmountable barriers
encountered in getting to 2C-G-4 and G-4.  The simple act of
methylating an aromatic hydroxyl group provided mixtures that could
only be resolved into components by some pretty intricate maneuvers.
And when that product was indeed gotten, the conversion of it into a
simple aromatic aldehyde resisted the classic procedures completely,
either giving complex messes, or nothing.  And even now, with these
two hurdles successfully passed, the presumed simple last step has not
yet been done.  The product 2C-G-4 lies just one synthetic step (the
LAH reduction) away from completion, and the equally fascinating G-4
also that one last reduction step from being completed.  Having gotten
through the worst of the swamp, let's get into the lab and finish up
this challenge.  They will both be active compounds.



From: [e-mail]
Newsgroups: sci.med,sci.chem,alt.drugs
Subject: PiHKAL: The Chemical Story.  File 2 of 6

(I'm posting this for a friend.)

This is part 2 of 6 of the second half of PiHKAL: A Chemical Love
Story, by Alexander Shulgin and Ann Shulgin.  Please forgive any typos
or misprints in this file; further, because of ASCII limitations,
many of the typographical symbols in the original book could not be
properly represented in these files.

If you are seriously interested in the chemistry contained in these
files, you should order a copy of the book PiHKAL.  The book may be
purchased for $22.95 ($18.95 + $4.00 postage and handling) from
Transform Press, Box 13675, Berkeley, CA 94701.  California residents
please add $1.38 State sales tax.

At the present time, restrictive laws are in force in the United
States and it is very difficult for researchers to abide by the
regulations which govern efforts to obtain legal approval to do work
with these compounds in human beings....  No one who is lacking legal
authorization should attempt the synthesis of any of the compounds
described in these files, with the intent to give them to man.  To do
so is to risk legal action which might lead to the tragic ruination of
a life.  It should also be noted that any person anywhere who
experiments on himself, or on another human being, with any of the
drugs described herin, without being familiar with that drug's action
and aware of the physical and/or mental disturbance or harm it might
cause, is acting irresponsibly and immorally, whether or not he is
doing so within the bounds of the law.





#30 2C-G-5; 3,6-DIMETHOXY-4-(2-AMINOETHYL)BENZONORBORNANE

SYNTHESIS: To a stirred solution of 25 g 3,6-dihydroxybenzonorbornane
(from Eastman Kodak Company) in 200 mL acetone there was added 200 mg
decyltriethylammonium iodide, 40 g of powdered anhydrous K2CO3, and 55
g methyl iodide.  The mixture was held at reflux with a heating mantle
overnight.  After re-moval of the solvent under vacuum, the residue
was added to 2 L of H2O, acidified with concentrated HCl, and
extracted with 3x100 mL CH2Cl2.  The pooled extracts were washed with
2x150 mL 5% NaOH and once with dilute HCl, and the solvent was removed
under vacuum to give 19.0 g of a black oil as a residue.  This was
distilled at 90-115 !C at 0.3 mm/Hg to yield 15.5 g of an orange oil
which set up as a crystalline solid.  The product,
3,6-dimethoxybenzonorbornane, had a mp of 35-37 !C from hexane or
40-41 !C from MeOH.  Anal. (C13H16O2) C,H.

A solution of 4.6 g POCl3 and 4.6 g N-methylformanilide was heated
briefly on the steam-bath until the color had become deep claret.
There was then added 3.05 g of 3,6-dimethoxybenzonorbornane and the
solution was heated on the steam bath for 12 h.  The black, tarry
reaction mixture was poured into H2O, and after hydrolysis, the H2O
was decanted and the insoluble residues were washed alternately with
H2O and with CH2Cl2.  The combined washes were separated, and the
aqueous phase extracted with 2x50 mL CH2Cl2.  The combined organic
fractions were washed with 5% NaOH, and the solvent removed under
vacuum.  The fluid, black residue was distilled at 130-140 !C at 0.3
mm/Hg to give 1.17 g of an almost white oil.  This was dissolved in 1
mL MeOH, and cooled to -50 !C to give a white crystalline solid that
was removed by filtration and washed sparingly with -50 !C MeOH and
air dried.  There was obtained 0.83 g
3,6-dimethoxy-4-formylbenzonorbornane with a mp of 37-40 !C which
could be increased, by wasteful recrystallization from MeOH, to 53-54
!C.  An intimate mixture of this product with the starting diether (mp
40-41 !C) was a liquid at room temperature.  Anal. (C14H16O3) C,H.

To a solution of 3.70 g 3,6-dimethoxy-4-formylbenzonorbornane in 20 g
nitromethane, there was added 1.3 g anhydrous ammonium acetate and the
mixture was heated on the steam bath for 45 min.  The excess
reagent/solvent was removed under vacuum, and the residue was
dissolved in 20 mL boiling MeOH.  A speck of seed crystal started a
heavy crystallization of orange crystals which were removed by
filtration and washed with MeOH.  After drying, the product
3,6-dimethoxy-4-(2-nitrovinyl)benzonorbornane was yellow, weighed 3.47
g, and had a mp of 88-89 !C.  Recrystallization of an analytical
sample from MeOH did not improve this mp.  Anal. (C15H17NO4) C,H.

A solution of LAH (46 mL of a 1 M solution in THF) was cooled, under
He, to 0 !C with an external ice bath.  With good stirring there was
added 1.25 mL 100% H2SO4 dropwise, to minimize charring.  This was
followed by the addition of 3.4 g
3,6-dimethoxy-4-(2-nitrovinyl)benzonorbornane in 30 mL anhydrous THF.
After a few min further stirring, the temperature was brought up to a
gentle reflux on the steam bath for 10 min, and then all was cooled
again to 0 !C.  The excess hydride was destroyed by the cautious
addition of 7 mL IPA, followed by 2 mL 15% NaOH and 5 mL H2O, which
gave an easily filtered white granular solid.  This was removed by
filtration, and the filter cake was washed with THF.  The combined
filtrate and washes were stripped of solvent under vacuum providing a
pale amber oil which was distilled at 150-160 !C at 0.3 mm/Hg to give
1.45 g of a white oil.  This was dissolved in 7 mL IPA, and
neutralized with 15 drops of concentrated HCl.  There was then added
25 mL anhydrous Et2O and, after a short delay, white crystals formed
spontaneously.  These were removed by filtration, Et2O washed, and air
dried to constant weight, yielding 1.13 g of
3,6-dimethoxy-4-(2-aminoethyl)benzonorbornane hydrochloride (2C-G-5).
The mp was 199-200 !C.  Anal. (C15H22ClNO2) C,H.

DOSAGE: 10 - 16 mg.

DURATION: 32 - 48 h.

QUALITATIVE COMMENTS: (with 14 mg) I was well aware of things at the
end of two hours, and I was totally unwilling to drive, or even go out
of the house.  I was reminded continuously of 2C-B with its erotic
push, and the benign interplay of colors and other visual effects.
But it is so much longer lived.  I am a full +++, very stoned, and
there is no believable sign of dropping for another several hours.
There is a good appetite (again, 2C-B like), and I managed to sleep
for a few hours, and all the next day I was spacey and probably still
a plus one.  The day yet following, I was finally at a believable
baseline.  Both of these days were filled with what might be called
micro doze-offs, almost like narcolepsy.  Maybe I am just sleep
deprived.

(with 16 mg) The first effects were felt within one hour, and full
effects between 2 1/2 and 3 hours. Tremendous clarity of thought,
cosmic but grounded, as it were. This is not at all like LSD, and is a
lot mellower than the 2C-T family.  For the next few hours it was
delightful and fun and I felt safe and good-humored.  I got to sleep
without much difficulty while still at a plus three, and my dreams
were positive and balanced, but I awoke irritable and emotionally
flattened.  I did not want to interact with anyone.  The first 16
hours of this stuff were great, and the second 16 hours were a bit of
a drag.  Just twice as long as it ought to be.

(with 16 mg) I was at full sparkle within three hours, and I
continued to sparkle for the longest time.  The tiredness that comes
after a while probably reflects the inadequacy of sleep.  I was aware
of something still going on some two days later.

EXTENSIONS AND COMMENTARY: In the eventual potency assessment of a
drug, there must be some consideration of not only the dosage needed,
but the duration of effects.  The area under the curve, so to speak.
By these measures, this phenethylamine is a record breaker, in that it
is not only amongst the most potent, but it goes on and on and on.

There are a couple of chemical commentaries.  One, the miserable
phenol-to-ether-to-aldehyde series of steps, so maddeningly
unsatisfactory in the 2C-G-4 process, was completely comfortable here.
The reactions rolled, and the yields were most satisfactory.
Secondly, this is one of the few phenethylamines that is a racemate.
The strange geometry of the norbornane ring carries within it a chiral
character, so this compound is potentially resolvable into two
optically active forms.  That might be quite a task, but it would have
the value of providing for the first time a pair of isomers that were
asymmetric in the 3,4-aliphatic part of the molecule.  To the extent
that some insight into the geometry of the receptor site can be
gleaned from the absolute configurations of active agonists, here is a
compound where the subtle variations are over there at the ring
substitution area of the structure, rather than at the well-explored
alpha-carbon atom.  Some day I might try to resolve this drug into its
optical isomers.  But I suspect that it might be quite difficult.

A number of chemical variations of 2C-G-5 are obvious.  The
dihydroxybenzonorbornane compound that was the starting point of all
this was certainly the adduct of cyclopentadiene and benzoquinone,
with the double bond reduced.  The same chemistry with
1,3-cyclohexadiene would give a two-carbon bridge instead of the
one-carbon bridge of norbornane and, after hydrogenation, would
provide a non-chiral analog with two ethylene bridges between the 3-
and 4-position carbons.  This is a cyclohexane ring connected, by its
1- and 4-positions, to the two methyl groups of 2C-G.  With six
carbons in this aliphatic mess, the compound is probably best called
2C-G-6.  It should be easily made, and it is certain to be very
potent.  And there are potentially several other Diels Alder dienes
that might serve with benzoquinone as the dieneophile.  There are
aliphatic things such as hexa-2,4-diene and 2,3-dimethylbutadiene.
The textbooks are filled with dozens of diene candidates, and
benzquinone will always provide the two oxygens needed for the
eventual 2,5-dimethoxy groups of the phenethylamine.











#31 2C-G-N; 1,4-DIMETHOXYNAPHTHYL-2-ETHYLAMINE

SYNTHESIS: A solution of 17.5 g 1,4-naphthaquinone in 200 mL MeOH was
heated to the boiling point, and treated with 28.5 g stannous chloride
at a rate that maintained a continuous rolling boil.  At the
completion of the addition, the reaction mixture was saturated with
anhydrous hydrogen chloride, and held at reflux on the steam bath for
2 h.  The reaction mixture was poured into 700 mL H2O and treated with
aqueous NaOH.  During the addition there was transient development of
a curdy white solid which redissolved when the system became strongly
basic.  This was extracted with 3x200 mL CH2Cl2 and the pooled
extracts were washed first with H2O, then with dilute HCl, and finally
again with H2O.  Removal of the solvent under vacuum yielded 15.75 g
of a low melting black flaky crystalline material which was distilled
at 160-180 !C at 0.05 mm/Hg to give 14.5 g of an amber, solid mass
with a mp of 78-86 !C.  Recrystallization from 75 mL boiling MeOH
provided 1,4-dimethoxynaphthalene as white crystals melting at 87-88
!C.

A mixture of 20.0 g POCl3 and 22.5 g N-methylformanilide was allowed
to stand at room temperature for 0.5 h which produced a deep claret
color.  To this there was added 9.4 g 1,4-dimethoxynaphthalene and the
mixture was heated on the steam bath.  The reaction mixture quickly
became progressively darker and thicker.  After 20 min it was poured
into 250 mL H2O and stirred for several h.  The solids were removed by
filtration, and washed well with H2O.  The wet crude product (a dull
yellow-orange color) was dissolved in 125 mL boiling EtOH to give a
deep red solution.  On cooling, this deposited a heavy crop of
crystals that was removed by filtration, and washed with cold EtOH.
There was obtained, after air-drying to constant weight, 7.9 g
1,4-dimethoxy-2-naphthaldehyde as white crystals with a mp of 119-121
!C.  This was not improved by further recrystallization.  The
malononitrile derivative, from the aldehyde and malononitrile in EtOH
with a drop of triethylamine, had a mp of 187-188 !C.

A solution of 3.9 g 1,4-dimethoxy-2-naphthaldehyde in 13.5 g
nitromethane was treated with 0.7 g anhydrous ammonium acetate, and
heated on the steam bath for 1 h.  The excess reagent/solvent was
removed under vacuum giving a residue that spontaneously crystallized.
This crude product was removed with the aid of a few mL MeOH, and
pressed on a sintered funnel with modest MeOH washing.  There was
obtained 3.6 g (when dry) of old-gold colored crystals with a mp of
146-148 !C.  Recrystallization from 140 mL boiling EtOH gave 3.0 g
1,4-dimethoxy-2-(2-nitro-vinyl)naphthalene as deep gold-colored
crystals with a mp of 146-147 !C.  A small sample, upon
recrystalization from MeOH, melted at 143-144 !C.  Anal. (C14H13NO4)
C,H.

A solution of LAH (50 mL of a 1 M solution in THF) was cooled, under
He, to 0 !C with an external ice bath.  With good stirring there was
added 1.32 mL 100% H2SO4 dropwise, to minimize charring.  This was
followed by the addition of 2.80 g
1,4-dimethoxy-2-(2-nitrovinyl)naphthalene in 40 mL anhydrous THF.
There was an immediate loss of color.  After 1 h stirring at 0 !C, the
temperature was brought up to a gentle reflux on the steam bath for 20
min, then all was cooled again to 0 !C.  The excess hydride was
destroyed by the cautious addition of 7 mL IPA followed by 5.5 mL 5%
NaOH.  The reaction mixture was filtered, and the filter cake washed
with several portions of THF.  The combined filtrate and washings were
stripped of solvent under vacuum providing 3.6 g of a pale amber oil
that was distilled at 145-160 !C at 0.2 mm/Hg to give 1.25 g of
product as an absolutely white oil.  This was dissolved in 7 mL IPA,
and neutralized with concentrated HCl forming immediate crystals of
the hydrochloride salt in the alcohol solvent.  Thirty mL of anhydrous
Et2O was added, and after complete grinding and mixing, the
hydrochloride salt was removed by filtration, Et2O washed, and air
dried to constant weight.  The spectacular white crystals of
1,4-dimethoxynaphthyl-2-ethylamine hydrochloride (2C-G-N) weighed 1.23
g and had melting properties of darkening at 190 !C, and decomposing
in the 235-245 !C area.  Anal. (C14H18ClNO2) C,H.

DOSAGE: 20 - 40 mg.

DURATION: 20 - 30 h.

QUALITATIVE COMMENTS: (with 24 mg) The effects were interestingly
colored by the reading of Alan WattsU Joyous Cosmology during the
coming-on period.  The only body negatives were some urinary retention
and a feeling of a shallow but continuing amphetamine stimulation.
But not enough to be actually jingly, nor to interfere with sleep that
evening.  There is not much psychedelic here, but there is something
really going on anyway.  This has some similarities to the
antidepressant world.

(with 35 mg) Much writing, much talking, and there was considerable
residual awareness the next day.  Somehow this material is not as
friendly as the other 2C-GUs.

(with 35 mg) Thinking is clear.  No fuzziness, no feeling of being
pushed.  None of the walking on the fine middle line between light and
dark that is the excitement and the threat of LSD.  This is just a
friend, an ally, which invites you to do anything you wish to.
[comment added two days later] RMy sleep was not deep enough, but it
was pleasant and relatively resting.  The whole next day I was feeling
happy, but with an overlay of irritability.  Strange mixture.  By
bedtime the irritability had become a mild depression.  I feel that
there might have been a threshold continuing for a couple of days.
The character of my dreaming had the stamp of drug on it.  This
compound, in retrospect, presents some problems that cause a faint
unease.

EXTENSIONS AND COMMENTARY: There is always a wish in the design of new
compounds to find something that is of interesting activity, with an
aromatic ring at some location pretty much away from the site of
activity.  This would then allow some subtle fine-tuning of the nature
of the action by putting any of a wide range of electron pushing or
electron pulling groups on that ring.  But here, with 2C-G-N, by the
time the ring got put into place, the activity was already on the
wane, and the action was too long, and there are indicators of some
not completely friendly effects.  Ah well, some other molecule, some
other time.









#32 2C-H; 2,5-DIMETHOXYPHENETHYLAMINE

SYNTHESIS: A solution of 50 g 2,5-dimethoxybenzaldehyde in 100 g
nitromethane was treated with 5 g of anhydrous ammonium acetate, and
heated on the steam bath for 4 h.  The solution was decanted from a
little insoluble material, and the solvent removed under vacuum.  The
clear oily residue was dissolved in 100 mL boiling IPA which, after
standing a moment, set up as dense crystals.  After returning to room
temperature, these were removed by filtration, the product was washed
with IPA and air dried, yielding 56.9 g 2,5-dimethoxy-'-nitrostyrene
as spectacular yum-yum orange crystals with a mp of 119-120 !C.  An
analytical sample, from ethyl acetate, melted at 120-121 !C.

A suspension of 60 g LAH in 500 mL anhydrous THF was placed under an
inert atmosphere, stirred magnetically, and brought up to reflux
temperature.  There was added, dropwise, 56 g of
2,5-dimethoxy-'-nitrostyrene dissolved in THF, and the reaction
mixture was maintained at reflux for 36 h.  After being brought to
room tem-perature, the excess hydride was destroyed with 40 mL IPA,
followed by 50 mL of 15% NaOH.  An additional 100 mL THF was required
for easy stirring, and an additional 150 mL H2O was needed for
complete conversion of the aluminum salts to a loose, white,
filterable consistency.  This solid was removed by filtration, and the
filter cake washed with additional THF.  The combined filtrate and
washes were stripped of solvent under vacuum, and the residue
dissolved in dilute H2SO4.  Washing with 3x75 mL CH2Cl2 removed most
of the color, and the aqueous phase was made basic with aqueous NaOH
and reextracted with 3x100 mL CH2Cl2.  Removal of the solvent yielded
39.2 g of a pale amber oil that was distilled.  The fraction boiling
at 80-100 !C at 0.4 mm/Hg weighed 24.8 g and was water-white product
amine.  As the free base, it was suitable for most of the further
synthetic steps that might be wanted, but in this form it picked up
carbon dioxide rapidly when exposed to the air.  It was readily
converted to the hydrochloride salt by dissolution in 6 volumes of
IPA, neutralization with concentrated HCl, and addition of sufficient
anhydrous Et2O to produce a permanent turbidity.  Crystals of
2,5-dimethoxyphenethylamine hydrochloride (2C-H) spontaneously formed
and were removed by filtration, washed with Et2O, and air dried.  The
mp was 138-139 !C.

DOSAGE: unknown.

DURATION: unknown.

EXTENSIONS AND COMMENTARY: I know of no record of 2C-H ever having
been tried by man.  It has been assumed by everyone (and probably
correctly so) that this amine, being an excellent substrate for the
amino oxidase systems in man, will be completely destroyed by the body
as soon as it gets into it, and thus be without action.  In virtually
all animal assays where it has been compared with known psychoactive
drugs, it remains at the Rless-activeS end of the ranking.

It is, however, one of the most magnificent launching pads for a
number of rather unusual and, in a couple of cases, extraordinary
drugs.  In the lingo of the chemist, it is amenable to Relectrophilic
attack at the 4-position.S And, in the lingo of the
psychopharmacologist, the R4-position is where the action is.S From
this (presumably) inactive thing have evolved end products such as
2C-B, 2C-I, 2C-C, and 2C-N.  And in the future, many possible things
as might come from a carbinol group, an amine function, or anything
that can stem from a lithium atom.









#33 2C-I; 2,5-DIMETHOXY-4-IODOPHENETHYLAMINE

SYNTHESIS: A mixture of 7.4 g phthalic anhydride and 9.05 g of
2,5-dimethoxyphenethylamine (see the recipe for 2C-H for its
preparation) was heated with an open flame.  A single clear phase was
formed with the loss of H2O.  After the hot melt remained quiet for a
few moments, it was poured out into a crystallizing dish yielding 14.8
g of a crude solid product.  This was recrystallized from 20 mL CH3CN,
with care taken for an endothermic dissolution, and an exothermic
crystallization.  Both transitions must be done without haste.  After
filtration, the solids were washed with 2x20 mL hexane and air dried
to constant weight.  A yield of 12.93 g of
N-(2-(2,5-dimethoxyphenyl)ethyl)phthalimide was obtained as
electrostatic yellow crystals, with a mp of 109-111 !C.  A sample
recrystallized from IPA was white, with a mp of 110-111 !C.  Anal.
(C18H17NO4) C,H,N.

To a solution of 12.9 g N-(2-(2,5-dimethoxyphenyl)ethyl)phthalimide in
130 mL warm (35 !C) acetic acid which was being vigorously stirred,
there was added a solution of 10 g iodine monochloride in 40 mL acetic
acid.  This was stirred for 1 h, while being held at about 30 !C.  The
reaction mixture was poured into 1500 mL H2O and extracted with 4x75
mL CH2Cl2.  The extracts were pooled, washed once with 150 mL H2O
containing 2.0 g sodium dithionite, and the solvent removed under
vacuum to give 16.2 g of
N-(2-(2,5-dimethoxy-4-iodophenyl)ethyl)phthalimide as yellow amber
solids with a mp of 133-141 !C.  This mp was improved by
recrystallization from 75 mL CH3CN, yielding 12.2 g of a pale yellow
solid with mp 149-151 !C.  A small sample from a large quantity of IPA
gives a white product melting at 155.5-157 !C.

A solution of 12.2 g
N-(2-(2,5-dimethoxy-4-iodophenyl)ethyl)phthalimide in 150 mL hot IPA
was treated with 6.0 mL of hydrazine hydrate, and the clear solution
was heated on the steam bath.  After a few minutes there was the
generation of a white cottage cheese-like solid
(1,4-dihydroxyphthalizine).  The heating was continued for several
additional h, the reaction mixture cooled, and the solids removed by
filtration.  These were washed with 2x10 mL EtOH, and the pooled
filtrate and washes stripped of solvent under vacuum giving a residue
which, when treated with aqueous hydrochloric acid, gave 3.43 g of
voluminous white crystals.  This, after recrystallization from 2
weights of H2O, filtering, washing first with IPA and then with Et2O,
and air drying, gave 2.16 g 2,5-dimethoxy-4-iodophenethylamine
hydrochloride (2C-I) as a white microcrystalline solid, with a mp of
246-247 !C.  Anal. (C10H15ClINO2) C,H,N.

DOSAGE: 14 - 22 mg.

DURATION: 6 - 10 h.

QUALITATIVE COMMENTS (with 0 mg) I was present at a group meeting,
but was only an observer.  With zero milligrams of 2C-I, I was able to
get to a delightful plus 2.5 in about five minutes after I arrived at
your place, and absorbed the ambience of the folks who had actually
imbibed the material.  My level lasted about four hours and came down
at about the same time as did the others.  There were no after-effects
experienced except for a pleasant languor.

(with 15 mg) Comfortable onset.  Most notable are the visuals,
patterning like 2C-B (Persian carpet type), very colorful and active.
Much more balanced emotional character, but still no feeling of
insight, revelation, or progress toward the true meaning of the
universe.  And at 5 1/2 hours drop-off very abrupt, then gentle
decline.  I would like to investigate museum levels.

(with 16 mg) There was an immediate alert within minutes.  As usual,
it was only an awareness, then nothing happened for a while.  In
retrospect, I see some type of activity or awareness within 40
minutes, which then builds up over time.  The peak was at 2 hours and
seemed to maintain itself for a while.  Near the peak, there was some
hallucinogenic activity, though not a lot.  The pictures in the dining
room had color and pattern movement that was fairly detailed.
Focusing on other areas, such as walls or the outside of the house,
produced little activity, though I tried.  There was certainly a lot
of color enhancement.  There was also that peculiar aspect of the
visual field having darkened or shadowed areas.  These darker areas
seemed to shift around to some degree.  That aspect seems to be
similar to 2C-B.  I donUt think I was more than +2.5 at the peak.
Coming down was uneventful.  I was down within 6 hours.  I had no
problems driving home, nor were there any difficulties with sleep.
There were no body problems with this material.  I ate like a horse.

(with 16 mg) The 16 was a bit much, I realized, because my body was
not sure of what to do with all the energy.  Next time IUll try 14 or
15.  However, my conversations were extremely clear and insightful.
The degree of honesty was incredible.  I was not afraid to say
anything to anyone.  Felt really good about myself.  Very centered, in
fact.  A bit tired at day's end.  Early bedtime.

(with 20 mg) I think there is slightly less than full immersion in
the sensual, with this material, compared with 2C-B, but I suspect
it's more a matter of getting used to the language of 2C-I and the
feelings Q getting tuned to a slightly different frequency, really Q
rather than that the material is less sensual or less easy to use
sensually.  Just different frequency, and we are very, very used to
2C-B.  Good on the body.  Transition, for me, not as strongly dark as
2C-B.  But it could certainly take a lot more exploring, if we were
able to give the time (about 9 hours) to it.  Next day: sleep
excellent.  Energy next day unusually good.  Quite tired by evening.

EXTENSIONS AND COMMENTARY: The frequent comparisons between 2C-I and
2C-B stem, without doubt, from a bit of chemical suggestion.  The two
compounds have structures that are truly analogous, in technical
terms.  In one, there is a strategically located iodine atom, and in
the other, an identically placed bromine atom.  These are directly
above and below one-another in the periodic table.  And what is
particularly maddening to the synthetic diddler, is that they cannot
be lengthened, or shortened, or squooshed around in any way.  You
canUt make a longer and narrower version of a bromine atom, as you can
do with, say, a butyl group.  YouUve got what youUve got, like it or
not.  No subtle variations.

But, on the brighter side of the picture, you have a heavy atom here,
and this atom is intrinsic to the central activity of the compound.
So, these materials are naturals for radio-labelling experiments.
2C-I has been made radioactive with radio-iodine, but the most
impressive findings have been made with the 3-carbon analog, DOI.

One quotation from an observer of a group experiment is enclosed; an
experiment with zero milligrams being taken.  This is a instructive
observation of what has been called a Rcontact high.

There is one Iodotweetio known.  In Scrabble, would you challenge a
word that had seven of its eleven letters as vowels?  Especially if
the vowels were, specifically, iooeeio?  It sounds just a little like
the noise coming out of Old McDonald's farm.  But a Tweetio there is,
namely, the 2-EtO-homologue of 2C-I.  This is
2-ethoxy-4-iodo-5-methoxyphenethylamine, or 2CI-2ETO.  The
hydrochloride salt was a white, crystalline product with a melting
point of 175-175.5 !C.  The threshold level of activity was seen at an
oral dose of 5 milligrams, and the generated effects were completely
dispersed in a couple of hours.  Most interestingly, larger doses, of
up to 50 milligrams orally, seem to produce no more intense an effect,
but simply to stretch out this threshold for an additional couple of
hours.  At no level that has been tried, has 2CI-2EtO produced even a
plus-two response.

Where else can one go, from 2C-I?  The iodine is the fourth, and the
last of the so-called halogens, at the bottom of the classical
periodic table.  But, thanks to the miracles that have accompanied us
into the nuclear age, there is a fifth halide now known, Astatine.
All of its isotopes are radioactive, however, and it seems unlikely
that there will ever be an entry (other than this one) for
2,5-dimethoxy-4-astatophenethylamine.  What might be speculated as to
its activity?  Probably similar in potency to 2C-I, requiring maybe 10
or 20 milligrams.  The duration would be dicey to measure, since the
isotope with the longest known half-life is half decayed in about 8
hours, and the longest lived natural isotope (for those who insist on
natural rather than man-made things) is half decayed in less than a
minute.  Two predictions would be pretty solid.  You might have quite
a job accumulating your 10 milligrams of Astatine, as the most that
has so far been made at one time is only about 0.05 micrograms,
approximately a millionth of the amount needed.  And the second
prediction?  You would not survive the screaming radiation that would
bombard you if you could get the needed 5 or 10 milligrams of
radio-astatine onto that magic 4-position, and the resulting 2C-A into
your tummy!









#34 2C-N; 2,5-DIMETHOXY-4-NITROPHENETHYLAMINE

SYNTHESIS: A cooled, stirred solution of 1.0 g
2,5-dimethoxyphenethylamine (see the recipe for 2C-H for its
preparation) in 20 mL glacial acetic acid was treated with 3.3 mL 70%
HNO3 in small portions, with the reaction temperature kept down with
periodic cooling.  After the addition was completed, the stirring was
continued until there was the spontaneous separation of a yellow
solid.  This was 2,5-dimethoxy-4-nitrophenethylamine nitrate (2C-N)
which was obtained after removal by filtration, washing with Et2O and
air drying, as a fluffy yellow solid.  This weighed 1.04 g and melted,
with decomposition, in the area of 170-180 !C, depending on the rate
of heating.  A solution of 0.8 g of this nitrate salt in 50 mL H2O was
made basic with aqueous NaOH.  Extraction with 3x50 mL CH2Cl2, and
removal of the solvent under vacuum gave the free base as a residue.
This was distilled at 130-150 !C at 0.35 mm/Hg to give an orange-red
oil that weighed 0.5 g and set up as crystals.  This was dissolved in
3 mL IPA, neutralized with 7 drops of concentrated HCl (the color
lightened considerably at the titration end point) and diluted with 5
mL anhydrous Et2O.  There was the formation of the hydrochloride salt
which was a pumpkin-colored crystalline mass.  After removal by
filtration, Et2O washing and air drying, these crystals weighed 0.44
g.  The mp, 193-195 !C, was not improved by recrystallization from any
of several solvents (MeOH, IPA, CH3CN).  The perchlorate salt was a
yellow solid from MeOH, with a mp of 211 !C, with decomposition.
Nitration of 2C-H in a mixture of acetic acid and acetic anhydride
produced the acetamide derivative of 2C-N as yellow crystals with a mp
142.5-143 !C.  For the nitrate salt: Anal. (C10H15N3O7) C,H.  This was
the form used for all human titrations.

DOSAGE: 100 - 150 mg.

DURATION: 4 - 6 h.

QUALITATIVE COMMENTS: (with 120 mg) This came on very fast Q I was
aware of it within a half hour, and it got as far as it would go by an
hour.  There are similarities to MDMA, but missing is the benign
anti-stress component.  I am light-headed, and there just might be a
little eye wiggling.  And then it dropped right off to nothing within
a couple of hours.

(with 150 mg) There may have been some visual changes, IUm not sure.
But the talking was extremely easy.  If there were no other things to
use, this would be excellent, but there are other compounds available.
This doesnUt have too high a priority.

(with 150 mg) Am I enjoying it?  Not exactly, but I am in a good
mood.  There is not the light-filled energy that some other materials
can provide.  By six hours, pretty much baseline.  Strange material,
but okay.  Final score: body +3, mind +2, barely.

EXTENSIONS AND COMMENTARY: A most consistent feature with 2C-N was the
fact that in every report, somewhere, there is the note that it
somehow came up just a little short of expectations.  From the
esthetic point of view, the pure salt is yellow rather than the usual
white color, so the solutions that are to be consumed are by
definition also yellow colored.  From the structural point of view,
the 4-nitro group, like the 4-bromo group of 2C-B, is a dead-end.  It
cannot be stretched or compressed or lengthened or shortened.  This
unique aspect demands that you have to live with what you have, as
there are no subtle ways of modifying the molecule.  With 2C-B, the
end product was a total winner; there was no wish to modify it.  With
2C-N the end product is something a little less, and there is no way
to modify it.









#35 2C-O-4; 2,5-DIMETHOXY-4-(i)-PROPOXYPHENETHYLAMINE

SYNTHESIS: To a solution of 3.10 g 85% KOH pellets in 30 mL warm MeOH
there was added 6.16 g 2,5-dimethoxyphenol (there was immediate
darkening) followed by 8.5 g isopropyl iodide.  The reaction mixture
was heated on the steam bath for 3.5 h.  White crystals of KI appeared
at the end of the first h.  The mixture was poured into 800 mL H2O (it
was still basic) and acidified with HCl.  This was extracted with
3x100 mL CH2Cl2, and the combined extracts washed with 2x100 mL 5%
NaOH.  The organic phase was stripped of solvent under vacuum, and the
residual dark amber oil (6.4 g) distilled at 110-130 !C at 0.7 mm/Hg.
There was obtained 5.7 g of 1,4-dimethoxy-2-(i)-propoxybenzene as a
white oil.

A mixture of 10 g N-methylformanilide and 10 g POCl3 was heated on the
steam bath for 10 min producing a deep claret color.  To this there
was added 5.1 g of 1,4-dimethoxy-2-(i)-propoxybenzene, and the
immediately exothermic reaction mixture was heated on the steam bath
for 45 min.  It was then poured into 800 mL H2O which was stirred
until the dark oil changed into loose, light-colored solids.  These
were removed by filtration giving 5.7 g of an amber crystalline
product with a mp of 76-78 !C.  This was dissolved in an equal weight
of MeOH, and heated to a solution which was clear at the boiling
point.  This was brought to 0 !C and held there for several hours,
yielding 2,5-dimethoxy-4-(i)-propoxybenzaldehyde as a fine, off-white
crystalline product which, after filtering and air drying, weighed
4.03 g.  The mp was 79-80 !C with prior shrinking at 71 !C.  Anal.
(C12H16O4) C,H.

A solution of 3.9 g 2,5-dimethoxy-4-(i)-propoxybenzaldehyde in 20 g
nitromethane was treated with 0.17 g anhydrous ammonium acetate and
heated on the steam bath for 1.25 h.  The progress of the condensation
was readily followed by a TLC analysis of the reaction mixture.  With
silica gel plates, the starting aldehyde and the product nitrostyrene
had Rf's of 0.16 and 0.50 resp., using CH2Cl2 as a developing solvent.
The excess solvent was removed under vacuum to give a red residue that
was dissolved in 10 mL boiling MeOH.  The solution spontaneously
crystallized giving, after filteration and air drying, 4.1 g of orange
crystals of 2,5-dimethoxy-'-nitro-4-(i)-propoxystyrene.

A solution of LAH (60 mL of a 1 M solution in THF) was cooled, under
He, to 0 !C with an external ice bath.  With good stirring there was
added 1.60 mL 100% H2SO4 dropwise, to minimize charring.  This was
followed by the addition of 4.0 g
2,5-dimethoxy-'-nitro-4-(i)-propoxystyrene as a solid, perhaps 200 mg
at a time.  There was an immediate loss of color after each addition.
The final pale salmon-colored solution was stirred for 2 h as it
returned to room temperature.  The excess hydride was destroyed by the
cautious addition of 8 mL IPA, which was followed by 5 mL 15% NaOH
followed, in turn, by sufficient additional THF to make the suspension
of inorganic salts loose and filterable.  The reaction mixture was
filtered, and the filter cake washed with additional THF.  The
filtrate and washings were combined and stripped of solvent under
vacuum providing 4.6 g of a pale amber oil.  This was dissolved in
dilute H2SO4, washed with 2x50 mL CH2Cl2, made basic with aqueous
NaOH, and extracted with 3x50 mL CH2Cl2.  Removal of the solvent under
vacuum yielded 2.3 g of residue which was distilled at 115-125 !C at
0.3 mm/Hg to give 0.94 g of a clear white oil.  This was dissolved in
5 mL IPA, neutralized with 12 drops of concentrated HCl, and diluted
with 10 mL anhydrous Et2O.  White crystals of
2,5-dimethoxy-4-(i)-propoxyphenethylamine hydrochloride (2C-O-4)
separated, and were removed by filtration, Et2O washed, and air dried.
The final weight was 0.58 g.

DOSAGE: greater than 60 mg.

DURATION: unknown

QUALITATIVE COMMENTS: (with 60 mg) I became aware of something in the
front part of my head, and there was a lot of yawning.  The body was
aware of the experiment.  But also there was a general exhilaration
and excitement, which lasted for a few hours.  At best, I am at a plus
one.

EXTENSIONS AND COMMENTARY: The full activity of 2C-O-4 is yet to be
discovered.  It represents an interesting hybrid lying in between
several fascinating compounds.

First and foremost, all these carry the 2,4,5-trisubstitution which
has consistently proven to be the most interesting and the most active
of the phenethylamines.  And with very few exceptions, the 2- and the
5- are methoxyl groups.

The sulfur analogues in this area, compounds with an alkylthio group
at the 4-position of the 2,5-dimethoxyphenethylamine backbone, are the
2C-T things.  The replacement of a sulfur with an oxygen, quite
rightly, should give rise to the 2C-O counterparts.  And they have
been given the same numbering system that was bestowed upon the RTS
series.  2C-T-4 was the 4-isopropylthio compound and one of the most
interesting of this family.  And so, quite reasonably, the oxygen
coun-terpart should be the 2C-O-4 analogue, and should be one of the
first explored.

The extension of the 4-alkoxy-group led to the discovery of the TMA-2
Q MEM Q MIPM Q MPM Q MBM series of amphetamine analogues.  The
2-carbon counterparts of these would be a fascinating series to
explore, I thought, if there was some encouragement to be had from a
preliminary try in this field.

This was a first shot in the dark, the actual trial example, and it
certainly didnUt provide much encouragement.  The three-carbon
analogue, MIPM, was made (q.v.) but not explored, following the
disappointing trials of MPM.  If this area is ever re-opened, the
numbering should reasonably follow the sulfur materials.  The 4-ethoxy
material would be 2C-O-2, the 4-(n)-propoxy compound 2C-O-7, and the
4-(n)-butoxy compound 2C-O-19.  These are the exact analogues of
2C-T-2, 2C-T-7, and 2C-T-19, resp., and the 2-carbon homologues of
MEM, MPM, and MBM.  The simplest member of this series, the methyl
counterpart, is 2C-O, and it is the obvious analogue of 2C-T.  This is
also called 2,4,5-TMPEA, and its story is presented elsewhere.

But, with the probable low eventual potency of 2C-O-4, I feel that the
2C-O series will not be an exciting one.









#36 2C-P; 2,5-DIMETHOXY-4-(n)-PROPYLPHENETHYLAMINE

SYNTHESIS: To a stirred solution of 138 g p-dimethoxybenzene in 400 mL
CH2Cl2 there was added a suspension of 172 g anhydrous AlCl3 in 500 mL
CH2Cl2 which contained 92.5 g propionyl chloride.  After stirring for
1.5 h the reaction mixture was poured into 2 L H2O containing ice.
The phases were separated, and the aqueous fraction was extracted with
2x100 mL CH2Cl2.  The organic phase and the extracts were pooled,
washed once with H2O, and then with 2x100 mL 5% NaOH.  The solvent
from the organic phase was removed under vacuum, yielding a deeply
colored residue.  This was distilled at 150-165 !C at 20 mm/Hg
yielding 170 g of 2,5-dimethoxypropiophenone as a pale amber-colored
oil.  Acidification of the sodium hydroxide extract, extraction with
CH2Cl2, and evaporation of the solvent, yielded 3 g of an oil that
slowly crystallized.  These solids, on recrystallization from MeOH,
provided 1.0 g of 2-hydroxy-5-methoxypropiophenone with a mp of 47-48
!C.  The same Friedel Crafts reaction, conducted on the same scale in
CS2 rather than in CH2Cl2, required reduced temperature (5 !C) and a
24 h reaction period.  This solvent variation, with the same workup
and isolation, gave 76 g of 2,5-dimethoxypropiophenone as a pale amber
oil boiling at 130-137 !C at 4 mm/Hg.

A total of 150 g mossy zinc was amalgamated by treatment with a
solution of 15 g mercuric chloride in 1 L H2O.  After swirling for 0.5
h, the H2O phase was removed by decantation and the zinc added to a 1
L three neck flask.  To this there was added 20 mL H2O and 20 mL
concentrated HCl, followed by 20 g of 2,5-di-methoxypropiophenone
dissolved in 50 mL EtOH.  This mixture was held at reflux with a
heating mantle overnight, with the occasional addition of HCl as
needed to maintain acidic conditions.  After cooling to room
temperature, the residual solids were removed by filtration, and the
filtrate extracted once with 100 mL CH2Cl2 (this was the upper phase).
Sufficient H2O was then added to allow extraction with 2x100 mL
additional CH2Cl2 with the organic solvent being the lower phase.  The
combined organic extracts were washed twice with 5% NaOH, followed by
one washing with dilute acid.  Removal of the solvent under vacuum
yielded 18 g of a dark brown oil that was distilled at the water pump
to yield 7.2 g of 2,5-dimethoxypropylbenzene as a light yellow oil
boiling at 90-130 !C.

A mixture of 22 g 2,5-dimethoxypropylbenzene, 23 g POCl3 and 22 g
N-methylformanilide was heated on the steam bath for 1.5 h.  The hot,
dark reaction mass was poured into 1 L H2O, which allowed the eventual
separation of 2,5-dimethoxy-4-(n)-propylbenzaldehyde as a clear yellow
oil weighting 14 g.  Although the homologous 4-ethyl and 4-butyl
benzaldehydes were clean crystalline solids, this propyl homologue
remained an oil.  Gas chromatographic analysis showed it to be about
90% pure, and it was used as obtained in the nitrostyrene steps with
either nitromethane (here) or nitroethane (under DOPR).

To a solution of 13 g 2,5-dimethoxy-4-(n)-propylbenzaldehyde in 100 mL
nitromethane, there was added 1.3 g anhydrous ammonium acetate and the
mixture held at reflux for 1 h.  Removal of the solvent/reactant under
vacuum yielded a spontaneously crystallizing mass of orange solids
that was removed with the help of a little MeOH.  After filtering and
air drying there was obtained 7.5 g
2,5-dimethoxy-'-nitro-4-(n)-propylstyrene with a mp of 118-122 !C.
Recrystallization from CH3CN gave an analytical sample with a mp
123-124 !C.  Anal. (C13H17NO4) N.

In a 1 L round bottomed flask with a magnetic stirrer under a He
atmosphere there was added 120 mL 1 M LAH in tetrahydrofuran.  This
stirred solution was cooled with an external ice bath, and there was
added, dropwise, 3.2 mL of 100% H2SO4, freshly made by the addition of
13.5 g 20% fuming H2SO4 to 15.0 g of ordinary 96% concentrated H2SO4.
When the addition was complete, a total of 7.2 g of dry
2,5-dimethoxy-'-nitro-4-(n)-propylstyrene was introduced as solids in
several batches, against a flow of He, over the course of 20 min.  The
reaction mixture was allowed to come to room temperature, and stirred
for an additional 0.5 h, then brought to reflux for 10 min on the
steam bath.  The excess hydride was destroyed with 18 mL IPA, and then
sufficient 15% NaOH was added which made the aluminum oxides
distinctly basic and of a filterable texture.  The inorganics were
removed by filtration, and the filter cake washed with additional THF.
The combined filrate and washes were stripped of solvent, yielding
several g of a pale yellow oil that was suspended in a large quantity
of dilute H2SO4.  The aqueous phase was filtered free of insolubles,
washed with a little CH2Cl2, and made basic with aqueous NaOH.  This
was extracted with 3x40 mL CH2Cl2 and, after the removal of the
solvent under vacuum, the residual 2 g of off-white oil was distilled.
A fraction that distilled at 100-110 !C at 0.3 mm/Hg was water white,
weighed 1.59 g and spontaneously crystallized.  This fraction was
dissolved in 7.5 mL warm IPA and neutralized with 0.6 mL concentrated
HCl.  The spontaneous crystals of
2,5-di-methoxy-4-(n)-propylphenethylamine hydrochloride (2C-P) were
suspended in 20 mL anhydrous Et2O, filtered, Et2O washed, and air
dried.  The weight was 1.65 g and the mp was 207-209 !C with prior
sintering at 183 !C., Anal. (C13H22ClNO2) N.

DOSAGE: 6 - 10 mg.

DURATION: 10 - 16 h.

QUALITATIVE COMMENTS: (with 6 mg) I was not feeling so good.
Hangover, I guess.  The material was so gentle in coming on, and soon
my body became jangled.  Thinking was easy.  Verbalizing was easy.
Being comfortable with my body was not.  My back hurt and then my legs
hurt.  My lower back was in spasm.  At first I did not particularly
like what this drug was doing to my body, but took a good look at it
and decided that I was the culprit.  Took a good look at my drinking
so much, and decided that I didnUt need it.  So much energy was going
through me I didnUt know what to do with it.  The whole day was spent
in physical discomfort.  Food tasted good, and we nibbled all day.  My
stomach was bloated.  Next day I was more or less like a zombie.  I
was wiped out.

(with 8 mg) Comes on slowly, not feeling intently until into 2nd
hour.  I feel slight discomfort but override it responding to music.
I take in air, directing it inside to heal uncomfortable places, open
up my clogged sinuses.  Wonderful experience of clean, fresh, healing
air.  Find that discomfort zone is places where I think there is
something wrong with me.  I dissolve these places with the feeling IUm
OK.  Like myself better and better, and find more reasons to enjoy and
appreciate myself.  I find this material powerful, and an excellent
working material.  Under other circumstances, would probably spend
more time working alone inside, where there were great openings, and
some of the most beautiful visuals I have seen for a long time.
Usually I do not get visuals.  I like the long action.  I feel that
this material worked for a good week after the experience, with
internal processes taking place, many insights, and energy running.
At times the energy was a little uncom-fortable, but could always be
quelled by taking a moment for deep relaxation or looking directly at
the internal process.  I feel that much good internal work has been
done, a lot of it unconscious.

(with 9 mg) At the one hour point, I am barely off of baseline.  It
is not until almost the third hour that the experience is fully
developed, and once there it is maintained for another four hours.  I
was well grounded but rather diffuse.  I explored writing (which went
quite well), interpretation (pictures and reading both OK) and talking
(very good).  This is an excellent level, and probably near the max.

(with 12 mg) Slow and even rise.  At five minutes to seven (suddenly
the clock time makes no sense at all) I am at a 3+ and feel that I
have not yet plateauUd.  Erotic was excellent.  Music good.
Eyes-closed imagery very different place than usual experiences.
Slow, calm, strong images from an area that has no apparent connection
with usual waking world, yet underlies all of it.  A cool, wise place
which has its own rules.  All emotions and feeling available, but
there is a cool perspective which informs all thinking.  Talking
superb and fun, and it was possible to feel our bodies healthy and
full of determination to remain so, despite obvious faults and
self-indulgences.  Could do a lot of learning with this material, but
probably not a group thing.  It would lend itself too easily to
hypnotic power-games, and it would be too easy to open up the shared
consciousness level, which would be frightening to a lot of people and
bring about necessary escapes such as sickness.  Excellent feeling the
next day.

EXTENSIONS AND COMMENTARY: There is certainly a broad mixture of
experiences with 2C-P but, on the whole, probably more favorable than
not.  There was one report of an experience in which a single dosage
of 16 mg was clearly an overdose, with the entire experiment labeled a
physical disaster, not to be repeated.  A consistent observation is
that there may not be too much latitude in dosage between that which
would be modest, or adequate, and that which would be excessive.  The
need for individual titration would be most important with this
compound.









#37 CPM; CYCLOPROPYLMESCALINE;
4-CYCLOPROPYLMETHOXY-3,5-DIMETHOXYPHENETHYLAMINE

SYNTHESIS: To a solution of 2.8 g homosyringonitrile (see under E for
synthesis) in 20 ml acetone containing about 50 mg
decyltriethylammonium iodide, there was added 3.0 g cyclopropylmethyl
chloride and 5.0 g NaI.  Stirring was continued during a color change
from pale yellow to blue.  There was then added 2.9 g of finely
powdered anhydrous K2CO3, resulting in a beautiful turquoise color.
The mixture was held at reflux on the steam bath for 3 h, which
discharged all color.  The solvent was removed under vacuum, and the
residues were added to 100 mL H2O.  This solution was extracted with
3x75 mL CH2Cl2, the extracts were pooled, washed with 2x50 mL 5% NaOH,
and the organic solvent removed under vacuum.  The residual oil
weighed 4.2 g, and was distilled at 140-155 !C at 0.4 mm/Hg to yield
4-cyclopropylmethoxy-3,5-dimethoxyphenylacetonitrile as a colorless
oil weighing 2.8 g which spontaneously crystallized.  Its mp was
44-44.5 !C after recrystallization from MeOH/H2O. Anal. (C14H17NO3)
C,H.

A suspension of 1.3 g LAH in 65 mL anhydrous THF under He was cooled
to 0 !C with stirring, and 0.85 mL of 100% H2SO4 was slowly added.
Then, with continued stirring, a THF solution of 2.7 g of
4-cyclopropylmethoxy-3,5-dimethoxyphenylacetonitrile in 50 mL THF was
added dropwise.  After the addition was complete, the mixture was
brought to a boil briefly on the steam bath, cooled, and treated with
sufficient IPA to destroy the excess hydride.  Then there was added an
amount of 15% NaOH sufficient to produce a loose filterable solid form
of aluminum oxide.  This was removed by filtration, and the filter
cake washed with THF.  The pooled filtrate and washes were stripped of
solvent, and the residue was dissolved in dilute H2SO4, washed with
2x50 mL CH2Cl2, made basic with aqueous NaOH, and then extracted with
2x50 mL of CH2Cl2.  After removal of the solvent, the residue was
distilled at 128-140 !C at 0.4 mm/Hg to yield 2.5 g of a white oil.
This was dissolved in 10 mL IPA, and treated with 30 drops of
concentrated HCl which was just sufficient to demonstrate acidity as
judged by external dampened pH paper.  The addition of 25 mL anhydrous
Et2O to the stirred solution allowed, in a few minutes, the product
4-cyclopropylmethoxy-3,5-dimethoxyphenethylamine hydrochloride (CPM)
to spontaneously crystallize as a fine white solid.  The yield was 1.8
g, and a second crop of 0.8 g was obtained from the IPA/Et2O mother
liquors.  The mp was 172-173 !C.  Anal. (C14H22ClNO3) C,H.

DOSAGE: 60 - 80 mg.

DURATION: 12 - 18 h.

QUALITATIVE COMMENTS: (with 70 mg) I was surprised at the fast
development of this drug, with the knowledge that it was a
long-laster.  Twenty minutes into it I was aware of some changes, and
by the end of one and a half hours there was a complete plus three.
The most remarkable property is the eyes-closed imagery.  No, not just
imagery but fantasy.  It is not completely benign, but it locks into
music with an extraordinary fit.  I was at one moment keenly aware of
my body touching the rug, the tactile aspects of my surroundings, and
then I would find that my world was simply my personal sphere of
reality that kept engulfing everything about me, all completely
augmented by the music.  Constructed by the music.  I hoped that I
wouldnUt offend anyone else around me with this growing world of mine.
Eyes open, there was not that much of note.  Not much insight.  Not
much in the way of visuals.  By the eighth hour an effort to sleep
showed me how exposed and vunerable I was, and when I closed my eyes I
needed my guards against this fantasy world.  Even at the twelth hour
there was no easy way to relax and sleep.  Use higher dosages with
caution.

(with 70 mg) There is a goodly amount of eyes-closed patterning but I
found external sounds to be irritating.  Voices, and even music,
seemed to be intrusive.  I didnUt want to share my space with anyone.
I was reminded of mescaline, in that I kept losing the awareness of
the drug's role in my experience.  Visual exaggerations are probably
right around the corner.  The residual effects were too much to
ignore, but 100 milligrams of phenobarb at about the twelth hour
allowed me to lie down quietly.

(with 80 mg) A wild day of profound philosophy, with discussions of
the art of molecules, the origins of the universe, and similar weighty
trivia.  Much day-dreaming in erotic areas, but by and large, it went
on a bit too long.  I was tired.

EXTENSIONS AND COMMENTARY: In the literary world, the guy who is on
your side, your leader, your champion, is the protagonist and the guy
he battles, your enemy, is the antagonist.  These same roles are
played in the world of pharmacology, but the names are slightly
changed.  A drug which does the needed or expected thing is called the
agonist rather than protagonist, but the drug that gets in its way is
still called the antagonist.

The cyclopropylmethyl group plays an interesting role in the world of
narcotics.  There are numerous examples of opiates with a methyl group
attached to a nitrogen atom which are famous for being valuable in
producing analgesia and sedation.  These run the gamut from natural
alkaloids such as morphine and codeine, to synthetic variants such as
Dilaudid and Percodan.  And yet, with most of these narcotics, when
the methyl on the nitrogen is removed, and a cyclopropylmethyl group
put into its place, the agonist becomes an antagonist.  Oxycodone (the
active narcotic thing in Percodan) becomes Naltrexone, a drug that
will immediately snap a heroin victim out of his overdose.

Cyclopropylmescaline (CPM) is a molecule that is very simply mescaline
itself, with a methyl group removed from an oxygen atom and a
cyclopropylmethyl group put on instead.  Might CPM be not only
inactive, but actually block the action of mescaline?  Interesting
concept.  But it turned out to be entirely wrong.

The amphetamine analog of CPM should be easily made from the
alkyl-ation of syringaldehyde with cyclopropyl chloride, followed by
conventional reaction of the resulting aldehyde with nitroethane, and
finally a reduction step.  There is no reason to believe that the
resulting compound 3,5-dimethoxy-4-cyclo-propyloxyamphetamine (3C-CPM)
would be any shorter acting than CPM.







#38 2C-SE; 2,5-DIMETHOXY-4-METHYLSELENEOPHENETHYLAMINE

SYNTHESIS: A suspension of 5.65 g 1,4-dimethoxybenzene in 100 mL
petroleum ether containing 6.5 mL N,N,NU,NU-tetramethylethylenediamine
was magnetically stirred, placed in an inert atmosphere, and cooled to
0 !C with an external ice bath.  There was then added 27 mL of 1.6 M
butyllithium in hexane.  The solids present went into solution, and
after a few min continued stirring, a fine precipitate appeared.  The
reaction was allowed to stir while coming up to room temperature.
There was then added 4.8 g dimethyl diselenide which led to an
exothermic reaction, bringing the petroleum ether up to a reflux and
showing a color change from white to yellow, to light green, to an
eventual brown, all over the course of 30 min.  After 2 h additional
stirring, the reaction was quenched by pouring into dilute NaOH.  The
organic phase was separated, and the aqueous phase extracted with 2x75
mL Et2O.  The pooled organics were washed first with dilute NaOH, then
with dilute HCl, and then the solvent was removed under vacuum.
Distillation of the residue at 0.4 mm/Hg gave an early fraction
(75-100 !C) that solidified in the receiver and was largely unreacted
dimethoxybenzene.  A pale yellow oil distilled from 100 to 120 !C
which proved to be largely 2,5-dimethoxyphenyl methyl selenide.
Microanalysis gave C = 49.86, 49.69; H = 5.32, 5.47.  As C9H12SeO2
requires C = 46.76, H = 5.23, there is approximately 13%
dimethoxybenzene present (C8H10O2 requires C = 69.54, H = 7.29).  This
mixture was used as such, without further purification.

A mixture of 1.25 g POCl3 and 1.1 g N-methylformanilide was warmed on
the steam bath for several min until the color had become a deep
claret.  There was then added 1.5 g of the 87% pure
2,5-dimethoxyphenyl methyl selenide and the steam bath heating
continued for an additional 25 min.  The very tarry reaction mixture
was poured into 100 mL H2O, producing fine yellow solids almost
immediately.  These were removed by filtration and distilled at 0.2
mm/Hg.  A first fraction distilling up to 100 !C was a mixture of
unreacted ethers and what appeared to be 2,5-dimethoxybenzaldehyde.  A
second cut distilled at 140-150 !C, solidified to a yellow solid in
the receiver, and weighed 1.2 g.  A small amount of this product (with
mp 91-96 !C) was recrystallized from MeOH to give an analytic sample
of 2,5-dimethoxy-4-(methylseleneo)benzaldehyde with a mp 88-92 !C.
All efforts to achieve a tighter melting range were unsuccessful.
Anal. (C10H12O3 Se) C,H.  Although this benzaldehyde migrates normally
on a silica gel TLC plate (Rf of 0.4 employing CH2Cl2 as a solvent)
when it is once completely dried on the plate, there seems to be some
irreversible reaction with the silica, and the spot will no longer
move at all.

To a solution of 0.85 g 2,5-dimethoxy-4-(methylseleneo)benzaldehyde in
10 mL nitromethane there was added 150 mg anhydrous ammonium acetate,
and the solution was heated for 35 min on the steam bath.  Removal of
the volatiles under vacuum yielded brick-red solids (1.1 g) which were
ground under a small amount of MeOH, filtered, and air dried.  This
yielded 0.88 g of solid 2,5-dimethoxy-4-methylseleneo-'-nitrostyrene
with a mp of 170.5-171.5 !C.  Recrystallization from IPA or from
toluene gave no improvement of mp.  Anal. (C11H13NO4Se) C,H.

A solution of LAH (20 mL of a 1 M solution in THF) was cooled, under
He, to 0 !C with an external ice bath.  With good stirring there was
added 0.53 mL 100% H2SO4 dropwise, to minimize charring.  This was
followed by the addition of 0.85 g
2,5-dimethoxy-4-methylseleneo-'-nitrostyrene in 20 mL hot anhydrous
THF.  There was an immediate discoloring.  After a few minutes further
stirring, the temperature was brought up to a gentle reflux on the
steam bath for 0.5 h, then all was cooled again to 0 !C.  The excess
hydride was destroyed by the cautious addition of IPA and, when there
was no further activity, the reaction mixture was poured into 500 mL
dilute H2SO4.  This was washed with 2x100 mL CH2Cl2, and then made
basic with 5% NaOH.  The milky aqueous phase was extracted with 2x100
mL CH2Cl2, and extensive centrifuging was required to obtain a clear
organic phase.  Evaporation of the pooled extracts gave 1.6 g of an
oil that crystallized.  This was distilled at 130-140 !C at 0.15 mm/Hg
providing 0.6 g of a white oil that set to a crystalline solid melting
at 87-89 !C.  This was dissolved in 4 mL boiling IPA, neutralized with
8 drops of concentrated HCl and the formed solids further diluted with
IPA with a little anhydrous Et2O.  This crystalline product was
removed by filtration, washed with Et2O, and air dried to constant
weight, yielding 2,5-dimethoxy-4-methylseleneophenethylamine
hydrochloride (2C-SE) with a mp of 240-241 !C.

DOSAGE: perhaps 100 mg.

DURATION: 6 - 8 h.

QUALITATIVE COMMENTS: (with 50 mg) My tongue feels as if I had eaten
hot food.  Overall I got up to a plus 1, and found the effects to be
completely benign.  I wandered about within the Graves exhibit at the
Oakland Museum but there seemed to be only minor enhancement of the
visual input.

(with 70 mg) The water solution of this material has an unspeakable
smell.  But there is no lasting taste, thank heaven.  This is up to a
1.5 + and probably half again would be an effective dose.  The first
awareness was at 45 minutes, and the plateau lasted from 1.5 hours to
about the fourth hour.  I was at certain baseline at 8 hours.

EXTENSIONS AND COMMENTARY: With an entirely new hetero atom in the
molecule (the selenium), and with clear indications that large dosages
would be needed (100 milligrams. or more), some discretion was felt
desirable.  There was certainly an odd taste and an odd smell.  I
remember some early biochemical work where selenium replaced sulfur in
some amino acid chemistry, and things got pretty toxic.  It might be
appropriate to get some general animal toxicity data before exploring
those dosages that might get to a +++.

What doors are opened by the observation that the selenium analog of
2C-T is an active compound?  The potency appears to be in the same
ball park, whether there is a sulfur atom or a selenium atom there.

From the point of view of the thing that is hung onto the hetero-atom,
the selenium, the most active (and as first approximation the most
safe) analogue would be the same ones that are the most potent with
sulfur.  These would probably be the Se-ethyl, the Se-propyl, or the
Se-isopropyl, the analogs of S-ethyl, S-propyl, and S-isopropyl.  If
one were to be systematic, these would be called 2C-SE-2, 2C-SE-4, and
2C-SE-7.  And a very special place might be held for 2C-SE-21, the
analogue of 2C-T-21.  Not only is this of high potential potency, but
it would certainly be the first time that both fluorine and selenium
are in the same centrally active drug.  In fact, might not this
compound, 2C-SE, be the first compound active within the human CNS
with a selenium atom in it?  It is certainly the first psychedelic
with this atom in it!

From the point of view of the hetero-atom itself, there are two more
known below selenium in the Periodic Table.  Each deserves some
special comment.  The next atom, directly below selenium, is
tellurium.  It is more metallic, and its com-pounds have a worse smell
yet.  I heard a story about a German chemist, many years ago, who was
carrying a vial of dibutyl telluride in his pocket in a passenger
coach from here to there in Germany, back at about the turn of the
century.  It fell to the floor and broke.  No one could remain in the
car, and no amount of decontamination could effectively make the smell
tolerable.  Scratch one railway coach.  But the compound, 2C-TE, would
be readily makeable.  Dimethyl ditelluride is a known thing.

However, the atom below tellurium (and at the bottom of that
particular column of the Periodic Table) is the element polonium.
Here one must deal in terms of theory, as far as human activity goes,
since there are no non-radioactive isotopes of polonium.  The only
readily available isotope is that with mass 210, which is also called
Radium F, and is an alpha-particle emitter.  If this were ever to be
put into a living organism, and if it were to seek out and hang around
some particular site of action, that area would be thoroughly and
completely cooked by alpha-particle emission.  It would be a fun
academic exercise to make 2C-PO
(2,5-dimethoxy-4-methylpoloneophenethylamine), but in no way could it
ever go into anyone.  I knew an eminent physiologist named Dr. Hardin
Jones (now dead) who always argued that the continuing use of drugs
would burn out the pleasure center of the brain.  It is a certainty
that 2C-PO would, quite literally, do this.  If I ever made it, I
would call it HARDINAMINE in his honor.

There was an interesting observation associated with the making of
2C-SE.  In the synthesis of many of the sulfur compounds (of the 2C-T
family) is was quite common to find, when there was a quantity of some
organic sulfide let go as a by-product of a reaction on a warm summer
night, a number of flies coming into the lab to pay a visit.  On the
first synthesis of the starting material for 2C-SE, a quantity of
CH3SeH was let go into the environment.  Within minutes, there were
two beautiful dragonflies in the lab.  A coincidence certainly, but
somehow, it was a nice message to receive.









#39 2C-T ; 2,5-DIMETHOXY-4-METHYLTHIOPHENETHYLAMINE

SYNTHESIS: A solution of 149 g sodium thiosulfate in 300 mL H2O was
vigorously stirred.  To this there was added, over the course of 10
min, a solution of 43.2 g benzoquinone in 200 mL acetic acid.  After
an additional 1 h stirring at room temperature, all volatiles were
removed under vacuum.  The residual syrup slowly set up as crystals
which, after grinding under brine, were removed by filtration and
washed with additional brine.  These were dissolved in MeOH, clarified
by filtration through a Celite bed, and the clear filtrate stripped of
solvent under vacuum.  The yellow, powdery sodium
2,5-hydroxyphenylthiosulfate weighed 67 g when dry.  This intermediate
was dissolved in aqueous HCl (50 g in 200 mL H2O containing 400 mL
concentrated HCl), cooled with an external ice bath, and treated with
250 g zinc dust added at a rate that kept the temperature below 60 !C.
About 1.5 h were required, and caution must be taken concerning the
poisonous hydrogen sulfide that evolves.  An additional 50 mL
concentrated HCl was added, and the aqueous phase decanted from the
unreacted zinc metal.  This was extracted with 6x100 mL Et2O, and
these extracts were pooled, washed with brine, and the solvent removed
under vacuum to yield 33.1 g of 2,5-dihydroxythiophenol as pale yellow
needles with a mp of 118-119 !C.

A solution of 118.6 g KOH pellets in 200 mL H2O was placed under N2,
and to it was added 24.0 g 2,5-dihydroxythiophenol.  With vigorous
stirring, there was then added 160 g methyl sulfate at a rate that
maintained the temperature at about 60 !C.  This took about 2 h.
After the addition was complete, the mixture was held at reflux for 3
h, and allowed to stir at ambient temperature overnight.  It was then
filtered, and the filtrate extracted with 6x100 mL Et2O, the extracts
pooled, washed with 2x50 mL brine, dried over anhydrous Na2SO4, and
the solvent removed under vacuum.  The residue was distilled at 86-88
!C at 0.04 mm/Hg to provide 25.9 g of 2,5-dimethoxythioanisole as a
white oil that crystallized on standing.  Its mp was 33-34 !C.  An
alternate preparation of this compound follows the direct methylation
of 2,5-dimethoxythiophenol (see under 2C-T-2 for the preparation of
this common intermediate) with methyl iodide.

To 40 mL dry CH2Cl2 there was added 6.07 g 2,5-dimethoxythioanisole,
and this was cooled to 0 !C under N2.  To this well stirred solution
there was added 13.02 g stannic chloride over the course of 2 min.
This was followed by the drop-wise addition of dichloromethyl methyl
ether over 5 min, and the reaction mixture allowed to stir for an
additional 15 min.  After returning to room temperature, it was
stirred for an additional 1 h.  The reaction mixture was poured over
15 g ice, and the organic phase separated, washed with 3x25 mL 3 N
HCl, with 3x50 mL brine and, after drying over anhydrous Na2SO4, the
solvent was removed under vacuum.  The residue was a solid and, after
recrystallization from MeOH/H2O, gave 5.86 g
2,5-dimethoxy-4-(methylthio)benzaldehyde with a mp of 95-97 !C.
Purification via the bisulfite complex provided an analytical sample
with mp of 99-100 C.  Anal. (C10H12O3S) C,H,S.  The malononitrile
derivative (from equal weights of the aldehyde and malononitrile in
EtOH with a drop of triethylamine as catalyst) was recrystallized from
an equal volume of EtOH to give orange crystals with a mp of 185-186
!C.  Anal. (C13H12N2O2S) C,H,N,S.

A solution of 2.1 g 2,5-dimethoxy-4-(methylthio)benzaldehyde in 7.5 mL
nitromethane was treated with 0.45 g anhydrous ammonium acetate and
held at steam bath temperature for 6 h.  The deep red solution was
stripped of solvent to give a residue that spontaneously crystallized.
This was ground up under 12 mL MeOH, filtered, and washed with MeOH to
yield, after air-drying, 1.7 g of
2,5-dimethoxy-4-methylthio-'-nitrostyrene as orange solids.
Recrystallization from EtOH provided rust-orange colored crystals with
a mp of 165.5-166 !C.  Anal. (C11H13NO4S) C,H,N; S: calcd, 12.56;
found, 11.96.

To a gently refluxing mixture of 1.4 g LAH in 40 mL anhydrous THF
under an inert atmosphere there was added, dropwise, 1.7 g
2,5-dimethoxy-4-methylthio-'-nitrostyrene in 25 mL THF.  The refluxing
was continued for 18 h, and the stirring continued for another day at
room temperature.  There was then added 1.5 mL H2O (diluted with a
little THF), 1.5 mL 15% NaOH, and finally 4.5 mL H2O.  The white
aluminum oxide salts were removed by filtration, and the filter cake
washed with THF.  The filtrate and washings were combined and stripped
of solvent under vacuum yielding a straw-colored residue that
crystallized (mp 81-92 !C without purification).  This residue was
dissolved in 25 mL IPA and neutralized with concentrated HCl.  The
slightly pink solution spontaneously crystallized.  There was added
100 mL anhydrous Et2O, and the white crystalline mass of
2,5-dimethoxy-4-methylthiophenethylamine hydrochloride (2C-T) was
removed by filtration, washed with Et2O, and air dried.  The final
weight was 1.0 g, and had a mp of 232-237 !C.  Recrystallization from
EtOH provided an analytical sample with mp 240-241 !C.  IPA was not a
good recrystallization solvent.  Anal. (C11H18ClNO2S) C,H,N,S.

DOSAGE: 60 - 100 mg.

DURATION: 3 - 5 h.

QUALITATIVE COMMENTS: (with 60 mg) Poetry was an easy and natural
thing.  Both the reading of it and the writing of it.  This is a
potential MDMA substitute since it opens things up but it doesnUt do
anything to get in the way.

(with 75 mg) I am already aware at a quarter of an hour into it!  It
develops very quickly but very quietly.  There are no visuals at all
but, rather, a tactile sensitivity, with warm close feelings.  This
could be very erotic.  There is some fantasy to music, but nothing
very demanding.  The viewing of pictures doesnUt do much either.  The
drop-off was extremely relaxed, with a good body feeling.  At the
fifth hour I was able to drift into an excellent, deep sleep with busy
dreams.  In the morning I felt refreshed and active, without apparent
deficit.

(with 75 mg) I got up to a thin and fragile plus two, but there was a
continuing feeling of a hooded cloak brought down over my head.
Nothing obvious Q it is transparent Q but it somehow separated me from
everything around me.  I do not think the overall experiment was worth
it.

(with 100 mg) Material all right, but a little bit along the lines of
a 'generic' psychedelic effect.  Sharper edges than 2C-B.  The one
true negative, which has been pretty consistent with this drug, is
that there is a certain emotional removal.  One teeny step removed.
One is connected with feelings, certainly, but there is a tendency for
the intellect to be more evident, in me, than the heart.  All this is
moderately so.  Nothing extreme.  Pretty good material, but there are
more inter-esting ones.  However, if you are looking for a really
short one, this is one of the answers.  For most people.  For me, itUs
still around 5 to 6 hours long.  I wish we had more shorties, indeed.

(with 125 mg) There was some physical tummy uncertainty, but once
that was past, talking was extremely easy.  This is probably really
psychedelic, but I am not really sure why, as there is not much in the
way of visuals.  Dropping was noted just after hour number three, and
I was at baseline three hours later.

EXTENSIONS AND COMMENTARY: The earliest work with the sulfur atom was
with the three-carbon chain materials, the ALEPHs.  It was only after
a considerable time of working with them, and trying to come to peace
with their property of being so different from person to person as to
potency, that the two-carbon homologues were looked at.  Although the
first of these (this compound, called 2C-T) was prepared at the same
time as ALEPH-1, there was a lapse of about four years between their
trials.  The relatively low potency of 2C-T was a bit discouraging.
But the methodical pursuit of the higher 2C-T's (to parallel the
higher ALEPHs) proved to be a treasure house, and they have been
explored much further than any of the ALEPHs.

A note on the RTS in 2C-T.  Many, in fact most, of the 2C's have their
name based on the last letter of the amphetamine prototype.  2C-B from
DOB, 2C-C from DOC, 2C-I from DOI, 2C-N from DON, etc.  And since the
original name for ALEPH-1 was DOT (the desoxy- and a thiomethyl group
at the 4-position), the 2C-T naming followed this general pattern.
And as a note on the subsequent numbering, they (both the ALEPHs and
the 2C-TUs) are assigned numbers as they are thought up.  There is no
structural significance in the number but they have been, like the
houses on the streets in residential Tokyo, assigned numbers in strict
historical order, documenting the sequence of construction rather than
the relative position down the side of the street.

Both of the homologous mono-ethoxy Tweetios of 2C-T have been
synthesized and evaluated.  The 2-EtO-homologue of 2C-T is
2-ethoxy-5-methoxy-4-methylthiophenethylamine, or 2CT-2ETO.  The
benzaldehyde (2-ethoxy-5-methoxy-4-(methylthio)benzaldehyde) was an
oil, the nitrostyrene intermediate had a melting point of 137-138 !C,
and the final hydrochloride a melting point of 215-216 !C.  The
effects were felt very quickly, and there was a blurring of vision.
However, the highest dose tried, 50 milligrams, was not able to
produce a greater-than-plus one state, and what did occur, lasted for
only 4 hours.

The 5-EtO-homologue of 2C-T is
5-ethoxy-2-methoxy-4-methylthio-phenethylamine, or 2CT-5ETO.  The
benzaldehyde (5-ethoxy-2-methoxy-4-(methyl-thio)benzaldehyde) was
impure, and had a melting point of about 66 !C, the nitrostyrene
intermediate a melting point of 133-134 !C, and the final
hydrochloride a melting point of 184-185 !C.  There was a body
awareness and modest eyes-closed visuals following the use of 30
milligrams of 2CT-5ETO.  The experience was quiet, peaceful,
contemplative, and insightful.  The duration was perhaps 15 hours and
Halcion was needed to allow sleep.  There were a lot of dreams, and
the next day was restful.









#40 2C-T-2; 2,5-DIMETHOXY-4-ETHYLTHIOPHENETHYLAMINE

SYNTHESIS: To a solution of 165 g 1,4-dimethoxybenzene in 1 L of
CH2Cl2, in a well ventilated place and well stirred, there was
cautiously added 300 mL chlorosulfonic acid.  With about half the acid
chloride added, there was a vigorous evolution of HCl gas and the
generation of a lot of solids.  As the addition was continued, these
redissolved to form a clear, dark green solution.  Towards the end of
the addition, some solids were again formed.  When everything was
stable, there was added 2 L H2O, a few mL at a time, commensurate with
the vigor of the reaction.  The two phases were separated, and the
aqueous phase extracted with 2x75 mL CH2Cl2.  The original organic
phase and the extracts were combined and the solvent removed under
vacuum.  The residue weighed 162 g and was quite pure
2,5-dimethoxybenzenesulfonyl chloride, a yellow crystalline solid with
a mp of 115-117 !C.  It need not be further purified for the next
step, and it appears to be stable on storage.  The sulfonamide, from
this acid chloride and ammonium hydroxide, gave white crystals from
EtOH, with a mp of 147.5-148.5 !C.

The following reaction is also a very vigorous one and must be
performed in a well ventilated place.  To a solution of 400 mL 25%
H2SO4 (V/V) in a beaker at least 2 L in size, there was added 54 g of
2,5-dimethoxybenzenesulfonyl chloride, and the mixture was heated on a
steam bath.  The yellow crystals of the acid chloride floated on the
surface of the aqueous layer.  There should be 80 g of zinc dust at
hand.  A small amount of Zn dust was placed at one spot on the surface
of this chapeau.  With occasional stirring with a glass rod, the
temperature was allowed to rise.  At about 60 or 70 !C an exothermic
reaction took place at the spot where the zinc was placed.  Additional
dollups of zinc were added, and each small exothermic reaction site
was spread about with the glass stirring rod.  Finally, the reaction
spread to the entire solid surface layer, with a melting of the acid
chloride and an apparent boiling at the H2O surface.  The remainder of
the 80 g of zinc dust was added as fast as the size of the reaction
container would allow.  After things subsided again, the heating was
continued for 1 h on the steam bath.  After the reaction mixture had
cooled to room temperature, it was filtered through paper in a Buchner
funnel, and the residual metal washed with 100 mL CH2Cl2.  The
two-phase filtrate was separated, and the lower, aqueous phase was
extracted with 2x75 mL CH2Cl2.  The addition of 2 L H2O to the aqueous
phase now made it the upper phase in extraction, and this was again
extracted with 2x75 mL CH2Cl2.  The organic extracts were pooled (H2O
washing is more trouble than it is worth) and the solvent removed
under vacuum.  The light amber residue (30.0 g) was distilled at 70-80
!C at 0.3 mm/Hg to yield 25.3 g 2,5-dimethoxythiophenol as a white
oil.  This chemical is certainly not centrally active, but it is a
most valuable precursor to all members of the 2C-T family.

To a solution of 3.4 g of KOH pellets in 75 mL boiling EtOH, there was
added a solution of 10.0 g 2,5-dimethoxythiophenol in 60 mL EtOH
followed by 10.9 g ethyl bromide.  The reaction was exothermic with
the immediate deposition of white solids.  This was heated on the
steam bath for 1.5 h, added to 1 L H2O, acidified with HCl, and
extracted with 3x100 mL CH2Cl2.  The pooled extracts were washed with
100 mL of 5% NaOH, and the solvent removed under vacuum.  The residue
was 2,5-dimethoxyphenyl ethyl sulfide which was a pale amber oil,
weighed about 10 g and which was sufficiently pure for use in the next
reaction without a distillation step.

A mixture of 19.2 POCl3 and 18.0 g N-methylformanilide was heated
briefly on the steam bath.  To this claret-colored solution there was
added the above 2,5-dimethoxyphenyl ethyl sulfide, and the mixture
heated an additional 20 min on the steam bath.  This was then added to
500 mL of well-stirred warm H2O (pre-heated to 55 !C) and the stirring
continued for 1.5 h by which time the oily phase had completely
solidified to a brown sugar-like consistency.  The solids were removed
by filtration, and washed with additional H2O.  After being sucked as
dry as possible, these solids were dissolved in 50 mL boiling MeOH
which, after cooling in an ice-bath, deposited almost-white crystals
of 2,5-dimethoxy-4-(ethylthio)-benzaldehyde.  After filtration, modest
washing with cold MeOH, and air drying to constant weight, there was
obtained 11.0 g of product with a mp of 86-88 !C.  Recrystallization
of a small sample again from MeOH provided an analytical sample with
mp 87-88 !C.  Anal. (C11H14O3S) C,H.

To a solution of 11.0 g 2,5-dimethoxy-4-(ethylthio)benzaldehyde in 100
g of nitromethane there was added 0.5 g of anhydrous ammonium acetate,
and the mixture was heated on the steam bath for 80 min (this reaction
progress must be monitored by TLC, to determine the point at which the
starting aldehyde has been consumed).  The excess nitromethane was
removed under vacuum leaving a residue that spontaneously set to
orange-red crystals.  These were scraped out to provide 12.9 g crude
2,5-dimethoxy-4-ethylthio-'-nitrostyrene with a mp of 152-154 !C.  A
sample recrystallized from toluene was pumpkin colored and had a mp of
148-149 !C.  Another sample from acetone melted at 149 !C sharp, and
was light orange.  From IPA came spectacular fluorescent orange
crystals, with a mp 151-152 !C.  Anal. (C12H15NO4S) C,H.

A suspension of 12.4 g LAH in 500 mL anhydrous THF was stirred under
He.  To this there was added 12.4 g
2,5-dimethoxy-4-ethylthio-'-nitrostyrene in a little THF, and the
mixture was held at reflux for 24 h.  After the reaction mixture had
returned to room temperature, the excess hydride was destroyed by the
cautious addition of 60 mL IPA, followed by 20 mL of 5% NaOH followed,
in turn, by sufficient H2O to give a white granular character to the
oxides.  The reaction mixture was filtered, and the filter cake washed
first with THF and then with MeOH.  Removing the solvents from the
combined filtrate and washings under vacuum provided 9.5 g of a yellow
oil.  This was added to 1 L dilute HCl and washed with 2x100 mL CH2Cl2
which removed all color.  After making the aqueous phase basic with
25% NaOH, it was extracted with 3x100 mL CH2Cl2, the extracts pooled,
and the solvent removed under vacuum to provide 7.3 g of a pale amber
oil.  Distillation at 120-130 !C at 0.3 mm/Hg gave 6.17 g of a clear
white oil.  This was dissolved in 80 mL IPA and neutralized with
concentrated HCl, forming immediate crystals of
2,5-dimethoxy-4-ethylthiophenethylamine hydrochloride (2C-T-2).  An
equal volume of anhydrous Et2O was added and, after complete grinding
and mixing, the salt was removed by filtration, washed with Et2O, and
air dried to constant weight.  The resulting white crystals weighed
6.2 g.

DOSAGE: 12 - 25 mg.

DURATION: 6 - 8 h.

QUALITATIVE COMMENTS: (with 12 mg) I donUt feel this for fully an
hour, but when I do it is quite a weight.  It feels good to work it
through.  It is OK to be with pain.  You canUt eliminate it.  And it
is OK to contact your deep pools of anger.  And all of it stems from
the lack of acknowledgment.  All the macho carrying on, the fights,
the wars, are ways of demanding attention, and getting even for not
having had it in one's life.  I am experiencing more deeply than ever
before the importance of acknowledging and deeply honoring each human
being.  And I was able to go through and resolve some judgments with
particular persons.

(with 20 mg) I chose 2C-T-2 at this dose level because the lateness
of getting started, and I wanted a shorter experience with my daughter
and her family around.  I feel, however, that I have somewhat less of
a body load with 2C-T-7.  Today I was badly in need of the help that
might possibly come from this material, and today it was my ally.  I
sorely needed the type of help that it afforded.  The result was to
work off the heavy feeling of tiredness and lack of motivation that
had been hounding me.  The next day I felt that I had dropped my
burden.

(with 20 mg) There is a neutralness to this.  I am at the maximum,
and I am asking myself, 'Am I enjoying this?'  And the answer is, 'No,
I am experiencing it.'  Enjoyment seems beside the point.  It is a
rather intensely matter-of-fact +3.  Is it interesting?  Yes, but
mostly in expectation of further developments.  Is it inspiring?  No.
Is it negative?  No.  Am I glad I took it?  Yes.  Not glad.  Satisfied
and contented.  This is a controlled +3.  No threat. The body is all
right.  Not superbly healthy Q but OK.  Of no interest, either way.
If I were to define the body's state, I would have to define it in
image.  The image is of a not comfortable state of being clenched.
Clenched?  Well, carefully bound in control.

(with 22 mg) A slow onset.  It took an hour for a plus one, and
almost another two hours to get to a +++.  Very vivid fantasy images,
eyes closed, but no blurring of lines between RrealityS and fantasy.
Some yellow-grey patterns a la psilocybin.  Acute diarrhea at about
the fourth hour but no other obvious physical problems.  Erotic
lovely.  Good material for unknown number of possible uses.  Can
explore for a long time.  Better try 20 milligrams next time.

(with 25 mg) I was at a +++ in an hour!  It is most difficult to do
even ordinary things.  I took notes but now I canUt find them.  This
is much too high for anything creative, such as looking at pictures or
trying to read.  Talking is OK.  And to my surprise I was able to get
to sleep, and a good sleep, at the seven hour point.

EXTENSIONS AND COMMENTARY: There is a considerable parallel between
2C-T-2 and 2C-T-7, and both have proven to be excellent tools for
introspection.  The differences are largely physical.  With 2C-T-2,
there is more of a tendency to have physical disturbances such as
nausea and diarrhea.  And the experience is distinctly shorter.  With
2C-T-7, physical disturbances are less common, but you are into the
effects for almost twice as long.  Both have been frequently used in
therapy as follow-ups to MDMA.

A point of potential misidentification should be mentioned here.
2C-T-2 has occasionally been called, simply, T-2.  This abbreviated
nickname has also been used for T-2 Toxin, a mycotoxin of the
Tricothecene group, formed mainly by the Fusarium spp.  This is the
infamous Rwarfare agentS in Southeast Asia, which was finally
identified as bee feces rather than a Soviet military adventure.  T-2
and 2C-T-2 are radically different compounds.

All three Tweetios of 2C-T-2 have been made and looked at through
human eyes.  The 2-EtO-homologue of 2C-T-2 is
2-ethoxy-4-ethylthio-5-methoxyphenethylamine, or 2CT2-2ETO.  The
benzaldehyde (2-ethoxy-4-ethylthio-5-methoxybenzaldehyde) had a
melting point of 73-75 !C, the nitrostyrene intermediate a melting
point of 122-123 !C, and the final hydrochloride a melting point of
202-204 !C.  Fifty milligrams was a completely effective level.  The
effects were felt very quickly.  Vision was blurred, and there were
intense eyes-closed visuals and the generation of a pleasant,
contemplative mood.  Baseline was re-established in five or six hours,
but sleep was restless, with weird dreams.  Nasal administration
showed considerable variation between individuals, but a typical dose
was 10 milligrams.

The 5-EtO-homologue of 2C-T-2 is
5-ethoxy-4-ethylthio-2-methoxyphenethylamine, or 2CT2-5ETO.  The
benzaldehyde (5-ethoxy-4-ethylthio-2-methoxybenzaldehyde) had a
melting point of 49 !C, but it was impure.  The nitrostyrene
intermediate melted at 107-108 !C, and the final hydrochloride had a
melting point of 180 !C.  At levels of 20 milligrams, there was a
slow, gentle climb to a full effect at the third or fourth hour.  The
flooding of thoughts and easy conversation lasted for many hours, and
on some occasion a sedative was needed at the 16 hour point.  There
was a feeling of being drained for the following day or two.  Some
intoxication was still noted in the second day.  Again it is true
here, as had been stated as a generality, that the 5-Tweetio analogues
have potencies similar to that of the parent compound, but show a much
longer duration.  The nickname of Rforever yoursS had been applied.
There may indeed be insight, but 24 hoursU worth is an awful lot of
insight.

The 2,5-DiEtO-homologue of 2C-T-2 is
2,5-diethoxy-4-ethylthiophen-ethylamine, or 2CT2-2,5DIETO.  The
benzaldehyde, 2,5-diethoxy-4-(ethylthio)benzaldehyde, had a melting
point of 84-85 !C, the nitrostyrene intermediate a melting point of
123-124 !C, and the final hydrochloride a melting point of 220-221 !C.
Levels that were evaluated from 10 to 50 milligrams were not
particularly different in intensity, but were progressively longer in
duration.  At 50 milligrams there was a nervousness and edginess
during the early part of the experience, but for the next several
hours there was evident both energy and high attentiveness.  There
were few if any sensory alterations.  There were no negatives on the
following day.  The duration was perhaps nine hours.









#41 2C-T-4; 2,5-DIMETHOXY-4-(i)-PROPYLTHIOPHENETHYLAMINE

SYNTHESIS: To a solution of 2.5 g of KOH pellets in 40 mL hot EtOH,
there was added 5.4 g 2,5-dimethoxythiophenol (see under 2C-T-2 for
its preparation) and 8.7 g isopropyliodide.  White solids appeared in
a few min, and the reaction mixture was heated on the steam bath
overnight.  This mixture was added to 200 mL H2O followed by
additional aqueous NaOH to raise the pH to a deep purple-blue on
universal pH paper.  This was extracted with 3x75 mL CH2Cl2.  The
pooled extracts were stripped of solvent under vacuum, and the residue
distilled at 100-110 !C at 0.2 mm/Hg to yield 6.9 g of
2,5-dimethoxyphenyl isopropyl sulfide as a pale yellow oil.  It has a
very light, pleasant smell of apples.

A mixture of 4.8 g POCl3 and 4.5 g N-methylformanilide was stirred and
allowed to stand at room temperature for 1 h To this claret-colored
solution was added 3.0 g of 2,5-dimethoxyphenyl isopropyl sulfide,
producing an exothermic reaction and immediate reddening.  This was
heated for 0.5 h on the steam bath, then quenched in 200 mL of warm
H2O producing immediate crystals.  Stirring was continued for a few
min, and then the solids were removed by filtration, washed with H2O
and sucked as dry as possible.  When they were ground up under an
equal weight of cold MeOH, refiltered and air dried, they gave 2.35 g
of 2,5-dimethoxy-4-(i-propylthio)benzaldehyde as pale yellow solids
(in some runs this was a pale lime-green color) with a mp of 89-90 !C.
A wasteful recrystallization from MeOH gave pale yellow crystals with
a mp of 90 !C sharp.

To a solution of 6.7 g 2,5-dimethoxy-(i-propylthio)benzaldehyde in 40
g of nitromethane there was added 0.10 g of anhydrous ammonium
acetate, and the mixture was heated on the steam bath for 2 h.  The
excess reagent/solvent was removed under vacuum yielding 8.9 g of
orange solids.  This was recrystallized from 200 mL boiling MeOH
providing 6.2 g of 2,5-dimethoxy-'-nitro-4-(i-propyl-thio)styrene as
lustrous golden orange platelets.

A solution of LAH (80 mL of a 1 M solution in THF) was cooled, under
He, to 0 !C with an external ice bath.  With good stirring there was
added 2.1 mL 100% H2SO4 dropwise, to minimize charring.  This was
followed by the addition of 5.74 g
2,5-dimethoxy-'-nitro-4-(i-propylthio)styrene as a solid, a bit at a
time.  After 15 min further stirring, the temperature was brought up
to a gentle reflux on the steam bath for another 15 min, then allowed
to stand at room temperature overnight.  After cooling again to 0 !C,
the excess hydride was destroyed by the addition of 7 mL IPA followed
by 6 mL 15% NaOH which was sufficent to give a white granular
character.  The reaction mixture was filtered and the filter cake
washed with THF.  The filtrate and washings were pooled, stripped of
solvent under vacuum providing 3.9 g of a pale amber oil which was
dissolved in 250 mL dilute H2SO4.  This was washed with 3x75 mL CH2Cl2
which removed the residual yellow color.  After making basic with 25%
NaOH, the product was extracted with 3x75 mL CH2Cl2 and the solvent
removed under vacuum to give 2.72 g of a residue which was distilled
at 140-145 !C at 0.2 mm/Hg to give 2.42 g of a clear white oil.  This
was dissolved in 25 mL IPA, and neutralized with concentrated HCl.
This gave a clear solution which, with good stirring, was diluted with
100 anhydrous Et2O to provide 2.40 g
2,5-dimethoxy-4-(i)-propyl-thiophenethylamine hydrochloride (2C-T-4)
as white crystals.

DOSAGE: 8 - 20 mg.

DURATION: 12 - 18 h.

QUALITATIVE COMMENTS: (with 8 mg) Visual effects set in at about two
hours.  There was much color enhancement, particularly of green, and
some flowing of colors.  The bright impressionistic picture of the
little girl, in the bathroom, was particularly good for the visuals to
take over, especially when I was concentrating on urinating.  The
shadows in the large picture above the fireplace would change
constantly.  I could not either control or turn off these effects
during the middle period (3-6 hours).  From the physical point of
view, something early in the experience simply didnUt feel right.
Both my lower legs tended to fall asleep, and this seemed to spread to
my hands and lower arms.  It was uncomfortable and although I was
apprehensive at first it didnUt get any worse with time so I ignored
it.  This is not one my favorite materials, and it takes too long to
wear off.  If I were to do it again I would settle for 4 or 5
milligrams.  It may well cut out the extremity problem amd still allow
for a pleasant experience.

(with 9 mg) An important characteristic of this experience was the
sense of letting go and flowing with it.  Just follow where it leads.
This seemed to lead to a growing euphoria, a feeling of clearing out
of body residues, and the handling of very impressive insights.  My
thinking continued to grow in clarity, visual perception was crystal
clear, and it was a joy to simply look over the scenery, enjoy the
beauty, enjoy the companionship, and ponder whatever came to mind.
This clarity of body and mind lasted the rest of the evening with a
wonderful feeling of peace and centeredness.  I still felt a lot of
push from the chemical at bed time, causing some tiredness, and
allowing very little sleep.  I kept working at what had taken place,
all night, just to release the experience.

(with 14 mg) Very rational, benign, and good humored.  The insight
and calm common to the 2C-T's are present, with less of the push of
body-energy which makes 2C-T-2 difficult for some people.  There are
no particular visuals, but then I tend to screen them out
consistently, except in cases of mescaline and LSD and psilocybin, so
I canUt judge what others would experience in the visual area.  The
eyes-closed imagery is very good without being compelling.  The
decline is as gradual and gentle as the onset.  I am fully capable of
making phone calls and other normal stuff.  Music is marvelous, and
the body feels comfortable throughout.

(with 14 mg) Persistent cold feet, and an uncertain stomach when
moving around.  Brilliant color trails reminiscent of 2C-B.  But a
change is occurring and I canUt talk myself out of it.  There are dark
corners.  If I were with other people, this would bring out the worst
in me, which can be pretty bad.

(with 19 mg) I was caught by the TV.  Leonard Bernstein conducting
West Side Story.  I think I know every note.  This was a 1985
rehearsal with the goofs and the sweat.  And now Peter, Paul and Mary,
grown older along with the songs we all sang.  Where Have All the
Flowers Gone Q and an audience of grown-older people singing Puff the
Magic Dragon like earnest children and probably crying along with me.
It is good to have lived through the 60's and not to be in them now.
Now there's a new song about El Salvador and itUs the battle all over
again on a different field, but it will always be so, until and
unless.  Now, in the 80Us, I donUt get really angry anymore.  I am
more warrior than angry protester, and that's a much better way to be.
In fact, I am quite happy to be where I am.  I know a lot more about
the game, and what it is, and why it is played, and I have a good idea
about my part in it, and I like the part IUve chosen.

(with 22 mg) The transition took place over three hours, an alert in
30 minutes followed by a slow and gentle climb.  I found it difficult,
not physically but mentally since I was for a while locked into the
illogical and disconnected aspects of human experiences and
expressions, particularly laws and pronouncements and unseeing
prejudices, most of which I was picking up from reading the Sunday
paper book reviews.  As time went on, things became less pushy and I
came to be at ease with very positive feelings about everything going
on.  No self-rejecting aspect at all.  Sleep was excellent, but the
next day things went slowly and I had to nap a bit.  Next time, maybe
18 milligrams.

EXTENSIONS AND COMMENTARY: There are shades of the variability of the
Alephs.  Some observers are overwhelmed with colors and visual
activity; others volunteer their absence.  And a very wide range of
dosages represented, from an estimated 4 or so milligrams for full
effects, to something over 20 milligrams without any loss of control.
That is an unusually wide lattitude of activity.  And a rich variety
of effects that might be experienced.  The same wide range of
effective dosages was also observed with the corresponding Tweetio.
The 2-EtO-homologue of 2C-T-4 is
2-ethoxy-5-methoxy-4-(i)-propylthiophenethylamine, or 2CT4-2ETO.  The
benzaldehyde (2-ethoxy-5-methoxy-4-(i-propylthio)benzaldehyde had a
melting point of 43-44 !C, the nitrostyrene intermediate a melting
point of 77-79 !C, and the final hydrochloride a melting point of
153.5-154 !C.  There were practically no differences between trials at
5 milligram increments within the 10 and 25 milligram range.  Each
produced a gentle plus two level of effect which lasted for some 10
hours.  A code name of RtendernessS was felt to be appropriate, as
there was a peaceful meditative inner receptiveness and clarity noted,
with an honest connection felt with those who were present during the
experience.  Sleep was not comfortable.

I have heard 2C-T-4 referred to as T-4.  There is a potent explosive
used by terrorists called cyclotrimethylenetrinitramine, known by the
code name RDX, or T-4.  There is also a T-4 term that refers to
thyroxine, an amino acid in the body.  The drug 2C-T-4 is neither an
explosive nor an amino acid, I am happy to say.









#42 Y-2C-T-4; 2,6-DIMETHOXY-4-(i)-PROPYLTHIOPHENETHYLAMINE)

SYNTHESIS: A stirred solution of 8.3 g 3,5-dimethoxy-1-chlorobenzene
and 7.2 g isopropylsulfide in 100 mL anhydrous Et2O was cooled with an
external ice bath, and then treated with 67 mL 1.5 M lithium
diisopropylamide in hexane which was added over the course of 10 min.
The reaction mixture was allowed to return to room temperature and the
stirring was continued for 0.5 h.  The mixture was poured into dilute
H2SO4, the organic layer was separated, and the aqueous phase
extracted with 3x75 mL EtOAc.  The organic phases were combined, dried
over anhydrous K2CO3, and the solvent removed under vacuum.  The
resulting 4.54 g of almost colorless oil was distilled at 85-95 !C at
0.1 mm/Hg to give 4.2 g of 3,5-dimethoxyphenyl isopropyl sulfide as a
colorless oil, showing a single spot on TLC with no indication of
starting chlorobenzene.  The product formed a picrate salt, but this
had an unsatisfactory mp character (partly melting at 45-47 !C, and
then completely at about 80-90 !C). The microanalysis for this picrate
was low in the carbon value, although the hydrogen and nitrogen were
excellent.  Anal. (C17H19N3O9S) H,N; C: calcd, 46.25; found, 44.58,
44.45.

To a well-stirred solution of 4.1 g 3,5-dimethoxyphenyl isopropyl
sulfide and 3.5 mL N,N,NU,NU-tetramethylethylenediamine in 25 mL
anhydrous Et2O that had been cooled to -78 !C with a dry-ice/acetone
bath, there was added 10 mL 2.5 M hexane solution of butyllithium.
The mixture was allowed to return to room temperature, and there was
added 3.5 mL DMF which caused the yellow color to progressively
darken.  The reaction mixture was poured into dilute H2SO4, the Et2O
layer was separated, and the aqueous phase extracted with 3x75 mL
EtOAc.  The solvent was removed from the combined organic phases, and
the residue distilled at 0.15 mm/Hg to give two fractions.  One,
boiling at 120-140 !C, was 0.98 g of a pale yellow mobile liquid,
which was part starting sulfide and part product aldehyde by TLC.  The
second cut, boiling at 160-180 !C, was a viscous liquid, weighed 1.66
g, and was largely 2,6-dimethoxy-4-(i-propylthio)benzaldehyde. This
formed a crystalline anil with 4-methoxyaniline (by fusing equimolar
amounts of the two with a flame) which, after recrystallization from
MeOH, gave fine yellow crystals with a mp of 87.5-89 !C.  Anal.
(C19H23NO3S) C,H.

A solution of 0.8 g 2,6-dimethoxy-4-(i-propylthio)benzaldehde in 10 mL
nitromethane was treated with 0.2 g anhydrous ammonium acetate and
heated on the steam bath for 1 h.  The excess reagent/solvent was
removed under vacuum, and the residue spontaneously solidified.  This
was recrystallized from 5 mL MeOH to give 0.70 g
2,6-dimethoxy-'-nitro-4-(i)-propylthiostyrene as a pale yellow fluffy
solid, with a mp of 83-84.5 !C.  Anal. (C13H17NO4S) C,H.

A solution of LAH (20 mL of a 1 M solution in THF) was cooled, under
He to 0 !C with an external ice bath.  With good stirring there was
added 0.54 mL 100% H2SO4 dropwise, to minimize charring.  This was
followed by the addition of 0.54 g
2,6-dimethoxy-'-nitro-4-(i)-propylthiostyrene in a small volume of
anhydrous THF.  The color was discharged immediately.  After a few
minutes further stirring, the temperature was brought up to a gentle
reflux on the steam bath for about 10 min, and then all was cooled
again to 0 !C.  The excess hydride was destroyed by the cautious
addition of IPA followed by sufficent 15% NaOH to give a white
granular character to the oxides, and to assure that the reaction
mixture was basic.  The reaction mixture was filtered, and the filter
cake washed well with THF.  The filtrate was stripped of solvent under
vacuum and the residue dissolved in 100 mL of dilute H2SO4.  This was
washed with 2x50 mL CH2Cl2 (the washes were saved, see below), made
basic with aqueous NaOH, and then extracted with 2x50 mL CH2Cl2.  The
residue remaining after the removal of the solvent was distilled at
130-140 !C at 0.05 mm/Hg to give 0.11 g of a white oil.  This was
dissolved in 10 mL IPA, neutralized with 5 drops of concentrated HCl
and diluted with 50 mL anhydrous Et2O.  After filtration of the formed
crystals, Et2O washing, and air drying, there was obtained 80 mg of
2,6-dimethoxy-4-(i)-propylthiophenethylamine hydrochloride (y-2C-T-4)
as fine white crystals.  The removal of the solvent from the CH2Cl2
washes of the dilute H2SO4 solution gave a H2O-soluble white solid
that proved to be the sulfate salt of the product.  This provided,
after making the H2O solution basic, extraction with CH2Cl2, and
solvent removal, the free base that was converted, as described above,
to a second crop of the hydrochloride salt.

DOSAGE: above 12 mg.

DURATION: probably short.

QUALITATIVE COMMENTS: (with 8 mg) I might actually be up to a plus 1,
and with a very good feeling.  But I cannot say how long it lasted,
and it was probably pretty short.  It just sort of faded away.

(with 12 mg) At the 25 minute point I am reminded of the experiment,
and in another quarter hour I am into something.  Will this be another
forever threshold?  I feel very good, but there is no sparkle.

EXTENSIONS AND COMMENTARY: Here is another example of the presentation
of a compound for which there has not yet been an effective level
determined.  Why?  For a very good reason.  This is an example of a
whole class of compounds that I have called the pseudos, or the
y-compounds.  Pseudo- as a prefix in the literary world generally
stands for Rfalse.S A pseudopod is a thing that looks like a foot, but
isnUt one.  A pseudonym is a fictitious name.  But in chemistry, it
has quite a different meaning.  If something has a common name, and
there is a second form (or isomer, or shape, or orientation) that is
possible and it doesnUt have a common name, it can be given the name
of the first form with a Rpseudo-S attached.  Ephedrine is the
erythro-isomer of N-methyl-'-hydroxyamphetamine.  There is a second
stereoisomer, the threo- isomer, but it has no trivial name.  So it is
called pseudoephedrine, or the RSudafedS of sinus decongestant fame.

The pseudo-psychedelics are the 2,4,6-trisubstituted counterparts of
the 2,4,5-trisubstituted psychedelics.  Almost all of the
2,5-dimethoxy-4-something-or-other compounds are active and
interesting whether they be phenethylamines or amphetamines, and it is
an exciting fact that the 2,6-dimethoxy-4-something-or-other compounds
are going be just as active and just as interesting.  A number of
examples have already been mentioned.  TMA-2 is
2,4,5-trimethoxyamphetamine (a 2,5-dimethoxy-substituted compound with
a methoxyl at the 4-position).  The pseudo- analogue is TMA-6
(2,4,6-trimethoxyamphetamine) and it is every bit as potent and
fascinating.  Z-7 could be called pseudo-DOM, and although it is quite
a bit down in potency, it is an active drug and will both demand and
receive much more clinical study some day.

Will the other 2,4,5-things spawn 2,4,6-things that are active?
Without a shadow of a doubt.  Chemically, they are much more difficult
to synthesize.  The 2,5-dimethoxy orientation made the 4-position a
natural and easy target.  The 2,6-dimethoxy orientation pushes for
3-substitution, and the 4-position is completely unnatural.  Tricks
are needed, but tricks have now been found.  The above synthesis of
pseudo-2C-T-4 shows one such trick.  This is, in my opinion, the
exciting chemistry and psychopharmacology of the next decade.  Well
over half of all the psychedelic drugs mentioned in Book II are
2,4,5-trisubstituted compounds, and every one of them has a
(potentially active) 2,4,6-pseudo-counterpart.

It goes yet further.  The antidepressant series of RAriadneS compounds
are 1-phenyl-2-aminobutanes.  But the 1-phenyl is again a
2,4,5-trisubstituted compound.  The 2,4,6-isomer will give rise to a
pseudo-Ariadne family, and I will bet that they too will be
antidepressants.  The 1-phenyl-2-aminobutane analog of y-2C-T-4 is the
2,4,6-analogue and it has been prepared as far as the nitrostyrene.
It has not yet been reduced, so it is not yet been evaluated, but it
could be a most remarkable psycho-pharmacological probe.

And it goes yet yet further.  Think back to the six possible TMAUs.
TMA and TMA-3 were relatively inactive.  And TMA-2 and TMA-6 were the
interesting ones.  The first gave rise to the last twenty years of
psychedelic chemistry, and the other (as speculated upon above) will
give rise to the forthcoming ten years.  But what of TMA-4 and TMA-5?
Both showed activity that was more than TMA but less than that of the
-2 or -6 isomers.  Could they, some day, provoke yet other families of
psychedelics?  Maybe the 3-position of these two might be focal points
of leverage as to psychological activity.  What are the letters that
follow y in the Greek alphabet?  If I remember correctly, the next
letter is the last letter, omega.  So, I guess that Nature is trying
to tell us something, that the -4 and -5 isomers will not engender
interesting families.  What a pity.  The chemistry is so unthinkably
difficult that it would have been a true challenge.  My next
incarnation, maybe?









#43 2C-T-7; 2,5-DIMETHOXY-4-(n)-PROPYLTHIOPHENETHYLAMINE

SYNTHESIS: To a solution of 3.4 g of KOH pellets in 50 mL hot MeOH,
there was added a mixture of 6.8 g 2,5-dimethoxythiophenol (see under
the recipe for 2C-T-2 for its preparation) and 7.4 g (n)-propylbromide
dissolved in 20 mL MeOH.  The reaction was exothermic, with the
deposition of white solids.  This was heated on the steam bath for 0.5
h, added to 800 mL H2O, additional aqueous NaOH added until the pH was
basic, and extracted with 3x75 mL CH2Cl2.  The pooled extracts were
washed with dilute NaOH, and the solvent removed under vacuum.  The
residue was 2,5-dimethoxyphenyl (n)-propyl sulfide which was obtained
as a pale yellow oil, and which weighed 8.9 g.  It had a light
pleasant fruity smell, and was sufficiently pure for use in the next
reaction without distillation.

A mixture of 14.4 g POCl3 and 13.4 g N-methylformanilide was heated
for 10 min on the steam bath.  To this claret-colored solution was
added 8.9 g of 2,5-dimethoxyphenyl (n)-propyl sulfide, and the mixture
heated an additional 25 min on the steam bath.  This was then added to
800 mL of well-stirred warm H2O (pre-heated to 55 !C) and the stirring
continued until the oily phase had completely solidified (about 15
minutes).  The resulting brown sugar-like solids were removed by
filtration, and washed with additional H2O.  After sucking as dry as
possible, they were dissolved in an equal weight of boiling MeOH
which, after cooling in an ice-bath, deposited pale ivory colored
crystals.  After filtration, modest washing with cold MeOH, and air
drying to constant weight, there was obtained 8.3 g of
2,5-dimethoxy-4-(n-propyl-thio)benzaldehyde with a mp of 73-76 !C.
Recrystallization from 2.5 volumes of MeOH provided a white analytical
sample with mp 76-77 !C.  The NMR spectrum in CDCl3 was textbook
perfect, with the two aromatic protons showing singlet signals at 6.81
and 7.27 ppm, giving assurance that the assigned location of the
introduced aldehyde group was correct.

To a solution of 4.0 g 2,5-dimethoxy-(n-propylthio)benzaldehyde in 20
g of nitromethane there was added 0.23 g of anhydrous ammonium
acetate, and the mixture was heated on the steam bath for 1 h.  The
clear orange solution was decanted from some insoluble material and
the excess nitromethane removed under vacuum.  The orange-yellow
crystalline material that remained was crystallized from 70 mL boiling
IPA which, on slow cooling, deposited
2,5-dimethoxy-'-nitro-4-(n)-propylthiostyrene as orange crystals.
After their removal by filtration and air-drying to constant weight,
they weighed 3.6 g, and had a mp of 120-121 !C.  Anal. (C13H17NO4S)
C,H.

A solution of LAH (132 mL of a 1 M solution in THF) was cooled, under
He, to 0 !C with an external ice bath.  With good stirring there was
added 3.5 mL 100% H2SO4 dropwise, to minimize charring.  This was
followed by the addition of 8.4 g
2,5-dimethoxy-'-nitro-4-(n)-propylthiostyrene in 50 mL anhydrous THF.
There was an immediate loss of color.  After a few min further
stirring, the tem-perature was brought up to a gentle reflux on the
steam bath, then all was cooled again to 0 !C.  The excess hydride was
destroyed by the cautious addition of IPA (21 mL required) followed by
sufficent 5% NaOH to give a white granular character to the oxides,
and to assure that the reaction mixture was basic (15 mL was used).
The reaction mixture was filtered and the filter cake washed first
with THF and then with IPA.  The filtrate and washes were combined and
stripped of solvent under vacuum providing about 6 g of a pale amber
oil.  Without any further purification, this was distilled at 140-150
!C at 0.25 mm/Hg to give 4.8 g of product as a clear white oil.  This
was dissolved in 25 mL IPA, and neutralized with concentrated HCl
forming immediate crystals of the hydrochloride salt in the alcohol
solvent.  An equal volume of anhydrous Et2O was added, and after
complete grinding and mixing,
2,5-dimethoxy-4-(n)-propylthiophenethylamine hydrochloride (2C-T-7)
was removed by filtration, Et2O washed, and air dried to constant
weight.  The resulting spectacular white crystals weighed 5.2 g.

DOSAGE: 10 - 30 mg.

DURATION: 8 - 15 h.

QUALITATIVE COMMENTS (with 20 mg) A wonderful day of integration and
work.  Took about 2 hours for the onset.  Some nausea on and off Q
that seemed to cycle periodically throughout the day.  Visuals were
great, much like mescaline but less sparkly.  Lots of movement and
aliveness Q velvety appearance and increased depth perception.  Neck
and shoulder tension throughout the day along with legs.  I would
periodically notice extreme tightness of muscles, and then relax.
Working was very integrative.  Back and forth constantly between
wonderful God-space Q similar to MDMA but more grounded Q then always
back to sadness.  I felt that it really showed me where I was
unfinished, but with self-loving and tolerance.  Tremendous processing
and letting go.  Seeing things very clearly and also able to laugh at
my trips.  Lots of singing.  In spite of shoulder tension, vocal
freedom and facility were very high.  I felt my voice integrated and
dropped in a way it never had before, and that remained for several
days.  Able to merge body, voice, psyche and emotions with music and
then let go of it as a role.  I also realized and gave myself
permission to do whatever it takes to get free.  I let go of Dad with
tragic arias.  The next day I let go of Mom by singing Kaddish for
her, and merging with it.

(with 20 mg) I lay down with music, and become engrossed with being
as still as possible.  I feel that if I can be totally, completely
still, I will hear the inner voice of the universe.  As I do this, the
music becomes incredibly beautiful.  I see the extraordinary
importance of simply listening, listening to everything, to people and
to nature, with wide open receptivity.  Something very, very special
happens at the still point, so I keep working on it.  When I become
totally still, a huge burst of energy is released.  And it explodes so
that it takes enormous effort to quiet it all down in order to be
still again.  Great fun.

(with 25 mg) This was a marvelous and strange evening.  This 2C-T-7
is good and friendly and wonderful as I remember it.  I think it is
going to take the place of 2C-T-2 in my heart.  It is a truly good
material.  I got involved with a documentary on television.  It was
about certain people of Bolivia, people living in the high mountains
and about a small village which Q perhaps alone among all the places
in the country Q maintains the old Inca ways, the old traditions, the
old language.  Which is, I gather, against the law in Bolivia.  It
showed a yearly meeting of shamans and it was quite clear that
hallucinogens played a major part in this meeting.  The shaman faces,
male and female, were startling in their intensity and earthy depth.
The Virgin Mary is worshipped as another version of the ancient Pacha
Mama, the Earth Mother.  Wonderful dark, vivid look at places and
people who are not usually to be seen or even known about.

(with 30 mg) The visuals have an adaptable character to them.  I can
use them to recreate any hallucinogenic substance I have known and
loved.  With open eyes, I can go easily into LSD flowing visuals, or
into the warm earth world of Peyote, or I can stop them altogether.
With closed eyes, there are Escher-like graphics with a lot of
chiaroscuro, geometric patterns with oppositional play of sculptured
light and dark values.  Green light.

EXTENSIONS AND COMMENTARY: If all the phenethylamines were to be
ranked as to their acceptability and their intrinsic richness, 2C-T-7
would be right up there near the top, along with 2C-T-2, 2C-B,
mescaline and 2C-E.  The range is intentionally extended on the lower
side to include 10 milligrams, as there have been numerous people who
have found 10 or so milligrams to be quite adequate for their tastes.

One Tweetio related to 2C-T-7 has been made and evaluated.  This is
the 2-EtO-homologue of 2C-T-7,
2-ethoxy-5-methoxy-4-(n)-propylthiophenethyl-amine, or 2CT7-2ETO.  The
benzaldehyde (2-ethoxy-5-methoxy-4-(n-propyl-thio)benzaldehyde had a
melting point of 69-71 !C, the nitrostyrene intermediate a melting
point of 106-106.5 !C, and the final hydrochloride a melting point of
187-189 C!.  At the 20 milligram level, the effects were felt quickly,
and the eyes-closed visuals were modest but real.  It was very
short-lived, with baseline recovery at about the fifth hour.  The next
day there was an uncomfortable headache which seemed on an intuitive
level to be an after-effect of the compound.

The unusual properties of a number of N-methyl-N-(i)-propyltryptamines
suggested the possibility of something like a similar set of
N-methyl-N-(i)-propylphenethylamines.  Why not try one from 2C-T-7?
The thought was, maybe N-methylate this compound, then put on an
isopropyl group with reductive alkylation, using acetone as the carbon
source and sodium cyanoborohydride.  Towards this end, the free base
of 2C-T-7 (from one gram of the hydrochloride) was refluxed for 2 h in
1.3 g butyl formate, and on removing the solvent/reactant the residue
spontaneously crystallized.  This formamide (0.7 g) was reduced with
lithium hydride in cold THF to provide
2,5-dimethoxy-4-(n)-propyl-N-methyl-phenethylamine, METHYL-2C-T-7,
which distilled at 150-170 !C at 0.4 mm/Hg.  A very small amount of
the hydrochloride salt was obtained (65 milligrams) and it had a brown
color.  Too small an amount of an impure product; the entire project
was dropped.









#44 2C-T-8; 2,5-DIMETHOXY-4-CYCLOPROPYLMETHYLTHIOPHENETHYLAMINE

SYNTHESIS: To a solution of 2.8 g of KOH pellets in 25 mL hot MeOH,
there was added a mixture of 5.9 g 2,5-dimethoxythiophenol (see under
2C-T-2 for its preparation) and 5.0 g of cyclopropylmethyl bromide.
There was an immediate exothermic reaction with spontaneous boiling
and the formation of white crystals.  This was heated on the steam
bath for 4 h, and then added to 400 mL of H2O.  After extraction with
3x75 mL CH2Cl2, the pooled extracts were washed first with dilute
NaOH, then with saturated brine, then the solvent was removed under
vacuum.  The residue, 8.45 g of crude 2,5-dimethoxyphenyl cyclopropyl
methyl sulfide, was distilled at 120-140 !C at 0.3 mm/Hg to give a
white oil weighing 7.5 g.

A mixture of 13.5 g POCl3 and 13.5 g N-methylformanilide was heated
for 10 min on the steam bath.  To this claret-colored solution was
added 7.28 g of 2,5-dimethoxyphenyl cyclopropylmethyl sulfide, and the
spontaneously exothermic mixture was heated for an additional 10 min
on the steam bath, and then quenched in 400 mL of 55 !C H2O with good
stirring.  After a few minutes a reddish solid phase separated.  This
was removed by filtration, and washed with additional H2O.  After
sucking as dry as possible, this 8.75 g of ochre-colored solid was
dissolved in 14 mL of boiling MeOH, and after cooling, filtering,
washing sparsely with MeOH, and air drying, gave 7.27 g of white solid
crystals of 2,5-dimethoxy-4-(cyclopropylmethylthio)benzaldehyde.  The
proton NMR spectrum was impeccable; CHO 9.38, ArH 7.27, 6.81 2 s.,
OCH3 3.93, 3.90 2 s., SCH2 t. 2.96, CH2, m. 1.72, and CH2, t. 1.11.

To a solution of 6.6 g 2,5-dimethoxy-4-(cyclopropylthio)benzaldehyde
in 82 g of nitromethane there was added 0.12 g of anhydrous ammonium
acetate, and the mixture was heated on the steam bath for 6 h.  The
reaction mixture was allowed to stand overnight producing a heavy
crystallization crop.  Filtration, washing lightly with MeOH, and air
drying gave 4.72 g of orange crystals of
2,5-dimethoxy-4-cyclopropylmethylthio-'-nitrostyrene as yellow
crystals.  The evaporation of the mother liquors and grinding of the
resulting solids with MeOH provided another 2.0 g of the product.

A solution LAH (40 mL of a 1 M solution in THF) was cooled, under He,
to 0 !C with an external ice bath.  With good stirring there was added
1.05 mL 100% H2SO4 dropwise over 10 min, to minimize charring.  This
was followed by the addition of 2.95 g
2,5-dimethoxy-4-cyclopropylmethylthio-'-nitrostyrene as a solid, over
the course of 10 min.  After a few min further stirring, the
temperature was brought up to a gentle reflux on the steam bath, then
all was cooled again to 0 !C.  The excess hydride was destroyed by the
cautious addition of 6 mL IPA followed by 3 mL 15% NaOH which gave the
aluminum oxide as a curdy white solid.  The reaction mixture was
filtered, and the filter cake washed with additional THF.  The
filtrate and washes were stripped of solvent under vacuum providing
about 1.8 g of a colorless oil.  The addition of dilute H2SO4 produced
a thick mass of white solids.  This was washed with CH2Cl2, and the
remaining aqueous phase, still containing solids, was made basic with
25% NaOH.  The aqueous phase was extracted with 3x75 mL CH2Cl2, and
the combined extracts stripped of solvent under vacuum.  The result
was 1.4 g of colorless oil.  This was distilled at 150-165 !C at 0.2
mm/Hg to give 1.2 g of a white oil.  This was dissolved in 6 mL IPA,
neutralized with 0.6 mL concentrated HCl producing spontaneous white
crystals.  These were diluted with 8 mL additional IPA, and suspended
under 60 mL anhydrous Et2O to provide, after filtering and air drying,
1.13 g of 2,5-dimethoxy-4-cyclo-propylmethylthiophenethylamine
hydrochloride (2C-T-8) as white crystals.

DOSAGE: 30 - 50 mg.

DURATION: 10 - 15 h.

QUALITATIVE COMMENTS: (with 30 mg) Bad taste, worse smell.  But I
like it.  I can paint easily, and wouldnUt hesitate to take a little
more next time, but this is enough with no one to talk to.  Manual
dexterity good.  Body rather warm.  WouldnUt mind fooling around.  In
retrospect, it has a smooth onset, and is not too stimulating.  This
is a good one.

(with 40 mg) This is beginning to develop at one and a half hours
into it.  High energy, good feeling.  I have had a heavy, dense
feeling between me and my work for several days now, but this is
rapidly dissolving, and with this loss, the day continues into one of
the most remarkable experiences I have ever had.  Excellent feelings,
tremendous opening of insight and understanding, a real awakening as
if I had never used these materials effectively before.  For the next
several hours it was an internal journey for me; I wished to interact
with myself.  I cannot recall all the details, but I did review many
aspects of myself and my personal relations.  I know that I am the
better for all of this.

(with 40 mg) I first noted the effects at three quarters of an hour,
and at two hours I have pain in my sinuses.  My head is split in two Q
this is not being two or three different people Q this is one person
with a head living in two different universes at the same time.  Not a
crisis experience, but one of extreme and prolonged discomfort.
Hypersensitivity to light, noise, motion, with the belief that it
would not go away when the chemical wore off.  My visual and spatial
perceptions were divided in two along a vertical axis, with both
halves moving in uncoordinated ways.  A feeling that the eyes were
working independently of each other.  Nausea without vomiting, even
when I tried to.  Vertigo became intolerable if I closed my eyes or
lay down, so I felt that I would never lie down or close my eyes
again.  Problems with 'boundaries.'  The outside environment seemed to
be getting inside my head.  The parts of myself seemed to either
separate uncontrollably or run together into someone I didnUt know.  A
late movie, and Tranxene, and a little sleep all helped me out of
this.  However, a buzzing in the head, an uncertain balance, and an
out-of-it feeling lasted for 3 days, and was still faintly present
after a week.

(with 43 mg) For the first two hours I rocked in place and felt quite
happy not trying to 'do' anything useful or expected, but watched some
excellent programs on TV.  Later I sat at the typewriter and felt the
energy and the opening of the particular kind of thinking-connection
that I associate with 2C-T-2.  I felt this very strongly; I was fully
into my own energy and capable of being aggressive if I decided to.  I
was very good humored and completely anchored to the earth.  In the
late evening I went to bed and felt that I would not allow myself to
sleep, since the tendency to go completely out of conscious body was
quite strong.  However, before I could get up and continue happily
writing, as I intended, I fell asleep.  I slept thoroughly, well, and
woke up the next day with good energy and a willingness to get on with
the day.

(with 50 mg) The whole experience was somewhat negative,
self-doubting, paranoid.  Basically, I am not in a good place.  No
constructive values ever knit, and although there was a lot of
talking, nothing positive developed.  I was glad of sleep at about
twelve hours into it, and this aspect of it was completely friendly.
Next day, no deficit.  Strange.  Maybe too much.

EXTENSIONS AND COMMENTARY: With 2C-T-8, there are as many negatives as
there are positives, and the particular substitution pattern is not
one to set the world on fire.  The first step was made towards the
synthesis of the 3-carbon counterpart,
2,5-dimethoxy-4-cyclopropylmethylthioamphetamine, ALEPH-8.  The above
benzaldehyde (2.2 g) was cooked overnight on the steam bath in
nitroethane (20 mL) containing ammonium acetate (0.4 g) and when the
solvent was removed, the residue was converted to orange crystals by
the addition of a little MeOH.  This was not pursued further.
Although the cyclopropylmethyl group was quite something on the
mescaline oxygen atom, it is less appealing on the 2C-T-X sulfur atom,
and there is even less enthusiasm to put it into an ALEPH.  That's the
way it is, and who could have guessed!









#45 2C-T-9; 2,5-DIMETHOXY-4-(t)-BUTYLTHIOPHENETHYLAMINE

SYNTHESIS: To a well-stirred ice-cold suspension of 2.8 g
p-dimethoxybenzene and 3.2 mL N,N,NU,NU-tetramethylethylenediamine in
100 mL petroleum ether under an inert atmosphere of He, there was
added 13 mL of a 1.6 N solution of butyllithium in hexane.  The
suspended dimethoxybenzene became opaque and there was a pale yellow
color generated.  The reaction mixture was warmed to room temperature
which converted it to light white solids.  After an additional 0.5 h
stirring, there was added, slowly, 3.6 g of di-(t)-butyldisulfide.
The yellow color deepened, the solids dissolved and, after 1 h, the
color was a clear deep brown.  This solution was poured into 100 mL
dilute HCl and the organic phase was separated.  The aqueous fraction
was extracted with 3x75 mL CH2Cl2.  The combined organic phases were
washed with dilute aqueous NaOH, with H2O, and then stripped of
solvents under vacuum.  The residue was distilled at 95-105 !C at 0.5
mm/Hg to provide 3.7 g of 2,5-dimethoxyphenyl (t)-butyl sulfide as a
white, mobile liquid.  Anal. (C12H18O2S) C,H.  A solid derivative was
found in the nitration product,
2,5-dimethoxy-4-(t)-butylthio-1-nitrobenzene, which came from the
addition of 0.11 mL of concentrated HNO3 to a solution of 0.23 g of
the above sulfide in 5 mL ice cold acetic acid.  Dilution with H2O
provided yellow solids which, on recrystallization from MeOH, had a mp
of 92-93 !C.  Anal. (C12H17NO4S) C,H.  Attempts to make either the
picrate salt or the sulfonamide derivative were not satisfactory.

A mixture of 72 g POCl3 and 67 g N-methylformanilide was heated for 10
min on the steam bath.  To this claret-colored solution was added 28 g
of 2,5-dimethoxyphenyl (t)-butyl sulfide, and the mixture heated for
10 min on the steam bath.  This was then added to 1 L of H2O and
stirred overnight.  The residual brown oil was separated from the
water mechanically, and treated with 150 mL boiling hexane.  The
hexane solution was decanted from some insoluble tars, and on cooling
deposited a dark oil which did not crystallize.  The remaining hexane
was removed under vacuum and the residue combined with the above
hexane-insoluble dark oil, and all distilled at 0.2 mm/Hg.  An early
fraction (70-110 !C) was largely N-methyl-formanilide and was
discarded.  Crude 2,5-dimethoxy-4-(t-butylthio)benzaldehyde came over
at 120-130 !C and weighed 12.0 g.  This was never satisfactorily
crystallized despite the successful formation of seed.  It was a
complex mixture by TLC, containing several components.  It was used
for the next step as the crude distilled fraction.

To a solution of 10 g impure 2,5-dimethoxy-(t-butylthio)benzaldehyde
in 75 mL of nitromethane there was added 1.0 g of anhydrous ammonium
acetate, and the mixture was heated on the steam bath 1.5 h.  Removal
of the excess solvent/reagent under vacuum produced an orange oil that
was (not surprisingly) complex by TLC and which would not crystallize.
A hot hexane solution of this oil was allowed to slowly cool and stand
at room temperature for several days, yielding a mixture of yellow
crystals and a brown viscous syrup.  The solids were separated and
recrystallized from 40 mL MeOH to give 3.7 g
2,5-dimethoxy-4-(t)-butylthio-'-nitrostyrene as fine lemon-yellow
crystals, with a mp of 93-94 !C.  A second crop of 1.4 g had a mp of
91-92 !C.  Anal. (C14H19NO4S) C,H.

A solution of LAH (70 mL of a 1 M solution in THF) was cooled, under
He, to 0 !C with an external ice bath.  With good stirring there was
added 2.1 mL 100% H2SO4 dropwise, over the course of 20 min.  This was
followed by the addition of 4.7 g
2,5-dimethoxy-4-(t)-butylthio-'-nitrostyrene in 20 mL anhydrous THF.
There was an immediate loss of color.  After a few min further
stirring, the mixture was allowed to come to room temperature, and the
stirring was continued for 5 h.  The excess hydride was destroyed by
the cautious addition of 10 mL IPA followed by 6 mL 15% NaOH and
finally 6 mL H2O.  The loose white solids were removed by filtration,
and the filter cake washed with THF.  The filtrate and washes were
combined and, after stripping off the solvent under vacuum, there was
obtained 4.66 g of a pale yellow oil.  Without any further
purification, this was distilled at 0.2 mm/Hg.  A first fraction came
over at up to 120 !C and was a light colorless oil that was not
identified.  The correct product distilled at 130-160 !C as a pale
yellow viscous oil that weighed 1.66 g.  This was dissolved in 10 mL
IPA, neutralized with 20 drops of concentrated HCl and diluted with 80
mL anhydrous Et2O.  After standing a few min there was the spontaneous
generation of white crystals of
2,5-dimethoxy-4-(t)-butylthiophenethylamine hydrochloride (2C-T-9)
which were removed by filtration, and air dried.  The weight was 1.10
g.

DOSAGE: 60 - 100 mg.

DURATION: 12 - 18 h.

QUALITATIVE COMMENTS: (with 90 mg) 2C-T-9 tastes the way that old
crank-case motor oil smells.  I was up to something above a plus two
at the third hour.  Although there were no visuals noted, I certainly
would not choose to drive.  Somehow this does more to the body than to
the head.  I feel that the effects are waning at maybe the sixth hour,
but there is a very strong body memory that makes sleeping difficult.
Finally, at sometime after midnight and with the help of a glass of
wine, some sleep.

(with 125 mg) There was a steady climb to a +++ over the first couple
of hours.  So far, the body has been quite peaceful without any strong
energy push or stomach problems, although my tummy insists on being
treated with quiet respect, perhaps out of habit, perhaps not.  At the
fifth hour, the body energy is quite strong, and I have the choice of
focusing it into some activity, such as love-making or writing, or
having to deal with tapping toes and floor-pacing.  For a novice this
would be a murderously difficult experience.  Too much energy, too
long a time.  I suppose I could get used to it, but let me judge by
when I get to sleep, and just what kind of sleep it is.  It turned out
that sleep was OK, but for the next couple of days there was a
continuing awareness of some residue in the body Q some kind of
low-level poisoning.  I feel in general that there is not the
excitement or creativity to connect with, certainly not enough to
justify the cost to the body.

EXTENSIONS AND COMMENTARY: The three-carbon analog of 2C-T-9 (this
would be one of the ALEPH series) has never been made and, for that
matter, none of the higher numbered 2C-T's have had the amphetamine
counterparts synthesized.  They are, as of the present time, unknown
compounds.  This nifty reaction with di-(t)-butyl disulfide worked so
well, that three additional disulfides that were at hand were
immediately thrown into the chemical program, with the quick
assignment of the names 2C-T-10, 2C-T-11, and 2C-T-12.

The lithiated dimethoxybenzene reaction with 2,2-dipyridyl disulfide
produced 2,5-dimethoxyphenyl 2-pyridyl sulfide which distilled at
135-150 !C at 0.4 mm/Hg and could be recrystallized from cyclohexane
containing 2% EtOH to give a product that melted at 66-67.5 !C.  Anal.
(C13H13NO2S) C,H.  This would have produced
2,5-dimethoxy-4-(2-pyridylthio)phenethylamine (2C-T-10) but it was
never pursued.

The same reaction with di-(4-bromophenyl) disulfide produced
2,5-dimethoxyphenyl 4-bromophenyl sulfide which distilled at 150-170
!C at 0.5 mm/Hg and could be recrystallized from MeOH to give a
product that melted at 72-73 !C.  Anal. (C14H13BrO2S) C,H.  This was
being directed towards
2,5-dimethoxy-4-(4-bromophenylthio)phenethylamine (2C-T-11) but it
also was abandoned.

The same reaction with N,N-dimorpholinyl disulfide produced virtually
no product at all, completely defusing any plans for the synthesis of
a novel sulfur-nitrogen bonded base
2,5-dimethoxy-4-(1-morpholinothio)phenethylamine (2C-T-12).  One
additional effort was made to prepare a 2C-T-X thing with a
sulfur-nitrogen bond.  The acid chloride intermediate in the
preparation of 2,5-dimethoxythiophenol (as described in the recipe for
2C-T-2) is 2,5-dimethoxybenzenesulfonyl chloride.  It reacted smoothly
with an excess of diethylamine to produce
2,5-dimethoxy-N,N-diethylbenzenesulfonamide which distilled at 155 !C
at 0.13 mm/Hg and which could be recrystallized from a 4:1 mixture of
cyclohexane/benzene to give a product with a melting point of 41-42 !C
and an excellent proton NMR.  This amide proved totally refractory to
all efforts at reduction, so the target compound,
2,5-dimethoxy-4-diethylaminothiophenethylamine, has not been made.  It
has not even been given a 2C-T-X number.









#46 2C-T-13; 2,5-DIMETHOXY-4-(2-METHOXYETHYLTHIO)PHENETHYLAMINE

SYNTHESIS: To a solution of 3.25 g of KOH pellets in 25 mL hot MeOH,
there was added 6.8 g of 2,5-dimethoxythiophenol (see under 2C-T-2 for
its preparation) followed by 4.73 g of 2-methoxyethylchloride.  This
mixture was heated on the steam bath for 0.5 h, then added to 500 mL
H2O.  This very basic aqueous phase was extracted with 3x100 mL
CH2Cl2, the extracts pooled, and back-washed with 5% NaOH.  The
solvent was removed under vacuum to give 8.82 g of a white oil.
Distillation gave 2,5-dimethoxyphenyl 2-methoxyethyl sulfide with a bp
115-125 !C at 0.3 mm/Hg, and a weight of 6.65 g.

A mixture of 10 g POCl3 and 10 g N-methylformanilide was heated for 10
min on the steam bath.  To this claret-colored solution was added 6.16
g of 2,5- dimethoxyphenyl 2-methoxyethyl sulfide. There was an
immediate exothermic reaction and gas evolution.  The mixture was
heated for 15 min on the steam bath, at which time there was no
starting sulfide present by TLC.  This was then added to 500 mL of
well-stirred warm H2O (pre-heated to 55 !C) and the stirring continued
until only a thin oily phase remained.  This was extracted with
CH2Cl2, the extracts were combined, and the solvent removed under
vacuum.  The residue was extracted with 5 sequential 20 mL portions of
boiling hexane which deposited crystals on cooling.  Filtering gave a
total of 4.12 g crystalline solids.  Recrystallization from MeOH gave
a poor yield of a cream-colored crystal with a mp of 68-69 !C.  A more
efficient purification was achieved by distillation (155-168 !C at 0.3
mm/Hg) yielding 3.50 g of
2,5-dimethoxy-4-(2-methoxyethylthio)benzaldehyde as a pale yellow
solid, with a mp of 67-68 !C.  A faster moving (by TLC) trace
component with an intense fluo-rescence persisted throughout the
entire purification scheme, and was still present in the analytical
sample.  Anal. (C12H16O4S) C,H.

To a solution of 3.41 g
2,5-dimethoxy-4-(2-methoxyethylthio)benzaldehyde in 50 g of
nitromethane there was added 0.11 g of anhydrous ammonium acetate, and
the mixture was heated on the steam bath for 2 h, at which time the
starting aldehyde had largely disappeared by TLC (silica gel plates
with CH2Cl2 as the developing solvent) and a faster moving
nitrostyrene product was clearly visible.  The clear orange solution
was stripped of the excess nitromethane under vacuum producing a
yellow oil that crystallized yielding 3.97 g of a yellow solid with a
mp of 99-104 !C.  Recrystallization of a small sample from MeOH
produced (when dry) yellow electrostatic crystals of
2,5-dimethoxy-4-(2-methoxyethylthio)-'-nitrostyrene with a mp of 107
!C sharp.  From IPA the product is a burnished gold color with the mp
106-107 !C.  Anal. (C13H17NO5S) C,H.

A solution of LAH (40 mL of a 1 M solution in THF) was cooled, under
He, to 0 !C with an external ice bath.  With good stirring there was
added 1.05 mL 100% H2SO4 dropwise, to minimize charring.  This was
followed by the addition of 3.07 g
2,5-dimethoxy-4-(2-methoxyethylthio)-'-nitrostyrene in small portions,
as a solid, over the course of 10 min.  There was a considerable
amount of gas evolved, and a little bit of charring.  After a few min
further stirring, the temperature was brought up to a gentle reflux on
the steam bath, and then all was cooled again to 0 !C.  The excess
hydride was destroyed by the cautious addition of 8 mL IPA followed by
3 mL 15% NaOH which gave the reaction mixture a curdy white granular
character.  The reaction mixture was filtered, the filter cake washed
with THF, and filtrate and washes were stripped of solvent under
vacuum providing about 3 g of a pale amber oil.  This was dissolved in
about 40 mL CH2Cl2 and extracted with 200 mL dilute H2SO4 in three
portions.  All of the color remained in the organic phase.  The pooled
aqueous extracts were washed with CH2Cl2, then made basic with 25%
NaOH, extracted with 3x75 mL CH2Cl2, and the combined extracts pooled
and stripped of solvent under vacuum.  The 2 g pale yellow oily
residue was distilled at 155-165 !C at 0.2 mm/Hg to give 1.23 g of a
clear white oil.  This was dissolved in IPA, neutralized with
concentrated HCl, and diluted with anhydrous Et2O to produce crystals
of 2,5-dimethoxy-4-(2-methoxyethylthio)phenethylamine hydrochloride
(2C-T-13).  After filtration, washing with Et2O, and air drying, this
white crystalline product weighed 0.89 g.

DOSAGE: 25 - 40 mg.

DURATION: 6 - 8 h.

QUALITATIVE COMMENTS: (with 25 mg) I felt it was somewhat noisy as we
went into the experience.  This noisiness lasted only about an hour,
then stopped.  At the peak, which seemed to be at about 1 to maybe 1.5
hours, some eyes-closed visuals appeared.  There was a white field
with colored visuals, at times geometric in shape. These eye-closed
images were pleasant and I enjoyed them when I did not concern myself
with, or listen to, the conversation.  There was an eyes-open change
in color, the ivy became a little lighter or maybe a little stronger
in color.  IUm not sure which.  I felt there was a gradual diminishing
of activity (whatever that undefined activity was) starting at 2 to
2.5 hours, and coming close to baseline at 6 PM.  The descent was
pleasant and I would say pleasurable.  The experience did not lead to
any confusion which I sometimes notice in other experiences.  There
was no problem with anorexia.  We ate constantly during the
experience.  The grapes and other fruit were lovely.  This is one of
the few times I would say that I would try a higher dose.  Maybe 30 or
33 milligrams.  I suspect the experience would be similar, with just a
heightened peak at 1 hour and perhaps a little more body effect.  It
may well be one to try with one's wife.

(with 28 mg) There was a strange, disturbing twinge exactly eight
minutes after starting this, that asked me, TShould I have done this?U
I answered, TYesU and the twinge disappeared.  And then there was
nothing until the expected time of development, at a half hour when I
felt a light head and slight dizziness.  There was a solid plus two
for a couple of hours.  I paid careful attention for auditory oddities
that I had noted before, but they were not there.  In an earlier trial
(with 20 milligrams) the radio had the sound of being located in the
outdoors with the sounds coming through the wall and into the room
where I was.  I was at a neutral baseline at about seven hours.

(with 35 mg) There was a quiet climb, but it was marred with some
tummy unquiet, and an annoying persistence of diarrhea.  I was very
impressed with eyes-closed patterning, which seemed to do its own
thing independently of the music.  I was clearly up to a +++, but
there was a feeling that as soon as it got there it started to go away
again.  There was no there, there.  Yet there were a couple of touches
of introspection, of seriousness which I had to respect.

(with 40 mg) There were four of us, and the entry was individual for
each of us.  Two of us were nauseous.  One volunteered a statement,
almost a confession, of too much food and drink in the immediate past.
One of us needed his cigarette right now, and then he saw that he was
killing himself, and he swore off.  DonUt know if it will last,
however.  At the two and a half hour point there is a consensus that
this has gone its route and will lose its impact, so three of us
decided to supplement on 2C-T-2.  Six milligrams proves to be a little
light so, some four hours later, we each took another six milligrams.
Excellent.  In a while we discoved that we were very hungry, and food
tasted marvelous.  Headaches acknowledged in the early evening, but
the extension from T-13 to T-2 seemed to be absolutely correct.  And
as of the next day, the non-smoker was still a non-smoker.

EXTENSIONS AND COMMENTARY: Most of the synthetic adventures of putting
a basic something aways out from the benzene ring, at the
four-position, have involved subtle things such as unsaturated bonds
or three-membered rings.  This was the first try with the actual use
of a different atom (an oxygen).  What about other heteroatoms such as
sulfur or nitrogen or silicon or phosphorus, or some-such?

The sulfur counterpart of 2C-T-13 was named 2C-T-14, and was
immediately launched.  The reaction of 2,5-dimethoxythiophenol and KOH
with 2-methyl-thioethyl chloride in hot MeOH gave 2,5-dimethoxyphenyl
2-methylthioethyl sulfide as a white oil (boiling point of 140-160 !C
at 0.3 mm/Hg).  This underwent a normal Vilsmeier reaction
(phosphorous oxychloride and N-methylformanilide) to give
2,5-dimethoxy-4-(2-methylthioethylthio)benzaldehyde with a melting
point of 64-64.5 !C from MeOH.  This, in nitromethane containing a
little ammonium acetate, was heated on the steam bath for 10 hours and
worked up to give an excellent yield of
2,5-dimethoxy-4-(2-methylthioethylthio))-'-nitrostyrene as garish
orange-red RLas VegasS colored crystals from acetonitrile, with a
melting point of 126-127 !C.  And as of the moment, this is sitting on
the shelf waiting to be reduced to the target compound
2,5-dimethoxy-4-(2-methylthioethylthio)phenethylamine hydrochloride,
or 2C-T-14.  Will it be active?  I rather suspect that it will be, and
IUll bet it will be longer-lived than the oxygen model, 2C-T-13.









#47 2C-T-15; SESQUI; 2,5-DIMETHOXY-4-CYCLOPROPYLTHIOPHENETHYLAMINE

SYNTHESIS: To a solution of 3.3 g of KOH pellets in 150 mL hot MeOH,
there was added 10 g 2,5-dimethoxythiophenol (see recipe for 2C-T-2
for its preparation) followed by 10 g 1-bromo-3-chloropropane.  The
reaction was exothermic, and immediately deposited white solids of
KCl.  The reaction mixture was warmed for a few min on the steam bath,
and then quenched in H2O.  The basic reaction mixture was extracted
with 3x75 mL CH2Cl2.  The pooled extracts were stripped of solvent
under vacuum.  The residual oil was distilled at 145-155 !C at 0.2
mm/Hg to give 16.5 g of 2,5-dimethoxyphenyl 3-chloropropyl sulfide as
a clear, colorless oil.

A solution of the lithium amide of 2,2,6,6-tetramethylpiperidine was
prepared by the addition of 20 mL of 2.6 M butyllithium in hexane to a
well stirred hexane solution of the piperidine in 100 mL hexane, under
an atmosphere of He.  The reaction was exothermic, formed a white
solid precipitate, and was allowed to continue stirring for a few min.
There was then added 6.5 g 2,5-dimethoxphenyl 3-chloropropyl sulfide,
and a strongly exothermic reaction ensued.  This was stirred for 30
min and then poured into dilute H2SO4 (the progress of the reaction
must be followed by TLC, silica gel plates, CH2Cl2:petroleum ether
50:50 to determine when it is done; in one run over 2 h were required
for completion of the reaction).  The organic phase was separated, and
the aqueous phase extracted with 3x75 mL EtOAc.  The combined organic
phases were washed first with dilute NaOH, then with dilute HCl, then
the solvents were removed under vacuum.  The residue was distilled to
provide 2,5-dimethoxyphenyl cyclopropyl sulfide as a pale yellow
liquid that boiled at 100-115 !C at 0.1 mm/Hg.  The use of other bases
to achieve this cyclization were less successful.  Incomplete
cyclization resulted from the use of lithium diisopropyl amide and, if
the conditions were made more vigorous, there was dehydrohalogenation
to the allyl sulfide.  An unexpected difficulty was that the allyl
sulfide (from elimination) and the 3-chloropropyl sulfide (starting
material) behaved in an identical manner on TLC analysis.  They were
easily separated, however, by GC analysis.

A completely different approach to the synthesis of this sulfide was
explored through the reaction of cyclopropyllithium with an aromatic
disulfide, thus avoiding the base-promoted cyclization step.  A
solution of 2.6 g di-(2,5-dimethoxyphenyl)disulfide (from
2,5-dimethoxythiophenol and hydrogen peroxide, bp 220-230 !C at 0.3
mm/Hg) was made in anhydrous Et2O, and well stirred.  In a separate
flask, under an atmosphere of He, 4 mL of 2.6 M butyllithium was added
to a solution of 1.2 g cyclopropyl bromide in 20 mL anhydrous Et2O.
This mildly exothermic combination turned a bit cloudy, was stirred
for 1 h, then trans-ferred with an air-tight syringe to the
above-described Et2O solution of the aromatic disulfide.  A heavy
precipitate formed, and stirring was continued for an additional 0.5
h.  The reaction mixture was then poured into H2O, the layers
separated, and the aqueous phase extracted with CH2Cl2.  The extracts
were pooled, washed with dilute aqueous KOH, and the solvents removed
under vacuum.  Distillation gave 0.7 g of 2,5-dimethoxyphenyl
cyclopropyl sulfide with identical gas chromatographic behavior to the
sample prepared by the cyclization of the chloropropylthio compound.

A mixture of 7.2 g POCl3 and 6.7 g N-methylformanilide was heated on
the steam bath until it was claret red.  To this there was added 4.5 g
of 2,5-di-methoxyphenyl cyclopropyl sulfide, and the exothermic
combination heated on the steam bath for about 5 min.  The deep red,
bubbling reaction mixture was added to 150 mL H2O and stirred until
all oils had been converted into loose solids.  These were then
removed by filtration, washed with H2O, and sucked as dry as possible.
They were dissolved in boiling MeOH which, after cooling in an
ice-bath, deposited yellow crystals of
2,5-dimethoxy-4-(cyclopropylthio)benzaldehyde that weighed 3.43 g
after air drying, and had a mp of 97-99 !C.  Anal. (C12H14O3S) C,H.

To a solution of 3.0 g 2,5-dimethoxy-4-(cyclopropylthio)benzaldehyde
in 40 g of nitromethane there was added 0.2 g of anhydrous ammonium
acetate, and the mixture was heated on the steam bath for 3 h.  The
excess nitromethane was removed under vacuum yielding 3.4 g orange
crystals.  These were recrystallized from 150 mL boiling IPA
containing a little toluene.  After cooling, filtering, and air drying
there were obtained 2.75 g of
2,5-dimethoxy-4-cyclopropylthio-'-nitro-styrene as pumpkin-colored
crystals with a mp of 159-160 !C.  Anal. (C13H15NO4S) C,H.

A solution of LAH (40 mL of a 1 M. solution in THF) was cooled, under
He, to 0 !C with an external ice bath.  With good stirring there was
added 1.05 mL 100% H2SO4 dropwise, to minimize charring.  This was
followed by the addition of 2.5 g
2,5-dimethoxy-4-cyclopropylthio-'-nitrostyrene in 40 mL anhydrous THF
over the course of 15 min.  There was an immediate loss of color.
After a few min further stirring, the temperature was brought up to a
gentle reflux on the steam bath and held there for 2 h.  After
recooling, there was added IPA (to destroy the excess hydride)
followed by sufficent 15% NaOH to give a white granular character to
the oxides, and to assure that the reaction mixture was basic.  The
reaction mixture was filtered, and the filter cake washed with THF.
The filtrate and washes were stripped of solvent under vacuum
providing a yellow oil that was treated with dilute H2SO4.  This
produced a flocculant white solid, apparently the sulfate salt of the
product.  This was washed with 4x75 mL CH2Cl2 which removed most of
the yellow color.  The aqueous phase was made basic with aqueous NaOH
and extracted with 3x75 mL CH2Cl2.  Removal of the solvent under
vacuum gave a light yellow colored oil that was distilled at 0.3
mm/Hg.  The fraction boiling at 140-150 !C was a colorless, viscous
oil that weighed 1.97 g.  This was dissolved in a few mL IPA, and
neut-ralized with concentrated HCl forming immediate cottage
cheese-like crystals of the hydrochloride salt.  This was diluted by
suspension in anhydrous Et2O, removed by filtration, and air dried to
give 1.94 g of 2,5-dimethoxy-4-cyclopropylthiophenethylamine
hydrochloride (2C- T-15) that had a mp of 203-5-204.5 !C.  Anal.
(C13H20ClNO2S) C,H.

DOSAGE: greater than 30 mg.

DURATION: several hours.

QUALITATIVE COMMENTS: (at 30 mg) I was somewhere between a threshold
and a plus one for several hours, and appeared to be quite talkative
in the evening.

EXTENSIONS AND COMMENTARY: The commonly used name for 2C-T-15, during
its synthesis, was SESQUI.  The general name for a 15-carbon terpene
is sesquiterpene, from the Latin prefix for one and a half.  The
active level of 2C-T-15 is not known.  The highest level yet tried was
30 milligrams orally, and there had been threshold reports pretty
regularly all the way up from 6 milligrams.  But no definite activity
yet. This compound is isosteric with the isopropyl group as seen in
the analogous compound 2C-T-4 (the three carbons are in exactly the
same positions, only the electrons are located differently) and it is
a little surprising that the potency appears to be considerably less.
Just over 20 milligrams of the latter compound was overwhelmingly
psychedelic.

The entire mini-project of hanging cyclic things onto the sulfur atom
was an interesting problem.  This is the three carbon ring.  The six
carbon ring (the cyclohexyl homologue) was discussed as 2C-T-5 in the
recipe for of ALEPH-2.  The cyclobutyl and cyclopentyl homologs were
assigned the names of 2C-T-18 and 2C-T-23, respectively, and their
preparations taken as far as the nitrostyrene and the aldehyde stages,
respectively, before the project ran out of steam.

Towards the cyclobutyl homologue, a solution of
2,5-dimethoxythiophenol and cyclobutyl bromide in DMSO containing
anhydrous potassium carbonate was stirred for several hours at room
temperature and yielded 2,5-dimethoxyphenyl cyclobutyl sulfide as a
white oil that boiled at 135-140 !C at 0.3 mm/Hg.  Anal. (C12H16O2S)
C,H.  This was brought to react with a mixture of phosphorus
oxy-chloride and N-methylformanilide producing
2,5-dimethoxy-4-(cyclobutylthio)benzaldehyde that had a melting point
of 108-109.5 !C from MeOH.  Anal. (C13H16O3S) C,H.  Coupling with
nitromethane in the presence of ammonium acetate produced
2,5-dimethoxy-4-cyclobutylthio-'-nitrostyrene as lustrous orange
crystals from boiling acetonitrile, melting point 160-161 !C.  Anal,
(C14H17NO4S) C,H.  This will some day be reduced to
2,5-dimethoxy-4-cyclobutylthiophenethylamine hydrochloride, 2C-T-18.

Towards the cyclopentyl homologue, a solution of
2,5-dimethoxythiophenol and cyclopentyl bromide in DMSO containing
anhydrous potassium carbonate was stirred for several hours at room
temperature and yielded 2,5-dimethoxyphenyl cyclopentyl sulfide as a
white oil that boiled at 135-145 !C at 0.3 mm/Hg.  This was brought to
react with a mixture of phosphorus oxychloride and N-methylformanilide
producing 2,5-dimethoxy-4-(cyclopentylthio)benzaldehyde as yellow
crystals from MeOH.  This will some day be converted to the
nitrostyrene and then reduced to
2,5-dimethoxy-4-cyclopentylthiophenethylamine hydrochloride, 2C-T-23.









#48 2C-T-17; NIMITZ; 2,5-DIMETHOXY-4-(s)-BUTYLTHIOPHENETHYLAMINE

SYNTHESIS: To a solution of 2.6 g of KOH pellets in 50 mL hot MeOH,
there was added a mixture of 6.8 g 2,5-dimethoxythiophenol (see under
2C-T-2 for its preparation) and 5.8 g (s)-butyl bromide.  The reaction
was exothermic, with the deposition of white solids.  This was heated
on the steam bath for a few h, the solvent removed under vacuum, and
the resulting solids dissolved in 250 mL H2O.  Additional aqueous NaOH
was added to bring universal pH paper to a full blue color.  This was
extracted with 3x40 mL CH2Cl2, the extracts pooled, and the solvent
removed under vacuum.  The residue was 2,5-dimethoxyphenyl (s)-butyl
sulfide which was a pale yellow oil, weighing 10.12 g.  It was
sufficiently pure for use in the next reaction without a distillation
step.

A mixture of 15.1 g POCl3 and 14.1 g N-methylformanilide was heated
for 10 min on the steam bath.  To this claret-colored solution was
added 9.4 g of 2,5-dimethoxyphenyl (s)-butyl sulfide, and the mixture
heated for 35 min on the steam bath.  This was then added to 200 mL of
well-stirred warm H2O (pre-heated to 55 !C) and the stirring continued
until the oily phase had completely solidified (about 15 min).  These
light brown solids were removed by filtration, and washed with
additional H2O.  After sucking as dry as possible, these solids (12.14
g wet) were ground under an equal weight of MeOH which produced a
yellowish crystalline solid with a mp of 76-81 !C.  Recrystallization
of a 0.4 g sample from an equal weight of boiling MeOH provided 0.27 g
of 2,5-dimethoxy-4-(s-butylthio)benzaldehyde as a pale cream-colored
crystalline material with a mp of 86-87 !C.

To a solution of 8.0 g of the crude
2,5-dimethoxy-4-(s-butylthio)benzaldehyde in 40 g of nitromethane
there was added 0.38 g of anhydrous ammonium acetate, and the mixture
was heated on the steam bath for 1 h.  The reddish colored solution
was decanted from some insoluble tan material and the excess
nitromethane removed under vacuum.  The heavy red oil that remained
was diluted with an equal volume of boiling MeOH, and allowed to
return to room temperature.  The orange-colored crystals that slowly
formed were removed by filtration and, after air drying, weighted 6.24
g.  This was again recrystallized from an equal volume of MeOH,
yielding 2,5-dimethoxy-4-(s-butylthio)-'-nitrostyrene as yellow,
somewhat beady crystals that weighed (when dry) 3.50 g and which had a
mp of 62-65 !C.  A small portion of this fraction was crystallized yet
again from MeOH to provide an analytical sample that was yellow-orange
in color, and had an mp of 68-69 !C.  Anal. (C13H17NO4S) C,H.

A solution of LAH (120 mL of a 1 M solution in THF) was cooled, under
He, to 0 !C with an external ice bath.  With good stirring there was
added 3.3 mL 100% H2SO4 dropwise, to minimize charring.  This was
followed by the addition of 8.83 g
2,5-dimethoxy-4-(s-butylthio)-'-nitrostyrene in 80 mL anhydrous THF
dropwise over the course of 2 h.  After a few min further stirring,
the temperature was brought up to a gentle reflux on the steam bath,
and then all was cooled again to 0 !C.  The excess hydride was
destroyed by the cautious addition of 18 mL IPA followed first by 5 mL
of 15% NaOH and then by 15 mL of H2O.  The reaction mixture was
filtered, and the filter cake washed with THF.  The filtrate and
washing were combined and stripped of solvent under vacuum providing
about 8.5 g of a pale amber oil.  Without any further purification,
this was distilled at 135-150 !C at 0.4 mm/Hg to give 6.12 g of a
clear white oil.  This was dissolved in 30 mL IPA, and neutralized
with 2.1 mL of concentrated HCl forming crystals immediately.  Another
10 mL of IPA was added to allow the solids to be finely dispersed, and
then about 100 mL of anhydrous Et2O were added.  The solids were
removed by filtration, Et2O washed, and air dried to constant weight.
The product, 2,5-dimethoxy-4-(s)-butylthiophenethylamine hydrochloride
(2C-T-17) was obtained as spectacular white crystals, weighing 5.67 g.

DOSAGE: 60 - 100 mg.

DURATION: 10 - 15 h.

QUALITATIVE COMMENTS: (with 60 mg) This material took fully three
hours to get into its maximum effect.  I never was at a +++, quite,
and I am not sure why it is really active, but I know it is.  There
does not seem to be any interference with my concentration or mental
coordination, but I wouldnUt want to drive right now.  Good appetite
in the evening, for a Chicago-style pizza, and there was no Tomso
effects (the rekindling of a psychedelic effect with alcohol) with a
glass of wine.  An over-all good and instructive ++, no visuals,
totally benign.  There is no hesitation in doing it again some day.

(with 100 mg) A small fragment hadnUt dissolved when I drank the
solution, and it must have stuck to the back of my mouth, because it
made a searing spot that burned for 5 minutes.  The first central
effects were noted at an hour.  The plateau stretched from the 3rd to
the 7th hour, then tapered off quite quickly.  My sleep was fitful,
with some hints of nervous sensitivity.  I felt that there were some
residuals even into the next morning.  A truly heavy psychedelic, but
with very few explicit sensual changes or unusual perceptions to
justify that comment.  Why is it heavy?  It just is.  This dosage is
high enough.

EXTENSIONS AND COMMENTARY: An interesting, and quite logical, habit
that seems to always pop up when a lot of talk and energy become
directed at a specific compound, is the habit of using a nickname for
it.  The Tweetios are an example, and in the 2C-T-X family I had
mentioned the term SESQUI.  Here, this compound was called NIMITZ, for
the obvious reason that the major freeway from Oakland to San Jose,
the Nimitz freeway, was also called State Highway 17.  Its name has
been changed to Interstate 880, and I guess it could now only be used
as a reference point if efforts were being made for a 2C-T-880.

The reason that 2C-T-17 is of special theoretic interest is that it is
one of the very first of the active psychedelic compounds (along with
2C-G-5) to have a potential optically active center on the side of the
ring away from the nitrogen atom.  One of the oldest and best studied
variants of the phenethylamine chain are the alpha-methyl homologues,
the substituted amphetamines.  Here there is an asymmetric carbon atom
right next to the amine group, allowing the molecule to be prepared in
either a right-hand way or a left-hand way.  The RRS or the RSS
isomer.  And in the several studies that have looked at such isomers
separately, it has always been the RRS isomer that has carried the
psychedelic effects.  This probably says something about the nitrogen
end, the metabolic end, the RnorthS end of the receptor site that
recognizes these compounds, and suggests that there is some intrinsic
asymmetry in the area that binds near to the basic nitrogen atom.

But very little is known of the receptor's RsouthS end, so to speak,
the geometry of the area where the opposite end of the molecule has to
fit.  Here, with 2-C-17, there is a secondary butyl group, and this
contains an asymmetric carbon atom.  But now this center of asymmetry
is clear across the benzene ring from the nitrogen, and should
certainly be in some entirely new part of the receptor site.  Why not
make this compound with the RRS and the RSS forms in this new and
unusual location?  Why not, indeed!  Why not call them the right-lane
and the left lane of the Nimitz?  Fortunately, both RRS and RSS
secondary butyl alcohols were easily obtained, and the synthesis given
above for the racemic compound was paralleled for each of these
isomers, separately.  Is there any chemistry that is different with
the specific optical isomers from that which has been reported with
the racemic?  There certainly is for the first step, since the butyl
alcohols rather than the butyl bromides must be used, and this first
step must go by inversion, and it cannot be allowed any racemization
(loss of the optical purity of the chiral center).

The synthesis of 2C-T-17 RRS required starting with the RSS isomer of
secondary butanol.  The RSS 2-butanol in petroleum ether gave the
lithium salt with butyllithium which was treated with tosyl chloride
(freshly crystallized from naphtha, hexane washed, used in toluene
solution) and the solvent was removed.  The addition of
2,5-dimethoxythiophenol, anhydrous potassium carbonate, and DMF
produced RSS 2,5-dimethoxyphenyl s-butyl sulfide.  The conversion to
RRS 2,5-dimethoxy-4-(s-butyl-thio)benzaldehyde (which melted at 78-79
!C compared to 86-87 !C for the racemic counterpart) and its
conversion in turn to the nitrostyrene,
RSS-2,5-dimethoxy-4-(s)-butylthio-'-nitrostyrene which melted at 70-71
!C compared to 68-69 !C for the racemic counterpart, followed the
specific recipes above.  The preparation of the intermediates to
2C-T-17 RSS follows the above precisely, but starting with RRS
2-butanol instead.  And it is at these nitrostyrene stages that this
project stands at the moment.

It would be fascinating if one of the two optically active 2C-T-17Us
carried all of the central activity, and the other, none of it.  What
is more likely is that the spectrum of effects will be teased apart,
with one isomer responsible for some of them and the other isomer
responsible for the others.  Then, again, maybe the south end of the
receptor site in the brain is totally symmetric, and the two optical
antipodes will be indistinguishable.

An incidental bit of trivia Q yet another bit of evidence that we are
all totally asymmetric in our personal body chemistry.  RRS and RSS
secondary butanols smell different.  The RRS has a subtle smell, which
is rather fragrant .  The RSS is stronger, hits the nasal passages
harder, and reminds one of isopropanol more than does the RSS isomer.









#49 2C-T-21; 2,5-DIMETHOXY-4-(2-FLUOROETHYLTHIO)PHENETHYLAMINE

SYNTHESIS: To a solution of 6.9 g of KOH pellets in 100 mL hot MeOH,
there was added 13.0 g 2,5-dimethoxythiophenol (see under 2C-T-2 for
its preparation) followed by 9.6 g 2-fluoroethyl bromide.  The
reaction was exothermic, with the immediate deposition of white
solids.  This was allowed to stand for 2 h, added to 1 L H2O, and
extracted with 3x75 mL CH2Cl2.  The extracts were pooled and the
solvent removed under vacuum.  The residue was 2,5-dimethoxyphenyl
2-fluoroethyl sulfide which was a colorless oil and weighed 17.2 g.
It was sufficiently pure for use in the next reaction without a
distillation step.

A mixture of 26.8 g POCl3 and 24.8 g N-methylformanilide was heated
for 10 min on the steam bath.  To this claret-colored solution was
added 17.0 g of 2,5- dimethoxyphenyl 2-fluoroethyl sulfide, and the
mixture heated an additional 25 min on the steam bath.  This was then
added to 1.5 L of well-stirred warm H2O (pre-heated to 55 !C) and the
oily phase that formed solidified almost immediately.  This brown
sugar-like product was removed by filtration, and washed with
additional H2O.  After sucking as dry as possible, the residual solids
(weighing 19.0 g wet) were dissolved in an equal weight of boiling
MeOH which, after cooling in an ice-bath, deposited pale ivory colored
crystals of 2,5-dimethoxy-4-(2-fluoroethylthio)benzaldehyde.  This was
air dried to constant weight, which was 15.1 g.

To a solution of 15.0 g 2,5-dimethoxy-(2-fluoroethylthio)benzaldehyde
in 75 mL nitromethane there was added 1.35 g of anhydrous ammonium
acetate, and the mixture was heated on the steam bath for 70 min (the
progress of the reaction must be followed by continuous TLC
monitoring).  The clear deeply-colored solution was decanted from some
insoluble material and the excess nitromethane removed under vacuum.
There resulted 17.78 g of almost dry brick-red crystals which were
dissolved in 110 mL boiling EtOAc.  After cooling overnight in the
refrigerator, the crystalline product was removed, washed with EtOAc,
and air dried.  There was obtained 14.33 g of
2,5-dimethoxy-4-(2-fluoroethylthio)-'-nitro-styrene as bright orange
crystals.

A solution of LAH (140 mL of a 1 M solution in THF) was cooled, under
He, to 0 !C with an external ice bath.  With good stirring there was
added 3.7 mL 100% H2SO4 dropwise, to minimize charring.  This was
followed by the addition of 8.9 g
2,5-dimethoxy-4-(2-fluoroethylthio)-'-nitrostyrene in 40 mL of hot
anhydrous THF (a heat lamp was needed to keep the nitrostyrene in
solution).  As the nitrostyrene entered the hydride solution, there
was an immediate loss of color.  After 1 h stirring at room
temperature, the temperature was brought up to a gentle reflux on the
steam bath, then all was cooled again to 0 !C.  The excess hydride was
destroyed by the cautious addition of 15 mL IPA and the inorganic
solids were made white and filterable by the addition of 15 ml 15%
NaOH.  The loose cottage-cheesy solids were removed by filtration, and
washed with additional THF.  The filtrate and washes were pooled and
stripped of solvent under vacuum providing 7.39 g of a pale amber oil.
This was dissolved in 600 mL dilute H2SO4, and washed with 3x50 mL
CH2Cl2 (which removed the light yellow color).  The aqueous phase was
made strongly basic with 25% NaOH, extracted with 3x75 mL CH2Cl2 and,
after pooling, the solvent was removed under vacuum leaving 4.91 g of
product as an oil.  This was distilled at 145-160 !C at 0.4 mm/Hg
giving 3.91 g of a white oil.  This was dissolved in 40 mL IPA and
neutralized with 35 drops of concentrated HCl.  The beautiful white
solids that formed were removed by filtration, and washed with IPA.
All were suspended in, and ground under, 40 mL anhydrous Et2O,
refiltered and air dried.  The final weight of
2,5-dimethoxy-4-(2-fluoroethylthio)phenethylamine hydrochloride
(2C-T-21) was 4.07 g of glistening white crystals.

DOSAGE 8 - 12 mg.

DURATION: 7 - 10 h.

QUALITATIVE COMMENTS: (with 6 mg) I noticed something undefined
within five minutes which went away.  Within 15 minutes I noticed a
definite awareness of activity.  There was a progressive increase in
awareness of something happening over the next two hours with a
plateau of perhaps an hour then occurring.  The nature of the
happening, as usual, was not clear.  During the experience I was more
talkative than I usually am.  I seemed to be interacting with all
others.  There was no euphoria but, then, there was no body load or
nausea, nor was there any nystagmus.  I found a little mental
confusion at the peak and there was some searching in my memory bank
for the right chips at times.  I lost the entire line of one of my
conversations at one point during the plateau and had to ask what I
was talking about.  I tested my visual field on a painting and with
sufficient concentration I could get the center part to wiggle a
little.  I didnUt try to observe anything with my eyes closed.  I feel
that there was something physical about the eyes.  In the evening,
after-images were quite intense, and the next day my eyes seemed tired
or bothered.  What can I say?  The material was pleasant and I
certainly got the feeling of being high but not getting too much out
of it.  There were no insights or Rah-hahs.S I wonder if periodic and
frequent use (say twice a day) at the one or two milligram level would
be a positive mood enhancer?S

(with 8 mg) Comes on very gradually and slowly.  Takes about an hour
to feel.  Reasonably intense in two hours, ++.  Very pleasant
material, enhancing communication, clear thinking, good feeling.
There is a feeling of closeness; the bondedness with the group grows
steadily during the day, reaching a highly rewarding level.  For me a
couple of firsts regarding food.  I was hungry only two hours into it.
I usually donUt want food 'til well down as I usually feel that it
interferes with the experience.  And, also, I nibbled constantly as I
felt that there was nothing in my body.  And I enjoyed it thoroughly,
feeling only the warmth and energy, with no contrary developments.
There was a nice feeling of inner strength and peace.

(with 8 mg) It was very difficult to fix the times of ascent or
descent.  Some chilling during onset but not later.  And there was
some yawning and ear-popping.  It is easy on the body, in no way
threatening.  This time I am very relaxed and somewhat lethargic; the
visuals are not too pronounced.  Excellent sleep.

(with 10 mg) I find I can use it if I set my energy in a direction I
really want to go in.  Otherwise I can just be stoned and
self-indulgent.  Not out-of-body cosmic at all.  But it's good
material, an ally, not presenting hidden negatives.

(with 12 mg) Well ... 12 milligrams is quite enough for a +3, which
was established within the first hour and plateauUd by the end of the
second.  Body felt quite safe, again, but there was considerable push
of energy.  I did not feel par-ticularly interested in doing anything
like writing and in fact preferred to watch television while rocking a
bit on the couch, to ease the push.  Mood was faintly grim, but not
more than faintly.  I noted something that I hadnUt seen before with
this material: time slowing.  The first two hours seemed to last a
very long time.  There was no anorexia.  It wasnUt until 10 PM [fifth
hour] that the idea of writing had any appeal at all.  By then, I was
still +3 but a lot more at ease.  I wrote two letters and enjoyed the
process.  Sleep was fine.  My mood next day was slightly introverted,
not very spontaneous for a while.  Late in the afternoon, it was a lot
better.

EXTENSIONS AND COMMENTARY: This is about as potent a phenethylamine as
they come.  There are a couple in the 2C-G family that are similar in
potency, but they are much longer lived.  The motivation for the use
of the beta-fluoroethyl group can be seen under the discussion of
DOEF, where there was an amalgamation of two lines of reasoning: the
imitation of potent serotonin agonists with a need of including an
atom (the fluorine) that is potentially labelable with a positron
emitter.  And the mass-18 isotope of fluorine, with a half-life of
just under 2 hours, is ideal for many biological studies.  In fact,
much of the research work being carried out by the Nuclear Medicine
group in Berkeley is based on the analogy between a halogen atom and a
beta-fluoroethyl group.  There are some similarities in pharmacology
so that if there is a bromine or an iodo atom present in a drug, it is
a fair guess that the corresponding beta-fluoroethyl would also be
active.  In a sense, the cute (and chemically impossible) idea of
putting a bromo atom on the sulfur of the 2C-T family is nicely
satisfied by using the beta-fluoroethyl group instead (which is
chemically completely possible).

A logical extension of 2C-T-21 is the three carbon amphetamine
analogue which should be, by comparing structures and activities, a
very potent and in-teresting material in its own rights.  This would
be 2,5-dimethoxy-4-(2-fluoroethylthio)amphetamine or, following the
nomenclature used with the earlier members of this series, ALEPH-21.
A solution of 2,5-dimethoxy-4-(2-fluoroethylthio)benzaldehyde (see
earlier in this recipe) in nitroethane with ammonium acetate gave
1-(2,5-dimethoxy-4-(2-fluoroethylthio)phenyl)-2-nitropropene as
yellow-orange crystals from MeOH with a melting point of 102-104 !C.
And that is where the project now stands.  It has not yet been reduced
to the amine.

This phenethylamine, 2C-T-21, was the last of the 2C-T's to be
completed.  A couple of other sulfur analogues have been given
numbers, and have been started, but the syntheses are still at some
intermediate state.

The (n)-butyl compound, named 2C-T-19, has been taken to the
nitrostyrene stage.  Reaction between 2,5-dimethoxythiophenol and
(n)-butylbromide with KOH gave 2,5-dimethoxyphenyl (n)-butyl sulfide
as a colorless oil.  This, with phosphorus oxychloride and
N-methylformanilide, provided
2,5-dimethoxy-4-(n-butylthio)benzaldehyde as pale orange solids from
MeOH, with a melting point of 78-79 !C.  This, with nitromethane and
ammonium acetate, gave 2,5-dimethoxy-4-(n-butylthio)-'-nitrostyrene,
with a melting point of 133-134 !C from either IPA or acetonitrile.

The 2,2,2-trifluoroethyl compound, which I have named 2C-T-22, has
been taken to the benzaldehyde stage.  Reaction between
2,5-dimethoxythiophenol and 2,2,2-trifluoroethyliodide with KOH gives
2,5-dimethoxyphenyl 2,2,2-trifluoroethyl sulfide as a very pale amber
oil.  This, with phosphorus oxychloride and N-methylformanilide
provided 2,5-dimethoxy-4-(2,2,2-trifluoroethyl)benzaldehyde as
crystals that proved to be exceedingly difficult to purify.  Yellow
solids can be obtained from several solvents, and they melt in the 70
!C area.  The initially isolated fraction melted at 69-72 !C and
showed three major spots by both TLC and GCMS.  The largest GC peak
was the correct product with a parent peak of 280 m/e, and cracking
fragments at 154 and 234 m/e.  A small sample was finally obtained
from hexane with a melting point of 78-79 !C but I am not sure that
even it is particularly pure.  Not surprisingly, the reaction of this
crude benz-aldehyde with nitromethane and ammonium acetate gave a
nitrostyrene product that was a complex mixture.  And there that
project also rests.

A couple of additional efforts warrant comment.  The reaction between
trifluoromethyliodide and 2,5-dimethoxythiophenol should have produced
2,5-dimethoxyphenyl trifluoromethyl sulfide, but it didnUt produce
anything.  And one more.  What about a bare thio group at the
4-position in this 2C-T-family?  Maybe this can be protected through
everything as the disulfide, and be reduced at the last step!  The
disulfide, 2,5-dimethoxyphenyl disulfide (see under 2C-T-15) was aimed
towards the needed bis-aldehyde with phosphorus oxychloride and
N-methylformanilide, but all that came out of this were black oils and
tars.  This has also been abandoned for now.

And it has just occurred to me that there is yet another effort that
is certain-ly worth making, inspired by the observation that
2,2-difluoroethyl iodide is commercially available and not
prohibitively expensive.  It, with 2,5-dimethoxythiophenol, and
following the obvious steps to the aldehyde, the nitrostyrene, and the
final amine, would produce
2,5-dimethoxy-4-(2,2-difluoroethylthio)phenethylamine hydrochloride.
It lies exactly half way between the highly potent 2C-T-21 (the
mono-fluoro), and the yet to be finished 2C-T-22 (the trifluoro).
Let's be weird, and call it 2C-T-21.5.  I will wager mucho that it
will be very potent.









#50 4-D; 3,5-DIMETHOXY-4-TRIDEUTEROMETHOXY-PHENETHYLAMINE

SYNTHESIS: To a solution of 34.0 g homosyringonitrile
(3,5-dimethoxy-4-hydroxyphenylacetonitrile, see under ESCALINE for its
preparation) in 350 mL acetone containing 0.5 g decyltriethylammonium
iodide, there was added 25 g trideuteromethyl iodide followed by 50 g
of finely powdered anhydrous K2CO3.  This mixture was held at reflux
on a steam bath for 12 h, added to 2 L of dilute HCl, and extracted
with 3x100 mL of CH2Cl2.  The extracts were washed with 5% NaOH, and
the solvent removed under vacuum, yielding 28.0 g yellow solids.
These were distilled at 135-150 !C at 0.5 mm/Hg providing 19.4 g
3,5-dimethoxy-4-trideuteromethoxyphenylacetonitrile which melted at
76.5-77.5 !C after crystallization from toluene, or 77-78 !C from
methylcyclohexane/CHCl3 3:1.  The mp of the proteo-reference compound,
from toluene, was 77-78.5 !C.  The OCD3 stretch in the infra-red
occured at 2072 cm-1.

A solution of 275 mL of 1.0 M LAH in THF was cooled under He to 0 !C
and treated with 7.25 mL 100% H2SO4 added very slowly with vigorous
stirring.  A solution of 19.3 g
3,5-dimethoxy-4-trideuteromethoxyphenylacetonitrile in 200 mL
anhydrous THF was added slowly, and following the addition stirring
was continued for 20 min.  The reaction mixture was brought to a
reflux for 30 min on a steam bath, cooled again to 0 !C, and the
excess hydride destroyed with 25 mL IPA.  About 15 mL of 15% NaOH was
required to convert the solids to a filterable white consistency.
These were removed by filtration, the cake washed with IPA, the
filtrates and washes were combined, and the solvent removed under
vacuum leaving a white oil as residue.  This was dissolved in 1.5 L
dilute H2SO4, washed with 3x75 mL CH2Cl2, made basic with aqueous
NaOH, and then extracted with 3x75 mL CH2Cl2.  Removal of the solvent
from these extracts under vacuum yielded 18.5 g of a colorless oil
which was distilled at 120-150 !C at 0.5 mm/Hg to provide 13.5 g of a
white oil.  This was dissolved in 70 ml IPA and neutralized with
concentrated HCl, producing spontaneous crystals.  These were removed
by filtration, washed first with IPA then with anhydrous Et2O.  After
air drying, the final yield of
3,5-dimethoxy-4-trideuteromethoxyphenethylamine hydrochloride (4-D)
was 13.50 g.

DOSAGE: 200 - 400 mg (as the sulfate salt); 178 - 356 mg (as the
hydrochloride salt).

DURATION: 12 h.

QUALITATIVE COMMENTS: (with 275 mg) The onset was smooth and gradual.
Within the hour, the slight queasiness I experienced (not as much as
with mescaline) completely disappeared.  Some visual enhancement, good
energy, good communication.  It was a very special day for me as I was
in a good place pretty much the whole day, and able to communicate
clearly without deeper feelings getting in the way.  While most
enjoyable, and at times remarkable fun, I did not experience the
intensity I am familiar with, with mescaline.

(with 300 mg) The taste was bitter to a moderate degree but faded
fast.  About 40 minutes later the first stirrings of pleasurable
experience came on.  It was very mild.  Twenty minutes after that an
unease of the stomach was apparent, and it stayed with me until I ate
some crackers an hour or so later.  I got no sharpened visual
reactions and no physical instability at any time.  I did feel a
quickening of thought and verbal flow; again, this was mild and unlike
my earlier mescaline patter.

(with 350 mg) A rapid onset Q alert in 20 minutes.  Climbed to a plus
two in about one hour and stayed there.  During the first two hours
had a slight queasiness or pre-nausea, and cold hands and feet, but
this all disappeared completely and I became very hungry during the
whole latter half of the experience.  I did not eat much at any one
time, but did a lot of snacking and everything tasted good. Very
pleasant after the plateau was reached.  Pretty good visuals with eyes
closed, but not as bright as 2C-B.  Very little visuals with eyes open
Q some movement and flow of objects Q pupils dilated.  Spent most of
the day lying down Q had no aversion to conversation but it felt good
just to be still.  I was in a funny place I canUt quite describe Q I
was in an 'alert lassitude,' a state of 'interested detachment,' or a
place of 'vibrating equanimity' or whatever.  While trying to
recapture the day, it seemed to me that it was a good day, but that
nothing much had really transpired.  However, upon reflection, I am
startled to find that several important shifts took place.  It was a
day that allowed some peaceful gear-shifting in the mind.

(with 400 mg) Not a great taste.  Some type of awareness at approx.
20 minutes.  Considerable nausea peaking at about 1 hr.  Some nausea
continued through the experience but became quite low.  I enjoyed the
color show considerably.  Trees outside would change color in a
wave-like manner.  The book-covers upstairs would also change colors
and become distorted.  Brightly lighted items would undergo the same
thing.  Believed I could suppress the vision, but concentrating on
something would cause it to easily undergo the color and visual
changes.  Evidently I had little problem following the conversation
downstairs, but I remained somewhat quiet.  Had an element of
confusion that seemed to last for some 4 or 5 hours.  Had no problems
dropping off to sleep that evening.

EXTENSIONS AND COMMENTARY: The effects of 4-D and '-D are similar to
one-another, both as to dosage and effect.  And with both, there is a
close parallel to those reported from mescaline.  It is reasonable to
assume that the human body handles these materials in the same manner,
although no metabolic studies have ever been published.

A similar deuterium substitution pattern is of course completely
feasible with TMA and related 3,4,5-trimethoxy-substituted analogues.
Some studies have supported the idea that the ability to remove methyl
groups from such aromatic ethers might be correlated to endogenous
schizophrenia.  It is possible to imagine that, in such individuals,
the effects of substituting trideuteromethyl groups for normal methyl
groups might result in psychopharmacological differences of action.
Two reports exist that describe metabolic products of mescaline that
have lost this methyl group on the 4-position oxygen.  It is possible
that these might be produced in abnormal quantities in mentally ill
subjects.  There are also similar reports of the 3-methoxyl group
being demethylated in man.  Here, studies with 3,5-D
(3,5-bis-trideuteromethoxy-4-methoxyphenethylamine) might reveal some
differences in quantitative responses in man.  These are extremely
minor metabolites, however.  I suspect that more extensive studies
will establish that 4-D, 3,5-D and '-D all have properties
indistinguishable from one-another, at least in healthy subjects.









#51 '-D; 3,4,5-TRIMETHOXY-','-DIDEUTEROPHENETHYLAMINE

SYNTHESIS: To a solution of 13.6 g homosyringonitrile (see under
ESCALINE for its preparation) in 150 mL acetone containing 200 mg
decyltriethylammonium iodide and 30 g of finely powdered anhydrous
K2CO3, there was added 20 g methyl iodide.  The mixture was held at
reflux for 18 h in a heating mantle with effective stirring.  This was
added to 1 L H2O, acidified with concentrated HCl, and extracted with
3x75 mL CH2Cl2.  The extracts were pooled, washed with 2x100 mL 5%
NaOH, once with dilute HCl, once with saturated brine, and the solvent
was removed under vacuum.  The pale yellow residue was distilled at
130-150 !C at 0.3 mm/Hg to yield 12.9 g of
3,4,5-trimethoxyphenylacetonitrile as an off-white solid.  Upon
crystallization from methylcyclohexane/CHCl3 it was white and had a mp
of 77-78 !C.  Attempts to prepare this compound by the theoretically
appealing route from 3,4,5-trimethoxybenzaldehyde to
N,N-dimethyl-3,4,5-tri-methoxybenzylamine (reductive amination with
dimethylamine), to 3,4,5-trimethoxy-N,N,N-trimethylbenzylammonium
iodide (methylation with methyl iodide), and then to 3,4,5-
trimethoxyphenylacetonitrile (with some source of cyanide ion) gave
excellent yields in the first two steps, and no product at all in the
last step.

A solution of 20.6 g of 3,4,5-trimethoxphenylacetonitrile in 70 g
pyridine was treated with 15 mL 99+% D2O and held at reflux for 24 h.
All volatiles were stripped first under vacuum and finally with a hard
vacuum at room temperature in a Kugelrohr apparatus.  The dark residue
was treated again with another 30 mL pyridine and another 15 mL 99+%
D2O.  The flask was protected with a drying tube and held at reflux
for another 24 h.  Again, all volatiles were stripped, and the residue
distilled at 110-130 !C at 0.25 mm/Hg to yield 16.77 g of an almost
white solid.  The GCMS verified this chemical to be
3,4,5-trimethoxy-','-dideuterophenylacetonitrile, with a parent peak
at m/e 209 and no visible peak at m/e 207.

A solution of 250 mL of 1 M LAH in THF was cooled under He to 0 !C and
treated with 6.8 mL 100% H2SO4 added very slowly with vigorous
stirring.  A solution of 18.23 g
3,4,5-trimethoxy-','-dideuterophenyl-acetonitrile in 200 mL anhydrous
THF was added slowly, and following the addition stirring was
continued for 20 min.  The reaction mixture was brought to a reflux
for 30 min on a steam bath, cooled again to 0 !C, and the excess
hydride destroyed with 15 mL IPA.  About 10 mL of 15% NaOH was
required to convert the solids to a filterable white consistency.
These were removed by filtration, the cake washed with IPA, the
filtrates and washes were combined, and the solvent removed under
vacuum leaving 17 g of a white oil as residue.  This was dissolved in
2 L dilute H2SO4, washed with 3x75 mL CH2Cl2, made basic with aqueous
NaOH, and then extracted with 3x75 mL CH2Cl2.  Removal of the solvent
from these extracts under vacuum yielded 10.3 g of a colorless oil
which was distilled at 120-130 !C at 0.3 mm/Hg to provide 9.2 g of a
white oil.  This was dissolved in 50 ml IPA and neutralized with
concentrated HCl, producing spontaneous crystals.  These were diluted
with 50 mL anhydrous Et2O, removed by filtration, washed first with
Et2O/IPA, and then with anhydrous Et2O.  After air drying, the final
yield of 3,4,5-trimethoxy-','-dideuterophenethylamine hydrochloride
('-D) was 10.0 g of white needles.

DOSAGE: 200 - 400 mg (as the sulfate salt); 178 - 356 mg (as the
hydrochloride salt).

DURATION: 12 h.

QUALITATIVE COMMENTS: (with 200 mg) The onset was very gradual and
very gentle. At about an hour and a half I was rather out of my body
(at least I wasnUt aware of my body, it felt so light).  I was
listening to Berlioz Requiem, and it took me to the highest realm.  I
was totally caught up in the magnificence of the music, of the genius
it took to compose it, the love it took to complete it, and the
devotion of the composer.  I felt as though this music had been
written for me.  What came next is hard to remember because I was so
taken with this experience which came only 1 1/2 hours after
ingestion.  I wondered what time it was and how come I was having a
peak experience so soon, because this material was supposed to reach
its peak after two hours.  Well, now we can revise the records, heh?
Incidentally this material is really good for interior work.  It was a
magnificent experience Q one of the best.

(with 275 mg) I begin to feel it in 15 minutes, stomach getting
squeamish.  Looking up into the clouds, becoming absorbed in them,
watching light grow in intensity, stomach feelings disappeared.
Became totally absorbed by the music.  Listening to Boito's Prologue
to Mephistopheles Q exquisitely beautiful, dramatic.  Lying on the
couch, the music continuing, I was suddenly filled with enormous
power.  I realized that raw, male power was pouring through me as I
had never before experienced it.  I was wild, totally self satisfied,
and completely oblivious of others and their needs.  I wanted to
strike out, to win, to conquer.  I felt what conquerers have felt in
the past, the unbridled passion to vanquish everything.  I could see
how such misguided power could lead nations to war.  Wanting still
more power, I was about to find out if God would grant me the power to
destroy the world if I wished it, when I felt a gentle kiss on my
brow.  My wife had leaned over just in time to save the world.

(with 275 mg) Never had I had such a magnificent appreciation of God.
It was clear that if I minded my business and turned to Him to learn
as I had been doing today, then I could continue to grow and learn in
a most wonderful way.  It became crystal clear to me that I didnUt
have to help anybody or heal anybody, as everyone can turn directly to
the source for their needs.  An earth-shaking experience.

(with 300 mg) I had extreme nausea, and vomited.  This had a very
hard impact on me, and I had to retreat with a paranoia that swept
over me without warning.  I lay down and let it sweep on, and through
this came several very important insights.  At least they were
important to me.  It was about the fourth hour before I could emerge
from my retreat, and at that time I knew that I had answered some
troublesome personal problems.  It was a satisfactory day, but I
probably shall not repeat it.

(with 350 mg) Strong body awareness started within 15 minutes.
Visual activity started within half an hour.  Visuals were typical
kinds, but seemed to arrive earlier.  A strong experience of
pleasantness started and continued throughout the experience.  I
tended to internalize to some extent.  Ended on a water bed at maybe
an hour and a half, pulled covers over me, and went inward with
considerable visuals but not much insight.  I felt good about where I
was.  I would not mind being there again, so something was going well.
I am not sure how long this continued.  The visuals decreased
somewhere around the 5th or 6th hour.  After 8 or 9 hours, activity
considerably decreased.  I felt quite clear and reasonably centered.
Would I do this again?  The answer is yes.

(with 500 mg) I consumed the material over a period of twenty
minutes, and at the 1 hour 45 minute point, havenUt had any nausea,
but I am still careful not to bounce around.  Am absolutely grounded
even though I am completely into the experience.  No more that state
in which it is possible to seriously consider trying to rise two
inches above the floor and skim, as I do so expertly in dreams.  As a
matter of fact I havenUt had those dreams for some time now.  This
material doesnUt allow the straddling of realities as does ordinary
mescaline.  I know where my realities are, and reality is, basically,
where my center is.  Thus I am grounded in the physical reality even
when the doors are open to non-physical levels.

EXTENSIONS AND COMMENTARY: The 4-D and the '-D are two of five obvious
deuterium isomer derivatives of mescaline.  The three remaining are:
(1) 3,5-D (4-methoxy-3,5-bis-trideuteromethoxyphenethylamine); (2)
2,6-D (2,6-di-deutero-3,4,5-trimethoxyphenethylamine); and (3) a-D
(a.a-dideutero-3,4,5-tri-methoxyphenethylamine).  I fully expect both
3,5-D and 2,6-D to be indistinguishable from mescaline in effect,
since it is known that not much metabolism takes place in man at these
locations of the molecule.

The last compound, a-D, could be quite a different matter.  The
principal metabolite of mescaline is 3,4,5-trimethoxyphenylacetic
acid, and this product requires enzymatic attack at the exact position
where the deuteriums will be located.  To the extent that they are
harder to remove (come off more slowly or to a lesser degree), to that
extent the molecule will be more potent in man, and the dosage
required for effects will be less.  The compound will be easily made
by the reduction of 3,4,5-trimethoxyphenylacetonitrile with lithium
aluminum deuteride.  And if there is a believable difference between
a-D and mescaline, it will be necessary to synthesize each of the two
optically active a-mono-deutero analogs.  That will be quite a
challenge.

Some years ago I performed a fascinating series of experiments with
another isotopically labeled mescaline derivative.  This was '-14C
labeled material, which I self-administered on three occasions, at
three different levels.  One dosage was with 350 milligrams, a second
a few weeks later was with 4 milligrams, and a third was a few weeks
later yet, with about 60 micrograms.  In each case, exactly the same
absolute quantity of radioactivity was administered, so the metabolic
distribution was equally visible.  Only the weight dosage was
different.  Urinary analysis was run for each experiment for the
presence of unchanged mescaline, and for the primary metabolite,
3,4,5-trimethoxyphenylacetic acid.  The smaller the dosage, the
proportionately larger amount of mescaline was oxidized to the
inactive acetic acid, and the smaller amount was excreted in an
unchanged state.  It seemed to me that there might be a finite
capacity of the body to oxidatively deaminate mescaline, and at larger
and larger dosages, this capacity became increasingly depleted.
Perhaps this is why mescaline requires such a large dosage to be
effective in man.









#52 DESOXY; 3,5-DIMETHOXY-4-METHYLPHENETHYLAMINE

SYNTHESIS: To a well-stirred solution of 31 g 2,6-dimethoxytoluene in
200 mL CH2Cl2 there was added 11 mL elemental bromine, a portion at a
time.  There was a copious evolution of HBr and the color gradually
faded from deep red to straw.  The reaction mixture was poured into
500 mL H2O, and the organic layer separated, washed first with dillute
NaOH and finally with dilute HCl.  The solvent was removed under
vacuum, and the residue distilled at 85-90 !C at 0.4 mm/Hg to provide
44 g of 3-bromo-2,6-dimethoxytoluene as a white oil.

A well-stirred solution of 42 mL diisopropylamine in 100 mL petroleum
ether was placed in a He atmosphere and cooled to 0 !C with an
external ice-water bath.  There was then added 120 mL of a 2.5 M
solution of n-butyllithium in hexane, producing a clear but viscous
solution of the lithium amide.  Maintaining this temperature, there
was added 100 mL of anhydrous THF, followed by 10 mL dry CH3CN, which
produced an immediate white precipitate.  A solution of 23 g of
3-bromo-2,6-dimethoxytoluene in 75 mL anhydrous THF was then added
which produced a light red color.  The reaction mixture was allowed to
come to room temperature.  The color became progressively darkened,
eventually becoming a deep red-brown.  After 0.5 h, the reaction
mixture was poured into 500 mL of dilute H2SO4, the layers were
separated, and the aqueous layer extracted with 2x75 mL CH2Cl2.  The
organics were combined, the solvent removed under vacuum, and the
residue distilled.  Discarding a first fraction, the cut boiling at
125-165 !C at 0.3 mm/Hg was collected.  This light yellow fraction
spontaneously crystallized and weighed 11.0 g.  Trituration under 20
mL petroleum ether provided 1.72 g of
3,5-dimethoxy-4-methylphenylacetonitrile as a yellowish solid.

A solution of LAH in anhydrous THF under nitrogen (20 mL of a 1.0 M
solution) was cooled to 0 !C and vigorously stirred.  There was added,
dropwise, 0.54 mL 100% H2SO4, followed by 1.5 g
3,5-dimethoxy-4-methylphenylacetonitrile as a solid.  The reaction
mixture was stirred at 0 !C for a few min, then brought to room
temperature for 1 h, and finally to a reflux on the steam bath for 30
min.  After cooling back to 0 !C there was added IPA until no more
hydrogen was evolved, followed by sufficient 15% NaOH to produce a
granular texture.  The white solids were removed by filtration, and
washed with THF.  The filtrate and washes were stripped of solvent
under vacuum, the residue added to 150 mL dilute H2SO4 and washed with
2x50 mL CH2Cl2.  The aqueous phase was made basic with 25% NaOH, and
extracted with 3x100 mL CH2Cl2.  These extracts were pooled, the
solvent removed under vacuum, and the residue distilled at 110-120 !C
at 0.45 mm/Hg to give a colorless viscous oil.  This was dissolved in
10 mL of IPA, neutralized with 10 drops of concentrated HCl and
diluted with 20 mL anhydrous Et2O.  The product was removed by
filtration, washed with Et2O, and air dried to give 0.55 g
3,5-dimethoxy-4-methylphenethylamine (DESOXY) as white crystals.

DOSAGE: 40 - 120 mg.

DURATION: 6 - 8 h.

QUALITATIVE COMMENTS: (with 40 mg) Initially I felt very chilled, so
I lay down under a blanket.  Eyes-closed imagery became very
dream-like and my general state was felt as having lost my center.
Also, not much in touch with feelings, sense of strangeness, almost
alien view of the world.  Not through recog-nizable eyes.  Neither
pleasant nor unpleasant, just strange.  Was able to drift into sleep
very easily, or sleep-like trance state, with disconnected, far-out
imagery.  After 3 hours the nausea was gone, I was able to get up and
explore.  A little food went down well.  No drive, no strong focus in
any direction.  Feel this was a quite fascinating experience.
Completely down by six hours.  Would go a bit slowly because of slight
hints of neurological sensitivity Q the instant chilling and a
tendency to dart on going to sleep.  The nervous system does not feel
over-exposed, but all of a sudden there will be a millisecond of
auditory hallucination, or an out-of-the-blue startle.  So take it
easy going up.S [Some 24 hours after this experiment had been
completed, and a normal baseline re-established, a complex and
psycho-logically disruptive syndrome occurred, that lasted for the
better part of a week.  The temporal juxtaposition between the use of
desoxy and the subsequent Rspiritual crisisS initially suggested some
possible connection, but in retrospect the events seem to be
unrelated].

(with 40 mg) I have offered to be a control on an experiment where
there had been a close relationship between a trial with desoxy and
what might have been a psychotic break, or some kind of so-called
spiritual emergency.  These two events lay within a day of one
another.  I was aware of my 40 milligram dosage at about
three-quarters of an hour into the experiment, and felt that there was
no more in-tensification at the two-hour point.  At that time I felt
distinctly spaced but with a very good feeling, and I could see no
reason not to increase the dosage at some future time.  There was a
good and mellow mood, and enjoyment in escapist reading.  The only
physical oddity that I noted was that there had been no urge to
urinate, and only a small amount of quite concentrated urine was
passed rather late in the experiment.  I was at baseline at the fifth
hour, and there was nothing unusual at any time during the following
week.

(with 100 mg) The stuff has a sweet taste!  There was a slight
heart-push in the early awareness period, with a pulse up to 100 and a
feeling of pressure in the chest.  There were no apparent visual
enhancements, but the eyes-closed imagery to music was noteworthy.
Thinking skills and conversation seemed to be fully under control, if
not enhanced.  There was none of the colorful psychedelic world of
mescaline, but this might be just around the corner; perhaps with a
larger dose.  This is a comfortable in-between level.  Sleep was not
possible at the sixth hour, but two hours later, it was easy and very
restful.  There was no negative price to pay the next day.

EXTENSIONS AND COMMENTARY: All substituents that are involved with the
several drugs being discussed in this writing are really things that
are stuck like warts on the benzene ring that is central to every
phenethylamine.  Some of these warts are things attached with a oxygen
atom; there are some of these in every single compound in this story.
No oxygen atom, no psychedelic effect.  Without them, one has
stimulants or, more frequently, no effects at all.

But the removal of an oxygen atom (in those cases where there is more
than one) can radically change the nature of the effects seen.  This
is the exact meaning of the term Rdesoxy.S RDesS, without, and RoxyS,
the oxygen.  Since this drug is simply the structure of mescaline with
the oxygen at the 4-position plucked out of the picture, the first
impulse was to abbreviate this compound as DOM for des-oxymescaline.
However, a long, long time ago, in a universe far, far away, a
compound was synthesized that had a methoxy group replaced by a
methyl, and it was already named DOM.  This was the first of the STP
analogs, and the initials stood for desoxy (DO, losing an oxygen) and
methyl (M, having it replaced with a methyl group).  These are two
different worlds.  One M stands for Mescaline, and the other M stands
for Methyl.  Let's call it 4-desoxymescaline, or simply DESOXY, and be
exact.

This drug is a prime example of a pharmacological challenge directed
to the metabolic attack at the 4-position as a mechanism for the
expression of biological activity.  A methoxy group there would allow
easy removal of the methyl group from the oxygen by some demethylation
process, but a bare methyl group there cannot be removed by any simple
process. It must be removed by a very difficult oxidation.

This is not the first time that oxygen atoms have been removed from
the mescaline molecule.  Both the 3,5-dideoxymescaline
(3,5-dimethyl-4-methoxyphenethylamine) and 3,4,5-trideoxymescaline
(also called desoxymescaline in the literature, but really
tri-desoxymescaline or 3,4,5-trimethylphenethylamine) have been
studied in the cat, and have shown extraordinary pharmacological
profiles of CNS action.  The trimethyl compound showed behavior that
was interpreted as being intense mental turmoil, accompanied by a
startling rise in body temperature.  The significance is hard to
determine, in that LSD gave similar responses in the cat, but
mescaline was without effects at all.  No human studies have been made
on these compounds, just animal studies.  But they might prove upon
trial in man to be most revealing.  They would have to be performed
with exceptional care.

The 3-carbon chain amphetamines that correspond to these mescaline
look-alikes with one or more methoxy groups replaced with methyl
groups, are largely untested and would require independent and novel
syntheses.  The 3,4,5-trimethylamphetamine is known, and is known to
be very hard on experimental cats.

A mescaline analogue with a bromo atom in place of the 4-methoxyl
group is an analogue of mescaline in exactly the same way that DOB (a
very potent am-phetamine) is an analog of TMA-2 (the original
trisubstituted amphetamine).  This analogue,
3,5-dimethoxy-4-bromoamphetamine, has been found to be a most
effective serotonin agonist, and it is a possibility that it could be
a most potent phenethylamine.  But, as of the present time, it has
never been assayed in man.









#53 2,4-DMA; 2,4-DIMETHOXYAMPHETAMINE

SYNTHESIS: To a solution of 10 g 2,4-dimethoxybenzaldehyde in 50 mL
nitroethane there was added 0.5 g anhydrous ammonium acetate, and the
mixture was heated on the steam bath for 2 h.  The excess
solvent/reagent was removed under vacuum, and the residue oil
dissolved in 25 mL boiling MeOH.  On cooling, this deposited yellow
crystals of 1-(2,4-dimethoxyphenyl)-2-nitropropene that, after
filtering, MeOH washing, and air drying, weighed 10.2 g and had a mp
of 78-79 !C.

A magnetically stirred suspension of 6.0 g LAH in 300 mL anhydrous
Et2O was brought up to a gentle reflux under a He atmosphere.  A total
of 8.5 g 1-(2,4-dimethoxyphenyl)-2-nitropropene was introduced into
the reaction mixture by allowing the condensed Et2O to leach it from a
modified Soxhlet condenser.  After the addition was complete, the
reaction was held at reflux for an additional 24 h.  After cooling
with an external ice bath, the excess hydride was destroyed by the
cautious addition of H2O.  When the exothermic reaction had subsided,
there was added 500 mL H2O, 150 g potassium sodium tartrate, and
sufficient base to bring the pH above 9.  The phases were separated,
the organic phase dried over anhydrous MgSO4, the drying agent removed
by filtration, and the clear filtrate then saturated with anhydrous
HCl gas to produce white crystals of 2,4-dimethoxyamphetamine
hydrochloride (2,4-DMA) with a mp of 146-147 !C.

DOSAGE: greater than 60 mg.

DURATION: short.

QUALITATIVE COMMENTS: (with 60 mg) This is definitely threshold, or
even a bit more.  There is a lot of amphetamine-like component, and a
certain blush of euphoria.  There is also a diffusion of association,
so it's more than just amphetamine, no question about it.  At the
three-hour point, it is definitely quieting down.

EXTENSIONS AND COMMENTARY: What can one say as to the active dosage of
2,4-DMA?  Nothing.  What can one say as to the duration?  Probably
short.  The 60 milligram report given above is the highest level that
I personally know of having been tried in man, and there is no hint as
to what might be found at a fully active dose, or just where that dose
might be.  It might be fully speedy.  It might be fully psychedelic.
It might give a cardiovascular push that would be scary.  Studies of
2,4-DMA on vascular strips (associated with serotonin action) were not
impressive in comparison with structurally related psychedelics, and
it seems as if its action might involve norepinephrine release.  It is
a reasonable guess that there would be cardio-vascular activity at
higher levels.  But it will only be with human trials, someday, that
the answer will be known for sure.

The meta-orientation of the two methoxyl groups does, however, greatly
increase the susceptibility of the aromatic ring to electrophilic
attack.  This is one of the three possible meta-dimethoxy substituted
amphetamines, and it is the best studied one in the pursuit of
potential radio-halogen substituted brain blood-flow agents.  This
strategy is discussed under IDNNA; the other two meta-compounds are
discussed under 3,4-DMA.

The homologues of 2,4-DMA that were iodinated (or occasionally
fluor-inated) were mono- or di-alkylated on the nitrogen, and the
precursor that was common to all was the corresponding acetone.  The
above nitrostyrene, 1-(2,4-dimethoxyphenyl)-2-nitropropene, was
reduced in acetic acid with elemental iron, and the base-washed
extracts stripped of solvent and distilled (125-145 !C at 0.5 mm/Hg)
to give 2,4-dimethoxyphenylacetone as a water-white oil.  The
principal reductive amination product of this, the one that was most
thoroughly explored with various halogenation schemes, was obtained by
the reaction of 2,4-dimethoxyphenylacetone with dimethylamine and
sodium cyanoborohydride.  This product,
2,4-dimethoxy-N,N-dimethylamphetamine or 2,4-DNNA, distilled at
105-115 !C at 0.4 mm/Hg and formed a perchlorate salt that melted at
98-98.5 !C.  This could be iodinated with the radio-iodide anion, when
oxidized with chloramine-T in buffered sulfuric acid, to give the
iodinated analogue (2,4-dimethoxy-N,N-dimethyl-5-iodoamphetamine) in
an excellent yield.  Radio-fluorination with acetyl hypofluorite gave
the 5-fluoroanalogue (2,4-dimethoxy-N,N-dimethyl-5-fluoroamphetamine)
in an acceptable yield.  Both compounds went into a rat's brain to a
pretty good extent, but both of them washed out too rapidly to be
clinically interesting.

A large family of other N-substituted homologues of 2,4-DMA were
similarly prepared from the above ketone and sodium cyanoborohydride.
Methylamine, ethylamine, propylamine, isopropylamine and hexylamine
gave the corresponding N-alkyl homologues.  The N,N-diethyl homologue
was made from the primary amine, 2,4-DMA itself, with acetaldehyde and
sodium cyanoborohydride but the product,
N,N-diethyl-2,4-dimethoxyamphetamine, could not be converted into a
crystalline hydrochloride salt.

Yet another variation on these structures was launched, again with the
design of making radio-iodination targets which are not psychedelic
and thus might be useful clinically.  In this variation, the nitrogen
atom substitution pattern was held constant, with two methyl groups,
as were the ring locations of the two oxygen atoms.  But the
identities of the alkyl groups on these oxygen atoms were varied.  The
synthetic procedure followed was to make the appropriate
2,4-dialkoxybenzaldehyde, convert it to the nitrostyrene with
nitroethane, reduce this to the phenylacetone with elemental iron, and
then reductively aminate this ketone with dimethylamine.  Following
this reaction scheme, five amphetamine homologues of 2,4-DMA were
made, three with the 4-methoxy group maintained but the 2-position
extended, and two with both groups extended symmetrically.  These are:
(1) N,N-dimethyl-2-ethoxy-4-methoxyamphetamine; (2)
2-(n)-butyloxy-N,N-dimethyl-4-methoxy-amphetamine; (3)
2-(n)-decyloxy-N,N-dimethylamphetamine; (4)
2,4-diethoxy-N,N-dimethylamphetamine; and (5)
N,N-dimethyl-2,4-di-(i)-propoxyamphetamine.  I believe that most of
these have been iodinated and assayed in rats, and several of them
appear quite promising.  But none of them have been assayed in man,
yet.  The bromination product of 2,4-DMA
(5-bromo-2,4-dimethoxyamphetamine, 5-Br-2,4-DMA) is way down in
activity (see its recipe, separately).  Since all iodo analogues are
of about the same potency as the bromo counterparts, and since the
addition of two methyl groups on the nitrogen does not appear to
enhance central activity, I feel the iodination products of these
N,N-dialkyl-dialkoxyamphetamines would not have any interesting
psychopharmacology.

There is something vaguely counterproductive, in my evaluation of
things, when the goal of a research project is to avoid activity
rather than to create it.  Although this chemistry was completely
fascinating and could have produced the world's best
positron-emitting, brain-scanning diagnostic compound, I feel it quite
unlikely that it would have produced the world's best
insight-revealing, empathy-enhancing psychedelic, so this research
direction never totally caught my fancy.  I went on to other things.









#54 2,5-DMA; DMA; 2,5-DIMETHOXYAMPHETAMINE

SYNTHESIS: A solution of 10.0 g 2,5-dimethoxybenzaldehyde in 50 mL
glacial acetic acid was treated with 6.8 g of nitroethane and 4.0 g of
anhydrous ammonium acetate.  This mixture was heated on the steam bath
for 3 h and then the reagent/solvent was removed under vacuum.  The
residue was suspended in H2O and extracted with CHCl3.  Removal of the
solvent from the pooled extracts yielded 11.2 g of an impure
1-(2,5-dimethoxyphenyl)-2-nitropropene which, on recrystallization
from 75 mL boiling MeOH, gave 6.7 g of product with a mp of 73-75 !C.
Anal. (C11H13NO4) C,H,N.  This nitrostyrene has been periodically
available commercially from a number of sources.

A solution of 17.0 g of 1-(2,5-dimethoxyphenyl)-2-nitropropene was
prepared in 500 mL anhydrous Et2O.  This solution was added slowly to
a well-stirred suspension of 12.0 g LAH in 700 mL anhydrous Et2O.  The
mixture was then brought up to a reflux and maintained there for 20 h,
cooled with an external ice bath, and the excess hydride destroyed by
the cautious addition of H2O.  Finally, a total of 500 mL H2O was
added, followed by the addition of 300 g potassium sodium tartrate,
and sufficient aqueous NaOH to bring the pH above 9.  The two phases
were separated, and the ether phase dried by the addition of anhydrous
MgSO4.  The drying agent was removed by filtration, and the clear
filtrate saturated with a stream of anhydrous HCl gas.  The formed
crystals of 2,5-dimethoxyamphetamine hydrochloride (2,5-DMA) were
removed by filtration, washed with anhydrous Et2O, and dried to
constant weight of 16.3 g.  Recrystallization from EtOH gave an
analytical sample with a mp of 114-116 !C.  The hydrobromide salt is
reported to melt at 129-131 !C.

DOSAGE: 80 - 160 mg.

DURATION: 6 - 8 h.

EXTENSIONS AND COMMENTARY: The qualitative information on 2,5-DMA is
very sparse.  I was up to a 1+ with 80 milligrams of the
hydrochloride, and since it appeared to be totally a physical trip
with tremors and some cardiovascular push and nothing of a sensory
nature, I chose to explore it no further.  A report from South America
found the intoxication to be largely pleasant (this, at 75
milligrams), with an enhanced interest in one's surroundings, but no
perceptual changes, no overt stimulation, and no gross physiological
effects other than a slight mydriasis (dilation of the pupils).  I
have also been told of a single trial of 250 milligrams of the
tartrate (this is equivalent to somewhere in the 150-200 milligram
range of the hydrochloride salt, depending upon the acid/base ratio of
the tartrate salt) with some RspeedyS effects but still no sensory
changes.  A seizure of capsules reported by the drug law enforcement
authorities some 20 years ago found that each contained some 200
milligrams of the hydrobromide salt.  This is equivalent to 170
milligrams of the hydrochloride salt, and suggests that level may be
an effective dosage.

An intriguing, but little studied, analogue of 2,5-DMA is the compound
with methyls in place of the methoxyls.  2,5-Dimethylamphetamine has
been looked at, in man, as a potential anorexic, but there is little
effect even at 150 milligrams.  The 3,4-isomer,
3,4-dimethylamphetamine or xylopropamine, is an adrenergic agent and
it has been found to be an analgesic in man at as little as 10
milligrams.  This was assayed, rather remarkably, by attaching
electrodes to the tooth fillings of the experimental subjects.  But
with this base, cardiovascular effects were not observed until doses
of about 100 milligrams were administered, and toxic effects (nausea
and vomiting) were reported at 150 milligrams.  There was no
suggestion of anything psychedelic.

All three isomers of monomethylamphetamine have also been looked at in
man.  The ortho- and meta-isomers, 2-methyl- (and 3-methyl- )
amphetamine are weak anorexics.  At doses of up to 150 milligrams
orally, there were signs of stimulation noted Q talkativeness and loss
of appetite.  The para-isomer, 4-methyl-amphetamine or Aptrol, is more
potent.  At 75 milligrams (orally, in man) there is clear adrenergic
stimulation, and at twice this dosage there are signs of mild toxicity
such as salivation, coughing and vomiting.

There is a mystery, at least to me, concerning the commercial
production of 2,5-DMA.  At regular intervals, there is a public
announcement of the production quotas that are requested or allowed by
the Drug Enforcement Administration, for drugs that have been placed
in Schedules I or II.  In the Schedule I category there are usually
listed amounts such as a gram of this, and a few grams of that.  These
are probably for analytical purposes, since there are no medical uses,
by definition, for drugs in this Schedule.  But there is a staggering
quantity of 2,5-DMA requested, regularly.  Quantities in the many tens
of millions of grams, quantities that vie with medical mainstays such
as codeine and morphine.  I have heard that this material is used in
the photographic industry, but I have no facts.  Somewhere I am sure
that there is someone who has to keep a lot of very careful books!

In the area of psychedelic drugs, the value of 2,5-DMA is mainly in
its role as a precursor to the preparation of materials that can come
from a direct electrophilic attack on the activated 4-position.  These
uses can be found under things such as DOB and DOI and DON.  The
radio-halogenation of N-substituted homologues of 2,5-DMA with
hypoiodite or hypofluorite is part of an extensive study underway in
the search for radio-labeled brain blood flow agents.  The rationale
for this work is to be found in the commentary under IDNNA.  In
essence it has been found that the N-substitution or
N,N-disubstitution of 2,5-DMA where the 4-position is unsubstituted
and thus available for the introduction of a radioactive nucleus can
give rise to potentially useful drugs.  Most of these 2,5-dimethoxy
exploratory compounds were made by the reductive alkylation of
2,5-dimethoxy-4-(radio)iodophenylacetone, using various mono or
dialkyl amines.  This, too, is described under IDNNA.

However, the study of various direct iodinations and fluoridations
that would have the N,N-dimethyl substitution on the amphetamine
nitrogen atom, would require the 4-proteo- analogue, and this was made
from the above nitrostyrene.  A solution of the above nitrostyrene,
22.3 g 1-(2,5-dimethoxyphenyl)-2-nitropropene in 100 mL acetic acid
was added to a suspension of elemental iron in acetic acid (45 g in
250 mL) and worked up with water and base washing to give, after
distillation at 92-106 !C at 0.35 mm/Hg, 13.8 g
2,5-dimethoxyphenylacetone as a pale yellow oil.  This underwent
reductive amination with dimethylamine hydrochloride in MeOH solution,
using sodium cyanoborohydride, to give the target compound
2,5-dimethoxy-N,N-dimethylamphetamine oxalate with a melting point of
133-134 !C (4.6 g ketone gave 1.38 g of salt).  Anal. (C15H23NO6) C,H.
It has also been prepared by the N,N-dimethylation of 2,5-DMA
directly, with formaldehyde and formic acid.  This has been called
2,5-DNNA, or IDNNA without the RI.S This intermediate, 2,5-DNNA,
underwent direct radioiodination with labeled iodine monochloride in
the presence of perchloric acid to give IDNNA with a 40% incorporation
of isotope.  Reaction with labeled acetyl hypofluorite, on the other
hand, gave only a 2% in-corporation of the radio-isotope.  This latter
compound is, chemically,
4-fluoro-2,5-dimethoxy-N,N-dimethylamphetamine and, using the
reasoning suggested above and with IDNNA, might best be encoded FDNNA.

The 2,5-dimethylamphetamine analogue mentioned above was also explored
in this IDNNA concept.  The commercially available
2,5-dimethylbenzaldehyde was converted to the nitrostyrene with
nitroethane (1-(2,5-dimethylphenyl)-2-nitropropene, yellow crystals
with a melting point of 24.5-25.5 !C) which reacted with elemental
iron in acetic acid to give the ketone 2,5-dimethylphenylacetone
(boiling at 140-150 !C at 0.4 mm/Hg).  Reductive amination with
dimethylamine and sodium cyanoborohydride gave 2,5-DMNNA
(2,5,N,N-tetramethylamphetamine) as a clear oil with a boiling point
of 115-125 !C at 0.35 mm/Hg.  It gave poor yields of the 4-fluoro
analogue with acetyl hypofluorite.

All of these latter materials remain unevaluated in man.









#55 3,4-DMA; 3,4-DIMETHOXYAMPHETAMINE

SYNTHESIS: A solution of 33.2 g of veratraldehyde in 15.0 g
nitroethane was treated with 0.9 g of n-amylamine and placed in a dark
place at room temperature.  In a day or so, separated H2O was apparent
and, after a couple of weeks, the mixture completely solidified.  The
addition of 50 mL EtOH and heating effected complete solution and, on
cooling, this provided 1-(3,4-dimethoxyphenyl)-2-nitropropene as
yellow crystals, 29.0 g, with mp of 70-71 !C.  The more conventional
reaction scheme, 6 h heating of a solution of the aldehyde and
nitroethane in acetic acid with ammonium acetate as catalyst, gave a
much inferior yield of product (33.2 g gave 14.8 g) of the same
purity.  Recrystallization from MeOH increased the mp to 72-73 !C.

To a refluxing suspension of 7 g LAH in 600 mL anhydrous Et2O, stirred
and under an inert atmosphere, there was added 7.5 g
1-(3,4-dimethoxyphenyl)-2-nitropropene by allowing the returning
condensed ether to leach out the material as a warm solution from a
Soxhlet thimble.  Following the completion of the addition of the
nitrostyrene, refluxing was maintained for 24 h, and the reaction
mixture allowed to stand several days at room temperature.  The excess
hydride was destroyed by the cautious addition of 500 mL H2O
containing 40 g H2SO4, and the phases were separated.  The aqueous
phase was washed with both Et2O and CH2Cl2.  There was then added 200
g potassium sodium tartrate, and the pH brought above 9 by the
addition of aqueous NaOH.  This clear solution was extracted with
3x150 mL CH2Cl2, the extracts were pooled, and the solvent removed
under vacuum to give a residual oil.  This was dissolved in Et2O,
saturated with anhydrous HCl gas, and the resulting solids removed by
filtration.  Recrystallization from 10 mL acetone gave 1.35 g
3,4-dimethoxyamphetamine hydrochloride (3,4-DMA) as beautiful white
crystals with a mp of 144-145 !C.

DOSAGE: a few hundred milligrams.

DURATION: unknown.

QUALITATIVE COMMENTS: (with 70 mg i.v.)  [One patient received 0.004
mM/Kg of the hydrochloride salt intravenously and exhibited only
slight increase in psychiatric symptoms; a comparable dosage in a
second individual also elicited only insignificant changes.]

(with 700 mg i.v.)  [When one of these patients was reinjected at a
later date with approximately 0.04 mM/Kg of 3,4-DMA a definite
Tmescaline-likeU state was induced.  The symptoms included colored
hallucinations of geometric figures and occasional structured forms.
The other individual experienced visual distortions, notable
after-imagery, feelings of unreality, and paranoid ideas.  Marked
mydriasis and gross body tremors also occurred but apparently no
hallucinations were experienced.]

EXTENSIONS AND COMMENTARY: These RQualitative CommentsS are not
explicit quotations from people who had taken 3,4-DMA.  They are
written descriptions by the observers who had given 3,4-DMA to
psychiatric patients.  This is one of the most outrageous chapters in
the books on military medicine.  The chemical warfare group within the
U.S. Army explored many potential psychedelics by administering them
to innocent patients with not even a thought of obtaining informed
consent.  These experiments took place at the New York State
Psychiatric Institute (amongst other places) in the early 1960Us.  The
Edgewood Arsenal code name for 3,4-DMA was EA-1316.  A few
non-military studies have indicated that 3,4-DMA is orally active at
160 milligrams, and so probably its potency by this more conventional
route would fall midway between that of mescaline and of MDA.  The
3-methoxy-4-other-than-methoxy things (such as hydroxy, ethoxy,
allyloxy and methyl) are mentioned in the recipe for MEPEA.  The
alpha-ethyl homologue of 3,4-DMA,
2-amino-1-(3,4-dimethoxyphenyl)butane, and of other DMA's are
discussed under the recipe for ARIADNE.

There are a total of six possible amphetamine molecules with two
methoxyl groups attached.  The 3,4-orientation has always been the
most appealing to the life scientists as this is the positional
substitution pattern found in the natural neuro-chemicals dopamine,
norepinephrine and epinephrine.  These latter two are called
noradrenalin and adrenalin in England.  Two adjacent hydroxy groups
represent the catechol in the well known word catecholamines.  You
might read in a textbook, RThis is where nature placed the groups when
she put the compounds in our brains.  So that is where the groups
might be the most interesting in a psychedelic.S Why?  I have never
understood this kind of reasoning.  If a possible psychedelic has just
the exact oxygen positioning of a neurotransmitter, then, voila,
that's why it is active.  And if a possible psychedelic has some
positioning of these oxygen atoms that is different than that of a
neurotransmitter?  Then voila again.  That's why it is active.  Both
sound equally reasonable to me, and neither one even begins to address
the fundamental question, how do the psychedelic drugs do what they
do?  A study in the human animal of the intimate effects of one of
these neurotransmitter analogues might bring us a little bit closer to
answering this fundamental question.  But maybe it wouldnUt, after
all.  Nothing has made much sense so far!  Anyway, 3,4-DMA is one of
the ten essential amphetamines that can, in theory, arise from the ten
essential oils of the spice and herb trade.  In this case, the origins
are methyl eugenol and methyl isoeugenol.

Two of these RdifferentS isomers, 2,4-DMA and 2,5-DMA, have already
been discussed in their own separate recipes.  And the remaining three
of the six possible DMA's that are RdifferentS have been made and
studied pharmacologically in animals but not in man.  These are the
2,3-DMA, 2,6-DMA and the 3,5-DMA isomers.  The products of their
reaction with elemental bromine are discussed under META-DOB.

Both the 2,6- and the 3,5-isomers, as the N,N-dimethyl homologues,
have been looked at as potential radio-halogen recipients in the
search for positron-emitting brain blood-flow indicators, as discussed
in the recipe for IDNNA.  Both were made from the appropriate
nitrostyrene via the corresponding phenylacetone.

The 2,6-isomer was derived from 2,6-dimethoxybenzaldehyde.  This, in
nitroethane and ammonium acetate, gave the nitrostyrene as
canary-yellow crystals from MeOH that melted at 101.5-102.5 !C.
Elemental iron in acetic acid converted this nitrostyrene to
2,6-dimethoxyphenylacetone (a water-white oil with boiling point of
95-105 !C at 0.4 mm/Hg. Anal. (C11H14O3) C,H) and reductive amination
with dimethylamine and sodium cyanoborohydride gave
2,6-dimethoxy-N,N-di-methylamphetamine perchlorate (2,6-DNNA) with a
melting point of 109-110 !C.  This base was readily fluorinated with
18F acetylhypofluorite and iodinated with chloramine-T-oxidized 122I
iodide ion.  It was also halogenated with (non-radioactive) bromine
and iodine monochloride to give the corresponding 3-bromo-(and
3-iodo)-2,6-dimethoxy-N,N-dimethylamphetamines but these, in turn, did
not react with radioactive acetyl hypofluorite.

The 3,5-isomer followed precisely the same flow sheet.
3,5-Dimethoxybenzaldehyde gave the nitrostyrene (with a melting point
of 87-88 !C), the phenylacetone (with a boiling point of 110-130 !C at
0.3 mm/Hg) and the product 3,5-dimethoxy-N,N-dimethylamphetamine
perchlorate (3,5-DNNA) with a melting point of 100-101 !C.  This also
reacted readily with 18F acetylhypofluorite and 122I-hypoiodite.
Several alpha-ethyl homologues of these compounds have also been
discussed in the recipe for ARIADNE.









#56 DMCPA; 2-(2,5-DIMETHOXY-4-METHYLPHENYL)CYCLOPROPYLAMINE

SYNTHESIS: To a solution of 25 g 2,5-dimethoxy-4-methylbenzaldehyde
(see the recipe for 2C-D for the preparation) and 29.2 g malonic acid
in 50 mL anhydrous pyridine, there was added 2 mL piperidine and this
was heated on the steam bath for several h.  The mixture was added to
a solution of 125 mL concentrated HCl in 500 mL H2O at 0 !C, and the
solid product that was formed was removed by filtration, and washed
with H2O.  Recrystallization from aqueous EtOH yielded 31 g
2,5-dimethoxy-4-methylcinnamic acid with a mp of 163-166 !C.  Anal.
(C12H14O4) C,H.

In a cooled high-pressure reaction vessel there was placed a
suspension of 30 g 2,5-dimethoxy-4-methylcinnamic acid in 150 mL
liquid isobutene.  This was treated dropwise with 0.6 mL concentrated
H2SO4, then sealed and brought to room temperature.  After 48 h
shaking, the vessel was cooled again to -10 !C, opened, and poured
into 200 mL of 10% Na2CO3.  This was extracted with hexane, the pooled
extracts washed with H2O, and the solvent removed to yield 17.0 g of
(t)-butyl 2,5-dimethoxy-4-methylcinnamate as an amber oil.  Anal.
(C16H22O4) C,H.

The cyclopropane ester was prepared by the reaction between 16 g
(t)-butyl 2,5-dimethoxy-4-methylcinnamate and dimethylsulfoxonium
methylide, prepared as described in the Kaiser reference in the
acknowledgements.  Hydrolysis of this ester gave 53%
trans-2-(2,5-dimethoxy-4-methylphenyl)cyclopropanecarboxylic acid
which, after recrystallization from a MeOH/H2O mixture, had a mp of
136 !C. Anal. (C13H16O4) C,H.

A suspension of 4 g of
trans-2-(2,5-dimethoxy-4-methylphenyl)cyclopropanecarboxylic acid in
an equal volume of H2O, was treated with sufficient acetone to effect
complete solution.  This was cooled to 0 !C and there was added,
first, 2.0 g triethylamine in 35 mL acetone, followed by the slow
addition of 2.5 g ethyl chloroformate in 10 mL acetone.  This was
stirred for 0.5 h, and then there was added a solution of 1.7 g NaN3
in 6 mL H2O, dropwise.  After 1 h stirring at 0 !C, the mixture was
quenched by pouring into H2O at 0 !C.  The separated oil was extracted
with Et2O, and extracts dried with anhydrous MgSO4.  Removal of the
solvent under vacuum gave a residue of the azide, which was dissolved
in 10 mL anhydrous toluene.  This solution was heated on the steam
bath until the nitrogen evolution was complete, and the removal of the
solvent under vacuum gave a residue of crude isocyanate as an amber
oil.  This intermediate isocyanate was dissolved in 5.4 g benzyl
alcohol and the reaction mixture was heated on the steam bath for 6 h.
The excess benzyl alcohol was removed by distillation, yielding
trans-2-(2,5-dimethoxy-4-methylphenyl)carbobenzoxyamidocyclopropane as
a crystalline residue.  This was recrystallized from an EtOAc/hexane
mixture to give 6.13 g of a crystalline product with a mp of 107-108
!C.  Anal. (C20H23NO4) C,H,N.

A solution of 1.5 g
trans-2-(2,5-dimethoxy-4-methylphenyl)carbobenzoxyamidocyclopropane in
120 mL MeOH containing 200 mg 10% Pd/C was shaken under hydrogen gas
at 35 psig for 45 min.  The solution was filtered through celite, and
a sufficient amount of a solution of 5% HCl in EtOH was added to the
filtrate to make it acidic.  Removal of all volatiles under vacuum
gave a solid residue that was recrystallized from an EtOH/ether
mixture to give 0.98 g of
trans-2-(2,5-dimethoxy-4-methylphenyl)cyclopropylamine hydrochloride
(DMCPA) as white crystals with a mp of 210-211 !C.

DOSAGE: 15 - 20 mg.

DURATION: 4 - 8 h.

QUALITATIVE COMMENTS: (with 10 mg) The effects were quite real at an
hour, but very hard to define.  Nothing left at four hours, but my
sleep was filled with bizarre and colorful dreams.  Something was
still working somewhere, at some level.

(with 20 mg) I found myself lightheaded, and the thinness seemed to
be, rather remarkably, on the left side of my brain.  The experience
was flighty.  I was reminded of the aura that has been described
preceding a convulsion.  I was decoupled from my experience and from
my environment.  Not all of the control is there, and I am
uncomfortable.  But in an hour, there is complete control again, and I
can relax my conscious guard which allows an easy plus three.  With
this, there was easy fantasy, erotic, quite a bit of movement in the
visual field, and mild anorexia.  The residual hyperreflexive thinness
is largely gone, and not at all worrisome.  This stuff is complicated,
with a little too much of the physical.  The next day was without any
residues at all.

EXTENSIONS AND COMMENTARY: Most of the human trials took place in the
fifteen to twenty milligram range.  Several reports describe some
muscular tremor, especially in the earliest part of the experience,
but this never seemed to be a concern.  The efforts to lock imagery to
music were not too successful.  All of these clinical studies were
conducted on the trans-compound, but on the racemic mixture.  This has
been resolved into the two optical isomers, but they have not been
compared in man.  The cis-mixture is unknown.

This material is intimately related to tranylcypromine, a clinically
proven antidepressant.  This drug is a known monoamine oxidase
inhibitor, and it is certainly possible that some of this
pharmacological property might be found in DMCPA if it were to be
looked for.  The hints of physical toxicity at the higher doses
assayed might suggest some such activity.

This compound, DMCPA, was modeled directly after the structure of DOM,
with the 2,5-dimethoxy-4-methyl substitution pattern.  Another
analogue of tranylcypromine, similarly modeled, is
3,4,5-trimethoxytranylcypromine, or
trans-2-(3,4,5-trimethoxyphenyl)cyclopropylamine (TMT).  It has been
evaluated at levels of only 13 milligrams orally, and at this dose
there were no hints of central activity.









#57 DME; 3,4-DIMETHOXY-'-HYDROXYPHENETHYLAMINE

SYNTHESIS: To a solution of 10.2 g 3,4-dimethoxybenzaldehyde in 10 mL
EtOH, cooled to 0 !C, there was added a solution of 4.2 g KCN in 40 mL
H2O.  With good stirring, there was slowly added 10 mL concentrated
HCl (caution: HCN is evolved) and the two-phase reaction mixture was
allowed to continue stirring until there was the spontaneous formation
of crystals.  After a few days standing, these were removed by
filtration and well washed with H2O.  All was recrystallized from 75
mL of 50% MeOH and air dried to provide 6.95 g of the cyanohydrin
3,4-dimethoxy-a-hydroxyphenylacetonitrile.  The mp was 104-106 !C,
which can be increased to 109 !C by recrystallization from benzene.

A well-stirred suspension of 4.7 g LAH in 500 mL anhydrous Et2O was
brought up to a gentle reflux, and 4.7 g
3,4-dimethoxy-a-hydroxyphenylacetonitrile was leached in from a
Soxhlet thimble, over the course of 3 h.  The color of the ether
solution progressed from yellow to green, to an eventual blue.  The
reflux was maintained for 16 h.  After cooling again, there was added
(carefully) a solution of 27 g H2SO4 in 500 mL H2O.  The completely
clear two-phase mixture was separated, and the aqueous phase treated
with 87 g potassium sodium tartrate.  The addition of 25% NaOH brought
the pH >9, and this phase was extracted with 4x100 mL CH2Cl2.  Removal
of all the organic solvents under vacuum gave a residue that was part
oil and part solid.  This was extracted with 4x50 mL boiling Et2O, the
extracts pooled, and saturated with anhydrous HCl gas.  The 0.95 g of
pale-yellow crystals that formed were removed by filtration, and
finely ground under 5 mL CH3CN.  There remained, after refiltration
and air drying, 0.85 g of 3,4-dimethoxy-'-hydroxyphenethylamine
hydrochloride, DME, with a mp of 170-172 !C.

DOSAGE: greater than 115 mg.

DURATION: unknown.

QUALITATIVE COMMENTS: (with 115 mg) I was faintly nauseous about an
hour after taking the compound, and perhaps I was more alert than
usual in the evening.  Substantially no effects.

EXTENSIONS AND COMMENTARY: The rationale for exploring the
beta-hydroxylated phenethylamines, especially those with oxygens at
the biologically important 3- and 4-positions, has already been
presented.  Norepinephrine is a '-hydroxylated phenethylamine with
oxygens at these two ring positions.  With DME, these are masked as
two methyl ethers, and the initials DME stand for
3,4-dimethoxyphenyl-'-ethanolamine.  This is an alternate name for
3,4-dimethoxy-'-hydroxyphenethylamine.

An exactly analogous compound is 3,4-methylenedioxy-'-ethanolamine,
where the masking is done with the biologically more fragile
methylenedioxy ether.  Originally I had called this compound MDE
(methylenedioxyethanolamine) but that code has been, since 1975, used
exclusively for 3,4-methylenedioxy-N-ethylamphetamine, which is a
recipe all by itself.  Under the discussion of members of the BOX
series, there is a methylenedioxyphenethylamine with a methoxyl group
at the '-position, and it is called BOH (q.v.).  There, a reasonable
code name for this specific compound is given, namely BOHH.  RBOS
stands for the beta-oxygen function on a phenethylamine; this is the
heart of the BOX family.  The RHS which is the third letter of BOHH
stands for the free hydroxyl group.  And the final RHS is for
homopiperonylamine (which is the trivial name for the compound without
the hydroxyl group).  BOHH, or
3,4-methylenedioxy-'-hydroxyphenethylamine, or
3,4-methylenedioxy-'-ethanolamine, has also be assayed in man at up to
100 milligrams without any effects, and must be considered, as of now,
to be inactive centrally.  The possible toxic roles of '-ethanolamines
as potential adrenolytic agents, have been discussed in the BOHD
recipe.  And beware of the use of the code name MDE in the very old
literature.  It might be this BOHH compound.









#58 DMMDA; 2,5-DIMETHOXY-3,4-METHYLENEDIOXYAMPHETAMINE

SYNTHESIS: Apiole, as the crystalline essential oil
1-allyl-2,5-dimethoxy-3,4-methylenedioxybenzene, is isolated directly
from commercial Oil of Parsley, by careful fractional distillation.
It is the fraction that boils at 165-167 !C at 27 mm/Hg.  A solution
of 19.8 g apiole in a mixture of 43 g KOH and 60 mL hot EtOH was
heated in the steam bath for 24 h.  With vigorous stirring, it was
diluted with H2O, at a rate which the crystals that formed
spontaneously could accumulate from the turbidity that was generated.
When no more H2O could be added (there was persistent oiling out of
material) the reaction mixture was filtered to give 12.1 g of an amber
solid material.  This was recrystallized from 20 mL boiling hexane,
which was filtered while hot to remove insolubles.  From the cooled
filtrate, there was obtained 9.3 g of
2,5-dimethoxy-3,4-methylenedioxy-1-propenylbenzene, isoapiole, as pale
cream-colored solids.

A stirred solution of 8.8 g
2,5-dimethoxy-3,4-methylenedioxy-1-propenylbenzene and 3.9 g pyridine
in 45 mL acetone was cooled to ice-bath temperatures, and treated with
7.9 g tetranitromethane.  This extremely dark reac-tion was stirred at
0 !C for 5 min, then quenched with a solution of 2.6 g KOH in 45 mL
H2O.  With continued stirring, there appeared yellow crystals of
1-(2,5-dimethoxy-3,4-methylenedioxyphenyl)-2-nitropropene which, after
filtering, washing with 50% acetone and air drying, weighed 8.0 g and
had a mp of 110-111 !C.

To a well-stirred and gently refluxing suspension of 6.3 g LAH in 500
mL anhydrous Et2O, under an inert atmosphere, there was added 7.5 g
1-(2,5-dimethoxy-3,4-methylenedioxyphenyl)-2-nitropropene by leaching
out the nitrostyrene from a thimble in a modified Soxhlet condenser
apparatus.  The addition took 1.5 h, and the refluxing was maintained
for an additional 3 h.  After cooling, the excess hydride was
destroyed by the cautious addition of 300 mL of 1.5 N H2SO4.  The
aqueous phase was brought to a pH of 6 with Na2CO3.  This was heated
to 80 !C and clarified by filtration though paper.  The addition of a
stochiometric amount of picric acid in boiling EtOH gave rise to
precipitation of the product picrate as globs that did not
crystallize.  These were washed with cold H2O, then dissolved in 30 mL
5% NaOH.  Extraction with 2x75 mL Et2O, and the stripping of the
solvent from the pooled extracts, gave 3.1 g of an oily residue which,
upon dissolving in 250 mL Et2O and saturation with anhydrous HCl gas,
gave white crystals.  These were removed by filtration, Et2O-washed,
and air dried, to give 2.9 g of
2,5-dimethoxy-3,4-methylenedioxyamphetamine hydrochloride (DMMDA) that
melted in the 165-175 !C range.

DOSAGE: 30 - 75 mg.

DURATION: 6 - 8 h.

QUALITATIVE COMMENTS: (with 25 mg) The intoxication was there at an
hour and a quarter, and I was hit with nausea with no particular
warning.  I am shaky, a little dilated in the eyes, and there is a
modest depersonalization (reminding me of LSD).  Time might be
slightly slowed, and there is a mild ataxia in the legs.  A couple of
hours later, all effects are going away fast.  I ate an apple, but
maybe my mouth didnUt work quite right.  The apple was incredibly
noisy.

(with 32 mg) I am up to a 2 1/2 plus at something after two hours,
with no apparent visuals, no push, no erotic.  And a few hours later
it is quietly slipping away.  It felt completely safe, and without any
conspicuous psychedelic action, at least at this level.

(with 50 mg) I took graded doses of 10 milligrams every thirty
minutes for a total of 50 milligrams, and there were no effects at
all.

(with 50 mg) In the middle of this all, I found myself getting into
abstract thinking, and maybe some imagery as well.  The effects were
disappointingly light.

(with 75 mg) This was equal to somewhere between 75 and 100
micrograms of LSD.  I was caught up with the imagery, and there was an
overriding religious aspect to the day.  The experience had an
esthetic value.  I liked it.

EXTENSIONS AND COMMENTARY: DMMDA was the first of the tetraoxygenated
amphetamine derivatives that was ever explored in man, back in 1962.
And it is not easy to find an acceptable single phrase to describe its
action or an acceptable number to describe its potency.  I have put
the value of 10 mescaline units (M.U.) into the literature and this
would imply that maybe 30 milligrams was an active dose.  This is
probably too low, and some day I would like to run an experiment with
the entire research group with this compound to see just what it
really does.

The essential oil that corresponds to DMMDA is, of course, apiole from
the Oil of Parsley, which again ties together the spice world and the
amphetamine world.  And there is isoapiole, also a natural thing.
This pair represents the ring-substitution pattern of one of the ten
essential oils and DMMDA is one of the ten essential amphetamines.

Several people have asked me what I thought about the potential
activity of a compound with a methyl group added to DMMDA.  One of
these possibilities would be the N-methylated derivative,
2,5-dimethoxy-N-methyl-3,4-methylenedioxyamphetamine, or METHYL-DMMDA
(or DMMDMA for the dimethoxy-methylenedioxy-methamphetamine
nomenclature).  It is a MDMA analogue, and is described in the recipe
for METHYL-MMDA-2.

The placement of an added methyl group onto the '-position of DMMDA,
rather than on the nitrogen atom, produces a pair of stereoisomeric
homologues.  These are the threo- (or-trans-) and erythro- (or
cis)-2,5-dimethoxy-'-methyl-3,4-methylenedioxyamphetamines.  They have
never been assigned trivial names (my original codes for them were
S-1495 and S-1496 which is not too intuitively informative).  Their
chemically proper names would have the 2-amino-3-substituted
phenylbutane form.  The synthesis of these DMMDA homologues started
with the reduction of the nitrosyrene to the ketone (see under
METHYL-MMDA-2 for this preparation), followed by methylation with
fresh sodium isopropoxide and methyl iodide, to give the beta-methyl
product.  This formed the two possible oximes, one with a mp of 120
!C, and the other from MeOH with a mp of 146 !C.  The 120 !C oxime,
with fresh sodium ethoxide gave
threo-2-amino-3-(2,5-dimethoxy-3,4-methylenedioxyphenyl)butane
hydrochloride.  This salt had a mp of 247-249 !C.  The 146 !C oxime
gave erythro-2-amino-3-(2,5-dimethoxy-3,4-methylenedioxyphenyl)butane
hydrochloride with a mp of 188-189 !C.  The threo-isomer showed a
possible threshold effect at 80 milligrams, with hyperventilation and
perhaps some mental muddiness.  The erythro-isomer showed no effects,
but it had been taken up only to 10 milligrams.

The only other '-methyl homologue of an active material that was
explored chemically, was related to MDA.  The ketone
(3,4-piperonylacetone, see under MDMA) was methylated with sodium
isopropoxide and methyl iodide, and a crystalline oxime was obtained.
Reduction with Zn dust gave what appeared to be
2-amino-3-(3,4-methylenedioxyphenyl)butane hydrochloride, but there
were sufficient uncertainties (possible dimethylation, only one oxime
isolated, the need of strong reducing conditions) that the entire
project was placed in, and still is in, an indefinite holding pattern.
The similar analogues for DOM are the two Classic Ladies, DAPHNE and
ELVIRA, and they, too, are for some time in the future.









#59 DMMDA-2; 2,3-DIMETHOXY-4,5-METHYLENEDIOXYAMPHETAMINE

DOSAGE: about 50 mg.

DURATION: unknown.

QUALITATIVE COMMENTS: (with 50 mg) I am into it; it is much like
MDA.

EXTENSIONS AND COMMENTARY: This is pretty sparse information upon
which to build a picture of biological activity.  First, the synthesis
was done by someone else and, as I have not been able to find where
the notes are, this will be the one recipe in the footnote without
explicit directions incorporated.  The procedure used was exactly the
same as that described for DMMDA, except that the starting material
was dillapiole rather than apiole.  The dillapiole was obtained by the
careful fractionation of Oil of Dill (as opposed to the isolation of
apiole from the careful fractionation of Oil of Parsley).
Isomerization to isodillapiole, nitration with tetra-nitromethane to
give 1-(2,3-dimethoxy-4,5-methylenedioxyphenyl)-2-nitropropene, and
its reduction with LAH in ether to give
2,3-dimethoxy-4,5-methylenedioxyamphetamine hydrochloride (DMMDA-2)
proceeded in a precisely analogous manner to the preparation of DMMDA.

And the pharmacological part is rather thin as well.  I was not the
taster, and can only quote what I had been given.  This same observer
found a threshold at 28 milligrams.  Under other circumstances, this
comment on DMMDA-2 would have been tucked into the commentary on DMMDA
where it belongs, but the activity level was called for in a large
review article, and on the basis of the above, both its initials and
the value of 5x the potency of mescaline were permanently enshrined in
the published literature.  What is it really like?  I donUt know.  Its
structure is an appealing amalgamation of that of MMDA and MMDA-2, and
it might be quite a winner if the dosage and the duration were known.
It is, after all, one of the ten essential amphetamines, since
dillapiole is one of the ten essential oils.

At the time that DMMDA and DMMDA-2 were synthesized, I had visions of
doing the same thorough study with these as I had set up with the
TMA's (six possible, six done) and the MMDAUs (six possible, five
done).  Here, too, with a pair of methoxy groups on an amphetamine
skeleton, with a methylenedioxy ring thrown in, six isomers are
possible but only these two have been prepared.  The unknown ones will
certainly be called DMMDA-3, -4, -5 and -6, but the assignments of
code to structure havenUt even been thought out yet.  The remarkable
and totally unexpected activity of DOM was discovered at about this
time and it was a much more tempting direction to follow.  The
remaining four possible DMMDA's have been left to that famous time, a
future Rrainy day.









From: [e-mail]
Newsgroups: sci.med,sci.chem,alt.drugs
Subject: PiHKAL: The Chemical Story.  File 3 of 6

(I'm posting this for a friend.)

This is part 3 of 6 of the second half of PiHKAL: A Chemical Love
Story, by Alexander Shulgin and Ann Shulgin.  Please forgive any typos
or misprints in this file; further, because of ASCII limitations,
many of the typographical symbols in the original book could not be
properly represented in these files.

If you are seriously interested in the chemistry contained in these
files, you should order a copy of the book PiHKAL.  The book may be
purchased for $22.95 ($18.95 + $4.00 postage and handling) from
Transform Press, Box 13675, Berkeley, CA 94701.  California residents
please add $1.38 State sales tax.

At the present time, restrictive laws are in force in the United
States and it is very difficult for researchers to abide by the
regulations which govern efforts to obtain legal approval to do work
with these compounds in human beings....  No one who is lacking legal
authorization should attempt the synthesis of any of the compounds
described in these files, with the intent to give them to man.  To do
so is to risk legal action which might lead to the tragic ruination of
a life.  It should also be noted that any person anywhere who
experiments on himself, or on another human being, with any of the
drugs described herin, without being familiar with that drug's action
and aware of the physical and/or mental disturbance or harm it might
cause, is acting irresponsibly and immorally, whether or not he is
doing so within the bounds of the law.




#60 DMPEA; 3,4-DIMETHOXYPHENETHYLAMINE

SYNTHESIS: A solution of 33 g 3,4-dimethoxybenzaldehyde in 140 mL
acetic acid was treated with 23 mL nitromethane and 12.5 g anhydrous
ammonium acetate, and heated on the steam bath for 45 min.  To this
there was slowly added, with good stirring, 300 mL H2O, and the
resulting solids were removed by filtration.  The product was finely
ground under a small amount of MeOH, filtered again, and air dried to
give 13.5 g 3,4-dimethoxy-'-nitrostyrene with a mp of 142-143 !C.

To a stirred suspension of 12.0 g LAH in 500 mL anhydrous Et2O that
was at a gentle reflux and under an inert atmosphere, there was added
11.45 g 3,4-dimethoxy-'-nitrostyrene by leaching it from a thimble in
a modified Soxhlet condenser.  The addition took 2 h and the refluxing
was maintained for another 16 h.  After cool-ing to room temperature,
the excess hydride was destroyed by the cautious addition of 500 mL
1.5 N H2SO4.  The phases were separated, and to the aqueous phase
there was added 250 g potassium sodium tartrate.  The pH was brought
to >9, and the clear solution was extracted with 3x100 mL CH2Cl2.
Remo-val of the solvent from the combined extracts under vacuum gave
5.2 g of a pale yellow oil.  This was dissolved in 300 mL anhydrous
Et2O and saturated with anhydrous HCl gas, giving 5.0 g of a slightly
sticky off-white solid.  This was recrystallized from 75 mL of boiling
CH3CN to give 3.3 g 3,4-dimethoxyphenethylamine hydrochloride (DMPEA)
as beautiful white crystals.

DOSAGE: greater than 1000 mg.

DURATION: unknown.

QUALITATIVE COMMENTS: (with 500 mg) Nothing.

(with 1000 mg) Nothing.

(with 10 mg i.v.)  RNothing.

(with 1000 mg of 3,4-dimethoxyphenylacetic acid, a major human
metabolite of DMPEA) RNothing.

(with 500 mg of N-acetyl-3,4-dimethoxyphenethylamine, a major human
metabolite of DMPEA) RNothing.

EXTENSIONS AND COMMENTARY: Why all the interest?  Why keep pursuing a
compound that is so obviously without activity?  Or a metabolite that
is also without activity?  The answer is that these are totally
fascinating compounds just because they have no activity!  By the way,
in this instance, I actually made up most of the quotations.  I am not
sure that the subjects actually said, RNothing,S but they did report
that there were no effects.  In my own experiments, my notes record
the phrase, RNo effects whatsoever.

A little background: one of the transmitter heavyweights in the brain
is dopamine.  Dopamine is called dopamine because it is an amine that
comes from an amino acid that is 3,4-dihydroxyphenylalanine and this,
in German, is Di-Oxo-Phenyl-Alanine, or DOPA.  The levo-optical (or
L-) isomer of DOPA has rather cutely been called the punch-drunk
Spanish matador, or El Dopa.  But that is not part of the story.

The story is really about the RPink Spot of Schizophrenia.S Many years
ago, an observation was made in a biochemical laboratory on the East
Coast that stirred up a rolling controversy.  It had been found that
if the urines of schizophrenic patients (sloppily called
Rschizophrenic urinesS) were extracted in such and such a way, and the
extracts chromatographed, a pink spot would develop at a particular
place on the chromatogram.  Well, if this proved to be true with
urines of a sick population, and were this proved to be different from
the urines of a healthy population, it would constitute an objective
diagnosis of schizophrenia.  A simple chemical test to confirm a
pathology that had defied all efforts to achieve consensus amongst the
psychiatrists of the world.

The literature was suddenly filled with dozens of papers.  Researcher
A confirmed that the pink spot was found with schizophrenics, and not
with normal controls.  Researcher B found the pink spot in all urines,
regardless of pathology.  Researcher C found it in no urines at all.
Researcher D argued that it was a factor from the hospital diet.
Researcher E found that the pink spot reflected the time of day that
the urine sample was collected.  Researcher F drew a conclusion about
where truth might lie by tallying the number of papers that supported
argument A, B, C, D, or E.

The only confirmable fact that endured was that the pink spot was due
to DMPEA.  So a bright spotlight was directed towards its possible
role in mental illness.  And this expressed itself in the simple
question: would it produce schizophrenia in a normal subject?  No.
And in a way I am comforted that that did not evolve into a simple
litmus test for a schizophrenic diagnosis.  There are so many
cultural, political, and social factors that come to bear on the
assignment of a diagnosis of mental illness, that I would have been
forever skeptical of a neat biochemical marker.

A chemical modification of DMPEA that has been explored in this
question of pink spots, mental pathology, and diagnostic markers, is
the corresponding acetamide.  One of the metabolites of DMPEA was
found to be the N-acetyl deriva-tive, N-acetyl-3,4-
dimethoxyphenethylamine.  It was found to be demethylated in man, and
to have pharmacological activity in animals.  Maybe this was the
active compound that could be involved in the schizophrenic process.
But human trials with it, as with the principal metabolite
3,4-dimethoxyphenylacetic acid, showed nothing at all in man.

Another chemical modification is the beta-hydroxy analogue of DMPEA.
It has been explored separately, and is the subject of its own recipe,
in its own rights.  See DME.

Pink was not the only colorful spot associated with schizophrenia.
Somewhere at about this same time, a research paper from Canada
reported the observation of a mauve spot in the chromatographic
analysis of urines of schizophrenic patients.  This had nothing to do
with DMPEA.  I was working closely with a researcher at the
psychiatric institute and we were fascinated by, again, a possible
diagnostic marker.  We assayed the urines of the next 10 patients
being admitted as acute schizophrenics.  No trace of mauve.  We wrote
to Canada, and verified the analytical procedure.  We were told that
the whatzis should have been added after, rather than before, the
whosey, and that we should have heated for 30, not 10 minutes.  Okay.
We assayed the urines of the next 10 patients being admitted using
these new directions.  No trace of mauve.  Another call to Canada, and
we were informed that we still werenUt doing it right.  They were
consistently batting a 100% positive correlation between mauve spots
and schizophrenics, and 0% with healthy controls.  In fact, they
actually gave this positive test the name of a disease, Malvaria.

Then, that little burst of insight!  Aha!  What if, just what if, they
had been seeing something given to their schizophrenics?
Chlorpromazine was the popular treatment of the day.  We took a
whopping dose of chlorpromazine, and over the next couple of days did
manage (barely) to collect our urine samples.  Both of us were
positive Malvarians!  And three days later, we were again negative.
We were most likely seeing a metabolite of chlorpromazine.  One last
call to Canada with the ultimate question Q had you given any
medication to your schizophrenics before your urine analysis?  Of
course (came the answer) Q it would not be ethical to leave them
untreated.  Another color down the drain, and still no objective
measure for mental illness.

By the way, I cannot say I like the chlorpromazine trip.  There is no
real communication either with others or with yourself, with that
stuff.  You are a zombie, but if you are both schizophrenic and a
zombie, you cannot possibly be troublesome for anybody in the
emergency room.









#61 DOAM; 2,5-DIMETHOXY-4-(n)-AMYLAMPHETAMINE

SYNTHESIS: A solution of 110 g p-dimethoxybenzene and 102 g valeric
acid in 168 g polyphosphoric acid was heated on the steam bath for 3
h, giving a deep red homogeneous solution.  This was poured into 1 L
H2O with good stirring.  The strongly acidic, cloudy suspension was
extracted with 3x200 mL CH2Cl2, the extracts pooled, washed with 4x150
mL 5% NaOH, and finally once with dilute HCl.  The solvent was removed
under vacuum, and the residual amber oil cooled overnight at 0 !C.
Some 30 g of crystalline, unreacted dimethoxybenzene were removed by
filtration, and the 85 g of residual oil distilled at the water pump.
Another 15 g of di-methoxybenzene came over as an early cut, but the
fraction boil-ing at 184-192 !C (mostly 188-192 !C) weighed 53.0 g and
was reasonably pure 2,5-dimethoxyamylophenone.  The reaction of the
acid chloride of valeric acid with p-dimethoxybenzene and anhydrous
AlCl3 in CH2Cl2 (parallel to the preparation of the butyrophenone
analog, see DOBU) gave an inferior yield (23.2 g from 92 g
dimethoxybenzene), but did provide a sizeable sample (12.2 g) of
2-hydroxy-5-methoxyamylophenone from the basic washes of the crude
reaction mixture.  This pale yellow solid, after recrystallization
from MeOH, had a mp of 62-62.5 !C.  Anal. (C12H16O3) C,H.

To 360 g mossy zinc there was added a solution of 7.2 g mercuric
chloride in 200 mL warm H2O, and this was swirled periodically for 2
h.  The H2O was drained off, and the amalgamated zinc added to a 2 L
three-neck round-bottomed flask, treated with 200 mL concentrated HCl,
and heated with an electric mantle.  A solution of 53.0 g of
2,5-dimethoxyamylophenone in 107 mL EtOH containing 30 mL concentrated
HCl was added drop-wise over the course of 4 h accompanied by 330 mL
of concentrated HCl added batchwise over this same period.  The
mixture was held at reflux overnight and, after cooling, diluted with
sufficient H2O to allowed CH2Cl2 to be the lower phase.  The phases
were separated, and the aqueous phase was extracted with 2x200 mL
additional CH2Cl2.  These organic phases were combined, washed first
with 5% NaOH and then with H2O, and the solvent removed under vacuum.
Distillation at the water pump yielded two fractions.  The first
distilled from about 100-130 !C, weighed 8.8 g, had a faint smell of
apples and fennel, and was free of a carbonyl group in the infra-red.
It proved to be only 50% pure by GC, however, and was discarded.  The
major fraction was a pale amber oil distilling between 152-170 !C and
was substantially free of smell.  It weighed 18.9 g, and was (by GC)
90% pure 2,5-dimethoxy-(n)-amylbenzene.

A mixture of 36.3 g POCl3 and 40.9 g N-methylformanilide was allowed
to incubate for 0.5 h.  To this there was then added 18.5 g of
2,5-dimethoxy-(n)-amylbenzene and the mixture heated on the steam bath
for 2 h.  This mixture was poured into a large quantity of H2O and
stirred overnight.  The black oily product was extracted with 3x100 mL
CH2Cl2, and the extracts combined and stripped of solvent under
vacuum.  The black residue was distilled at 180-205 !C at 20 mm/Hg to
give 12.5 g of a pale amber oil that slowly set up to a crystalline
mass.  An analytical sample was recrystallized from MeOH to provide
2,5-dimethoxy-4-(n)-amylbenzaldehyde with a mp of 25-26 !C.  Anal.
(C14H20O3) H; C: calcd, 71.16: found, 71.92, 71.74.

A solution of 12.3 g 2,5-dimethoxy-4-(n)-amylbenzaldehyde in 50 mL
acetic acid was treated with 4.0 g anhydrous ammonium acetate and 12
mL nitroethane.  This mixture was heated on the steam bath for 4 h,
then poured into a large quantity of H2O.  This was extracted with
3x200 mL CH2Cl2, the extracts washed with H2O, and the solvent removed
to give a deep red oil that, on standing in the refrigerator, slowly
set to a crystalline mass weighing 13.5 g.  An analytical sample was
recrystallized from MeOH to provide
1-(2,5-dimethoxy-4-(n)-amylphenyl)-2-nitropropene as fine yellow
microcrystals with a mp of 44 !C sharp.  Anal. (C16H23NO4) C,H,N.

To a gently refluxing suspension of 10 g LAH in 500 mL anhydrous Et2O
under a He atmosphere, there was added by 13.2 g
1-(2,5-dimethoxy-4-(n)-butyl-phenyl)-2-nitropropene by allowing the
condensing ether drip into a Soxhlet thimble containing the
nitrostyrene which effectively added a warm saturated solution of it
dropwise to the reaction mixture.  Refluxing was maintained for 18 h,
and the cooled reaction flask stirred for several additional days.
The excess hydride was destroyed by the cautious addition of 1 L 8%
H2SO4.  When the aqueous and Et2O layers were finally clear, they were
separated, and the aqueous layer was washed with an additional 2x100
mL Et2O.  Removal of the solvent from the organic phase and washings
provided 4.7 g of a thick red oil that was discarded.  The aqueous
phase was then extracted with 2x200 mL CH2Cl2 which actually removed
the product as the sulfate salt.  This organic phase was washed with
2x100 mL 5% K2CO3 (removing the H2SO4) and with the evaporation of the
solvent there was obtained 6.2 g of an oily amber residue.  This was
dissolved in 200 mL Et2O and saturated with anhydrous HCl gas.  Fine
white crystals of 2,5-dimethoxy-4-(n)-amylamphetamine hydrochloride
(DOAM) separated, were removed by filtration, Et2O-washed and air
dried, and weighed 5.2 g.  The mp of 136-139 !C was increased to
145-146 !C by recrystallization from CH3CN. Anal. (C16H28ClNO2) C,H,N.

DOSAGE: greater than 10 mg.

DURATION: unknown.

QUALITATIVE COMMENTS: (with 10 mg) There was a clear threshold that
in no way interfered with my day's activities.  I was quite gay and
voluble at lunch and bubbled on into the afternoon with puns and high
spirits.  There may have been a little motor incoordination as noted
in handwriting, and there was a strange tenseness during driving.
There were no sequelae, there was no trouble sleeping, and with this
potency way down from the lower homologues, I have no pressing desire
to take this compound to a higher dose.

EXTENSIONS AND COMMENTARY: The actual procedure that was published for
the isolation of this final amine was a different one, one that would
certainly work, but which was based on the procedures tried and proven
with the lower homologues.  The process described above is just a bit
bizarre (a sulfate salt extracting into methylene chloride) but it was
the actual thing that was done.  The work was started towards two
additional compounds but these never got past the first Rketone and
phenolS stage.  p-Dimethoxybenzene was brought into reaction with
n-caproic acid with polyphosphoric acid (aiming towards
2,5-dimethoxy-4-(n)-hexylamphetamine, DOHE) but this was dropped when
DOAM proved to be down in potency.  And the reaction between
p-dimethoxybenzene and benzoyl chloride with anh. aluminum chloride
went well (aiming towards 2,5-dimethoxy-4-benzylamphetamine, DOBZ).  A
goodly amount of the phenol (2-hydroxy-5-methoxybenzophenone) was
obtained as fine yellow crystals, but this line of inquiry was also
dropped.

The preparation of DOAM was, as a matter of fact, the last of the
homol-ogous series of compounds actually completed, which stemmed from
the original discovery of DOM.  The RTen Classic LadiesS concept was
mentioned under ARIADNE, and the adding of a methyl group in the place
of a hydrogen atom at the 4-position-methyl led to the synthesis of
Ms. HECATE and gave rise to DOET.  The whole series of
methyl-ethyl-propyl-butyl-amyl compounds was appealing to me, in that
the potency seemed to increase initially as the chain got longer, and
then it abruptly dropped off.  WouldnUt it be nice, I thought, if I
could interest some pharmacologist in looking at this tight set of
drugs with some animal model, to see if there is some neurotransmitter
activity that would show a parallel action.

I learned of a curious young researcher in Washington who had an
elegant procedure for measuring serotonin agonist action using the
(otherwise) discarded sheep umbilical artery strips.  These become
available each year at lambing time, do not cost the life of anything,
and require very little compound.  He assayed my compounds and, lo and
behold, the serotonin activity also went through a maximum in the
middle of this series.  We published a short paper to this effect,
which served as a excellent vehicle to get the cogent human data into
the scientific literature.

I have never understood the reasons that there might be connection
between the twitching of a umbilical artery in a sheep and the
appearance of an insight in the mind of man.  And, I have never
personally met this pharmacologist.  Some day, I hope to do both.









#62 DOB; 2,5-DIMETHOXY-4-BROMOAMPHETAMINE

SYNTHESIS: To a well-stirred solution of 1.95 g of the free base of
2,5-dimethoxyamphetamine (2,5-DMA) in 12 mL glacial acetic acid, there
was added 1.8 g elemental bromine dissolved in 4 mL acetic acid over
the course of 5 min.  The slightly exothermic reaction was allowed to
stir for 3 h, and then added to about 200 mL H2O.  The cloudy solution
was washed with 2x100 Et2O, made basic with aqueous NaOH, and
extracted with 3x100 mL CH2Cl2.  Evaporation of the solvent from the
pooled extracts gave about 3 mL of a pale amber oil which was
dissolved in 250 mL anhydrous Et2O and saturated with anhydrous HCl
gas.  The fine white crystals of 2,5-dimethoxy-4-bromoamphetamine
hydrochloride, DOB, were removed by filtration, Et2O washed, and air
dried.  These weighed 1.7 g and had a mp of 195-196 !C.
Recrystallization from IPA brought this up to 207-208 !C.  Proton NMR
spectroscopy of the hydrochloride salt in D2O gave confidence that the
bromine atom had uniquely entered the 4-position, in that there were
only two unsplit aromatic hydrogen atoms present, at 6.97 and at 7.20
ppm downfield from external TMS.

DOSAGE: 1.0 - 3.0 mg.

DURATION: 18 - 30 h.

QUALITATIVE COMMENTS: (with 0.4 mg) There was a distinct enhancement
of visual perception, and some strengthening of colors.  A clean, cold
feeling of wind on the skin.  I felt an enriched emotional affect, a
comfortable and good feeling, and easy sleeping with colorful and
important dreams.

(with 2.0 mg) There was a continuous tremor at the physical level,
and an incredible Moebius strip representation of reality at the
intellectual level.  I was able to enter into personal problems
easily, and get out again when I chose to.  During the next day, there
were brief lapses of attention, or little fugue states, and it was not
until the following evening that I was completely myself again.

(with 2.8 mg) About three hours into this I had a severe cramp, and
had a near fainting response to the pain, and yet there was no pain!
I felt that I was very near a loss of consciousness, and this was most
disturbing.  There were flashes of depersonalization.  I saw rings
around the moon with prismatic colors, and there were long-lasting
Rafter-imagesS following any viewings of points of light.  I was still
a good plus 1 at 14 hours, but did manage to sleep.  It was the next
day before I was again at baseline.

(with 3.0 mg) This was a complex, but a very good day.  It involved
making a large pot of chicken-vegetable soup, and listening to H.L.,
my favorite Saturday morning fundamentalist Christian radio preacher,
bless Tim.  The Democrats are not exactly all anti-American dupes of
Moscow (or the Devil), but to H.L., they are practically, almost,
next-door to it.  The Rapture is supposed to happen tomorrow according
to a certain book, newly published (just in time, looks like) and he
is busy softening the possible disappointment of those who may find
themselves unchanged Monday morning.  Wunnerful.  It's been one heck
of a good experiment, and I canUt understand why we waited nine years
to try this gorgeous stuff.  Without going into the cosmic and
delicious details, let's just say itUs a great material and a good
level.

(with 0.5 mg of the RRS isomer) I am underway, and this is a smooth
intoxication.  I am completely functional, but still really a plus
two.  I would not choose to drive a car.  Not very far.  I felt a
rather quick dropping to a plus-one at the fifth hour, but there is a
residual stimulation still the following morning.

(with 1.0 mg of the RRS isomer) By the fourth hour I am absolutely a
+++ and am searching the kitchen for food.  But what I eat is only
so-so.  There is not the introspection or intensity of 2.0 milligrams
of the racemate material, but this is a rewarding place nonethless.
At the 18th hour, there was some fitful sleep, with bizarre dreams.
The next day I was still hungry for altered spaces, and successfully
challenged the residual plus one with LSD and, as is usually the case,
acid cut right through the detritus and allowed a direct shot up to a
+++ again.

(with 1.5 mg of the RRS isomer) This is a +++ but it is vaguely
irrational.  I feel a heavy body load, but then the temperature
outside is over a hundred degrees and I may not be in the best of all
physical environments.  I would not wish any higher dosage.  There
were cat-naps at the twelth hour, but most symptoms were still there
at the 18th hour.  A good experience.  It would be interesting to
compare this, some day, with 3.0 milligrams of the racemate.

(with 0.5 mg of the RSS isomer) There are no effects at all.

(with 1.0 mg of the RSS isomer) There is something warm and nice at a
couple of hours into this, but I am no more than threshold, and the
effects are very slight.  By the fifth hour there are no longer any
effects.

EXTENSIONS AND COMMENTARY: The stars had clearly lined up in favor of
making DOB and exploring its biological activity.  This preparation
had been completed in 1967 and the report of this compound and its
unprecedently high potency published in 1971.  And very shortly, two
additional papers appeared completely independently.  One described
DOB made via a different route, and describing high activity in rats.
The other described DOB and a couple of closely related brominated
amphetamines and their action in man.

This is one of the last of the experimental compounds within the
phenethylamine family on which any animal toxicity studies were
performed by me prior to human studies.  A mouse injected with 50
mg/Kg (ip) showed considerable twitching and was irritable.  Another,
at 100 mg/Kg (ip), had overt shaking at 20 minutes, which evolved into
persistent hyperactivity that lasted several hours.  Yet another, at
125 mg/Kg (ip), lost much of her righting reflex within 15 minutes,
entered into convulsions at 50 minutes, and was dead a half hour
later.  A fourth mouse, at 150 mg/Kg (ip), entered into spontaneous
convulsions within 10 minutes, and expired in what looked like an
uncomfortable death at 22 minutes following injection.  What was
learned?  That the LD/50 was somewhere between 100 and 125 mg/Kg for
the mouse.  And an effective dose in man of maybe 2 mg (for an 80 Kg
man) is equivalent to 25 ug/Kg.  Therefore the index of safety (the
therapeutic index, the lethal dose divided by the effective dose) is
well over a thousand.  I feel that two mice were killed without
anything of value having been received in return.

Actually, it is very likely that the damaging, if not lethal, level of
DOB in man is a lot lower than this ratio would imply.  There was a
report of a death of a young lady following the snorting of an amount
of DOB so massive, there was the actual recovery of over nine
milligrams of the drug from her body tissues in the post-mortem
examination.  It was said that she and her companion had thought that
the drug they were using was MDA and, taking a dosage appropriate for
this, effectively overdosed themselves.  He survived, following
convulsions and an extended period (several weeks) of being in a
comatose state.  Tragic examples have been reported that involve
arterial vascular spasm.  But in most overdose cases ascribed to DOB,
the identity of the drug has remained unestablished.

As with DOI, the presence of a heavy atom, the bromine atom, in DOB
makes the radioactive isotope labelled material a powerful research
tool.  Studies with DOB labelled with either 82Br or 77Br have been
used in human subjects to follow the distribution of the drug.  The
use of a whole body scanner permits the imaging of the intact body,
with the travelings of the radioactivity easily followed from outside.
A fascinating finding is that DOB goes first and foremost to the human
lung where it accumulates for a couple of hours.  It is only
afterwards that the brain level builds up.  There is a strong
implication that some metabolic conversion occurs in the lung, and it
is only after this that the truly active metabolite is available for
central action.  This is consistent with the relatively slow onset of
effect, and the very long duration of action.

As with all the other psychedelics which can and have been studied as
their optical isomers, it is the RRS isomer of DOB that is the more
active than the racemic mixture, and the RSS is certainly much less
active, but it has never been run up to fully active levels.  The
alpha-ethyl homologue of DOB is mentioned under ARIADNE.  The
positionally rearranged isomers of DOB are discussed under META-DOB.









#63 DOBU; 2,5-DIMETHOXY-4-(n)-BUTYLAMPHETAMINE

SYNTHESIS: A well stirred suspension of 140 g anhydrous AlCl3 in 400
mL CH2Cl2 was treated with 102 g butyryl chloride.  This mixture was
added in small portions, over the course of 20 min, to a well-stirred
solution of 110.4 g p-dimethoxybenzene in 300 mL CH2Cl2.  After an
additional 1 h stirring, the mixture was poured into 1 L H2O, and the
two phases separated.  The aqueous phase was extracted with 2x100 mL
CH2Cl2, and the organic fractions pooled.  These were washed with
4x125 mL 5% NaOH which removed both unreacted butyric acid as well as
a small amount of 2-hydroxy-4-methoxybutyrophenone.  Removal of the
CH2Cl2 under vacuum gave 156.7 g of a residue that was distilled at
170-178 !C at the water pump.  The isolated 2,5-dimethoxybutyrophenone
was a pale yellow oil that weighed 146 g and was about 85% pure by GC
analysis.  The principal impurity was unreacted dimethoxybenzene.  The
identical preparation with CS2 as a solvent, rather than CH2Cl2 gave a
somewhat smaller yield of product.

To 150 g mossy zinc there was added a solution of 3 g mercuric
chloride in 60 mL H2O, and this was swirled periodically for 2 h.  The
H2O was drained off, and the amalgamated zinc added to a 1 L
three-neck round-bottomed flask, treated with 80 mL concentrated HCl,
and heated on the steam bath.  A solution of 20.8 g of
2,5-dimethoxybutyrophenone in 45 mL EtOH containing 10 mL concentrated
HCl was added in increments over a 4 h period.  During this period an
additional 140 mL of concentrated HCl was added periodically to the
ketone solution.  Heating was maintained for an additional 4 h.  After
cooling, the aqueous filtrate was extracted with 3x100 mL CH2Cl2 and
these pooled extracts washed with 2x200 mL 5% NaOH to remove a small
amount of phenolic impurity.  After removal of the solvent under
vacuum, the residual 16.1 g of clear oil was distilled over the
100-160 !C range (largely at 141-145 !C) at the water pump to give 10
g of 2,5-dimethoxy-(n)-butylbenzene as a white oil.  This was about
90% pure by GC analysis, and was used without further purification in
the next step.

A mixture of 98 mL POCl3 and 108 mL N-methylformanilide was allowed to
incubate for 0.5 h.  To this there was then added 47.3 g of
2,5-dimethoxy-(n)-butylbenzene and the mixture heated on the steam
bath for 1.5 h.  This mixture was poured into 1 L H2O and stirred
overnight.  The H2O was drained from the extremely gooey black
crystals that were formed, and extracted with 2x100 mL portions of
hexane.  The black residue was diluted with these extracts and, on
slow evaporation there was deposited 26.4 g of oily amber crystals.
Filtering these through a medium porous funnel and sucking the oily
phase away from the solids yielded 14.8 g of yellow crystals that
could be recrystallized from 50 mL MeOH to give, after filtration and
air drying to constant weight, 6.4 g of
2,5-dimethoxy-4-(n)-butylbenzaldehyde as pale yellow crystals with a
mp of 47-48 !C.  The recovery of all organic soluble things from the
above process gave, after removal of the extraction solvents and
making boiling hexane extractions of the residues, a second crop of
aldehyde of equal weight and of identical mp.  An analytical sample,
from hexane, had the same mp.  Anal. (C13H18O3) C,H.

A solution of 13.2 g 2,5-dimethoxy-4-(n)-butylbenzaldehyde in 50 mL
acetic acid was treated with 4.0 g anhydrous ammonium acetate and 10
mL nitroethane.  This mixture was heated on the steam bath for 4 h,
then poured into a large quantity of H2O.  This was extracted with
2x200 mL CH2Cl2, the extracts washed with H2O, and the solvent removed
to give 19 g of a deep red oil.  This was dissolved in 35 mL hot MeOH
and slowly cooled, depositing yellow-orange crystals.  These were
removed by filtration, washed with cold MeOH, and air-dried to
constant weight.  Thus there was obtained 11.8 g of
1-(2,5-dimethoxy-4-(n)-butylphenyl)-2-nitropropene with a mp of 54-56
!C.  Recrystallization of an analytical sample from MeOH tightened the
mp to 55-56 !C.  Anal. (C15H21NO4) C,H,N.

To a gently refluxing suspension of 8.5 g LAH in 300 mL anhydrous Et2O
under a He atmosphere, there was added 11.0 g
1-(2,5-dimethoxy-4-(n)-butylphenyl)-2-nitropropene by allowing the
condensing ether to drip into a Soxhlet thimble containing the
nitrostyrene, thus effectively adding a warm saturated solution of it
dropwise.  Refluxing was maintained overnight, and the cooled reaction
flask stirred for several additional days.  The excess hydride was
destroyed by the cautious addition of 600 mL H2O containing 55 g
H2SO4.  When the aqueous and Et2O layers were finally clear, they were
separated, and 250 g of potassium sodium tartrate was dissolved in the
aqueous fraction.  Aqueous NaOH was then added until the pH was above
9, and this was then extracted with 3x200 mL CH2Cl2.  Evaporation of
the solvent produced 12 g of an amber oil that gelatinized to a waxy,
amorphous mass.  This was leached as thoroughly as possible with
anhydrous Et2O which was clarified by filtration, then saturated with
anhydrous HCl gas.  After a few minutes delay, there commenced the
separation of fine white crystals of
2,5-dimethoxy-4-(n)-butylamphetamine hydrochloride (DOBU).  These
weighed, after filtration, Et2O washing, and air drying to constant
weight, 5.8 g.  Recrystallization from boiling CH3CN (this is an
unusually exothermic crystallization) yielded 5.4 g of a fluffy white
product with mp 151-152 !C.  Anal. (C15H26ClNO2) C,H,N.

DOSAGE: uncertain.

DURATION: very long.

QUALITATIVE COMMENTS: (with 2.2 mg) It was almost the fourth hour
before I noticed something.  Then I felt an increasing manic
intoxication, winding up tighter and tighter.  Sleep was impossible
until some 18 hours after the start of the trial.  There was some
paresthesia, but no mydriasis.  This might be a stimulant, but it is
not a psychedelic, at least at this level.  Go up slowly.

(with 2.8 mg) Nothing for over seven hours.  Then there was what
seemed to be an irritability and shortness of temper.  Mentally I am
completely clear, but no more alert than usual.  There was no sleep
that evening, and the next day there was a feeling of overall
depression.  Perhaps that was due to the lack of sleep, but there were
no signs of residual sleepiness.

EXTENSIONS AND COMMENTARY: It is not possible to give a dosage range
for DOBU.  There is no question but that whatever is occurring is slow
of onset, and very long lived.  In general, the effects resemble
stimulation more that anything else.

A butyl group has four carbons, and they can be interconnected in four
ways (as long as you donUt connect them in rings).  If all four of
them are in a straight chain, you have the so-called normal butyl (or
n-butyl) group, and this is the exact arrangement that is found in the
DOBU.  The atoms can be numbered #1 through #4, going outwards from
the point of attachment.  The chain can, however, be only three
carbons long, and the fourth or extra carbon attached on the #2 carbon
atom; this is called the iso-butyl (or i-butyl) group.  Or the extra
left-over carbon can be attached to the #1 carbon atom; this is called
the secondary butyl (or sec-butyl or s-butyl) group.  Or lastly, the
atoms can be all scrunched up, with the chain only two carbons long,
and the other two left-over methyl carbons attached to the #1 carbon
atom.  This isomer is called the tertiary butyl (or tert-butyl or
t-butyl) group.  In animal studies, and in preliminary human studies,
the activity of these compounds drops as the butyl group gets more and
more scrunched.

The isomer with the iso-butyl group has been synthesized by the
Friedel- Crafts reaction of isobutyryl chloride with
p-dimethoxybenzene, followed by reduction of the ketone to an alcohol,
dehydration to a dimethylstyrene, and final hydrogenation to a
hydrocarbon.  The formation of the benzaldehyde, reaction with
nitroethane, and final lithium aluminum hydride reduction to
2,5-dimethoxy-4-(2-methylpropyl)-amphetamine hydrochloride (DOIB, mp
164-166 !C) were completely conventional.  In drug discrimination
studies in rats, DOIB was only a third as active as DOM, and in humans
the activity falls in the 10 to 15 milligram area.  The isomer with
the sec-butyl group was made in a somewhat similar manner, from
2,5-dimeth-oxyacetophenone.  The addition of ethyl magnesium bromide
gave an alcohol which with dehydration yielded a pair of
dimethylstyrenes isomeric to the compound mentioned above.  From there
an identical sequence of steps (hydrogenation, benzaldehyde synthesis,
nitrostyrene, and lithium aluminum hydride reduction) produced
2,5-dimethoxy-4-(1-methylpropyl)amphetamine hydrochloride (DOSB, mp
168-170 !C.).  In the rat studies it was only a twelfth the potency of
DOM, and in man the active dose is in the 25 to 30 milligram area.  As
with the normal butyl compound, there is a strong stimulation factor,
with real and long-lasting sleep disturbance.

The last of the butyl isomers, the tert-butyl compound, was made from
a much more obvious starting material.  This is the commercially
available tert-butyl hydroquinone.  It was methylated in sodium
hydroxide with methyl iodide, and then carried through the above
sequence (benzaldehyde. mp 124 !C from cyclohexane, nitrostyrene,
yellow crystals from methanol, mp 95-96.5 !C, and lithium aluminum
hydride reduction) to give
2,5-dimethoxy-4-(1,1-dimethylethyl)amphetamine hydrochloride (DOTB, mp
168 !C).  Rats trained in a process called the Sidman Avoidance
Schedule gave behavior that suggested that DOTB had no activity at
all, and in human trials, doses of up to 25 milligrams were totally
without effect.

An effort was made to prepare a butyl analogue containing a ring, but
it was never completed.  This was the cyclopropylmethyl isomer,
2,5-dimethoxy-4-cyclo-propylmethylamphetamine hydrochloride, DOCPM.
Only the first step of its synthesis was complete (the reaction of
cyclopropylcarboxylic acid chloride with p-dimethoxybenzene) and even
it went badly.  The desired ketone (2,5-dimethoxyphenyl cyclopropyl
ketone) was most difficult to separate from the recovered starting
ether.  A promising approach would be the isolation of the phenol
(2-hydroxy-5-methoxyphenyl cyclopropyl ketone) which is a beautiful
yellow solid with a melting point of 99-100 !C from methanol.  Anal.
(C11H12O3) C,H.  It then could be methylated to the wanted
intermediate.  It is the major product when the reaction is conducted
with anhydrous aluminum chloride in methylene chloride.

The 2-carbon phenethylamine homologues of these compounds could all,
in principle be easily made by using nitromethane instead of
nitroethane with the intermediary benzaldehydes.  But, as of the
present time, none of them have been made, so their pharmacology
remains completely unknown.









#64 DOC; 2,5-DIMETHOXY-4-CHLOROAMPHETAMINE

SYNTHESIS: A solution of 6.96 g 2,5-dimethoxyamphetamine hydrochloride
(2,5-DMA) in 250 mL H2O was made basic with aqueous NaOH and extracted
with 3x75 mL CH2Cl2.  After removal of the solvent from the pooled
extracts under vacuum, the residual free base was dissolved in 36 g
glacial acetic acid and, with good stirring, cooled to 0 !C with an
external ice bath.  There was then added, with a Pasteur pipette, 3 mL
of liquid chlorine.  The generation of HCl was evident, and the
reaction was allowed to stir for an additional 3 h.  The mixture was
then poured into 300 mL H2O and washed with 3x100 mL Et2O.  The
aqueous phase was made basic with NaOH and extracted with 3x150 mL
CH2Cl2.  After removal of the solvent from the pooled extracts, the
residue was dissolved in Et2O and saturated with anhydrous HCl gas.
There was the formation of a heavy oily precipitate.  The ether
supernatent was decanted, and the residue was intimately mixed with
200 mL of fresh anhydrous Et2O.  Everything set up as an off-white
crystalline mass weighing 2.3 g.  This was dissolved in 12 mL of
boiling MeOH and diluted with 230 mL boiling Et2O.  The clear solution
was quickly filtered to give a clear, pale amber mother liquor, which
soon started depositing lustrous white crystals.  After filtering,
Et2O washing, and air drying to constant weight, there was obtained
1.4 g of 2,5-dimethoxy-4-chloroamphetamine hydrochloride (DOC) From
the mother liquors (from the original HCl saturation) an equal amount
of product could be obtained by exploiting the acetone insolubility of
the hydrochloride salt of the product.  The published mp of this salt,
from acetone/EtOH, is 187-188 !C.  A sample of this hydrochloride
salt, prepared from the amino analogue via diazotization and eventual
hydrolysis of an acetylated precursor, was recrystallized from
EtOH/ether and had a mp of 193-194.5 !C.

DOSAGE: 1.5 - 3.0 mg.

DURATION: 12 - 24 h.

QUALITATIVE COMMENTS: (with 1.6 mg) I was hit with a slightly light
head; the effects were quite real.  I was disconnected, and somehow
spacey, but this was a favorable spacey which was kind of fun.
Somewhere at about the sixth hour I realized that I was beginning to
drop off a bit, but six hours later yet, there was still a lot of
memory.  This is a long thing.

(with 2.4 mg) This is what I might call an archetypical psychedelic.
Everything is there in spades, with few if any of the subtle graces,
the Tgentle imagesU and Tgentle fantasiesU of the 2-carbon
phenethylamines.  This is the works.  There are visuals, and there are
interpretive problems with knowing just where you really are.  The
place where nothing makes sense, and yet everything makes sense.  I
have just slept for a few hours, and now I am awake and it has been
eighteen hours, and there is a lot still going on, although I have a
relaxed, good feeling.  Anyone who uses this had better have 24 hours
at their disposal.

(with 2.4 mg) Here I am at the sixth hour, and I am still roaring
along at a full plus three.  I have established that this material is
neither anti-erotic nor anorexic.  The body is very comfortable, and
so is the mind.  There is an interesting aspect, perhaps peculiar only
to this experiment and under these conditions.  With my eyes closed
the fantasy is a completely dark screen, lovely and seductive, subtle,
and yet light must be deliberately brought in.  This is not in any way
negative for being in the dark, but is just unusual.  I will have to
try this in the daylight next time, to see what the eyes-closed brings
to the mind-screen.  At 24 hours, I have found that my sleep was not
too great.  My dreams were tight, and I kept defending against
trouble; the nervous system was too alert.  I was in a good humor,
though, and I still am.  This is excellent stuff, but start early in
the day.

EXTENSIONS AND COMMENTARY: It is clear that the three halo-amphetamine
derivatives, DOI, DOB and DOC, are all pretty much of the same
potency.  And all of them very long lived.  The difference between the
various halogen atoms was brought up under the 2C-C discussion.  DOC
is clearly a long-lasting, dyed-in-the-wool psychedelic.

In the making of this, by the procedures that have been followed in
Canada, there are two chemical intermediates which might, some day, be
looked at as potential psychedelics under their own colors.  Reduction
of the compound that is called DON in this Book II
(2,5-dimethoxy-4-nitroamphetamine hydrochloride) with Pd/charcoal and
hydrogen, gives the 4-amino derivative.  This is
2,5-dimethoxy-4-aminoamphetamine dihydrochloride, DOA, which melts at
248-250 !C.  And the reduction of an oxime intermediate gives rise to
the acetamido analogue, 2,5-dimethoxy-4-acetamidoamphetamine
hydrochloride, DOAA, with a mp of 249-250 !C.  Neither compound has
been tasted, but someday this omission will be corrected.  DOA and
DOAA have a sinister ring to them, however, and some changes of
terminology might be needed.  DOA, in the coroner's vocabulary, means
Dead-On-Arrival.  But then, AMA (the American Medical Association)
just happens to also mean (in the jargon of emergency medicine)
Against-Medical-Advice.  Everything averages out, somehow.  Remember
that the amyl homolog (amyl at the 4-position) follows the 4-letter
convention of all of the DOM homo-logues, and has the code name of
DOAM.  Thus, DOA, amino; DOAA, acetamido, and DOAM, amyl.

One must learn to keep one's sense of humor.  The immortal humorist
Wavy Gravy once said, RIf you canUt laugh at life, it just isnUt funny
anymore.S The code name of this compound,
2,5-dimethoxy-4-chloroamphetamine is, after, all, DOC.  This should
certainly appeal to some physicians.









#65 DOEF; 2,5-DIMETHOXY-4-(2-FLUOROETHYL)-

AMPHETAMINE

SYNTHESIS: A well-stirred solution of 0.45 g free base DOB in 2 mL
CH2Cl2 was treated with 0.37 g triethylamine, cooled to 0 !C, and
there was then added a solution of 0.39 g
1,1,4,4-tetramethyl-1,4-dichlorodisilylethylene in 2 mL CH2Cl2.  The
reaction mixture was allowed to return to room temperature, with
stirring continued for 2 h.  The solvent was removed under vacuum, the
residue suspended in hexane, and the insoluble by-products removed by
filtration through celite.  Removal of the solvent under vacuum gave
0.60 g
1-(4-bromo-2,5-dimethoxyphenyl)-2-(1-aza-2,5-disila-2,2,5,5-tetramethylcyclopentyl)propane
as a gold-colored impure semi-solid mass which was used without
further purification.

To a solution of 0.60 g
1-(4-bromo-2,5-dimethoxyphenyl)-2-(1-aza-2,5-disila-2,2,5,5-tetramethylcyclopentyl)propane
in 10 mL anhydrous Et2O under an inert atmosphere and cooled to -78 !C
there was added 1.8 mL of a 1.7 M solution of t-butyl lithium in
hexane.  The resulting yellow solution was stirred for 20 min, and
then treated with 1.65 mL of a 1.4 M solution of ethylene oxide in
Et2O, the stirring was continued for 40 min, then the reaction mixture
allowed to come to room temperature over an additional 40 min.  There
was added 20 mL hexane, and the temperature increased to 50 !C for an
additional 2 h.  The reaction mixture was treated with 3 mL H2O and
diluted with 60 mL Et2O.  The organic phase was washed with saturated
NH4Cl, dried over anhydrous MgSO4, and after filtering off the
inorganic drying agent, the organic solvents were removed under
vacuum.  The gold-colored residual oil was dissolved in 10 mL MeOH and
treated with a 10% KOH.  This mixture was heated for 30 min on the
steam bath, returned to room temperature, and the volatiles removed
under vacuum.  The residue was dissolved in 3% H2SO4, washed twice
with CH2Cl2, brought to pH 12 with 25% NaOH, and extracted with 3x50
mL CH2Cl2.  The pooled extracts were combined, dried with anhydrous
Na2SO4, and the solvent removed under vacuum to give 0.24 g of
2,5-dimethoxy-4-(2-hydroxyethyl)amphetamine (DOEH) as a white solid
with a mp of 102-104 !C.

To a suspension of 0.94 g DOEH in ice-cold anhydrous Et2O containing
1.4 g triethylamine, there was added 2.4 g trifluoroacetic anhydride
dropwise over the course of 10 min.  The reaction mixture was brought
to reflux temperature, and held there with stirring for 1 h.  After
cooling, 60 mL of CH2Cl2 was added, and the organic phase washed with
saturated NaHCO3.  The solvent was removed under vacuum, providing a
gold-colored solid as a residue.  This was dissolved in 50 mL MeOH,
diluted with 30 mL H2O and, following the addition of 0.76 g solid
NaHCO3 the reaction mixture was stirred at room temperature for 3 h.
The excess MeOH was removed under vacuum, and the remaining solids
were suspended in CH2Cl2 and washed with H2O.  After drying the
organic phase with anhydrous Na2SO4 and removal of the solvent under
vacuum, there was obtained 1.34 g
1-(2,5-dimethoxy-4-(2-hydroxyethyl)phenyl)-2-(2,2,2-trifluoroacetamido)propane
as white solid with a mp of 129-131 !C.  Anal. (C15H20F3NO4) C,H.

A well-stirred solution of 0.09 g
1-(2,5-dimethoxy-4-(2-hydroxyethyl)phenyl)-2-(2,2,2-trifluoroacetamido)propane
in 15 mL CH2Cl2 was cooled to -78 !C and treated with 0.05 g
diethylaminosulfur trifluoride (DAST) added dropwise.  The pale yellow
reaction solution was stirred an additional 5 min and then brought up
to room temperature and stirred for 1 h.  There was then added
(cautiously) 3 mL H2O followed by additional CH2Cl2.  The phases were
separated, the organic phase washed with H2O, dried with anhydrous
Na2SO4 and, after filtering off the drying agent, stripped of solvent
under vacuum.  There was thus obtained 0.088 g of
1-[2,5-dimethoxy-4-(2-fluoroethyl)phenyl]-2-(2,2,2-trifluoroacetamido)propane
as a white solid with a mp of 102-104 !C.

A solution of 0.12 g
1-[2,5-dimethoxy-4-(2-hydroxyethyl)phenyl]-2-(2,2,2-trifluoroacetamido)propane
in a mixture of 5 mL CH2Cl2 and 5 mL IPA was treated with 0.2 mL 2 N
KOH, heated on the steam bath for 30 min, and then stripped of
solvents under vacuum.  The residue was suspended in CH2Cl2 and washed
with 20% NaOH.  The organic phase was dried with anhydrous Na2SO4
which was removed by filtration, and the combined filtrate and
washings stripped of solvent under vacuum.  The residual glass (0.08
g) was dissolved in IPA, neutralized with concentrated HCl and diluted
with anhydrous Et2O to provide
2,5-dimethoxy-4-(2-fluoroethyl)amphetamine hydrochloride (DOEF) as a
white crystalline solid with a mp of 205-208 !C.  Anal. (C13H21ClFNO2)
C,H.

DOSAGE: 2 - 3.5 mg.

DURATION: 12 - 16 h.

QUALITATIVE COMMENTS: (with 2.2 mg) Somewhere between the first and
second hour, I grew into a world that was slightly unworldly.  Why?
That is hard to say, as there was no appreciable visual component.  I
just knew that the place I was in was not completely familiar, and it
was not necessarily friendly.  But it was fascinating, and the music
around me was magical.  Time was moving slowly.  I had to drive across
the bay at about ten hours into this, and I was comfortable.  That
evening I slept well, but my dreams were pointless.

(with 3.0 mg) It took almost three hours to full activity.  The first
signs of effects were felt within a half hour, but from then on the
progress was slow and easy, without any discernible jumps.  There was
absolutely no body discomfort at all.  Completely comfortable.  There
was a general humorousness about my state of mind which is always a
good sign.  We went to the bedroom at the two and a half hour point,
and proceeded to establish that the material is far from anti-erotic.
Beautiful response, without a mention of any feeling of risk at
orgasm.  I myself was not able to reach orgasm until about 5th to 6th
hour, and then it was full and exceptionally delicious.  So was the
second one, a couple of hours later, if I remember correctly.  All
systems intact, body, mind and emotion.  Gentle.  Good for writing.
No dark corners apparent at all.  For me, not highly visual.  Would
take again, higher.

(with 3.0 mg) There was no body threat at any time Q very
comfortable.  Good eyes closed, with complex imagery to music, but not
too much with eyes-open.  My attention span is relatively short, and
easily diverted into new directions Q all quite reminiscent of DOI
both as to dosage and effect.  At 13 hours, I am still too alert to
sleep, but a couple of hours later, OK.  In the morning there is still
a trace of something going on.  This was a valid +++.

EXTENSIONS AND COMMENTARY: I was asked by a student of mine a while
ago, when I told him of this material, just why would anyone just
happen to place a fluorine atom at the end of the 4-ethyl group of
DOET?  It wasnUt the sort of thing that someone would just happen to
do.  If there were a rationale, then that's fine.  But by capricious
impulse, no.  But there is a rationale of sorts, which I just hinted
at in the discussion under 2C-T-21.

This argument of reason goes as follows.  Assume that I would like to
put a fluorine atom into a drug that does not normally have one.  Why
would I want to?  Because I want to have the molecule carry a
radioactive fluorine atom into some inner recess of the brain.  Why?
Because by using a positron-emitting fluorine I could possibly
visualize the area of the brain that the drug went to.  And if it went
there in some abnormal way, the exact measure of that abnormality
might give some clue as to potential brain misfunctioning.

But, if you put a fluorine atom on a drug, it becomes a totally new
drug and, quite reasonably, a pharmacologically different drug.
However, a body of evidence is being accumulated that if a halogen,
such as a bromine or an iodine atom, is replaced by a beta-fluoroethyl
group, the electronic and polar properties of the drug can be pretty
much the same.  So, what psychedelics have a bromo or an iodo group?
Obviously, DOB and DOI.  Thus, DOEF is a natural candidate for
fluorine-18 positron emission tomography, and also a natural candidate
for clinical trials.  And, voila, it is an active material.

And IUll bet you dollars to doughnuts, that if one were to make the
two-carbon analog 2,5-dimethoxy-4-(2-fluoroethyl)-phenethylamine, it
would be every bit as much a treasure and ally as is 2C-B or 2C-I.  In
fact, I am sure enough about this prediction that I am willing to name
the stuff 2C-EF.  It will be easily made from 2C-B by the same
reaction scheme that was used above for DOEF.  And I will even guess
that its activity level will be in the 20-30 milligram area.









#66 DOET; HECATE; 2,5-DIMETHOXY-4-ETHYLAMPHETAMINE

SYNTHESIS: To a solution of 19.7 g 2,5-dimethoxy-4-ethylbenzaldehyde
(see the recipe for 2C-E for its preparation) in 72 g glacial acetic
acid there was added 6.5 g anhydrous ammonium acetate and 10.2 g
nitroethane.  After heating for 1.75 h on the steam bath, the reaction
mixture was cooled in a wet ice bath, diluted with 10 mL H2O, and
seeded with a small crystal of product.  The yellow crystals were
removed by filtration (7.6 g wet with acetic acid) and another 2.25 g
was obtained from the mother liquors with additional H2O.  The
combined fractions were recrystallized from 25 mL boiling MeOH, to
give 6.5 g fine yellow crystals of
1-(2,5-dimethoxy-4-ethyl)-2-nitropropene, with a mp of 67.5-68.5 !C.
Anal. (C13H17NO4) C,H,N.

A suspension of 6.5 g LAH in 500 mL well stirred anhydrous Et2O was
held at reflux under an inert atmosphere, with the return of the
condensed solvent passing through a Soxhlet thimble containing 6.5 g
1-(2,5-dimethoxy-4-ethylphenyl)-2-nitropropene.  After the addition of
the nitrostyrene was complete, the stirred suspension was maintained
at reflux for an additional 18 h, then cooled to room temperature.
The excess hydride was destroyed with 500 mL 8% H2SO4, added
cautiously until the hydrogen evolution ceased, then at a speed that
allowed the formed solids to disperse.  The phases were separated, the
aqueous phase washed once with Et2O, treated with 150 g potassium
sodium tartrate, and finally made basic (pH >9) with 5% NaOH.  This
was extracted with 3x100 mL CH2Cl2, the extracts pooled, and the
solvent removed under vacuum.  The residue, 7.9 g of a clear oil, was
dissolved in 100 mL anhydrous Et2O and saturated with anhydrous HCl
gas.  After standing at room temperature for 2 h, the crystalline
2,5-dimethoxy-4-ethylamphetamine hydrochloride (DOET) was removed by
filtration, washed with Et2O, and air dried to constant weight.  There
was obtained 5.9 g of lustrous white crystal with a mp of 190-191 !C.
Recrystallization from CH3CN or EtOAc increased the mp to 194-195 !C.
Anal. (C13H22ClNO2) C,H,N.

DOSAGE: 2 - 6 mg.

DURATION: 14 - 20 h.

QUALITATIVE COMMENTS: (with 1.0 mg) This was a very gentle, relaxing
level, but there were no psychedelic effects that were apparent.
Easy, and relaxed, and I am in no way intoxicated or turned on.  But I
was in the throes of my menstrual period, and the cramps (and the
accompanying irritability) were completely knocked out.  Perhaps this
is why I felt so relaxed and at peace.

(with 2.5 mg) There is much, too much, movement with my eyes closed.
And an awful lot there with my eyes open.  The movement on the
concrete floor in the basement when I went downstairs for wood for the
fireplace, was too much.  I felt almost sea-sick.  And I am having
reality problems Q I cannot seem to find my centering point of
reference.  There has to be a place to pin myself down to, and it is
not findable anywhere I look.  And my legs are twitching, and feeling
as if they are falling asleep, and I had a crawling sensation on my
body, so the body is not at peace either.  In the morning I was still
++, but there is a clear indication that I am repairing.  Anyway, I
survived the experience.  This is definitely not my thing.

(with 4 mg) Just after an hour into the experiment, I was surprised
by the awareness of some effects Q I had forgotten that I had taken
something.  At the second hour, it was real, but subtle.  As a
psychotomimetic or STP-like thing, there is very little there.  But as
a mood energizer, it is really a ++ or more.  The clinical literature
is right Q none of the hallucinogenic effects, but one brings into
play whatever one wants to.  Worked at cleaning up the office until 11
PM.  I slept well.  This has none of the LSD or STP seriousness.

(with 6 mg) The onset was slow, and subtle.  But the effects are
fully there in about three or so hours.  Everything I smelled was
vivid, as are all the colors and shapes; they are clean, beautiful,
serenely self-contained.  No visual movement.  The eyes-closed fantasy
images tend to take off on their own, however, and they are extremely
rich.  I donUt see any dark corners.  I believe it might well be
possible to be creative with this, and there is no suggestion of body
depletion, of body load.

(with 7 mg) A hot day.  Unbelievably lovely erotic-to-divine, deep
loving, open, not much visual, eyes-closed form-image-symbol.  Sleep
attempts very shallow, slight TthinnessU, with an anticipation of
darts.  Intellect and feeling-emotion area intact and functioning at
all times.  Next morning still at a plus one.  Incredible material.
Perhaps best at 6 to 7 milligrams, no higher due to body load.

EXTENSIONS AND COMMENTARY: The original code for this compound was
DOE, which was completely logical based on DOM being the methyl member
of this series (DO for the removal of the oxygen, desoxy, and M for
putting a methyl in its place).  And the putting of the ethyl thence
should be DOE.  This was fine until it was pointed out to me by a
close colleague that DOE was a classic abbreviation for
desoxyephedrine, a synonym for methamphetamine.  The pressure to add
the RTS of the RETS of the ethyl was heightened by looking ahead to
other members of the series.  DOA became DOAM, DOE became DOET, but
DOM was already too firmly set in popular usage.  And, anyway, DOME
really looked strange.

The original publications of the action of DOM clearly documented the
compound as being a psychedelic and one with a sizeable measure of
potential abuse.  And, it is not a surprise that it was quickly
shuffled into a legal classification that effectively precluded any
further study of it.  So, when this immediate homologue of DOM was
studied and discussed in the literature, all reported dosages were
those that were at the lowest levels, and no disturbing hints of
abusability were mentioned.  And this particular homologue has so far
escaped the attention and restrictive action of the drug enforcement
agencies, although the specific wording of the Controlled Substance
Analogue Enforcement Act of 1986 might make this point moot, at least
as far as human trials are concerned.  At modest levels, DOET has the
reputation of being a cognitive enhancer and is largely free of those
sensory distortions that would catch the attention of the authorities
who cannot tolerate drugs that distort the senses.  The higher levels
mentioned here have never been put into the published literature.  It
must be noted that there is a considerable variation of individual
responses to this material.  The effective dose range stated is quite
broad.  Some people are quite sensitive.  This is, after all, one of
the Classic Ladies, namely HECATE.

The young experimental subject who had the dramatic relief from
menstrual cramps at the one milligram dose tried the compound again
the following month, and again had complete relief.  But another
volunteer, also plagued with severe cramping at that particular time
of month, found no relief at all.  A 50% success rate.  No one else
has, to my knowledge, explored this particular property.









#67 DOI; 2,5-DIMETHOXY-4-IODOAMPHETAMINE

SYNTHESIS: A mixture of 14.8 g phthalic anhydride and 19.5 g of
2,5-dimethoxyamphetamine (2,5-DMA) as the free base was heated
gradually to about 150 !C with an open flame.  A single clear phase
was formed with the loss of H2O.  After the hot melt remained quiet
for a few moments, it was allowed to cool to about 50 !C and then
diluted with 100 mL of hot MeOH.  The solution was stirred until
homogenous, seeded with product, and then cooled in an ice bath to
complete the crystallization.  After removal of the product by
filtration, washing sparingly with MeOH, and air drying, there was
obtained 24.6 g of N-(1-(2,5-dimethoxyphenyl)-2-propyl)phthalimide as
off-white crystals, with a mp of 105-106 !C.  Anal. (C19H19NO4) C,H,N.

To a solution of 2.0 g N-(1-(2,5-dimethoxyphenyl)-2-propyl)phthalimide
in 15 mL warm acetic acid which was being vigorously stirred, there
was added a solution of 1.2 g iodine monochloride in 3 mL acetic acid.
This was stirred for 2 h at about 40 !C during which time there was a
definite lightening of color, but no solids formed.  The reaction
mixture was poured into 600 mL H2O which produced a reddish glob
floating in a yellow-orange opaque aqueous phase.  The glob was
physically removed, dissolved in 30 mL boiling MeOH which, on cooling
in an ice bath, deposited off-white crystals.  These were removed by
filtration, washed with MeOH, and air dried to give 1.5 g of
N-[1-(2,5-dimethoxy-4-iodophenyl)-2-propyl]phthalimide as fine white
crystals with a slight purple cast.  The mp was 103-105.5 !C and the
mixed mp with the starting non-iodinated phthalimide (mp 105-106 !C)
was depressed (85-98 !C).  Extraction of the aqueous phase, after
alkalinification, provided an additional 0.15 g product.  Anal.
(C19H18NO4) C,H,N.

A solution of 0.75 g
N-(1-(2,5-dimethoxy-4-iodophenyl)-2-propyl)phthalimide in 10 mL EtOH
was treated with 0.3 mL of hydrazine hydrate, and the clear solution
was held at reflux on the steam bath overnight.  After cooling, there
was a crystallization of 1,4-dihydroxyphthalizine that started as
small beads but finally became extensive and quite curdy.  These
solids were removed by filtration and had a mp of about 340 !C
(reference samples melted over a five to ten degree range in the area
of 335-350 !C).  The filtrate was dissolved in 100 mL CH2Cl2 and
extracted with 2x150 mL 0.1 N HCl.  The aqueous extracts were washed
once with CH2Cl2, made basic with 5% NaOH, and extracted with 3x100 mL
CH2Cl2.  Removal of the solvent under vacuum gave 0.5 g of a colorless
oil which was dissolved in 300 mL anhydrous Et2O and saturated with
anhydrous HCl gas.  There was obtained, after filtration, and air
drying, 0.35 g of 2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI)
as white crystals that melted at 200.5-201.5 !C.  This value did not
improved with recrystallization.  Anal. (C11H17ClINO2) C,H,N.

DOSAGE: 1.5 - 3.0 mg.

DURATION: 16 - 30 h.

QUALITATIVE COMMENTS: (with 0.6 mg) There was a nice spacey
light-headedness for a few hours, and time seemed to move quite
slowly.  Then a generic sadness came over me, as I reminisced about
earlier days (recalling pleasures now gone) and wondered if I would be
allowed to be here on the Farm when I am old and not important.  There
is so much to be done, and I cannot do it all, and no one else cares.
My mood became present-day and healthy by about the seventh hour.

(with 1.6 mg) The general nature of the experience was depressing,
with a sad view of life.  There was no way I could connect with my
emotions.  Even my sadness was vague.  At about the ninth hour I
decided that enough was enough, and this strangely disappointing
about-plus-two was aborted with 125 micrograms of LSD.  The emotions
became present and living within a half hour.  I was greatly relieved.
The erotic was not a mechanical attempt but a deeply involved feeling
with an archetype of orgasm easily available.  It was shaped like a
flower, richly colored, with an unusual RSS shape to it.  This was a
lovely end to a difficult day.

(with 3.0 mg) This is a clear, clean psychedelic.  The eyes-closed
imagery is excellent, with clearly delineated patterns, pictures, and
colors.  Perfect for an artist, and next time IUll devote some time to
painting.  Total ease for the body, but no help for my smoking
problem.  I still want to smoke.  And at sixteen hours into this I am
still at 1.5+ but IUll try to go to bed anyway, and sleep.

(with 3.5 mg) I was at a full crashing +++ for about three or four
hours.  There was none of the LSD sparkle, but there were moments of
Tlight-headednessU where one could move sideways with reality.  I
could leave where I was right over there, and come over here and get a
strange but authentic view of where the TthereU was that I had left.
It would be out-of-body, except that the body came over here with me
rather than staying there.  This doesnUt make sense now, but it sure
did then.  There was no trace of body impact, and I slept late that
evening, but with some guardedness due to the intense imagery.  This
was no more intense than with 3.0 milligrams, but it was a little bit
more to the unreal side.

(with 1.0 mg of the RRS isomer) There was a clear ++ from the second
to the eighth hour, but somehow there was not quite the elegance or
the push of the racemate.  I was sensible, and managed to do several
technical chores in a reasonable way.  Easy sleep at 15 hours into
it.

(with 2.3 mg of the RRS isomer) The water solution of the
hydrochloride salt has a slightly sweetish taste!  I was at a +++
without question, but there was a slight down mood towards the end.
And it lasted a really long time; I was distinctly aware of residual
stuff going on, well into the next day.

(with 6.3 mg of the RSS isomer) I was at a benign one-and-a-half plus
at about two hours, and finally flattened out at a ++.  Would I double
this dose?  Probably not, but half again (to 9 or 10 milligrams) would
feel safe for a plus 3.  By evening I was near enough baseline to
drive into town for a social obligation, but even when trying to sleep
later that night there was some residue of imagery; remarkably, it was
all in slow motion.  The fantasies were slow-paced and sluggish.  It
would have been interesting to have explored eyes-closed during the
day.

EXTENSIONS AND COMMENTARY: Again, as with every other psychedelic
amphetamine analogue which has a chiral center and has been explored
as the individual optical isomers, it is the RRS isomer that is the
more potent.  And again, the other isomer, the RSS isomer, still shows
some activity.  The same was true with DOB, and DOM, and MDA.  The
only exception was MDMA, but then that is more of a stimulant, and
there is virtually no psychedelic component to its action.  Rat
studies, where there is a measure of the discrimination of a test
compound from saline, have shown the RRS isomer to have about twice
the potency of the RSS isomer.  That the RRS is more potent is
certain, but the above reports would suggest that the factor would be
closer to times-four rather than times-two.

A number of studies with DOI in animal models have shown it to have an
extremely high binding capacity to what are called the 5-HT2
receptors.  Serotonin is a vital neurotransmitter in the brain, and is
strongly implicated in the action of all of the phenethylamine
psychedelics.  The place where it acts, at the molecular level, is
called its receptor site.  As an outgrowth of the cooperative studies
of the medicinal chemists working closely with the
neuropharmacologists, a number of compounds have emerged that interact
with these sites.  But this one interacts with these sites and not
those, and that one interacts with those sites and not these.  So,
there has developed a collection of sub-divisions and sub-subdivisions
of receptor sites, all related to serotonin, but each defined by the
particular compound that interacts most tightly with it.

Thus, there were serotonin R1S receptors, and then there were R1S and
R2S receptors, and then R1a and R1bS and R2aS and R2bS receptors, and
on and on.  These are called 5-HT receptors, since the chemical name
for serotonin is 5-hydroxytryptamine, and the scientist would never
want to let the layman know just what he is talking about.  DOI has
been synthesized with a variety of radioactive iodine isotopes in it,
and these tools have been of considerable value in mapping out its
brain distribution.  And by extrapolation, the possible localization
of other psychedelic compounds that cannot be so easily labelled.  A
small neurochemical research company on the East Coast picked up on
these properties of DOI, and offered it as a commercial item for
research experiments.  But I doubt that they are completely innocent
of the fact that DOI is an extremely potent psychedelic and that it is
still unrecognized by the Federal drug laws since, in their most
recent catalog, the price had almost doubled and a note had been added
to the effect that telephone orders cannot be accepted for this
compound.

The four-carbon butylamine homologue (the ARIADNE analogue) of DOI has
been synthesized.  A mixture of the free base of
1-(2,5-dimethoxyphenyl)-2-aminobutane (see preparation under DOB) and
phthalic anhydride was fused, cooled, and recrystallized from either
methanol or cyclohexane to give crystals of
N-[1-(2,5-dimethoxyphenyl)-2-butyl]phthalimide with a melting point of
76-77 !C and an analysis (C20H21NO4) C,H,N.  This was iodinated with
iodine monochloride in acetic acid to give
N-[1-(2,5-dimethoxy-4-iodophenyl)-2-butyl]phthalimide which was
chromatographically distinct from the uniodinated starting material
(silica gel, CH2Cl2 ), but which did not crystallize.  This was
treated with hydrazine hydrate in ethanol to provide
1-(2,5-dimethoxy-4-iodophenyl)-2-aminobutane hydrochloride which was
crystallized from CH3CN/EtOH to give white crystals with a mp of
217-218.5 !C and an analysis (C12H19CINO2) C,H,N.  This butyl homolog
of DOI has been assayed at up to four milligrams, and is without any
central effects whatsoever.  An experiment with 12.4 microcuries of
131I labelled material with the whole body scanner showed most of it
accumulating in the gut and liver, with almost none to the brain.

For those who find such statistics interesting, the parent compound
DOI vies with DOB as probably the most potent of the phenethylamine
psychedelics as of the moment, and certainly one of the most long
lived.

A very important, centrally pivotal, and completely paradoxical
compound in this area, is the N,N-dimethyl homologue of DOI, or
2,5-dimethoxy-N,N-dimethyl-4-iodoamphetamine (IDNNA).  This compound
was the starting point of the study of a large number of homologues
and it deserves, and has received, a separate recipe.









#68 DOM; STP; 2,5-DIMETHOXY-4-METHYLAMPHETAMINE

SYNTHESIS: To a solution of 54.9 g 2,5-dimethoxy-4-methylbenzaldehyde
(see the recipe for 2C-D for its preparation) in 215 g glacial acetic
acid there was added 19.5 g anhydrous ammonium acetate and 30.6 g
nitroethane.  This mixture was heated for 3 h on the steam bath, the
reaction mixture was cooled in a wet ice bath, allowing the
spontaneous formation of yellow crystals.  As much H2O as possible was
added (just short of a persistant cloudy oily character) and after a
few additional h standing, the crystalline
1-(2,5-dimethoxy-4-methylphenyl)-2-nitropropene was removed by
filtration and recrystallized from boiling acetic acid.  The yield,
after drying to constant weight, was 28.3 g and the mp was 87-88 !C.
Anal. (C12H15NO4) C,H,N.

A suspension of 9.5 g LAH in 750 mL well stirred anhydrous Et2O was
held at reflux under an inert atmosphere, with the return of the
condensed solvent passing through a Soxhlet thimble containing 9.5 g
1-(2,5-dimethoxy-4-methylphenyl)-2-nitropropene.  After the addition
of the nitrostyrene was complete, the stirred suspension was
maintained at reflux for an additional 4 h, then cooled to room
temperature and allowed to continue stirring overnight.  The excess
hydride was destroyed by the addition of 750 mL 8% H2SO4, cautiously,
until the hydrogen evolution ceased, then at a speed that allowed the
formed solids to disperse.  The phases were separated, the aqueous
phase washed once with Et2O, treated with 225 g potassium sodium
tartrate, and finally made basic (pH >9) with 5% NaOH.  This was
extracted with 3x150 mL CH2Cl2, the extracts pooled, and the solvent
removed under vacuum.  The residue was 9.6 g of a clear oil which
spontaneously formed crystals with a mp of 60.5-61 !C from hexane.
These solids were dissolved in 150 mL anhydrous Et2O, and saturated
with anhydrous HCl gas.  After standing at room temperature for 2 h,
the crystalline 2,5-dimethoxy-4-methylamphetamine hydrochloride (DOM)
was removed by filtration, washed with Et2O, and air dried to constant
weight.  There was obtained 8.25 g of glistening white crystals that
had a mp of 190.5-191.5 !C.  The sulfate had a mp of 131 !C.  Anal.
(C12H20ClNO2) C,H,N.

The above nitrostyrene may also be converted to the final amine
product through the intermediary of the corresponding phenylacetone.
To a well stirred suspension of 10.4 g powdered iron in 20 mL glacial
acetic acid held at reflux temperature, there was added 4.9 g
1-(2,5-dimethoxy-4-methylphenyl)-2-nitropropene as a solid.  Refluxing
was continued for 2 h and then all was filtered through wet Celite.
After washing with 300 mL H2O followed by 300 mL Et2O, the combined
filtrate and washes were separated, and the aqueous phase extracted
with 2x100 mL Et2O.  The organic phase and extracts were combined and
washed with 2x100 mL saturated K2CO3 and the solvent was removed under
vacuum yielding a reddish oil weighing 3.3 g.  This was distilled at
111-115 !C at 0.5 mm/Hg to give a pale green solid.  After
recrystallization from benzene, there was obtained 2.8 g
1-(2,5-dimethoxy-4-methylphenyl)-2-propanone as white crystals with a
mp of 57-59 !C.  This ketone has also been described as a pale-yellow
oil with a bp of 115-118 !C at 0.4 mm/Hg.  A solution of 0.7 g
1-(2,5-dimethoxyphenyl-4-methyl)-2-propanone in 20 mL MeOH was treated
with 6.0 g ammonium acetate, 0.3 g sodium cyanoborohydride, and 3 g
Linde 3 A molecular sieves.  The mixture was stirred overnight, the
solids removed by filtration, and the filtrate dissolved in 100 mL
H2O.  The solution was acidified with dilute H2SO4, and washed with
2x25 mL CH2Cl2.  The aqueous phase was made basic with aqueous NaOH,
and the product extracted with 2x25 mL CH2Cl2.  The solvent was
removed under vacuum, and the residue distilled (at 160 !C at 0.2
mm/Hg) to give colorless product which was dissolved in 3 mL IPA,
neutralized with concentrated HCl, and diluted with 50 mL anhydrous
Et2O.  There was obtained 0.18 g of 2,5-dimethoxy-4-methylamphetamine
hydrochloride (DOM) as a white solid with a mp of 187-188 !C.

The optical isomers of DOM have been prepared in two ways.  The
racemic base has been resolved as the ortho-nitrotartranilic acid salt
by recrystallization from EtOH.  The (+) acid provides the (+) or RSS
isomer of DOM preferentially.  Also, the above-mentioned
1-(2,5-dimethoxy-4-methylphenyl)-2-propanone can be reductively
aminated with optically active alpha-methyl benzylamine with Raney
Nickel.  This amine is isolated and purified by recrystallization of
the hydrochloride salt.  When optically pure, the benzyl group was
removed by hydrogenolysis with palladium on carbon.  The mp of either
of the optical isomers, as the hydrochloride salts, was 204-205 !C.

DOSAGE: 3 - 10 mg.

DURATION: 14 - 20 h.

QUALITATIVE COMMENTS: (with 1.0 mg) There is almost certainly an
effect.  Physically there is a slight dryness in the mouth, and my
eyes are noticeably dilated.  There is an eerie feeling overall.

(with 2.3 mg) Mood elevation at 2-3 hrs.  After 3 hours, emotional
effects become more pronounced, enhancement of color also.  Very
little distortion of perception, no disorientation, no creeping or
flowing, but color enhancement considerable.  The emotional content
and empathy for others was closer to mescaline than to amphetamine, a
welcome change.  No suggestion of nausea at any time.  Unable to sleep
at ten hours, so I took 3/4 grain Seconal.  Headache and listlessness
next morning, probably due to the Seconal.

(with 3 mg) In the middle of the experience I found that I was able
to separate components of complex things so as to evaluate them
separately.  There is no need to respect their normal purpose.  The
sharpness of observation is enhanced, but one can focus at every
different depth of a thing or a concept.  Colors are not just
brighter; there are more of them.  There is a profoundness of meaning
inherent in anything that moves.  A line of thought or a bit of
personal history ties the thinker to the objects that had been thought
of, or once experienced.  It is this relationship that will prove
productive.  Not like in a movie which is circular in its totalness,
but as in true life where the future is the result of your own
involvement with everything about you.

(with 4 mg) The first four hours were largely directed to the body.
There was a shuddering, and a tight jaw, and I am not particularly
motivated to talk to anyone.  It is more arousing (like amphetamine)
than depressing (like phenobarb).  I am feeling just a little sick at
the three hour point, but a bit of regurgitation clears this up.  Then
at the fourth hour, it went totally outside of me.  I saw the clouds
towards the west.  THE CLOUDS!!!  No visual experience has ever been
like this.  The meaning of color has just changed completely, there
are pulsations, and pastels are extremely pastel.  And now the oranges
are coming into play.  It is a beautiful experience. Of all past joys,
LSD, mescaline, cannabis, peyote, this ranks number one.  Normally I
have no color effects with mescaline.  A dynamic experience.  Feels
good, too.

(with 5 mg) There was the magnification of light, color and odors.
It was all very pleasant and beautiful, except that I had an
overwhelmingly negative feeling.  This at times grew to considerable
intensity, and I feel it was clearly due to anger.  At times the
negativity disappeared completely, and I broke into the most
enjoyable, even hilarious experiences.  I alternated about 50-50
between joy and discomfort.  As the evening drew on, I became
withdrawn and pensive.  It seemed clear that I had made all the wrong
decisions Q choice of partner, place to live, isolation, no meaningful
activity.  The greatest shocker was that my practice of meditation,
which is one of my central focuses, and which I thought had brought me
much peace and understanding, seemed to be a delusional solution to my
unhappiness and isolation.  The experience continued unabated
throughout the night with much tension and discomfort.  I was unable
to get any sleep.  I hallucinated quite freely during the night, but
could stop them at will.  While I never felt threatened, I felt I knew
what it was like to look across the brink to insanity.

(with 8 mg) The very quiet development picks up speed betweeen the
first and second hour.  There is a rich curly-imaged eyes-closed show
that interlocks closely with music.  It is occasionally an off-beat
fantasy and not directly knit together, and even occasionally
unenjoyable.  But always intense and completely appropriate to the
music.  There is a continuous thirst, and little urine.  Napping seems
OK at 16 hours, but real sleep must wait until the 20 hour point.
Overall a rolling +++, and I am looking forward to a repeat some day.

(with 10 mg) If on this page I shall have expressed it to you then it
is true that DOM has the glory and the doom sealed up in it.  All
that's needed to unseal it is to surround it with a warm living human
for a few hours.  For that human for those hours all the dark things
are made clear.

(with 12 mg) The first awareness was at 30 minutes and it was in the
tummy.  The development was extremely rapid, something more like LSD
than previously remembered.  The body tremor feels like poisoning,
there is no escaping the feeling of being disabilitated, but at least
there is no nausea.  This transition ended and the trauma cleared
completely at about the second hour.  The music was exceptional, the
erotic was exceptional, the fantasy was exceptional.  Listz's RA
Christmas Cantata #1,S part 1, with eyes closed was an experience
without precedent.  There were some residual effects still noted the
next day.  This may be a bit much for me.

(with 0.3 mg of the RRS isomer) Maybe slightly wiry?  No effects.

(with 0.5 mg of the RRS isomer) There is a real effect, and it is
significant that the first effects of the racemate were noted at 1.0
milligram.  There is a trace of time slowing and in general a pretty
full manic state.  There is some mydriasis.  Everything had pretty
much cleared up by evening.

(with 2.0 mg of theSSS isomer) No effects.  There was an unexpected
slight tachycardia at the two hour point, but nothing suggesting
psychotropic action.

(with 2.6 mg of the RSS isomer) There are signs of both pulse
increase and blood pressure increase.  There is some teeth-rubbiness,
but still no psychological turn on at all.

EXTENSIONS AND COMMENTARY: The rationale for the design and making of
DOM has already been discussed.  One could predict that it could have
been, theoretically, a totally inactive compound and maybe an
effective blocker for whatever receptor sites are being occupied by
other psychoactive drugs and even for strange things that some
unbalanced people might actually make within their bodies, using their
own personal chemistry.  On the other hand, it could have been a
potent psychedelic in its own rights, and if so, probably long lived.
The latter Rcould have beenS proved to be so.

The very modest amount of study of the individual optical isomers
clearly indicates that the RRS isomer is the more active.  The sparse
comments suggest that some of the heavier physical aspects of the
racemate might be due to contributions from the RinactiveS RSS isomer.
It is, after all, the RSS isomer of amphetamine that carries the major
punch of that stimulant.  Maybe if that isomer were removed, and one
were to explore the pure RRS isomer of DOM, the dramatic visual
aspects of the larger dosages might not be complicated with a
troublesome physical component.

This compound, unbeknownst to me, was scattered widely and plentifully
in the heyday of the Haight-Ashbury in San Francisco, in mid-1967.  It
was distributed under the name STP, which was said to stand for
Serenity, Tranquility, and Peace.  It was also claimed to represent
Super Terrific Psychedelic, or Stop The Police.  The police called it:
Too Stupid to Puke.  Actually, the name was taken from the initials of
a motor additive which was completely unrelated chemically.
Incredibly, and sadly, one of the avowed experts in the area of the
Rsensuous drugsS actually stated that STP, the motor oil additive, was
really one and the same as STP, the highly dangerous psychedelic.  The
motor oil additive, he wrote in a book of his, had properties somewhat
related to those of LSD, mescaline, and the amphetamines.  How
fortunate that the love children of the time didnUt do much reading,
for they might have gotten into yet deeper pharmacological troubles
with drug raids on the local gasoline stations.

Two complications became apparent during this first appearance and
they led to serious difficulties.  One, there was no equation made
between STP and DOM.  No one knew what this drug was which had been
distributed in a cavalier way throughout the city.  There could be no
educated guess as to the best treatment of overdose emergencies.  And
secondly, the initial tablets that had been distributed apparently
contained 20 milligrams of DOM per tablet; later, it was dropped to 10
milligrams.  Either of these, in retrospect, is now known to be a
thoroughly whopping dose.  The overdose situation was aggravated by
the slow onset of DOM.  The user may be aware of some initial effects
at the half-hour point, there will be what might be called a + or ++
at the end of the first hour, and the full impact of the drug is not
appreciated until some two hours have elapsed.  But many of the
recipients of the free handouts of DOM were familiar with LSD which
can show its alert in 15 to 20 minutes, or even sooner with a large
dose, and there is already a deep and compelling intoxication felt at
the half-hour point.  They, quite reasonably, expected this familiar
activity pattern with STP and assumed, when there was little if any
activity noted at the half-hour point, that the potency was less than
expected.  They took one or even two additional dosage units.  Thus,
some of the overdose victims of that period may well have taken as
much as 30 mg of DOM.  The slow onset of action, coupled with the
remarkably long duration, caught many innocent users unprepared.

Clinical studies have documented the rapid tolerance development from
repeated exposures to DOM.  Five volunteers were given 6 milligrams
daily for three days.  Objectively, psychological tests showed a
decrease in responses.  Subjectively, all found extremely intense
effects on the first day, and all but one found it unpleasant.  By the
third exposure on the third day, all had diminished responses, ranging
from only Rmoderately strongS to Rfelt absolutely nothing.S One
actually slept during the experience on the third day.

The hexadeutero-analogue (deuterium atoms on the two methoxyl groups)
has been prepared as an internal standard for analytical work, but
there are no reports of its human pharmacology.  A study with this
sort of derivative would be a fine companion to the studies already
underway with the mescaline analogues that are similarly substituted.
A difference exists, however.  With mescaline, it is believed that the
loss of a methoxyl group is a step towards the inactivation of the
compound, whereas with DOM this loss may be associated with the
formation of an active metabolite.  The several fascinating questions
raised by possible differences in both the rates and the degree of
demethylation of these two compounds are well worth trying to answer.

A number of compounds related to DOM had been synthesized and studied
at the University of California at San Francisco, at about this time.
Two of these were simply the juggling of the two methoxyl groups and
the methyl group on the ring, still maintaining the 2,4,5-ness
relative to the amphetamine chain.  These are
2,4-dimethoxy-5-methylamphetamine and
4,5-dimethoxy-2-methylamphetamine.  Since the slang name for DOM in
and about the medical center was STP, and since STP was the name of a
motor oil additive, it is not unreasonable that the first of these to
be synthesized, the 2,4-dimethoxy-5-methyl isomer, was referred to by
the name of another motor oil additive popular at that time, F-310.
The Vilsmeier reaction between 2,4-dimethoxytoluene and the Vilsmeier
complex of POCl3 and N-methylformanilide gave the benzaldehyde (mp
117-118 !C) with a yellow malononitrile derivative from EtOH with a mp
of 193-194 !C.  The nitrostyrene from this and nitroethane formed
yellow crystals from CH3CN, with a mp 138-139 !C.  The amine formed
easily with LAH in ether, and the product F-310 (or 5-DOM) gave white
crystals from CH3CN with a mp of 182-183 !C.

And the other isomer, the 4,5-dimethoxy-2-methyl counterpart, became
known familiarly as F-320, or sometimes simply 2-DOM.  Its preparation
followed an identical procedure, starting from 3,4-dimethoxytoluene.
I have been told that F-310 is not active even at 20 milligrams in
man, which would make it several times less potent than DOM (STP).  I
know of no trials with F-320.  The use of the letter RFS does not
imply any relationship between these two compounds and the series
described elsewhere with the RFS code followed by other numbers, such
as F-2 and F-22.  These latter are F's because they are furans, not
motor oil additives.  And yet another oil additive, well known at the
time as Z-7, became associated with the synthesis of the DOM (STP)
isomer with its groups in the 2,4,6-positions.  This is entered
separately under y-DOM.









#69 Y-DOM; Z-7; 2,6-DIMETHOXY-4-METHYLAMPHETAMINE

SYNTHESIS: To a solution of 2,6-dimethoxy-4-methylbenzaldehyde (mp
92-93 !C from the lithiation of 3,5-dimethoxytoluene followed by
reaction with N-methylformanilide) in 10 mL nitroethane, there was
added 0.1 g anhydrous am-monium acetate and the mixture was heated on
the steam bath for 16 h.  Removal of the solvent under vacuum gave a
slightly oily red-orange crystalline mass which was finely ground
under 1 mL of MeOH.  Filtration and a sparing wash with MeOH gave,
after air drying, 0.8 g of a light yellow crystalline solid with a mp
of 121-122.5 !C.  Recrystallization from 4 mL boiling absolute EtOH
gave 0.6 g of 1-(2,6-dimethoxy-4-methylphenyl)-2-nitropropene as very
light yellow platelets, which melted at 123-124 !C.

To a solution of 0.25 g LAH in 25 mL refluxing THF, well stirred and
under He, there was added a solution of 0.3 g
1-(2,6-dimethoxy-4-methylphenyl)-2-nitropropene in 5 mL dry THF.  Upon
the completion of the addition, the reaction mixture was held at
reflux for 48 h.  After cooling with an external ice bath there was
added, in sequence, 0.5 mL H2O, 0.5 mL 15% NaOH, and finally 1.5 mL
H2O.  The inorganic solids were removed by filtration, and the filter
cake washed with THF.  The solvent from the combined filtrate and
washings was removed under vacuum, and the residue (0.3 g) was a
crystal clear colorless oil with a high refractive index.  This was
dissolved in 2 mL IPA, neutralized with concentrated HCl, and diluted
with 35 mL of anhydrous Et2O.  After a minute's standing, the solution
became turbid, followed by the slow deposition of very fine white
crystals.  After standing 1 h at room temperature, these were removed
by filtration, Et2O washed, and air dried to constant weight.  There
was thus obtained 0.3 g 2,6-dimethoxy-4-methylamphetamine
hydrochloride (y-DOM) with a mp of 203 !C. sharp.

DOSAGE: 15 - 25 mg.

DURATION: 6 - 8 h.

QUALITATIVE COMMENTS: (with 14 mg) I am really quite spacey.  I can
go from a train of thought straight up into thin air.  Then, to get to
another one there must be a careful choice of words.  Logic has
nothing to do with any of it.  There is no trace of the MDMA-like
magic.  This is an interpretive drug, not simply an ASC [altered state
of consciousness] opening.

(with 18 mg) There is a light-headedness, and a somewhat starry-eyed
stoned state.  Nothing visual, and no body concern except for what
seems to be a very fine inner tremor.  I think that with a little
more, things might very well begin to move in the visual field.  But I
have no feeling of great concern about taking a somewhat higher
dosage.

(with 25 mg) I was at a +++ for about three hours, and it was a very
weird place.  There were some visuals, but they were not at all
commensurate with the degree to which I was simply stoned.  The erotic
does not knit, and it's hard to get involved with music.  It is as if
you were going down some totally unknown street in a completely
familiar city.  You know the territory, but yet it is strangely all
new.  Eyes closed fantasy and shaped imagery was quite remarkable.
But some heart arrhythmias and a pretty constant diarrhea made the
experience less than totally ideal.  My sleep was good and with good
dreams.

EXTENSIONS AND COMMENTARY: I canUt remember the exact names of the
companies that went with the oil additives.  STP was, I believe, itUs
own thing, and originally stood for Scientifically Treated Petroleum.
And F-310 was, I believe, a Chevron Oil product.  F-320 was, of
course, the product of the wild and happy chemists at the
Pharmaceutical Chemistry Department at the University of California in
San Francisco, playing with what they fondly called Rfunny drugs.S And
when the 2,4,6-orientation became an obvious positional isomer, the
Pennzoil Oil Company's additive, Z-7, was a natural to have its name
volunteered to the cause.  There was one additional isomer possible,
with the methyl in the 2-position and the methoxyl groups at the 4-
and 6-positions.  This followed the more conventional aldehyde made
from 3,5-dimethoxytoluene via the Vilsmeier process, with POCl3 and
N-methylformanilide.  This material
(2,4-dimethoxy-6-methylbenzaldehyde with mp 64-65 !C from cyclohexane
or from MeOH) is completely distinct from the isomer used above
(2,6-dimethoxy-4-methylbenzaldehyde with a mp of 92-93 !C from MeOH).
The amphetamine from this isomer is 2,4-dimethoxy-6-methylamphetamine,
and had been christened by the chemistry crowd as Z-7.1.

Much effort had been put forth in research by this medical school
group of graduate students and graduate advisors, to try to explain
the biological activity of the 2,4,5-things such as TMA-2 and DOM
(STP).  And a considerable investment had been made in the attempt to
tie together the amphetamine world of psychedelics with the indole
world of psychedelics.  The convenience of having two methoxy groups
para to one another was a clear invitation to speculate upon the
formation of a benzoquinone intermediate of some kind, and this would
require the loss of the methyl groups which were already known to be
metabolically labile.  This Rquinone-likeS intermediate was the
cornerstone of a Rhydroquinone hypothesis,S as it allowed further
condensation within the molecule itself involving the primary amine
group, to form something called an indolene which, with some arcane
electron pushing and removal, could eventually become an indole.
There.  We now have a tie-in to the tryptamine world, and to
serotonin, and that entire neurotransmitter magic.

There was only one small fly in the ointment.  No matter how the
2,4,5-things were explained, none of the proposed mechanisms could
allow for the 2,4,6-things to also be active.

How can one accommodate such blasphemy?  The first and obvious
approach was the simplest.  Denial.  The 2,4,6-things arenUt really
active at all.  Placebo stuff.  There is a commonly used phrase, Rbad
scienceS which is an in-famous term used to belittle findings that do
not fit with one's theories or purposes.  But that simply didnUt wash,
because I knew, as did a few others who chose not to identify
themselves too publicly, that TMA-2 and TMA-6 were both fully active
in the 40 to 50 milligram area.  And although not as potent as DOM,
the compound of this recipe, y-DOM or Z-7, was certainly an active
one.  So, since approach number one didnUt work, try approach number
two.  Make the shoe fit the wearer, without respect to the size of his
foot.  One single size shoe fits all.  One single mechanistic
hypothesis explains all.  It was obvious that for the RhydroquinoneS
hypothesis to survive, Z-7 would have to undergo some metabolic
oxidation Q phenol formation Q in the 3-position.

And guess who was actually euchred into embarking onto the synthesis
of this hypothetical metabolic Lucy [that's the anthropological-type,
not the LSD-type Lucy]?  Moi!  On to a new methoxylated amphetamine
which would be called Z-7.2.  Oxidation of the above
2,4-dimethoxy-6-methylbenzaldehyde with metachloroperoxybenzoic acid
gave 2,4-dimethoxy-6-methylphenol which smoothly methylated (KOH,
CH3I) to give 2,3,5-trimethoxytoluene as a white oil, bp 59-62 !C at
0.1 mm/Hg.  This formed the anion between the meta-methoxy groups with
butyllithium, and N-methylformanilide gave the new compound
2,3,6-trimethoxy-4-methylbenzaldehyde, also an oil (bp 130-140 !C at
0.7 mm/Hg) with an excellent NMR spectrum.  This formed the 3-carbon
nitrostyrene with nitroethane, as bright yellow crystals from methanol
with a mp 67-68.5 !C (and excellent NMR and microanalysis, C,H,N).
Lithium aluminum hydride reduction gave rise to what I was assuming
would be the target amphetamine, 4-methyl-2,3,6-trimethoxyamphetamine
or Z-7.2.  This formed a hydrochloride salt which, although
analytically excellent, insisted in remaining as an ether and
chloroform-soluble oil which had an excellent NMR spectrum.  This was
certainly MY target compound, but it was not THEIR target compound.
The upper echelons who were running the show were serious about this
hydroquinone thing.  Therefore, this product Z-7.2, that should have
been entered into human evaluation, was instead processed further by
the substitution of a t-BOC on the amine group, oxidation to the
quinone with ceric ammonium nitrate, reduction to the hydroquinone
with dithionite, and finally deprotection of the blocking t-BOC group
by hydrochloric acid.  The final product,
2,5-dihydroxy-6-methoxy-4-methylamphetamine hydrochloride, was an
extremely light-sensitive solid which was looked at by NMR (excellent
spectrum in D2O) and by cyclic voltimetry (destructive and
uninformative) but which would have been totally worthless to have
tasted.

In fact, the whole 2,4,6 substitution concept is just now beginning to
explode.  Fully half of the drugs described in this Book II are of the
classical 2,4,5-trisubstitution pattern, and it is becoming evident
that every one of them will have a 2,4,6-trisubstituted counterpart
that bids fair to be an active psychedelic.  Diligence could thus
easily double the number of known psychedelics.  The nickname RpseudoS
is really the Greek letter RpsiS which looks like a candelabrum
standing on the table holding up three candles.  If I can find the
type in some font, I will simply precede each known drug with this
letter, to indicate that the 2,4,5-ness has become a 2,4,6-ness.
Therefore, Z-7 is also pseudo-DOM.

Z-7.2 might have been an interesting compound to taste.  But the
academic climate was not appropriate at that time (early 1977) for
such honesty.  The Rhydro-quinone hypothesisS is now not much more
than a minor bit of history.  And anyhow, it was just about this time
that I had uncovered a slick way of getting a sulfur atom into the
amphetamine molecule.  I quickly lost interest in the pursuit of other
people's hypotheses that didnUt seem to lead anywhere.  Maybe,
someday, some single earth-shaking mechanism will emerge to explain
everything.  But in the meantime, the best contribution I can make to
this Rgrand unified theory of psychedelic activityS is to continue to
make new and unexpected things which, if they are active, will
effectively destroy any hypothesis that just happens to be popular at
the moment.  It is a lot more exciting, too.









#70 DON; 2,5-DIMETHOXY-4-NITROAMPHETAMINE

SYNTHESIS: A solution of 8.4 g 2,5-dimethoxyamphetamine base in 40 mL
acetic acid was added dropwise over the course of 0.5 h to 43 mL of
50% nitric acid which was well stirred and cooled with an external ice
bath.  The resulting solution was quenched with ice water, made basic
with aqueous NaOH, and extracted with a benzene-ether mixture.  The
residue that remained after the removal of the solvent was dissolved
in dilute HCl which, upon evaporation of the H2O, yielded a nearly
colorless residue.  Recrystallization from an ethanol/ether mixture
gave, after drying, 10.5 g of 2,5-dimethoxy-4-nitroamphetamine
hydrochloride (DON) with a mp of 206-207 !C.  The acetamide derivative
melted at 166-168 !C.  The formamide derivative was easily hydrolyzed
with 3N HCl.  And the R-isomer of DON hydrochloride had a mp of
231-232 !C.

DOSAGE: 3.0 - 4.5 mg.

DURATION: 8 - 15 h.

QUALITATIVE COMMENTS: (with 3.0 mg) There was an amphetamine-like
stimulation that was apparent an hour into it, and considerable
anxiety.  I had stomach cramps, but there were indications that there
might be something hallucinogenic at a higher dose.

(with 4.5 mg) An enhancement of color perception, and some auditory
distortion, that was still noticeable some eight hours into the
experience.  The visual changes were intense.  I felt I was running a
slight fever, and was restless, but there was almost no physical
malaise.  I was still somewhat wound up even at the 14th hour.

EXTENSIONS AND COMMENTARY: These qualitative comments are not true
quotations, but have been reconstructed from the published summaries
of the human trials reported by several South American researchers.  I
have personally never tasted DON and have only these fragments from
which to create a portrait of activity.  A brief quotation, from a
note published by these researchers in a bulletin that is restricted
to forensic scientists serving law enforcement agencies, is certainly
subject to a number of interpretations.  It reads as follows: RThis
action [a strong stimulant action reminiscent of amphetamine] seems to
reduce the incidence of insightful, and therefore potentially
unpleasant experiences, and thus [DON seems likely] to appear on the
market as an illicit recreational drug.S I must admit that I have
tried, and I am still not able, to interpret this quotation.









#71 DOPR; 2,5-DIMETHOXY-4-(n)-PROPYLAMPHETAMINE

SYNTHESIS: A suspension of 285 g mossy zinc in 285 mL H2O containing
5.7 g mercuric chloride was treated with 285 mL concentrated HCl and
shaken as needed to effect amalgamation.  The H2O was then drained
off, the zinc washed with fresh water and drained again.  There was
added a solution of 74 g 2,5-dimethoxypropiophenone (from the reaction
of propionic acid and p-dimethoxybenzene in the presence of
polyphosphoric acid, see under DOAM for an effective general
procedure) in 140 g EtOH.  The reaction mixture was held at reflux for
24 h with the periodic addition of concentrated HCl.  It was then
cooled, diluted with H2O and CH2Cl2, and the organic phase separated.
The aqueous phase was extracted with 2x100 mL additional CH2Cl2.  The
combined organic phases were washed with 5% NaOH until the washes
remained basic, once with H2O, and then the solvent was removed under
vacuum.  The residue was distilled at the water pump, giving an early
fraction quite rich in starting p-dimethoxybenzene, and a second
fraction (61 g, bp 140-160 !C) which was free of carbonyl group by
infra-red, and which was largely 2,5-dimethoxypropylbenzene.  It was
used without further purification in the following aldehyde synthetic
step.

A mixture of 124 g N-methylformanilide and 140 g POCl3 was allowed to
stand until there was the development of a strong red color.  There
was then added 60 g of the above 2,5-dimethoxypropylbenzene and the
mixture was held on the steam bath for 2 h.  The mixture was added to
2 L H2O and stirred until the excess acid chloride had completely
decomposed.  The mixture was extracted with 3x100 mL CH2Cl2 and, after
the removal of the solvent from the combined extracts, the residue was
extracted with 3x100 mL boiling hexane.  Removal of the solvent gave
the product 2,5-dimethoxy-4-propylbenzaldehyde as an oil, 23 g, which
was characterized as its malononitrile derivative.  Equal weights of
the product and malononitrile in EtOH with a catalytic amount of
triethylamine gave yellow crystals which, on recrystallization from
toluene, had a mp of 113-114 !C.

A solution of 21.5 g of the above crude
2,5-dimethoxy-4-propylbenzaldehyde in 75 g acetic acid, was treated
with 10.4 g nitroethane and 6.6 g anhydrous ammonium acetate.  This
was heated on the steam bath for 1.75 h, then cooled and diluted with
H2O to the point of turbidity.  With long standing and scratching,
there finally was the deposition of crystals which were removed by
filtration and sucked as dry as possible.  This 23 g of crude product
cake was triturated under MeOH, filtered again, and air dried to give
11 g of dull orange crystals.  Recrystallization from boiling MeOH
gave 1-(2,5-dimethoxy-4-(n)-propylphenyl)-2-nitropropene as fine
orange crystals which weighed, after filtering, washing, and drying,
7.4 g, and which had a mp of 94-96 !C.

To a suspension of 6.0 g LAH in 500 mL anhydrous Et2O, which was being
stirred and also held as a gentle reflux, there was added a saturated
solution of (2,5-dimethoxy-4-(n)-propylphenyl)-2-nitropropene in warm
THF.  The reaction mixture was held at reflux for 24 h, then cooled to
room temperature.  The excess hydride was destroyed by the cautious
addition of 500 mL dilute H2SO4.  The phases were separated, and the
aqueous phase washed with additional Et2O.  There was then added 150 g
potassium sodium tartrate, and the pH was brought to >9 with aqueous
NaOH.  The product was extracted with Et2O and, after removal of the
solvent, the residue was dissolved in 200 mL anhydrous Et2O and
saturated with anhydrous HCl gas.  The solids that formed were removed
by filtration, giving 6.15 g 2,5-dimethoxy-4-(n)-propylamphetamine
hydrochloride (DOPR) as an electrostatic, white crystalline powder,
with a mp of 182.5-183 !C.  This was not improved by recrystallization
from either IPA or CH3CN.

DOSAGE: 2.5 - 5.0 mg.

DURATION: 20 - 30 h.

QUALITATIVE COMMENTS: (with 2.0 mg) The onset is slower than any
other thing I can think of.  There was nothing at all at the end of an
hour, and only a threshold a half hour later.  By the middle of the
third hour, I was up to 1+, and that seemed to be about as high as it
intended to take me.  Attempts to sleep at the ninth hour were not
successful, as there were strange patterns of not-quite logical
thinking going on.  Stuff like: TThe block events (like a babyUs
rectangular building blocks) that were gotten, along with other
things, from the full octaves of the left hand in Listz's Hungarian
Rhapsody, events that allowed an easy recognition of the odds of
achieving successful re-entry from any of several erotic codes.U
Clearly this was not a baseline state.  After six hours of successful
sleep, I was still off-baseline , and on into the following day.  Go
on up with curiosity but with caution.

(with 3.6 mg) Imagery that was constructed in response to the music
turned out to be necessary to organize and contain it. The trio is the
nucleus that transforms the written to the heard, but it has created
its own bubble without connections to the real world, and must play on
and on and on to keep itself afloat and never touching the stage
again.

(with 5.0 mg) I am now at midnight, and still strongly +++.  This is
certainly maximum dosage, at least for a long time.  There are faint
intimations of nervous system scrungies.  You know, the kind of thing
that makes you figure it's going to be a while before youUll try to
relax into sleep.  This material, like all the other DOUs, is a heavy
duty psychedelic, the kind that says to you, 'Forget all that stuff
about screening out visuals,' and then proceeds to prove it.  Sort of
indole-like in that way.  Your body as well as your mind tells you
youUre into it, baby, and better relax and enjoy the trip, because
youUve left the shore way behind.  When it was time for bed, I got to
sleep with surprising ease, and slept for only about six hours.  My
dreams were excellent, balancing, and good humored.  But the next day
I realized I was still carrying the DOPR in me, and that baseline was
definitely not there.  But it was OK.  No problems except for
sleepiness.  The next evening I went to bed at unheard-of hour of 9 PM
and slept for 13 hours, give or take.  Fascinating compound, but I
wonUt go out of my way to take it again soon.

EXTENSIONS AND COMMENTARY: There is a thread of disconnection and of
inconsistent reference that pervades most of the reports that I have
received concerning the use of DOPR.  The word that comes to mind is
hypnogogic.  There is a drifting into that place that lies between a
not-quite-awake and a not-quite-asleep state seems to characterize
this compound.  There is no question but that it is very potent, and
that it is very long-lived.  But there is a nagging suggestion of the
out-of-body, out-of-center character that is the hallmark of the
anesthetic and delusional drugs such as scopolamine or ketamine.  With
them, the psychedelic effects become clouded with touches of amnesia.
If DOPR shows this with it's three carbon alkyl group, thereis every
reason to pay close attention as the chain becomes longer.

There had been quite a bit of speculation in the literature that the
metabolic attack on DOM was at the 4-position, and this was an
oxidation process.  In a moment of inspiration, I decided to explore a
similar oxidation step in DOPR, since it is probably the most potent
of the DO-series.  Why not make the compound which would be the first
step in this oxidation, the 1-hydroxypropyl analogue?  This I did, by
using the phthalimide derivative of 2,5-dimethoxyamphetamine
(described in the synthesis of DOI) and making the propiophenone using
propionic acid as both reagent and solvent, and polyphosphoric acid as
the condensing agent.  The ketone product (a white crystalline solid
from methanol) was dissolved in warm methanol and reduced to the
alcohol with sodium borohydride.  This product, also a white
crystalline solid, was stripped of the phthalimide blocking group with
overnight refluxing with hydrazine in ethanol.  The product,
2,5-dimethoxy-4-(1-hydroxypropyl)-amphetamine (hydroxy-DOPR) had a mp
of 148-150 !C from IPA.  Its activity is not yet known, but there were
no effects at all at trials, orally, of up to 200 micrograms.

But this is all with the normal-propyl compound.  There is a rich
collection of misinformation and potential discovery that is
associated with the isopropyl isomer.  This structural isomer,
2,5-dimethoxyl-4-(i)-propylamphetamine is properly called DOIP for
des-oxy-iso-propyl.  It has been synthesized and explored in animals
and, to a modest extent, in man.  The synthesis has proceeded from
2,5-dimethoxyacetophenone by the addition of a methyl group to the
carbonyl followed by reduction to the hydrocarbon.  Aldehyde
formation, nitropropene synthesis with nitroethane, and lithium
aluminum hydride reduction are uneventful, providing the hydrochloride
salt DOIP, which has a mp of 183-184 !C as an analytical sample.
Animal tests (such as rabbit hyperthermia assays), have indicated that
the isopropyl compound DOIP is less potent than the propyl prototype,
DOPR, by between one and two orders of magnitude.  In man, a dose of
four milligrams, a rousing dose of DOPR, is without any effects.  At
10 milligrams, there is some disturbance but substantially no effects.
I have been told that with doses in the 20 to 30 milligram range there
are valid changes in mental state, but I have not been told the nature
of these changes.

A fascinating red herring had been drawn across all of these exacting
lines by a strange visitor to this research project.  An olive-faced
M.D., Ph.D., passed through this confusing scene briefly, and when he
left, a small supply of DOPR left with him.  He promptly published in
an obscure journal some animal behavioral responses which he ascribed
to the isopropyl analogue, DOIP.  But what he had studied could only
have been DOPR since DOIP, at that time, had not yet been synthesized
either by me, or by either of the other two active synthesists of that
moment.  It was not yet a known material.  We all made it some time
later, but by that time our olive-face had disappeared.  There is a
magnificent French phrase that applies here as nowhere else; Il a
foutu le camp.  Its idiomatic meaning is equivalent to our, RHe took
off,S or RHe split the scene,S but the literal translation is, RHe
fucked the camp.









#72 E; ESCALINE; 3,5-DIMETHOXY-4-ETHOXYPHENETHYLAMINE

SYNTHESIS: To a solution of 72.3 g 2,6-dimethoxyphenol in 400 mL MeOH,
there was added 53.3 g of a 40% solution of aqueous dimethylamine
folowed by 40 g of a 40% aqueous solution of formaldehyde.  The dark
solution was heated under reflux for 1.5 h on a steambath.  The
volatiles were then removed under vacuum yielding a dark oily residue
of 2,6-dimethoxy-4-dimethylaminomethylphenol.  This residue was
dissolved in 400 mL of IPA, to which there was added 50 mL of methyl
iodide.  The spontaneously exothermic reaction deposited crystals
within 3 min, and was allowed to return to room temperature and
occasionally stirred over the course of 4 h.  The solids were removed
by filtration, washed with cold IPA, and allowed to air dry yielding
160 g of the methiodide of 2,6-dimethoxy-4-dimethylaminomethylphenol
as a cream-colored crystalline solid.

A suspension of 155 g of the above methiodide of
2,6-dimethoxy-4-dimethylaminophenol in 600 mL H2O was treated with a
solution of 130 g KCN in 300 mL H2O.  The reaction mixture was heated
on a steam bath for 6 h during which time there was a complete
dissolving, the development of a brownish color with a bright blue
film on the surface and the walls of the flask, and the gentle
evolution of fine gas bubbles.  The hot reaction mixture was poured
into 1.2 L H2O and acidified with concentrated HCl (careful, HCN
evolution).  The aqueous solution was extracted with 3x150 mL CH2Cl2,
the extracts pooled, washed with saturated NaHCO3 which removed much
of the color.  The solvent was removed under vacuum yielding about 70
g of a viscous black oil.  This was distilled at 0.4 mm/Hg at 150-160
!C to provide 52.4 g of homosyringonitrile
(3,5-dimethoxy-4-hydroxyphenylacetonitrile) as a white oil that
spontaneously crystallized to lustrous white crystals that melted at
57-58 !C.

A solution of 5.75 g of homosyringonitrile and 12.1 g ethyl iodide in
50 mL dry acetone was treated with 6.9 g finely powdered anhydrous
K2CO3 and held at reflux for 18 h.  The mixture was diluted with 100
mL Et2O, filtered, and the filtrate solvent removed under vacuum The
residue was recrystallized from Et2O/hexane to yield 5.7 g
3,5-dimethoxy-4-ethoxyphenylacetonitrile with a mp 57-58 !C.  Anal.
(C12H15NO3) C,H,N.

A solution of 2.21 g 3,5-dimethoxy-4-ethoxyphenylacetonitrile in 25 mL
EtOH containing 2.5 mL concentrated HCl and 400 mg 10% palladium on
charcoal, was shaken in a 50 lb/sq.in. atmosphere of hydrogen for 24
h.  Celite was added to the reaction suspension and, following
filtration, the solvents were removed under vacuum.  The residue was
recrystallized from IPA/Et2O to yield 2.14 g
3,5-dimethoxy-4-ethoxyphenethylamine hydrochloride (E) with a mp of
166-167 !C.

Synthesis from syringaldehyde: A well-stirred suspension of 21.9 g
syringaldehyde in 45 mL H2O was heated to reflux in a heating mantle.
There was then added a solution of 15 g NaOH in 60 mL H2O.  The
heating and stirring was continued until the generated solids
redissolved.  Over a period of 10 min, there was added 23 g diethyl
sulfate, then refluxing was continued for 1 h.  Four additional
portions each of 5 g diethyl sulfate and of 6 mL 20% NaOH were
alternately added to the boiling solution over the course of 2 h.  The
cooled reaction mixture was extracted with Et2O, the extracts pooled
and dried over anhydrous MgSO4, decolorized with Norite, and stripped
of solvent.  The crude 3,5-dimethoxy-4-ethoxy-benzaldehyde weighed
21.8 g and melted at 51-52 !C.

A solution of 14.7 g 3,5-dimethoxy-4-ethoxybenzaldehyde and 7.2 mL
nitromethane in 50 mL glacial acetic acid was treated with 4.4 g
anhydrous am-monium acetate and held at reflux for 30 min.  Cooling
the reaction allowed the formation of yellow crystals which were
removed by filtration and washed sparingly with cold acetic acid.  The
dried 3,5-dimethoxy-4-ethoxy-'-nitrostyrene weighed 11.5 g and melted
at 108-109 !C after recrystallization from EtOH Anal. (C12H15NO5) C,H.
Alternately, this product may be prepared from 3.9 g.
3,5-dimethoxy-4-ethoxybenzaldehyde in 60 mL nitromethane containing
0.7 g ammonium acetate and heated on a steam bath for 1 h.  The
solvent was removed under vacuum, and the residue dissolved in a
minimum of hot MeOH.  Cooling provided, after filtration and air
drying, 2.3 g of bright yellow crystals of
3,5-dimethoxy-4-ethoxy-'-nitrostyrene, with a mp of 105-107 !C.

A solution of 2.25 g LAH in 45 mL anhydrous THF was vigorously stirred
and cooled to 0 !C under He.  There was added 1.5 mL 100% H2SO4
dropwise, followed by 2.3 g 3,5-dimethoxy-4-ethoxy-'-nitrostyrene in
anhydrous THF.  After the addition was complete, the mixture was
allowed to stir for 30 min, and then brought to room temperature.  The
unreacted hydride was decomposed with 2.3 mL H2O in THF, followed by
the addition of 9.2 mL of 15% NaOH.  The white suspension was
filtered, the filter cake was washed with THF, the filtrate and
washings combined, and the solvent removed under vacuum.  The residue
was dissolved in 300 mL dilute H2SO4, washed with 2x75 mL CH2Cl2, made
basic with 25% NaOH, and the product extracted with 3x75 mL CH2Cl2.
After removal of the solvent, the residue was distilled at 110-120 !C
at 0.3 mm/Hg yielding 1.4 g of a colorless oil.  A solution of this
oil in 20 mL IPA was neutralized with 17 drops of concentrated HCl and
diluted with 100 mL anhydrous Et2O.  After a few minutes there was the
spontaneous formation of white crystals of
3,5-dimethoxy-4-ethoxyphenethylamine hydrochloride (E) which was
recrystallized from 40 mL boiling EtOAc containing 1 mL MeOH.  The mp
was 165-166 !C.

DOSAGE: 40 - 60 mg.

DURATION: 8 - 12 h.

QUALITATIVE COMMENTS: (with 40 mg) This is a powerful and complex
intoxicant Q I could not have coordinated any rational muscular
activity.  I could not walk; I could not tie my shoe-laces.  There is
analgesia and an incoordination that I cannot shake.  My menstrual
flow started a bit ahead of time, but it was light.

(with 50 mg) I felt that the body tensions outweighed the
psychological and sensory rewards, in that I had a lot of dehydration
and my sleep had a nightmare quality.  This pretty much offset the few
virtues that I felt I had obtained.

(with 60 mg) There is a quality of rational analysis and insight that
is totally impressive.  Many subtle factors in my life can be viewed
with insight, and usefully dissected.  I got into a deep discussion,
but I was not argumentative or even defensive and I remained detached
and kept a tone of cool impersonality.  I had a good appetite.  But I
also had some tachycardia and muscular tension.  There was
unquestionable sensory enhancement, but without an intellectual
component.  Overall it was most pleasant.

EXTENSIONS AND COMMENTARY: In an isolated situation, there is easy
fantasy, but little synthesis of external sensory inputs such as music
or visual stimulae.  A gradual decline brings the subject back to a
restful baseline somewhere before the 12th hour.  The following day is
often seen as one of tiredness and low energy.  An anonymous flyer
appeared in the California drug community in 1984 stating an effective
range to be 50 to 100 milligrams, but it described the drug as the
sulfate.  The above data all pertain to the hydrochloride salt.

The replacement of that one methyl group with an ethyl group leads to
a nice jeu de mots.  The play on words depends on a remarkable
coincidence.  The name of the alkaloid mescaline stems from an ancient
Nahuatl word for a drink (Mexcalli) which also provided the source of
the term Mescal (an Agave of entirely different pharmacology).  The
prefix for the simplest, the one carbon organic radical, is methyl.
This is from the Greek word RmethyS and represents wine from wood.
Such is, indeed, methyl alcohol, or methanol, or wood alcohol, the
simplest one-carbon drink and a rather dangerous one for the human
animal.  And this is the group that is on the central oxygen of
mescaline.

It is customary to refer to homologs (bigger-by-one) of methanol by
their classical chemical names, so the natural extension of methyl is
ethyl, and that of mescaline would be escaline.  One carbon-chain on
the 4-position oxygen becoming a two-carbon chain.  This is all
entymologically appealing, but there is no botanical support for any
of it.  The ethyl group is much more rare in nature.  It is just a
happy coincidence that mescaline (the plant), and methyl (the alkyl
group involved), and methoxy (the group on the 4-position of the
aromatic ring) all happen to start with the letter RMS.

Very few of the homomescaline phenethylamines have been synthesized as
their three-carbon chain counterparts, the corresponding analogues of
amphetamine.  And only three of them have been explored in man (four,
if you count the amphetamine analogue of mescaline itself, TMA).  The
obvious names for these compounds have, unfortunately, already been
used.  It would be logical to use the letter M for a methoxy, and the
letter E for ethoxy, etc. and simply read the groups from around the
ring.  But this is the naming system for the 2,4,5-trisubstituted
amphetamines.  MEM is, for example, 2,5-dimethoxy-4-ethoxyamphetamine
(in sequence, methoxy, ethoxy, methoxy reading around the ring, and a
fascinating compound talked about at length in this book), so this
term cannot represent 3,5-dimethoxy-4-ethoxyamphetamine.

A truly simple code employs the length of the carbon chain.  The
phenethylamine chain is two carbons long, and the amphetamine chain is
three carbons long.

If a drug has been initially developed (and initially named) as an
amphetamine derivative (three carbon chain) then the two-carbon chain
analogue will use the original name (or a symbolic part of it) with
the term 2C ahead of it.  The two-carbon analogue of DOB (a
three-carbon chain compound) will become 2C-B.  DOI becomes 2C-I, DON
becomes 2C-N, and DOET becomes 2C-E.  Each of these is a substituted
amphetamine derivative lacking one carbon atom, thus becoming a
phenethylamine derivative.  Most of these have 2,4,5-substitution
patterns.

And if a drug has been initially developed (and initially named) as a
phenethylamine derivative (two carbon chain) then the three-carbon
chain analogue will use the original name with the term 3C ahead of
it.  The three carbon analogue of E (escaline, a two-carbon chain
compound) will become 3C-E.  P becomes 3C-P and CPM becomes 3C-CPM.
Most of these have 3,4,5-substitution patterns.

Thus, R2-CS implies that a known amphetamine drug has been shortened
to a phenethylamine, and R3-CS inplies that a known phenethylamine has
been lengthened to an amphetamine.  A great number of the former have
been made and have proven to be most rewarding.  Only a few of the
latter are known, but most of them will eventually prove to be potent
psychedelics.









#73 EEE; 2,4,5-TRIETHOXYAMPHETAMINE

SYNTHESIS: A solution of 13.3 g 3,4-diethoxyphenol (see the recipe for
MEE for its preparation) in 20 mL MeOH, and a solution of 4.8 g KOH in
100 mL hot MeOH were combined.  There was added 8.2 g ethyl bromide
and the mixture was held at reflux on the steam bath for 2 h.  The
reaction was quenched by the addition of three volumes H2O, made
strongly basic by the addition of 10% NaOH, and extracted with 3x150
mL CH2Cl2.  The solvent was removed from the pooled extracts under
vacuum giving a residue of 9.1 g 1,2,4-triethoxybenzene that
solidified to a crystalline mass.  The mp was 28.5-29.5 !C, but the
infra-red analysis showed the presence of unreacted phenol.  The
CH2Cl2 solution was again washed thoroughly with 10% NaOH and, after
removal of the solvent, the solidified residue weighed 6.0 g and
appeared free of impurities.  The mp of this sample was 33-34 !C.

To a mixture of 10.5 g N-methyl formanilide and 11.9 g POCl3 that had
incubated at room temperature for 0.5 h (it had become quite red in
color) there was added 6.4 g of the solid ether,
1,2,4-triethoxybenzene.  The mixture was heated on the steam bath for
2.5 h, then poured into 500 mL of shaved ice.  After a few minutes
stirring, crystals appeared.  The reaction was allowed to stand for a
few h, then filtered and sucked as dry as possible.  The damp 14.4 g
of slate-green crude solids were dissolved in 30 mL boiling MeOH, and
allowed to cool to room temperature overnight.  Filtration of the
cream-colored product, and air drying, gave 6.1 g of
2,4,5-triethoxybenzaldehyde with a mp of 94-95 !C.  A solution
containing 0.5 g of this aldehyde and 0.4 g malononitrile in 7 mL
absolute EtOH was treated with three drops of triethylamine.  There
was an immediate formation of granular yellow crystals of
2,4,5-triethoxybenzalmalononitrile which, on filtering and air drying,
weighed 0.4 g and had a mp of 169-170 !C.

A solution of 5.0 g 2,4,5-triethoxybenzaldehyde and 2.6 g nitroethane
in 14.8 g glacial acetic acid was treated with 1.6 g anhydrous
ammonium acetate and heated on the steam bath for 2 h.  The addition
of an equal volume of H2O gave a slightly turbid solution which, upon
the administration of a small amount of externally developed seed,
smoothly set up as orange crystals as the reaction mix returned to
room temperature.  The product was removed by filtration, washed with
a little 50% acetic acid, and allowed to air dry to constant weight.
There was thus obtained 2.5 g of fluffy yellow-orange (almost yellow)
crystals of 2-nitro-1-(2,4,5-triethoxyphenyl)propene with a mp of
91-92.5 !C.  Anal. (C15H21NO5) C,H.

To a gently refluxing suspension of 1.7 g LAH in 200 mL anhydrous Et2O
under a He atmosphere, there was added 2.5 g
2-nitro-1-(2,4,5-triethoxyphenyl)propene by allowing the condensing
Et2O to drip into a shunted Soxhlet thimble containing the
nitrostyrene, thus effectively adding a warm saturated solution of the
nitrostyrene dropwise.  Refluxing was maintained for 5 h, and then the
reaction mixture was cooled with an external ice bath.  The excess
hydride was destroyed by the cautious addition of 300 mL 1.5 N H2SO4.
When the aqueous and Et2O layers were finally clear, they were
separated, and 50 g of potassium sodium tartrate were dissolved in the
aqueous fraction.  Aqueous NaOH was then added until the pH was above
9, and this was extracted with 3x200 mL CH2Cl2.  Removal of the
solvent under vacuum produced an amber oil that was dissolved in
anhydrous Et2O and saturated with anhydrous HCl gas.  After a few min
delay, there com-menced the separation of fine white crystals of
2,4,5-triethoxyamphetamine hydro-chloride, (EEE).  These weighed,
after filtration, Et2O washing, and air drying to constant weight,
1.75 g and had a mp of 167-168 !C, with prior softening at 162 !C.
Anal. (C15H26ClNO3) C,H,N.

DOSAGE: unknown.

DURATION: unknown.

EXTENSIONS AND COMMENTARY: This amphetamine, the final item on the
ethoxy homologue of TMA-2 project, has never been tried in man.  I do
not know how it tastes, but I suspect that it is probably bitter.  An
interesting sidelight concerning this project, and one which can serve
as a measure of the enthusiasm that went into it, is that (except for
the 2-ethoxy homologue EMM) all of the possible ethoxy homologues of
TMA-2, including MEM, MME, EEM, EME, MEE and EEE, their precursor
nitrostyrenes, the precursor aldehydes (and their malononitrile
derivatives), the precursor ethers, and the precursor phenols, for a
total of 33 compounds, were all synthesized, purified, and
characterized within a period of just over three weeks.  Actually it
was 23 days, and that was a magically exciting time.

And there were two true treasures that came out of it all.  The
compound MEM, and the knowledge that the 4-position was where the
action is.









#74 EEM; 2,4-DIETHOXY-5-METHOXYAMPHETAMINE

SYNTHESIS: To a solution of 12.3 g 3-ethoxy-4-methoxyphenol (see
recipe for MEM for the preparation of this phenol) in 20 mL MeOH,
there was added a warm solution of 4.8 g KOH in 100 mL MeOH.  There
was then added 8.2 g ethyl bromide, and the mixture held at reflux on
the steam bath.  Within 0.5 h, severe bumping ensued.  An additional 3
g ethyl bromide were added, refluxing continued for another 0.5 h,
then the reaction mixture was allowed to come to room temperature and
to stand overnight.  It was poured into 3 volumes H2O which produced
crystals spontaneously.  There was added additional base, and the
mixture was extracted with 3x150 mL CH2Cl2.  Removal of the solvent
from the pooled extracts under vacuum gave 6.4 g of
2,4-diethoxyanisole as tan crystals with a mp of 48-48.5 !C.

A mixture of 10.9 g N-methylformanilide and 12.3 g POCl3 was allowed
to stand at room temperature for 0.5 h producing a deep red claret
color.  There was then added 6.2 g 2,4-diethoxyanisole and the mixture
was heated on the steam bath for 2 h.  All was poured into 200 g
chipped ice, and stirred mechanically.  The dark viscous gummy oil
gradually became increasingly granular and finally appeared as
jade-green solids.  These were removed by filtration and washed with
H2O, giving a wet cake weighing 18 g and having a mp (from a porous
plate) of 95.5-96.5 !C.  The entire crop was recrystallized from 75 mL
boiling MeOH which gave, after filtering, washing lightly with cold
MeOH, and air drying, 5.4 g of 2,4-diethoxy-5-methoxybenzaldehyde with
a mp of 98-99 !C.  A solution of 0.2 g of this aldehyde, and 0.3 g
malononitrile in 2.0 mL warm EtOH was treated with a drop of
triethyl-amine.  There was an immediate generation of crystals which
were removed by filtration, EtOH-washed, and dried to constant weight.
The bright yellow needles of 2,4-diethoxy-5-methoxybenzalmalononitrile
weighed 0.15 g and had a mp of 172-172.5 !C.

A solution of 5.0 g 2,4-diethoxy-5-methoxybenzaldehyde in 16 g glacial
acetic acid was treated with 2.7 g nitroethane followed by 1.7 g
anhydrous ammonium acetate.  The mixture was heated for 2.5 h on the
steam bath, then removed and diluted with a equal volume of H2O.  With
cooling there was the generation of a heavy crop of orange crystals
which was removed, washed with 50% acetic acid, and sucked as dry as
possible.  The product had a mp of 97-104 !C, and there was
spectrographic evidence of some unreacted starting aldehyde.  A small
sample was recrystallized from boiling MeOH, with considerable loss,
to give an analytical sample of
1-(2,4-diethoxy-5-methoxyphenyl)-2-nitropropene as orange-yellow
crystals with a mp of 112-113 !C.  Anal. (C14H19NO5) C,H.  The
unpurified first crop was employed in the following synthesis of the
corresponding amphetamine.

To a gently refluxing suspension of 2.9 g LAH in 400 mL anhydrous Et2O
under a He atmosphere, there was added 4.0 g of impure
1-(2,4-diethoxy-5-methoxyphenyl)-2-nitropropene by allowing the
condensing ether to drip into a shunted Soxhlet thimble apparatus
containing the nitrostyrene.  This effectively added a warm saturated
solution of the nitrostyrene dropwise over the course of 1 h.
Refluxing was maintained for 5 h and the reaction mixture was cooled
with an external ice bath with the stirring continued.  The excess
hydride was destroyed by the cautious addition of 400 mL of 1.5 N
H2SO4.  When the aqueous and Et2O layers were finally clear, they were
separated, and 100 g of potassium sodium tartrate was dissolved in the
aqueous fraction.  Aqueous NaOH was then added until the pH was above
9, and this was then extracted with 3x150 mL CH2Cl2.  Removal of the
solvent under vacuum produced 2.7 g of a pale amber oil that was
dissolved in 300 mL anhydrous Et2O and saturated with anhydrous HCl
gas.  After a few minutes delay, there commenced the separation of
fine white crystals of 2,4-diethoxy-5-methoxyamphetamine hydrochloride
(EEM).  After the crystallization was complete, these were removed by
filtration, washed with Et2O and air dried, providing 2.55 g of a fine
white crystalline solid with mp 158-159 !C.  Anal. (C14H24ClNO3)
C,H,N.

DOSAGE: unknown.

DURATION: unknown.

EXTENSIONS AND COMMENTARY: This particular identity and arrangement of
the alkoxy groups on the amphetamine molecule, EEM, is a totally
unexplored molecule.  It is reasonable to assume that it would be way
down in potency, but there is no way of guessing what the nature of
its activity might be at the dosage that would be active.









#75 EME; 2,5-DIETHOXY-4-METHOXYAMPHETAMINE

SYNTHESIS: To a solution of 14.0 g 4-ethoxy-3-methoxyphenol (see the
recipe for MME for the preparation of this starting material) in an
equal volume of EtOH, there was added a solution of 5.3 g KOH in 100
mL hot MeOH.  This was followed with 9.1 g ethyl bromide, and the
mixture was held at reflux for 2 h.  The first deposition of KBr was
apparent in 5 min, and there was rather severe bumping by the end of
the reaction.  The mixture was diluted with 3 volumes H2O and 1 volume
5% NaOH, and extracted with 2x200 mL Et2O.  The extracts were pooled,
and the solvent removed under vacuum, yielding 14.3 g of a pale amber
oil that set to crystals of 2,5-diethoxyanisole with a mp of 44-45 !C.
The compound had been reported in the literature from the action of
diethyl sulfate on methoxyhydroquinone.

To a mixture of 24.1 g N-methylformanilide and 27.3 g POCl3 that had
been allowed to stand at room temperature until strongly red-colored
(about 0.5 h) there was added 13.8 g solid 2,5-diethoxyanisole and the
mixture was heated on the steam bath for 2 h.  The black, thick
reaction product was poured over chipped ice and, with continuous
stirring, the color lightened and there was the formation of a
yellowish powder.  After a few h standing, this was removed by
filtration and sucked as dry as possible.  The 32 g of damp product
showed the presence of isomeric contaminatiion by GC, and the aqueous
mother liquor, upon extraction with CH2Cl2 and concentration, showed
yet more aldehyde-like impurities.  The isolated solids were
recrystallized from 125 mL boiling MeOH giving 15.8 g yellowish
crystals (wet weight) that still showed detectable impurities by GC.
A second recrystallization from 100 mL boiling MeOH gave off-white
fluffy crystals of 2,5-diethoxy-4-methoxybenzaldehyde which weighed,
after air drying, 8.5 g.  The mp was 109-110 !C.  The combined mother
liquors from the two MeOH crystallizations were stripped of solvent,
and the resulting solid mass crystallized again from MeOH to give a
second crop of aldehyde, 5.7 g, with a mp of 110-111 !C.  A solution
of 1.0 g of this aldehyde and 0.7 g malononitrile in 40 mL warm
absolute EtOH was treated with a few drops of triethylamine.  In a
minute or so, there was the formation of crystals.  These were removed
by filtration, washed with EtOH, and air dried, giving 0.6 g of
2,5-diethoxy-4-methoxybenzalmalononitrile as brilliant yellow crystals
with a mp of 156.5-158 !C.

A solution of 6.7 g 2,5-diethoxy-4-methoxybenzaldehyde in 21 g glacial
acetic acid was treated with 3.1 g nitroethane and 1.93 g anhydrous
ammonium acetate, and heated on the steam bath for 2.5 h.  The
addition of a small amount of H2O to the hot reaction mixture
instituted crystallization of an orange product which, after the
mixture had come to room temperature and stood for several h, was
removed by filtration, H2O washed, and air dried.  The product,
1-(2,5-diethoxy-4-methoxyphenyl)-2-nitropropene, was dull orange in
color, weighed 3.0 g and had a mp of 84-86 !C.  An analytical sample
from toluene had a mp of 85-86 !C.  Anal. (C14H19NO5) C,H.

To a gently refluxing suspension of 2.0 g LAH in 250 mL anhydrous Et2O
under a He atmosphere, there was added 2.8 g
1-(2,5-diethoxy-4-methoxyphenyl)-2-nitropropene by allowing the
condensing Et2O to drip into a shunted Soxhlet thimble containing the
nitrostyrene.  This effectively added a warm saturated solution of the
nitrostyrene dropwise.  The addition took 1 h and the refluxing was
continued for an additional 6 h.  The reaction mixture was brought
down to ice-bath temperature, and the excess hydride was destroyed by
the cautious addition of 150 mL 1.5 N H2SO4.  When the aqueous and
Et2O layers were finally clear, they were separated and 50 g of
potassium sodium tartrate were dissolved in the aqueous fraction.
Aqueous NaOH was then added until the pH was >9, and this was then
extracted with 3x150 mL CH2Cl2.  Removal of the solvent under vacuum
produced 2.3 g of a clear white oil that was dissolved in 300 mL
anhydrous Et2O and saturated with anhydrous HCl gas.  At first the
solution remained completely clear, and finally there was the start of
the formation of fine white crystals.  When the crystallization was
complete, these solids were removed by filtration, Et2O washed, and
air dried.  There was thus obtained 2.2 g of
2,5-diethoxy-4-methoxyamphetamine hydrochloride (EME) with a mp of
162-164 !C with prior softening at 154 !C.  Anal. (C14H24ClNO3) C,H,N.

DOSAGE: unknown.

DURATION: unknown.

EXTENSIONS AND COMMENTARY: This is another of the collection of all
possible ethoxy homologues of TMA-2.  The latter and heavier members
of this series were synthesized and completed before the directions of
biological activity had become evident from the earlier ones.  This
compound has never been assayed, and it is a reasonable guess that it
will have a very low potency, with hints of toxicity at higher dose
levels.  I suspect that it will never be assayed, certainly not by me.









#76 EMM; 4,5-DIMETHOXY-2-ETHOXYAMPHETAMINE

SYNTHESIS: A solution of 166 g 3,4-dimethoxybenzaldehyde in 600 mL
acetic acid was well stirred, and brought up to an internal
temperature of exactly 25 !C.  There was added, in very small
portions, a 40% solution of peracetic acid in acetic acid.  The
evolved heat was removed with an external ice bath, and the rate of
addition was dictated by the requirement that the internal temperature
should not exceed 25 !C.  A total of 210 g of the 40% peracetic acid
was used.  The reaction mixture was poured into 3 L H2O, and the
acetic acid neutralized by the addition of solid K2CO3.  The neutral
aqueousphase was extracted with 5x150 mL Et2O, and the solvent from
the pooled extracts was removed under vacuum.  To the red-colored
residue there was added 300 mL 10% NaOH, and the mixture was heated
for 1 h on the steam bath.  This was cooled, washed once with CH2Cl2,
acidified with HCl, and extracted with 5x150 mL Et2O.  The pooled
extracts were washed once with saturated NaHCO3 (which removed most of
the color) and the removal of the solvent under vacuum gave 105 g of
3,4-dimethoxyphenol as an amber oil that slowly set up to crystals.

The above crude 3,4-dimethoxyphenol was dissolved in 200 mL EtOH, and
treated with a solution of 38.1 g KOH in 300 mL hot EtOH.  The clear
solution of the potassium salt was a deep red color, and was promptly
treated with 94.3 g allyl bromide, at a rate commensurate with the
exothermic reaction.  The mixture was held at reflux for 2 h.  This
was then added to 1 L H2O and extracted with 5x100 mL Et2O.  The
extracts were pooled, and removal of the solvent under vacuum gave a
residue of 98 g of a black oil.  This was distilled at 104-108 !C at
0.7-1.0 mm/Hg to give 59.3 g 1-allyloxy-3,4-dimethoxybenzene as a pale
yellow oil with a greenish cast.

A total of 59 g of the neat 1-allyloxy-3,4-dimethoxybenzene was
provided with an internal thermometer, and heated with an open flame.
The color quickly became purple, then lightened to a red at 70 !C, and
finally to a pale pink by 210 !C.  At 240 !C an exothermic reaction
set in with the temperature going up to almost 290 !C.  It was held in
the 270-280 !C range for several min, then allowed to return to room
temperature.  GC analysis showed two peaks, the second and major one
being the desired 1,2,4,5-isomer.  A small sample was caught by
prep-GC, and it successfully seeded the crude Claissen rearrangement
product.  The isolated 2-allyl-4,5-dimethoxyphenol, pressed on a
porous plate, had a mp of 39.5-40.5 !C which was improved to 41.5-42
!C by recrystallization from hexane.

To a solution of 9.7 g 2-allyl-4,5-dimethoxyphenol in a few mL EtOH,
there was added a solution of 2.8 g KOH in 25 mL boiling EtOH followed
by 5.5 g ethyl bromide.  The mixture was held at reflux for 3.5 h and
then poured into 200 mL H2O and extracted with 3x100 mL CH2Cl2.
Pooling the extracts and removal of the solvent under vacuum gave a
residue of 10.4 g of 4,5-dimethoxy-2-ethoxy-1-allylbenzene as a clear,
mobile oil.  It was substantially a single component by GC and was
used in the following isomerization step without further purification.

A solution of 9.4 g 4,5-dimethoxy-2-ethoxy-1-allylbenzene in 10 mL
EtOH was treated with 20 g flaked KOH, and heated on the steam bath.
The progress of the isomerization was followed by the assay of
isolates by GC.  After 5 h, the reaction mixture was poured into 250
mL H2O which immediately generated a pasty solid.  This was sucked
free of solvent and other liquids on a sintered funnel, giving 5.5 g
of trans-4,5-dimethoxy-2-ethoxy-1-propenylbenzene as an amber solid
with a mp of 65-67 !C.  A small analytical sample from hexane had a mp
of 68 !C.

A solution of 5.0 g trans-4,5-dimethoxy-2-ethoxy-1-propenylbenzene in
27 g acetone that contained 2.2 g pyridine was magnetically stirred
and cooled to 0 !C.  There was then added 4.5 g tetranitromethane and,
after 2 minutes stirring at this temperature, the reaction mixture was
quenched with a solution of 1.5 g KOH in 26 mL H2O.  The reaction
mixture remained a clear deep orange color, and additional H2O was
required to institute crystallization.  There was the slow deposition
of bright yellow crystals of
1-(4,5-dimethoxy-2-ethoxyphenyl)-2-nitro-propene which weighed, after
EtOH washing and air drying to constant weight of 4.4 g.  The mp was
75-76 !C.

To a gently refluxing suspension of 3.5 g LAH in 250 mL anhydrous Et2O
under a He atmosphere, there was added 3.9 g
1-(4,5-dimethoxy-2-ethoxyphenyl)-2-nitropropene by allowing the
condensing Et2O to drip into a shunted Soxhlet apparatus with the
thimble containing the nitrostyrene.  This effectively added a warm
saturated solution of the nitrostyrene dropwise; the nitrostyrene was
very soluble in Et2O.  Refluxing was maintained for 2.5 h and the
reaction continued to stir at room temperature for an additional 3.5
h.  The excess hydride was destroyed by the cautious addition of 225
mL 1.5 N H2SO4.  When the aqeous and Et2O layers were finally clear,
they were separated, and 75 g of potassium sodium tartrate was
dissolved in the aqueous fraction.  Aqueous NaOH was then added until
the pH was >9, and this was then extracted with 3x100 mL CH2Cl2.
Evaporation of the solvent under vacuum produced 2.8 g of a clear,
almost colorless oil that was dissolved in anhydrous Et2O and
saturated with anhydrous HCl gas.  This initially generated a solid
that then oiled out.  After a few minutes stirring, this began to
solidify again and it finally transformed into a loose fine white
solid.  This was recrystallized by dissolution in 50 mL warm IPA
followed by dilution with 300 mL Et2O.  After a few minutes, crystals
of 4,5-dimethoxy-2-ethoxyamphetamine hydrochloride (EMM) formed which
were removed by filtration, Et2O washed, and air dried.  These weighed
2.7 g and had a mp of 171-172 !C.  Anal. (C13H22ClNO3) C,H,N.

DOSAGE: greater than 50 mg.

DURATION: unknown.

QUALITATIVE COMMENTS: (with 50 mg) There were no effects.

EXTENSIONS AND COMMENTARY: This was the first of the ethoxy homologues
of TMA-2, and it was immediately (well, within a couple of months) run
up from an initial dab to 25 milligrams.  This was in early 1963, and
the lack of activity of EMM was keenly disappointing.  This was a
level at which the prototype, TMA-2, was very active, and the
conclusion was that maybe any change on the molecule would result in a
loss of activity.  So this approach was shelved for a while, and all
efforts were directed into the relocation, rather than the elongation,
of the methoxy groups.  A few months later, the ethoxy question was
addressed again, and the discovery of MEM rekindled full interest in
this ethoxy question.









#77 ETHYL-J; 2-ETHYLAMINO-1-(3,4-METHYLENEDIOXYPHENYL)BUTANE;

N-ETHYL-1-(1,3-BENZODIOXOL-5-YL)-2-BUTANAMINE

SYNTHESIS: A stirred solution of 9.0 g
1-(3,4-methylenedioxyphenyl)-2-butanone (see the recipe for J for its
preparation) in 150 mL MeOH was treated with 9.0 g ethylamine
hydrochloride, 4.0 g anhydrous NaOAc, and 3.0 g sodium
cyanoborohydride.  The pH was maintained between 6 and 7 by the
periodic addition of HCl.  After the base formation had stabilized,
there was added an additional 9.0 g ethylamine hydrochloride, 9.0 g
NaOAc and 2.0 g sodium cyanoborohydride.  With continuous stirring,
there was HCl added over the course of 1 h until the final pH was
approximately 2.  The reaction mixture was poured into 700 mL dilute
NaOH, and extracted with 3x75 mL CH2Cl2.  These extracts were pooled,
and back-extracted with dilute H2SO4.  This was washed with 2x50 mL
CH2Cl2, then made basic with dilute NaOH and extracted with 2x75 mL
CH2Cl2.  Removal of the solvent under vacuum gave a 0.81 g residue
which was dissolved in 10 mL IPA.  Neutralization with concntrated HCl
formed white crystals spontaneously.  These were diluted with Et2O,
filtered, Et2O washed and air dried to provide 0.85 g
2-ethylamino-1-(3,4-methylenedioxy-phenyl)butane hydrochloride
(ETHYL-J), with mp of 176-177 !C.  Anal. (C13H20ClNO2) C,H.  The
neutral fraction that remained in the organic phase following the
dilute sulfuric acid extraction, was recovered by removal of the
solvent under vacuum.  There was obtained about 5 g of an amber liquid
that was largely 2-hydroxy-1-(3,4-methylenedioxyphenyl)butane.

DOSAGE: greater than 90 mg.

DURATION: probably short.

QUALITATIVE COMMENTS: (with 65 mg) Perhaps aware at 20 minutes.
Definitely aware at 45 minutes.  Diffusing to nothing at 3-4 hours.

(with 90 mg) I am somewhere between 1 and +.  And everything became
lost in the evening with a couple of glasses of wine and talk that
went on to 3 AM.

EXTENSIONS AND COMMENTARY: And nothing higher has ever been looked at.
If the analogy with the amphetamine counterparts (J with MDA, METHYL-J
with MDMA, and this, with MDE) were to hold up (a drop of about a
third in potency with the lengthening of the chain by a carbon atom),
one might guess that this compound would be an interesting intoxicant,
but probably not until you got up into the area at or above a 200
milligram dose.  And that is a lot of chemical for the body to have to
handle.  Some day, maybe.









#78 ETHYL-K; 2-ETHYLAMINO-1-(3,4-METHYLENEDIOXYPHENYL)PENTANE;

N-ETHYL-1-(1,3-BENZODIOXOL-5-YL)-2-PENTYLAMINE

SYNTHESIS: A solution of 120 mg mercuric chloride in 160 mL H2O was
poured over 4.7 g aluminum foil (Reynolds Wrap, regular weight, cut
into 1 inch squares) and allowed to stand until the amalgamation was
well underway (about 30 min).  The H2O was then drained and the foil
washed with 2x200 mL H2O with thorough draining.  There was then
added, in sequence and with good swirling and agitation between each
addition, 8.5 g ethylamine hydrochloride dissolved in 7 mL H2O, 21 mL
IPA, 17 mL 25% NaOH, 7.1 g 1-(3,4-methylenedioxyphenyl)-2-pentanone
(see the recipe for METHYL-K for its preparation), and finally 40 mL
IPA.  The reaction mixture was periodically heated on the steam bath
to keep the reaction moving and active.  After all the metal had been
consumed, the mixture was filtered, and the filter cake washed with
MeOH.  The solvent was removed from the combined filtrate and
washings, and the residue suspended in 800 mL dilute HCl.  This was
washed with 3x100 mL Et2O, made basic with 25% NaOH, and extracted
with 3x100 mL CH2Cl2.  The pooled extracts were stripped of solvent
under vacuum yielding a residue of 6.3 g of an amber oil.  This was
distilled at 115-125 !C at 0.4 mm/Hg to give 5.61 g of an almost white
liquid which was dissolved in 28 mL IPA, neutralized with concentrated
HCl, and diluted with 100 mL anhydrous Et2O.  The resulting clear
solution became cloudy, then set up in a cottage cheese texture, and
then all broke up to a beautiful loose solid.  This was filtered, Et2O
washed and air dried to give 5.99 g
2-ethylamino-1-(3,4-methylenedioxyphenyl)pentane hydrochloride
(ETHYL-K) with a mp of 157-158 !C.  Anal. (C14H22ClNO2) C,H.

DOSAGE: (greater than 40 mg).

DURATION: unknown.

QUALITATIVE COMMENTS: (with 40 mg) There was a paresthetic twinge in
my shoulder area at about an hour Q other than that, absolutely
nothing.

EXTENSIONS AND COMMENTARY: And that is as high a dose as has
apparently ever been tried with ETHYL-K.  The compounds with the
hexane chain (L-series) rather than the pentane chain of the K-series
have been made, but they have been spun into the recipe for METHYL-K.









#79 F-2; 2-M;
6-(2-AMINOPROPYL)-5-METHOXY-2-METHYL-2,3-DIHYDROBENZOFURAN

SYNTHESIS: To a solution of 43.2 g KOH pellets in 250 boiling EtOH
there was added 96 g 4-methoxyphenol followed by the slow addition of
131.2 g allyl bromide, and the mixture was held under refluxing
conditions for 16 h.  After cooling, the reaction was added to 1.6 L
H2O, and made strongly basic with 25% NaOH.  This was extracted with
3x100 mL CH2Cl2, the extracts pooled, washed once with dilute NaOH and
then once with dilute HCl.  Removal of the solvent under vacuum gave
93.8 g of 4-allyloxyanisole as a pale amber oil, which was used in the
following reaction without further purification.

A round-bottomed flask containing 93 g crude 4-allyloxyanisole was
equipped with an immersed thermometer and heated with an external
flame until an exothermic reaction set in at 230 !C.  The temperature
rose to 270 !C and it was maintained there with the flame for five
minutes.  After cooling to room temperature, the reaction mix was
poured into 2 L H2O and made strongly basic with the addition of 25%
NaOH.  This dark aqueous phase was washed with 2x200 mL CH2Cl2, and
then acidified with HCl.  This was then extracted with 2x200 mL
CH2Cl2, and the pooled extracts washed first with saturated NaHCO3 and
then with H2O.  Removal of the solvent under vacuum gave 65.6 g of
2-allyl-4-methoxyphenol as a clear, amber oil.  To a solution of 1.66
g of this crude phenol in 5 mL hexane with just enough CH2Cl2 added to
effect a clear solution, there was added 1.3 g phenyl isocyanate
followed with three drops of triethylamine.  An exothermic reaction
ensued which spontaneously deposited white crystals.  These was
removed and hexane washed to give 2-allyl-4-methoxyphenyl N-phenyl
carbamate, with a mp of 88-89 !C.  The acetate ester, from the phenol
and acetic anhydride in pyridine, did not crystallize.

To a solution of 37.7 g 2-allyl-4-methoxyphenol in 125 mL glacial
acetic acid there was added 19 g zinc chloride followed with 63 mL
concentrated HCl.  The mixture was held at reflux temperature for 40
min, then cooled to room temperature, diluted with 300 mL H2O, and
extracted with 2x200 mL CH2Cl2.  The pooled extracts were washed
repeatedly with 8% NaOH until the washings remained basic.  Removal of
the solvent under vacuum gave a clear pale yellow oil that was
distilled at the water pump.  A fraction boiling at 150-165 !C was
5-methoxy-2-methyl-2,3-dihydrobenzofuran which weighed 25 g and which
was a highly refractive colorless oil.  The infra-red spectrum
indicated that some small amount of hydroxy group was present, but the
NMR spectrum was in complete accord with the benzofuran structure.  A
higher cut in this distillation gave 4.5 g of a phenolic product
tentatively assigned the structure of 4-methoxy-2-propenylphenol.  The
target dihydrobenzo-furan has also been synthesized from the open-ring
o-allyl phenol in acetic acid solution with the addition of a
catalytic amount of concentrated H2SO4.

To a half-hour pre-incubated mixture of 69 g POCl3 and 60 g
N-methylformanilide there was added 29.0 g
5-methoxy-2-methyl-2,3-dihydrobenzofuran and the mixture was heated on
the steam bath for 2 h.  The reaction mixture was poured into 1 L H2O,
and allowed to stir overnight.  The brown gummy solids were removed by
filtration, and air dried as completely as possible.  These weighed 32
g and were shown by GC on OV-17 to consist of two benzaldehyde isomers
in a ratio of 7:2.  This was triturated under 18 mL MeOH, and the
undissolved solids removed by filtration and washed with 6 mL
additional MeOH.  The mother liquor and washings were saved.  The 17.8
g of dull yellow solids that were obtained were repeatedly extracted
with 75 mL portions of boiling hexane (4 extracts were required) and
each extract, on cooling, deposited yellow crystals of the major
aldehyde.  The dried crystals of
6-formyl-5-methoxy-2-methyl-2,3-dihydrobenzofuran were combined (9.5
g) and had a mp of 80-82 !C.  The methanol washes saved from above
were stripped of solvent, and the sticky, orange solids that remained
were enriched in the minor aldehyde isomer (3:2 ratio).  Several
injections of this crude material into a preparative GC OV-17 column
gave sufficient quantities of the RwrongS isomer for NMR
characterization.  The 2-methyl group was intact (eliminating the
possibility of a dihydrobenzopyran isomer) and the ring meta-proton
splitting required that the formyl group be in the benzofuran
7-position.  This crystalline solid was, therefore,
7-formyl-5-methoxy-2-methyl-2,3-dihydrobenzofuran.

A solution of 9 g of 6-formyl-5-methoxy-2-methyl-2,3-dihydrobenzofuran
in 35 mL glacial acetic acid was treated with 6 mL of nitroethane
followed with 3.1 g anhydrous ammonium acetate.  This mixture was
heated on the steam bath for 4 h, diluted with half its volume with
warm H2O, and seeded with a bit of product that had been obtained
separately.  The slightly turbid solution slowly crystallized as it
cooled, and was finally held at 0 !C for several h.  The deep orange
product was removed by filtration, washed with 50% acetic acid, and
air dried to constant weight.  There was thus obtained 7.0 g
5-methoxy-2-methyl-6-(2-nitro-1-propenyl)-2,3-dihydrobenzofuran with a
mp of 89-90 !C from MeOH.

A suspension of 5.0 g LAH in 500 mL of well stirred anhydrous Et2O at
a gentle reflux, was treated with a warm, saturated solution of 7.0 g
5-methoxy-2-methyl-6-(2-nitro-1-propenyl)-2,3-dihydrobenzofuran in
Et2O added dropwise.  The mixture was kept at reflux temperature for
36 h, allowed to stand 2 days, and then the excess hydride destroyed
by the cautious addition of 500 mL 6% H2SO4.  The phases were
separated, and the aqueous phase washed with 2x200 mL CH2Cl2.  A total
of 125 g potassium sodium tartrate was added to the aqueous phase, and
sufficient 25% NaOH added to bring the pH to about 10.  This phase was
extracted with 3x150 mL CH2Cl2, and the pooled extracts were stripped
of solvent under vacuum.  The residual oil (4.8 g, amber in color) was
dissolved in 300 mL anhydrous Et2O which, upon saturation with
anhydrous HCl gas gave a clear solution that suddenly deposited white
crystals.  The hydrochloride salt of
6-(2-aminopropyl)-5-methoxy-2-methyl-2,3-dihydrobenzofuran weighed 2.3
g and was not satisfactory as a solid derivative, but it appears that
the oxalate salt is both nonhygroscopic and quite stable.  It (F-2)
had a mp of 216-218 !C and it displayed a textbook NMR.

DOSAGE: greater than 15 mg.

DURATION: unknown.

EXTENSIONS AND COMMENTARY: This material, which is certainly a mixture
of two diastereoisomeric pairs of racemates since there are two chiral
centers present, showed no effects at levels of up to 15 milligrams
orally.  Doses of 100 mg/Kg were without effects in mice following
i.p. injections, although half again this amount proved to be lethal.
In rats trained to discriminate LSD from saline, F-2 proved to be
about 40 times less potent than the reference compound DOM, requiring
some 5 mg/Kg for positive responses.  But the human trials were only
up to about 0.2 mg/Kg.

This was the prototype compound that was originally put together to
justify giving a paper at a marijuana conference in Sweden, in 1968.
Although I had never done much with marijuana or with its principal
ingredients, I thought maybe I could bend the topic a bit to embrace
some potentially active phenethylamines.  There is a story of an
international conference held in Geneva a few years earlier to discuss
the worrisome decrease in the elephant population.  A German zoologist
invested a full eight-hour day in a summary of his 21 volume treatise
on the anatomy and the physiology of the elephant.  A French
sociologist presented a lively slide show on the mating rituals and
rutting behavior of the elephant.  And a rabbi from Tel Aviv entitled
his talk: RElephants and the Jewish Problem.S My Swedish talk should
have been named RMarijuana and the Psychedelic Amphetamines.S The
memorable story of meeting the chief of the Swedish equivalent of the
Bureau of Narcotics, and ending up playing Mozart sonatas in the attic
of his home, has been spun out elsewhere in the book.

The original concept was a grand plan to imitate two of the three
rings of tetrahydrocannabinol.  There is an aromatic ring (with an
alkyl group and two oxygens on it) and it is fused to a pyran ring
with a couple of methyl groups on it.  So, if one were to tie the
methyl group at the 4-position of DOM around with a short carbon chain
into the oxygen atom at the five position, one could squint and say
that the resulting amphetamine was kinda something like an analogue of
THC.  Thus, the resulting six-membered ring (a pyran) or five-membered
ring (a furan) could be peppered with methyl groups at different
locations (and up to two per location).  If the ring was a
five-membered structure, then the parent system would be a benzofuran,
and the location of methyl groups on the ring would be indicated by
the appropriate numbers following the letter RFS which would stand for
RfuranS.  And if it were to be a six-membered ring, the resulting
benzopyran would be indicated with a RPS for pyran, and again the
methyl group or groups would be indicated by the substitution
position.  This code would cover all polymethylated homologues with
codes that would look like F-22 and P-2234.  If any of them showed up
with fascinating activities, I would extend methyls to ethyls, and
work out some whole new naming code at some future time.  An early
system, naming this compound 2-M for a methyl group on the 2-position
of the furan ring, was abandoned when it became apparent that the
pyran world would screw everything up.

The isolation of characterizable quantities of
7-formyl-5-methoxy-2-methyl-2,3-dihydrobenzofuran from the
benzaldehyde recipe above gave a fleeting fantasy of a whole new
direction that this little project might go.  If this unexpected
benzaldehyde were to be converted to the corresponding amphetamine,
one would have
7-(2-aminopropyl)-5-methoxy-2-methyl-2,3-dihydrobenzofuran.  Suddenly
here would be a 2,3,5-trisubstituted thing with a ring at the
2,3-position, similar to the still unmade MMDA-4.  The temptation to
be diverted in this way lasted, fortunately, only a few minutes, and
the project was shelved.  Someday, when there are buckets of spare
time or hosts of eager graduate students, some fascinating chemistry
might lie this way, and maybe some fascinating pharmacology, even.

The plain furan analogue, without any methyl groups on it, has been
made.  Five-methoxybenzofuran formed the 6-formyl derivative (the
aldehyde) with a mp of 79-80 !C and from it the nitrostyrene (orange
needles, mp 89-91 !C) and the final amphetamine (white solids, as the
methane sulfonate, mp 141-144 !C) were prepared in a manner similar to
the preparation of F-2 above.  In the rat studies, it was three times
more potent than F-2, but still some 15 times less potent than DOM.
And in initial human trials (of up to 30 milligrams) there were again
no effects noted.  Naming of this material is easy chemically
(6-(2-aminopropyl)-5-methoxy-2,3-dihydrobenzofuran) but tricky as to
code.  If the numbers that follow the RFS give the location of the
methyl groups, then this material, without any such groups, can have
no numbers following, and should properly be simply RF.S OK, it is
RF.S The preparation or the attempted preparations of other homologues
such as F-23 and F-233 are outlined under the recipe for F-22.









#80 F-22;
6-(2-AMINOPROPYL)-2,2-DIMETHYL-5-METHOXY-2,3-DIHYDROBENZOFURAN

SYNTHESIS: To a solution of 43.2 g flaked KOH in 250 mL hot EtOH there
was added 96 g 4-methoxyphenol followed by 90 g 2-methylallyl chloride
over the course of 2 h.  The mixture was held at reflux for 24 h, then
added to 1.6 L H2O.  There was sufficient 25% NaOH added to make the
phase strongly basic, and this was then extracted with 3x200 mL
CH2Cl2.  The pooled extracts were washed with H2O, and the solvent
removed under vacuum.  The residue, 125 g of a pale amber oil, was
crude 4-(2-methylallyloxy)anisole and was used without further
purification in the following reaction.

In a round-bottomed flask containing an internal thermometer, there
was placed 125 g of unpurified 4-(2-methylallyloxy)anisole, and this
was heated with an open flame.  At an internal temperature of 190 !C
an exothermic reaction set in, raising the temperature to 250 !C,
where it was held for an additional 2 min.  After the reaction mixture
had cooled to room temperature, it was poured into 500 mL H2O, made
strongly basic with 25% NaOH, and extracted repeatedly with 100 mL
portions of CH2Cl2 until the extracts were essentially colorless.
These extracts were pooled and the solvent removed to provide 80.0 g
of a deeply colored oil that proved to be largely the appropriately
substituted dihydrobenzofuran.  The aqueous residue from above was
acidified with concentrated HCl, and again extracted with CH2Cl2.
Removal of the solvent gave 17.7 g of
4-methoxy-2-(2-methylallyl)phenol as an amber oil which eventually set
down as white crystals with a mp of 52.5-54 !C.

A solution of 17 g of 4-methoxy-2-(2-methylallyl)phenol in 56 g acetic
acid was treated with 8.4 g zinc chloride followed with 28 mL
concentrated HCl.  This mixture was heated at reflux temperature with
a mantle for 1 h.  After cooling, this was poured into H2O and
extracted with 2x150 mL CH2Cl2.  The pooled extracts were washed with
several portions of 8% NaOH, until the extracts were colorless.  The
organic fraction was then washed with H2O, and the solvent removed to
yield 5.8 g of 2,2-dimethyl-5-methoxy-2,3-dihydrobenzofuran as a pale
amber oil with a pungent smell.  This was purified by distillation,
giving a fraction of an off-white oil with a bp of 136-138 !C at 33
mm/Hg.

To a mixture of 8.0 g N-methylformanilide and 9.2 g POCl3 which had
been allowed to stand for 0.5 h, there was added 4.0 g
2,2-dimethyl-5-methoxy-2,3-dihydrobenzofuran, and the mixture held at
the steam bath temperature for 2.5 h.  This was then poured into 200
mL H2O which produced a black oily phase that gave no hint of
crystallization.  This mixture was extracted with 3x150 mL CH2Cl2 and
the solvent was removed from the pooled extracts under vacuum.  The
residual oil (which was shown by GC to contain approximately equal
quantities of two isomeric benzaldehydes A and B) was extracted with
three 75 mL portions of boiling hexane, each of which on cooling
deposited a reddish oil that partially crystallized.  A fourth hexane
extract gave nothing more.  The solvent was decanted from these three
extracts, and the semi-solid residues were ground under 3.0 mL MeOH
giving 1.4 g of pale yellow crystals of
2,2-dimethyl-6-formyl-5-methoxy-2,3-dihydrobenzo-furan, isomer RBS.
After recrystallization from MeOH, the color was almost white, and the
mp was 79.5-80.5 !C.  The combined mother liquors were enriched in
isomer RAS which proved, following preparative GC separation and NMR
analysis, to be the 7-formyl isomer.  The 80 g of impure
dihydrobenzofuran isolated from the Claisen rearrangement above was
distilled and a fraction (43.8 g) that boiled from 138-153 !C at 30
mm/Hg was processed as described here to the aldehyde mixture.
Following similar hexane extractions, a yield of 4.0 g of a 95% pure
isomer RBS was finally obtained.  The remaining components of this
fraction were not determined, but it is possible that there were some
that contained the six-membered benzopyran ring system.

To a solution of 5.2 g of
2,2-dimethyl-6-formyl-5-methoxy-2,3-dihydro-benzofuran in 20 mL
glacial acetic acid there was added 3 mL nitroethane followed by 1.6 g
anhydrous ammonium acetate.  This mixture was heated for 4 h on the
steam bath, and then a small amount of H2O was added to the hot
solution.  This instigated the formation of a copious deposition of
brick-red crystals which were, after cooling, removed by filtration,
and recrystallized from 50 mL boiling MeOH.  After air drying there
was thus obtained 2.7 g of day-glo yum-yum orange crystals of
2,2-dimethyl-5-methoxy-6-(2-nitro-1-propenyl)-2,3-dihydrobenzofuran.
An additional 0.6 g of product was obtained by working the mother
liquors.

A suspension of 2.5 g LAH in 300 mL refluxing anhydrous Et2O was
treated with a solution of 3.1 g
2,2-dimethyl-5-methoxy-6-(2-nitro-1-propenyl)-2,3-dihydrobenzofuran in
Et2O.  The mixture was held at reflux temperature for 18 h.  After
cooling, the excess hydride was destroyed by the cautious addition of
400 mL H2O which contained 15 g H2SO4.  The aqueous phase was
separated, washed once with Et2O, and then once with CH2Cl2.  There
was then added 60 g potassium sodium tartrate, and the pH was brought
to above 10 by the addition of 25% NaOH.  This was extracted with
3x250 mL CH2Cl2, the extracts pooled, and the solvent removed under
vacuum.  There remained 2.8 g of an amber oil with an ammoniacal
smell.  This was dissolved in 200 mL anhydrous Et2O, and saturated
with anhydrous HCl gas.  There was the immediate formation of an oil,
from which the supernatent Et2O was decanted.  The residual oil was
resuspended in a second 200 mL anhydrous Et2O, again decanted, and
finally a third 200 mL Et2O effected the dissolving of the remaining
oil to give a clear solution.  All three solutions became gelatinous
over the following few h, and each deposited a crop of white crystals
over the following few days.  From the first there was obtained 1.4 g
of product with a mp of 153-154 !C; from the second, 0.2 g with a mp
of 153-154 !C; and from the third, 1.2 g with a mp of 155-156 !C.
These crops were combined, and recrystallized from 10 mL of boiling
CH3CN to give 1.7 g
6-(2-aminopropyl)-2,2-dimethyl-5-methoxy-2,3-dihydrobenzofuran
hydrochloride (F-22) as a white crystalline solid which had a mp of
154-155 !C.  This material, even when dry, showed a tendency to
discolor with time.

DOSAGE: greater than 15 mg.

DURATION: unknown.

EXTENSIONS AND COMMENTARY: And here is yet another dihydrobenzofuran
which is not of a very high potency if, indeed, it is active at all.
This particular dihydrobenzofuran analogue, F-22, had sort of tickled
my fancy as being an especially good candidate for activity.  It had a
certain swing to it.  F-22, like LSD-25.  And here it was finished,
just five days before I had to deliver a paper concerning the
syntheses (and activities!) of all these dihydrobenzofurans to the
marijuana congress.  Could this possibly be another LSD?  I was
sufficiently convinced that the possibility was real, that I actually
started the screening process at a most unusually low level of 10
micrograms.  Two days later, I upped this to a dose of 25 micrograms
(no activity again) and three days after that, at 1 AM on the polar
flight to Copenhagen, I swallowed the RmonstrousS dose of 50
micrograms.  Shoot the works.  If I were to blossom all over the
tourist section of the SAS plane, well, it would be quite a paper to
give.  If not, I could always say something like, RThe active level
has not yet been found.S No activity.  Another Walter Mitty fantasy
down the tubes.

And, as it turned out, the entire project pretty much ran out of
steam.  A number of clever analogs had been started, and would have
been pursued if there had been any activity promised of any kind with
any of these dihydrobenzofurans.  The RotherS benzaldehyde described
above, could have been run in a manner parallel to that proposed for
the counterpart with F-2, to make the eventual amphetamine,
7-(2-aminopropyl)-2,2-dimethyl-5-methoxy-2,3-dihydrobenzofuran.  Great
strides had been made towards F-233 (I have discussed the naming
system under F-2, with the F standing for the furan of benzofuran and
the 2 and 3 and 3 being the positions of the methyl groups on it).
The reaction of 4-methoxyphenol with 1-chloro-3-methyl-2-butene gave
the ether which underwent the thermal Claisen rearrangement to
2-(1,1-dimethylallyl)-4-methoxyphenol with a bp of 148-157 !C at 30
mm/Hg.  This was cyclized to the intermediate cycle
2,3,3-trimethyl-2,3-dihydrobenzofuran which, after distillation, was
shown to be only 80% pure by GC analysis.  This was, nonetheless, (and
with the hope that is in the very fiber of a young innocent chemist),
pushed on to the benzaldehyde stage (and there were a
not-too-surprising four benzaldehydes to be found in the oil that was
produced, which refused to crystallize).  And then (when sheer
desperation replaced hope) these were condensed with nitroethane to
form an even worse mixture.  Maybe something might crystallize from
it?  Nothing ever did.  Junk.  Everything was simply put on the shelf
where it still rests today, and F-233,
6-(2-aminopropyl)-5-methoxy-2,3,3-trimethyl-2,3-dihydrobenzofuran,
remains the stuff of speculation.

And a start towards F-23,
6-(2-aminopropyl)-2,3-dimethyl-5-methoxy-2,3-dihydrobenzofuran, got
just as far as the starting ether, when it occurred to me that the
final product would have an unprecedented three chiral centers, and so
a total of four racemic pairs of diastereoisomers.  And then I
discovered that the starting allyl halide, crotyl chloride, was only
80% pure, with the remaining 20% being 3-chloro-1-butene.  This would
have eventually produced a 2-ethyl-analogue,
6-(2-aminopropyl)-2-ethyl-5-methoxy-2,3-dihydrobenzofuran, with its
two chiral centers and two more pairs of stereoisomers (not to speak
of the need to devise an entirely new coding system).  Unless
something were to fall into my lap as a crystalline intermediate, the
final mess could have had at least six discreet compounds in it, not
even considering optical isomers.  And I havenUt even begun to think
of making the six-membered dihydrobenzopyrans which were the THC
analogues that presented the rationale that started the whole project
in the first place.  A recent issue of the Journal of Medicinal
Chemistry has just presented an article describing the reaction of
6-methoxytetrahydrobenzopyran with dichloromethyl methyl ether, and
approximately equal amounts of all three of the possible isomers were
obtained.  That would have been the first step towards making the
prototypic compound 7-(2-aminopropyl)
6-methoxy-1,2,3,4-tetrahydrobenzopyran.  Just as the benzofurans were
all named as F-compounds, this, as a benzopyran, would have been a P
compound, but P also is used for proscaline, and there would have been
some repair-work needed for these codes.

Time to abandon ship.  The fact that I had just synthesized and
discovered the strange activity of ARIADNE at about this time, made
the ship abandonment quite a bit easier to accept.









#81 FLEA; N-HYDROXY-N-METHYL-3,4-METHYLENEDIOXYAMPHETAMINE

SYNTHESIS: (from 3,4-methylenedioxyphenylacetone) A solution of 2.1 g
N-methylhydroxylamine hydrochloride and 4.4 g
3,4-methylenedioxyphenylacetone in 5.5 mL MeOH was added to a
suspension of 4.5 g NaHCO3 in 30 mL boiling MeOH.  There was added
about 5 mL H2O (which gave a clear solution) followed by another 50 mL
H2O which produced a pale yellow color.  To this solution of the
unisolated nitrone there was added 1.7 g sodium cyanoborohydride,
which generated a goodly amount of foaming.  There was HCl added as
needed to maintain the pH at about neutrality.  The reaction appeared
to have stopped after a day or two, so all was poured into 500 mL H2O,
acidified with HCl, and washed with 2x75 mL CH2Cl2.  The addition of
base brought the pH >9, and this was then extracted with 3x75 mL
CH2Cl2.  Removal of the solvent from the pooled extracts gave a
residue of 1.65 g of crude
N-hydroxy-N-methyl-3,4-methylenedioxyamphetamine.  Efforts to obtain
solid seed samples of the salts with hydrochloric acid, perchloric
acid, sulfuric acid, phosphoric acid, and with a number of organic
acids, all failed.  The salt formation from this free-base will be
discussed below.

(from MDOH) A solution of 0.75 g crystalline free-base MDOH in a few
mL MeOH was treated with a solution of 0.4 g sodium cyanoborohydride
in 10 mL MeOH, and there was then added 2 mL of 35% formaldehyde.  The
stirred reaction mixture was kept at a neutral pH with the occasional
addition of HCl.  After several days (when additional acid was no
longer required) the excess solvent was removed under vacuum, and the
residue poured into dilute H2SO4.  This was washed with 2x75 mL CH2Cl2
and then, following the addition of base, this was extracted with 3x75
mL CH2Cl2.  Removal of the solvent from the pooled extracts gave a
viscous oil residue of 0.53 g.  The free-base product from these
preparations was distilled at 110-120 !C at 0.2 mm/Hg to give the
N-hydroxy-N-methyl product as a white oil.  An alternate methylation
procedure used a solution of MDOH in a 4:1 MeOH/acetic acid solution
containing formaldehyde which was reduced with sodium borohydride at
dry ice temperatures.  Its work-up is identical to that involving
sodium cyanoborohydride.

The distilled product was dissolved in an equal volume of MeOH, and
treated with a half-equivalent of oxalic acid dihydrate, dissolved in
10 volumes of MeOH.  This combination gave the slow deposition of
crystals of the full oxalate salt (one acid, two bases) as a white
crystalline product.  The mp of the crude salt was in the 130-150 !C
range, and after recrystallization from CH3CN,
N-hydroxy-N-methyl-3,4-methylenedioxyamphetamine oxalate (FLEA) had a
mp of 146-147 !C.

DOSAGE: 100 - 160 mg.

DURATION: 4 - 8 h.

QUALITATIVE COMMENTS: (with 90 mg) The material tastes terrible, like
grapefruit juice that has stayed in the can too long.  There was no
nausea, no feeling of difficulty in swallowing at any time during the
day.  I felt a dry mouth and was thirsty Q sipped water throughout the
day.  At the beginning of the experiment, there was a glimmer of the
MDMA warmth, but later I felt separated and a bit isolated.  I was
just floating around, seeing the beauty of colors and objects in the
house and outdoors and listening first to this conversation, then to
that one.  All senses seemed enhanced.  I found the material pleasant.
I was happy with the amount I took but would not be afraid to take
more or to take a supplement.  I found it similar to, but not the same
as, MDMA.

(with 110 mg) We found this very similar to MDMA, but perhaps
slightly slower.  I plateauUd at 2:30 hours and had a very gradual
descent.  My friend had a marvelous and private 'cone of silence' that
was to him unique to MDMA or to 2C-T-8.  Teeth problems were minor,
and the descent from the top of the experience showed less
interactive, and more contemplative action, than with MDMA.  Very
similar to MDMA, but with its own character.

(with 110 mg) The onset was at about a half-hour.  The come-on was
more gradual and much easier than with MDMA, and it seemed to be more
head than body oriented.  I had about two hours of very complex and
personal self-evaluation, and I am not at peace in putting all of it
down here in writing.  Overall I like it, and I would be interested to
see if there's a difference in conjunction with MDMA.  Thanks very
much.

(with 110 mg + 35 mg) I saw my onset at 20 minutes, and it was
subtle, and very pleasant, and had a mild amphetamine-like elevation
for me (body lightness, cognitive functions seemed clear and clean,
heightened visual awareness and with some enhancement of color).  It
seemed as if I were on the fringe of LSD-like visual changes, but that
never materialized.  The affect was very good, communicative,
friendly, accepting, but without the profound emotional bonding of
MDMA.  The following day felt very much like a post-LSD day; we felt
great.  The body was light, energy good, emotions high, several
insights throughout the day, interactions clear and open Q a
magnificent gift of a day.  I started a menstrual period the day of
the experience and it lasted 6 to 7 days; all of this was a couple of
weeks early.  I have a very favorable impression of FLEA although the
body penalty seems high.

EXTENSIONS AND COMMENTARY: Most people who were involved with the
evaluation of FLEA quite logically compared it with MDMA, as it was
presented as being a very close analogue which might share some of the
latter's properties.  And to a large measure, the comparison was
favorable.  The dosages are almost identical, the chronological course
of action is almost identical, and there are distinct similarities in
the effects that are produced.  If there is a consensus of
similarities and differences it would be that it is not quite as
enabling in allowing a closeness to be established with others.  And
perhaps there is more of a move towards introspection.  And perhaps a
slightly increased degree of discoordination in the thought processes.
But also, part of this same consensus was that, were MDMA unknown,
this material would have played its role completely.

And from the scientific point of view, it lends more weight to a
hypothesis that just might be a tremendous research tool in
pharmacology.  I first observed the intimate connection between an
amine and a hydroxylamine with the discovery that N-hydroxy-MDA (MDOH)
was equipotent and of virtually identical activity to the
non-hydroxylated counterpart (MDA).  And I have speculated in the
recipe for MDOH about the possible biological interconversions of
these kinds of compounds.  And here, the simple addition of a hydroxyl
group to the amine nitrogen atom of MDMA produces a new drug that is
in most of its properties identical to MDMA.  The concept has been
extended to 2C-T-2, 2C-T-7, and 2C-T-17, where each of these three
active compounds was structurally modified in exactly this way, by the
addition of a hydroxyl group to the amine nitrogen atom.  The results,
HOT-2, HOT-7 and HOT-17 were themselves all active, and compared very
closely with their non-hydroxylated prototypes.

Just how general might this concept be, that an N-hydroxyl analog of
an active amine shall be of similar action and duration as the parent
drug?  What if it really were a generality!  What havoc it would wreak
in the pharmaceutical industry!  If I could patent the concept, then I
would be able to make parallel best sellers to all of the primary and
secondary amines out there in the industry.  Perhaps 90% of all the
commercially available drugs that are concerned with the human mental
state are amines.  And a goodly number of these are primary or
secondary amines.  And each and every one of these could be converted
to its N-hydroxyl analogue, effectively by-passing the patent
protection that the originating corporation so carefully crafted.  An
example, just for fun.  A run-away best seller right now is an
antidepressant called fluoxetine, with the trade name Prozac.  I will
make a small wager that if I were to synthesize and taste
N-hydroxy-N-methyl-3-phenyl-3-((a,a,a-trifluoro-p-tolyl)oxy)propylamine,
I would find it to be an active antidepressant.  Remember, Mr. Eli
Lilly and Company; you read about it first, right here!

Of course, I was asked, why call it FLEA?  The origin was in a classic
bit of poetry.  A commonly used code name for MDMA was ADAM, and I had
tried making several modest modifications of the MDMA structure in the
search for another compound that would maintain its particular music
without the annoying tooth-grinding and occasional nystagmus, or
eye-wiggle, that some users have mentioned.  One of these was the
6-methyl homologue which was, with some perverse logic, called MADAM.
And, following this pattern, the 6-fluoroanalogue was to be FLADAM.
So, with the N-hydroxy analogue, what about HADAM?  Which brought to
mind the classic description of Adam's earliest complaint, an
infestation of fleas.  The poem was short and direct.  RAdam had Uem.
So, in place of HAD UEM, the term FLEA jumped into being.









#82 G-3; 2,5-DIMETHOXY-3,4-(TRIMETHYLENE)AMPHETAMINE;

5-(2-AMINOPROPYL)-4,7-DIMETHOXYINDANE

SYNTHESIS: A solution of 3.7 g of
2,5-dimethoxy-3,4-(trimethylene)benzaldehyde (see preparation under
2C-G-3) in 15 mL nitroethane was treated with 0.7 g anhydrous ammonium
acetate and heated on the steam bath for 2.5 h.  The excess solvent
was removed under vacuum leaving some 5 mL of a deep orange-red oil
which on cooling, spontaneously crystallized.  This was finely ground
under 10 mL MeOH, filtered, washed sparingly with MeOH, and air dried
to give 3.6 g of orange crystals with a strong smell of old acetamide.
The mp was 92-93 !C.  All was recrystallized from 30 mL boiling MeOH
to give, after filtering and drying, 2.9 g of
1-(2,5-dimethoxy-3,4-(trimethylene)phenyl)-2-nitropropene as yellow
crystals with a mp of 93-94 !C.  Anal. (C14H17NO4) C,H,N.

Fifty milliliters of 1 M LAH in THF was placed in an inert atmosphere,
well stirred, and cooled to 0 !C with an external ice-bath.  There was
added, dropwise, 1.35 mL of 100% H2SO4 at a rate slow enough to
minimize charring.  There was then added, dropwise, 2.8 g
1-(2,5-dimethoxy-3,4-(trimethylene)phenyl)-2-nitropropene in 15 mL
THF.  At the end of the addition, the stirring was continued for an
additional 0.5 h, and then the reaction mixture was held at reflux on
the steam bath for another 0.5 h.  After cooling again to ice-bath
temperature, the excess hydride was destroyed with the addition of 11
mL IPA, followed by 5.5 mL 5% NaOH which converted the inorganic mass
through a cottage cheese stage into a loose, filterable texture.  The
solids were removed by filtration, washed with additional THF, and the
combined filtrates and washes stripped of solvent under vacuum.  There
was obtained 2.51 g of a white oil that was distilled at 115-135 !C at
0.2 mm/Hg to give 1.83 g of a clear colorless oil.  This was dissolved
in 8 mL IPA, neutralized with 28 drops of concentrated HCl, and
diluted with 140 mL anhydrous Et2O.  In about 0.5 h there started a
slow snowfall of fine fluffy white crystals which was allowed to
continue until no additional crystals appeared.  After filtering, Et2O
washing and air drying, there was obtained 1.81 g of
2,5-dimethoxy-3,4-(trimethylene)amphetamine hydrochloride (G-3) with a
mp of 157-159 !C.  Anal. (C14H22ClNO2) C,H.

DOSAGE: 12 - 18 mg.

DURATION: 8 - 12 h.

QUALITATIVE COMMENTS: (with 12 mg) There was a warmth, a mellowness,
as things developed.  No body disturbance at all, but then there were
no visuals either which, for me on this particular occasion, was
disappointing.  The day was consumed in reading, and I identified
completely with the character of my fictional hero.  It was a
different form of fantasy.  I think I prefer music as a structural
basis for fantasy.

(with 18 mg) I am at a plus three, but I am not at all sure of why it
is a plus three.  With my eyes closed, there are puffy clouds, but no
drama at all.  Music was not exciting.  There could well have been
easy eroticism, but there was no push in that direction.  No great
amount of appetite.  Not much of anything, and still a plus three.
Simply lying still and surveying the body rather than the visual scene
gave some suggestions of neurological sensitivity, but with getting up
and moving about and doing things, all was fine.  The next morning I
was perhaps moving a bit more slowly than usual.  I am not sure that
there would be reward in going higher.

EXTENSIONS AND COMMENTARY: In a comparison between the 2-carbon
compound (2C-G-3) and the 3-carbon compound (G-3) the vote goes
towards the phenethylamine (the 2-carbon compound).  With the first
member of this series (2C-G versus GANESHA) this was a stand-off, both
as to quantitative effects (potency) and qualitative effects (nature
of activity).  Here, with the somewhat bulkier group located at the
definitive 3,4-positions, the nod is to the shorter chain, for the
first time ever.  The potency differences are small, and maybe the
amphetamine is still a bit more potent.  But there are hints of
discomfort with this latter compound that seem to be absent with the
phenethylamine.  The more highly substituted compounds (q.v.) more
clearly define these differences.









#83 G-4; 2,5-DIMETHOXY-3,4-(TETRAMETHYLENE)AMPHETAMINE;
6-(2-AMINOPROPYL)-5,8-DIMETHOXYTETRALIN

SYNTHESIS: A solution of
1,4-dimethoxy-5,6,7,8-tetrahydro-'-naphthaldehyde (see preparation
under 2C-G-4) in 20 mL nitroethane was treated with 0.13 g anhydrous
ammonium acetate and heated on the steam bath overnight.  The
volatiles were removed under vacuum and the residue, on cooling,
spontaneously crystallized.  This crude rust-colored product (1.98 g)
was recrystallized from 15 mL boiling MeOH yielding, after filtering
and air drying to constant weight, 1.33 g of
1-(2,5-dimethoxy-3,4-(tetramethylene)phenyl)-2-nitropropene as dull
gold-colored crystals.  The mp was 94-94.5 !C.  Anal. (C15H19NO4) C,H.

DOSAGE: unknown.

DURATION: unknown.

EXTENSIONS AND COMMENTARY: The discussion that appeared in the
commentary section under 2C-G-4 applies here as well.  The major
struggles were in the preparation of the aldehyde itself.  And
although the final product has not yet been made, this last synthetic
step should be, as Bobby Fischer once said in his analysis of a
master's chess game following a blunder by his opponent, simply a
matter of technique.

As with the phenethylamine counterpart, G-4 has a structure that lies
intermediate between G-3 and G-5, both potent compounds.  It is
axiomatic that it too will be a potent thing, and all that now needs
be done is to complete its synthesis and taste it.









#84 G-5; 3,6-DIMETHOXY-4-(2-AMINOPROPYL)BENZONORBORNANE

SYNTHESIS: A solution of 3.70 g 3,6-dimethoxy-4-formylbenzonorbornane
(see under 2C-G-5 for its preparation) in 20 g nitroethane was treated
with 0.88 g anhydrous ammonium acetate and held at steam bath
temperature overnight.  The excess solvent and reagent was removed
under vacuum to yield a residual yellow oil.  This was allowed to
stand at ambient temperature for a period of time (about 3 years) by
which time there was a spontaneous crystallization.  The dull yellow
crystals were removed by filtration and, after air drying, weighed
4.28 g.  A small sample was recrystallized repeatedly from MeOH to
provide a pale yellow analytical sample of
3,6-dimethoxy-4-(2-nitropropenyl)benzonorbornane with a mp of 90-91
!C.  Anal. (C16H19NO4) C,H.

A solution of LAH (50 mL of 1 M solution in THF) was cooled, under He,
to 0 !C with an external ice bath.  With good stirring there was added
1.32 mL 100% H2SO4 dropwise, to minimize charring.  This was followed
by the addition of 4.1 g
3,6-dimethoxy-4-(2-nitropropenyl)benzonorbornane in 20 mL anhydrous
THF over the course of 10 min.  The reaction mixture was stirred and
brought to room temperature over the course of 1 h.  This was then
brought to a gentle reflux on the steam bath for 0.5 h, and then all
was cooled again to 0 !C.  The excess hydride was destroyed by the
cautious addition of 10 mL IPA followed by 5 mL 5% NaOH and sufficient
H2O to give a white granular character to the oxides.  The reaction
mixture was filtered, and the filter cake washed with THF.  The
filtrate was stripped of solvent under vacuum providing a pale amber
oil that was distilled at 125-140 !C at 0.2 mm/Hg to give 2.5 g of an
almost white oil.  This was dissolved in 10 mL IPA, neutralized with
25 drops of concentrated HCl, and then diluted with 140 mL anhydrous
Et2O.  There appeared, after about two minutes, white crystals of
3,6-dimethoxy-4-(2-aminopropyl)benzonorbornane hydrochloride (G-5)
which, after filtration and air drying, weighed 2.47 g.

DOSAGE: 14 - 20 mg.

DURATION: 16 - 30 h.

QUALITATIVE COMMENTS: (with 15 mg) As part of the audience at the San
Francisco conference, Angels, Aliens and Archtypes, I could simply
listen and observe without having to participate.  Each speaker stood
in a cone of light that was beautifully bright and colorful, casting
everything else on the stage into obscurity.  Maybe angels really are
illuminated from above, and the aliens lurk out of sight until it is
their turn.  Where does one look for the archetypes?  A half of a
cream cheese sandwich was all I could eat, and even at dinner that
evening I was not hungry.  Sleep that evening was difficult.

(with 20 mg) Very slow to come on, but then it was up there all of a
sudden.  There is an unexpected absence of visual activity despite
being at a full +++.  The mental activity is excellent, with easy
writing and a positive flow of ideas.  But an absence of the bells and
whistles that are expected with a psychedelic in full bloom.  There is
a real drop by the 16th hour and the next day was free of effect
except for occasional cat-naps.

(with 20 mg) The transition period, which usually lasts for most
compounds for the first hour or two, with this seems to be much
longer.  This presages a long-acting material, as usually the slow-in
slow-out rule applies.  But there are exceptions.  There is an
indifference towards the erotic, but no separation at all from
personal interactions and emotions.  I believe in integration, not
separation of all parts of ourselves, distrusting any drug states
(particularly those that have the reputation of being strongly
Tcosmic)U which divorce the consciousness from the body.  And with
this material there is no separation from feelings, only from my
particular color language.

EXTENSIONS AND COMMENTARY: This is as potent as any of the
three-carbon Ganesha compounds, but it somehow lacks a little
something that would have made it a completely favorite winner.
Perhaps it is the generally commented upon absence of visual and
related sensory entertainment.  There seems to be no bodily threat to
discourage further exploration, but there simply was not the drive to
explore it much.  The comments concerning the enlargement of the ring
system (mentioned under 2C-G-5) are equally valid here.  The
RshrubberyS that is the hallmark of the Ganesha family is, with G-5,
about as bulky as has ever been put onto a centrally active molecule.
The norbornane group has a one carbon bridge and a two carbon bridge
sticking out of it at odd angles.  The replacement of the one-carbon
bridge with a second two-carbon bridge would make the compound G-6.
It would be makeable, but is there really a driving reason to do so?
There is a simplification intrinsic in this, in that G-5 actually has
two centers of asymmetry (the a-carbon atom on the amphetamine chain,
and the norbornyl area itself) and so it is really a mixture of two
racemic diastereoisomers.  G-6 would still be a racemate, but it would
be only a single compound, as are all the other substituted
amphetamine derivatives.

Someday I may try making G-6, but it's not a high priority right now.









#85 GANESHA; G; 2,5-DIMETHOXY-3,4-DIMETHYLAMPHETAMINE

SYNTHESIS: A solution of 15.4 g 2,5-dimethoxy-3,4-dimethylbenzaldehyde
(see under 2C-G for the preparation) in 50 mL nitroethane was treated
with 3 g anhydrous ammonium acetate and heated on the steam bath for
12 h.  The excess nitroethane was removed under vacuum, and the
residual oil was diluted with a equal volume of MeOH.  There was the
slow generation of deep red cottage-cheese-like crystals which were
removed by filtration and air-dried to constant weight (9.3 g) with a
mp 71-74 !C.  Recrystal-lization from MeOH (10 ml/g) gave an
analytical sample of
1-(2,5-dimethoxy-3,4-dimethylphenyl)-2-nitropropene with a mp of 82 !C
sharp.  Anal. (C13H17NO4) C,H,N.  The NMR spectra (in CDCl3) and CI
mass spectrograph (MH+ = 252) were proper.

To a suspension of 3.3 g LAH in 200 mL refluxing THF, well stirred and
maintained under an inert atmosphere, there was added 4.2 g
1-(2,5-dimethoxy-3,4-dimethylphenyl)-2-nitropropene in 25 mL THF.  The
mixture was held at reflux for 48 h.  After cooling, 3.3 mL H2O was
added cautiously to decompose the excess hydride, followed by 3.3 mL
15% NaOH and finally another 10 mL H2O.  The inorganic solids were
removed by filtration, and washed with additional THF.  The combined
filtrate and washes were stripped of solvent under vacuum, and the
residue (4.7 g of a deep amber oil) dissolved in dilute HCl.  This was
washed with CH2Cl2 (3x75 mL), then made basic with 5% NaOH and
extracted with CH2Cl2.  Removal of the solvent under vacuum yielded an
amber oil that was distilled (105-115 !C at 0.4 mm/Hg) to give 1.2 g
of a white oil.  This was dissolved in 8 mL IPA, neutralized with 15
drops of concentrated HCl, and diluted with 250 mL anhydrous Et2O.
After a period of time, there was a spontaneous appearance of white
crystals which were removed by filtration, Et2O washed, and air dried.
Thus was obtained 1.0 g of 2,5-dimethoxy-3,4-dimethylamphetamine
hydrochloride (GANESHA) with a mp of 168-169 !C.  This was not
improved by recrystallization from either EtOAc or nitroethane.  Anal.
(C13H22ClNO2) N.

DOSAGE: 20 - 32 mg.

DURATION: 18 - 24 h.

QUALITATIVE COMMENTS: (with 24 mg) There was a slow buildup to a ++
or more over the course of about three hours.  Extremely tranquil, and
no hint of any body toxicity whatsoever.  More than tranquil, I was
completely at peace, in a beautiful, benign, and placid place.  There
was something residual that extended into the sleep period, and was
possibly still there in the morning.  Probably I was simply tired from
an inadequate sleep.

(with 32 mg) A rapid and full development.  Lying down with music,
the eyes-closed visuals were quite something.  There was sudden
awareness of a potential toe cramp which I possibly exaggerated, but
it kept spinning itself into my awareness, and somehow locked in with
my visual imagery.  It was not easy to keep the visual/somatic/
cognitive worlds in their proper places.  The almost-cramp went away
and I forgot about it.  There was a back spasm somewhere in this
drama, and it really didnUt matter either.  This dosage may be a bit
much for good housekeeping, though!  Towards the end of the
experiment, I looked at a collection of photos from a recent trip to
Europe, and the visual enhancement was wonderful. A rolling +++.

EXTENSIONS AND COMMENTARY: This compound was the seventh of the ten
possible Classic Ladies.  I have mentioned the concept already under
the discussions on ARIADNE.  This is the teutonic replacement of each
of the distinguishable hydrogen atoms of DOM with a methyl group.  The
findings with GANESHA were a total surprise.  The extension of a
hydrogen in the 3-position of DOM with a methyl group should have a
minor influence on its steric association with whatever receptor site
might be involved.  A much greater impact might come not from the size
of the group but from its location.  This, coupled with a full order
of magnitude of decrease in potency, seemed to call for an involvement
of that particular position as being one that is affected by
metabolism.  And since the activity is decreased, the obvious role is
in the blocking of the metabolic promotion of DOM-like things to
active intermediates.

The remarkable point being emphasized here is that the placement of a
dull methyl group at a dull position of the DOM molecule actually
inactivated (for all intents and purposes) the activity of DOM.  It is
not the presence of the methyl that has decimated the potency, but the
removal of the hydrogen atom.

How can such a hypothesis be explored?  A historic premise of the
medicinal chemist is that if a structure gives an unusual response in
a receptor, vary it slightly and see how the response varies.  This is
exactly the principle that led to the ten Classic Ladies, and with
this particular Lady (who actually turned out to be a gentleman), the
same concept should hold.  There are two involved methyl groups in
GANESHA, one at the 3-position and one at the 4-position.  Why not
homologate each to an ethyl group, and as a wrap up make both of them
into ethyl groups.  Look at the differences along two lines of
variation; the effects of the homologation of the 3- and 4-positions,
coupled with the effects of the homologation intrinsic in the
comparison of the two-carbon chain of the phenethylamine with the
three-carbon chain of the amphetamine.

There are thus six compounds involved in such a study.  And they have
been named (as have all the other GANESHA analogues) in accordance
with the collective carbon inventory in and about these two ring
positions.  The first two compounds are related to DOET and to 2C-E.
Maintain the methyl group at the 3-position but homologate the
4-position to an ethyl.  The ring pattern would become
2,5-dimethoxy-4-ethyl-3-methyl, and the phenethylamine and amphetamine
would be called 2C-G-12 and G-12 respectively (a one carbon thing, the
methyl, at position-3 and a two carbon thing, an ethyl, at
position-4).  Reversal of these groups, the 3-ethyl homologues of 2C-D
and DOM would thus become 2C-G-21 and G-21.  And, finally, the diethyl
homologues would be 2C-G-22 and G-22.  In each of these cases, the
paired numbers give the lengths of the chains at the two positions,
the 3- and the 4-positions that are part of the GANESHA concept.  And
this code is easily expandable to longer things such as 2C-G-31 and
2C-G-41, which would be the 3-propyl-4-methyl, and the
3-butyl-4-methyl homologues, resp.

Unfortunately, these six initially proposed compounds have so far
resisted all logical approaches to synthesis, and are at present still
unknown.  What has been successfully achieved, the building up of a
big bulky hydrocarbon glob at these positions, has rather unexpectedly
led to a remarkable enhancement of potency.  As with all true
exploration into areas of the unknown, the deeper you get, the less
you understand.









#86 G-N; 1,4-DIMETHOXYNAPHTHYL-2-ISOPROPYLAMINE

SYNTHESIS: To a solution of 3.9 g 1,4-dimethoxy-2-naphthaldehyde (see
under 2C-G-N for the preparation) in 13.5 mL nitroethane there was
added 0.7 g anhydrous ammonium acetate, and the mixture heated on the
steam bath for 5 h.  The deep orange reaction mixture was stripped of
excess solvent under vacuum.  The residue was a red oil that, upon
dilution with two volumes MeOH, immediately set to orange crystals.
This crude product (mp 115-118 !C) was recrystallized from 70 mL EtOH
to yield, after filtering and air drying, 3.3 g of
1-(1,4-dimethoxy-2-naphthyl)-2-nitropropene as gold-orange crystals,
with a mp of 121-123 !C.  Recrystallization from MeOH gave a
gold-colored product with a mp of 119-120 !C.  Anal. (C15H15NO4)
C,H,N.

A solution of LAH (50 mL of 1 M solution in THF) was cooled, under He,
to 0 !C with an external ice-bath.  With good stirring there was added
1.32 mL 100% H2SO4 dropwise, to minimize charring.  This was followed
by the addition of 3.12 g 1-(1,4-dimethoxy-2-naphthyl)-2-nitropropene
in 40 mL anhydrous THF.  After stirring for 1 h, the temperature was
brought up to a gentle reflux on the steam bath for 0.5 h, and then
all was cooled again to 0 !C.  The excess hydride was destroyed by the
cautious addition of 16 mL IPA followed by 6 mL 5% NaOH to give a
white, filterable, granular character to the oxides, and to assure
that the reaction mixture was basic.  The reaction mixture was
filtered, and the filter cake washed with additional THF.  The
combined filtrate and washes were stripped of solvent under vacuum
providing 3.17 g of a deep amber oil.  Without any further
purification, this was distilled at 140-160 !C at 0.3 mm/Hg to give
1.25 g of a pale yellow oil.  This was dissolved in 8 mL IPA,
neutralized with 20 drops of concentrated HCl, and diluted with 60 mL
anhydrous Et2O which was the point at which the solution became
slightly turbid.  After a few min, fine white crystals began to form,
and these were eventually removed, washed with Et2O, and air dried to
provide 1.28 g 1,4-dimethoxynaphthyl-2-isopropylamine hydrochloride
(G-N) as the monohydrate salt.  The mp was 205-206 !C.  Even after 24
h drying at 100 !C under vacuum, the hydrate salt remained intact.
Anal.  (C15H20ClNO2aH2O) C,H.

DOSAGE: unknown.

DURATION: unknown,

EXTENTIONS AND COMMENTARY: The evaluation of this compound is not yet
complete.  An initial trial at the 2 milligram level showed neither
central action, nor toxicity.  It could be guessed from the activity
of the two-carbon counterpart, that an active level will be found in
the tens of milligrams area.  But, as of the moment, this level is not
known to anyone, anywhere, because no one has yet defined it.  And
when the potency is finally found out, the nature of the activity will
also have been found out, all the result of a magical interaction of a
virgin compound with a virgin psyche.  At the immediate moment, the
nature of G-N is not only unknown, it has not yet even been sculpted.
There can be no more exciting area of research than this, anywhere in
the sentient world.









#87 HOT-2; 2,5-DIMETHOXY-4-ETHYLTHIO-N-HYDROXYPHENETHYLAMINE

SYNTHESIS: A solution of 5.50 g
2,5-dimethoxy-4-ethylthio-'-nitrostyrene (see under 2C-T-2 for its
preparation) was made in 80 mL boiling anhydrous THF.  On cooling,
there was some separation of a fine crystalline phase, which was kept
dispersed by continuous stirring.  Under an inert atmosphere there was
added 3.5 mL of a 10 M borane dimethylsulfide complex, followed by 0.5
g sodium borohydride as a solid.  There was a slight exothermic
response, and the color slowly faded.  Stirring was continued for a
week.  There was then added 40 mL H2O and 20 mL concentrated HCl, and
the reaction mixture heated on the steam bath for 15 minutes, with the
THF at reflux.  After cooling again to room temperature, all was
poured into 1 L H2O and washed with 3x75 mL CH2Cl2, which removed all
of the color but little of the product.  The aqueous phase was made
basic with 25% NaOH, and extracted with 3x75 mL CH2Cl2.  The extracts
were pooled and the solvent removed under vacuum to give a residue of
3.88 g of an amber oil.  This was dissolved in 30 mL IPA, acidified
with concentrated HCL to a bright red on universal pH paper, and then
diluted with 200 mL anhydrous Et2O.  After a short period of time,
crystals started to form.  These were removed by filtration, washed
with Et2O, and air dried to constant weight.  Thus was obtained 2.86 g
2,5-dimethoxy-4-ethylthio-N-hydroxyphenethylamine hydrochloride
(HOT-2) as off-white crystals, with a melting point of 122 !C with
decomposition.  Anal. (C12H20ClNO3 S) H; C: calcd, 49.05; found,
50.15, 49.90.

DOSAGE: 10 - 18 mg.

DURATION: 6 - 10 h.

QUALITATIVE COMMENTS: (with 12 mg) Tastes OK.  Some activity noticed
in 30 minutes.  Very smooth rise with no body load for next two hours.
At that time I noted some visuals.  Very pleasant.  The bright spots
in the painting over the fireplace seemed to be moving backwards (as
if the clouds were moving in the painting).  Upon concentrating on any
item, there was perceptual movement with a little flowing aspect.  The
visuals were never all that strong, but could not be turned off during
the peak.  At hour three there was still some shimmering, and it was
hard to focus when reading.  Additionally, there was difficulty
concentrating (some mental confusion).  The material seemed to allow
erotic actions; there was no problem about obtaining an erection.  I
ate very well, some crazy dips, as well as a fabulous cake.  A very
gentle down trend and I became close to baseline by 6 or 7 PM.  I had
no trouble driving.  The dosage was good for me.  I did not want more
or less.

(with 12 mg) Comes on smoothly, nicely.  In 40 minutes I feel nice
euphoria, feel home again.  Then I begin to get uncomfortable
feelings.  Gets more and more uncomfortable, feel I am sitting on a
big problem.  Blood pressure, pulse, go up considerably.  Have hard
time communicating, lie down for a while, get insight that most
important thing for me to do is learn to listen, pay attention to what
is going on.  I do this the rest of the day, at first with
considerable difficulty, then easier and easier.  Discomfort stays
with me for several hours, and although I get more comfortable towards
the end of the day, I am never animated or euphoric.  I feel very
humbled, that I have a great deal to work out in my life.  The next
day I find myself very strong and empowered.  I see that all I have to
do is let things be as they are!  This feels marvelous, and a whole
new way to be Q much more relaxed, accepting, being in the moment.  No
more axes to grind.  I can be free.

(with 18 mg) I found myself with complete energy.  I was completely
centered with an absolute minimum of the dark edges that so often
appear as components of these experiences.  The ease of talking was
remarkable.  There was some blood-pressure run-up in the early part of
the day, but that quickly returned to normal.  I would repeat without
hesitation.

EXTENSIONS AND COMMENTARY: Again, a case of where the potency range of
the Rhot,S or hydroxylated compound (HOT-2, 10 to 18 milligrams) is
very similar to that of the non-hydroxylated prototype (2C-T-2, 12-25
milligrams).  It seems to be a well tolerated, and generally pleasant
material, with a mixture of sensory as well as insightful aspects.
Something for everyone.









#88 HOT-7; 2,5-DIMETHOXY-N-HYDROXY-4-(n)-PROPYLTHIOPHENETHYLAMINE

SYNTHESIS: A well-stirred solution of 1.77 g
2,5-dimethoxy-'-nitro-4-(n-propylthio)styrene (see under 2C-T-7 for
its preparation) in 20 mL anhydrous THF was placed in an He atmosphere
and treated with 1.5 mL of 10 M borane-dimethyl sulfide complex.  This
was followed by the addition of 0.2 g sodium borohydride, and the
stirring was continued at room temperature for a week.  The volatiles
were removed under vacuum, and the residue was treated with 20 mL
dilute HCl and heated on the steam bath for 30 min.  The cooled yellow
solution set up as solids.  The addition of H2O was followed by
sufficient K2CO3 to make the aqueous phase basic.  All efforts to work
with an acidified aqueous phase resulted in terrible emulsions.  The
basic phase was extracted with 3x75 mL CH2Cl2, and the pooled extracts
washed with H2O, then stripped of solvent under vacuum.  The residual
yellow oil was dissolved in 20 mL IPA, neutralized with 15 drops of
concentrated HCl, and then diluted with 50 mL anhydrous Et2O.  After a
few minutes stirring, a white crystalline solid separated.  This was
removed by filtration, washed with Et2O, and air dried to constant
weight to provide 0.83 g of
2,5-dimethoxy-N-hydroxy-4-(n)-propylthiophenethylamine hydrochloride
(HOT-7).

DOSAGE: 15 - 25 mg.

DURATION: 6 - 8 h.

QUALITATIVE COMMENTS: (with 15 mg) I am lightheaded, and maybe a
little tipsy.  I am well centered, but I donUt want to go outside and
meet people.  Shades of alcohol woozy.  The effects were going already
by the fifth hour and were gone by the seventh hour.  I would call it
smoothly stoning.

(with 22 mg) The transition into the effects was a bit difficult,
with a faint awareness in the tummy.  But by the second hour it was
quite psychedelic, and the body was not thought of again, except in
terms of sexual fooling around.  Very rich in eyes-closed imagery, and
very good for interpretive and conceptual thinking.  But the eyes-open
visuals were not as much as they might have been.  At the seventh
hour, drifted into an easy sleep.

(with 22 mg) The experience was very positive, but at each turn there
seemed to be a bit of sadness.  Was it a complete plus three
experience?  Not quite.  But it didnUt miss by much.  The erotic
explorations somehow just failed to knit by the thinnest of margins.
It was a truly almost-magnificent experience.

EXTENSIONS AND COMMENTARY: There is a working hypothesis that has been
growing in substance over the last few years in this strange and
marvelous area of psychedelic drugs.  It all was an outgrowth of the
rather remarkable coincidence that I had mentioned in the discussion
that followed MDOH.  There, an assay of what was thought to be MDOH
gave a measure of activity that was substantially identical to MDA,
and it was later found out that the material had decomposed to form
MDA.  So, MDA was in essence rediscovered.  But when the true, valid,
and undecomposed sample of MDOH was actually in hand, and assayed in
its own rights, it was found to have a potency that really was the
same as MDA.  So, the working hypothesis goes something like this:

AN N-HYDROXY AMINE HAS APPROXIMATELY THE SAME POTENCY AND THE SAME
ACTION AS ITS N-HYDROGEN COUNTERPART.

Maybe the N-hydroxy compound reduces to the N-H material in the body,
and the latter is the intrinsically active agent.  Maybe the N-H
material oxidizes to the N-hydroxy material in the body, and the
latter is the intrinsically active agent.  Either direction is
reasonable, and there is precedent for each.  The equivalence of MDA
and MDOH was the first suggestion of this.  And I have made a number
of NH vs. NOH challenges of this hypothesis.  The interesting 2C-T-X
series has provided a number of amines that are amenable to
N-hydroxylation, and this is the first of them.  And, after all, if
you put a hydroxy (HO) group on a thio material (T), you have a HOT
compound.

So, as far as nomenclature is concerned, the family of N-hydroxy
analogues of N-H amines is known as the HOT family.

How does HOT-7 compare with 2C-T-7?  They are almost identical.  The
same range of dose (centering on 20 milligrams) and if anything,
perhaps slightly less long lived.  Lets try some other N-hydroxys!



#89 HOT-17; 2,5-DIMETHOXY-4-(s)-BUTYLTHIO-N-HYDROXYPHENETHYLAMINE

SYNTHESIS: To a well-stirred solution of 6.08 g
2,5-dimethoxy-4-(s)-butylthio-'-nitrostyrene (see under 2C-T-17 for
its preparation) in 80 mL anhydrous THF under a He atmosphere, there
was added 3.5 mL 10 M borane dimethylsulfide complex, followed by 0.5
g of sodium borohydride.  As the stirring continued, the slightly
exothermic reaction slowly faded from bright yellow to pale yellow,
and eventually (after three days stirring) it was substantially
colorless.  There was then added 80 mL of 3 N HCl and the mixture
heated on the steam bath for 1 h, and then allowed to return to room
temperature.  An additional 600 mL H2O was added (there was a
combination of crystals and globby chunks in the aqueous phase) and
this was then extracted with 3x75 mL CH2Cl2.  The color went
completely into the organic phase.  This was washed with 2x50 mL
aqueous K2CO3, yielding a rusty-red colored CH2Cl2 solution, which on
removal of the solvent, yielded 4.5 g of a red oil.  A side effort to
make the sulfate salt at this stage with H2O and a little H2SO4,
indeed gave solids, but all of the color remained in the sulfate salt.
The red oil was dissolved in 45 mL IPA and neutralized with
concentrated HCl to bright red, not yellow, on universal pH paper.
The addition of 350 mL anhydrous Et2O instituted the slow
precipitation of white crystals.  After filtering and air drying,
there was obtained 1.32 g
2,5-dimethoxy-4-(s)-butylthio-N-hydroxyphenethylamine hydrochloride
(HOT-17).  The aqueous phase from above was just neutralized with 25%
NaOH (cloudy, slightly pink color) and then made basic with K2CO3 (the
color becomes green).  This was extracted with 3x75 mL CH2Cl2, the
extracts pooled, and the solvent removed to yield 0.5 g of a white
oil.  This was dissolved in 5 mL IPA, neutralized with concentrated
HCl, and diluted with a equal volume of Et2O.  An additional 0.36 g of
product was thus obtained.

DOSAGE: 70 - 120 mg.

DURATION : 12 - 18 h.

QUALITATIVE COMMENTS: (with 70 mg) There was a light feeling, a
little off-the-ground feeling, which made walking about a most
pleasant experience.  No distortion of the senses.  And there was no
sense of the beginning of a drop of any kind until about the eighth
hour.  Sleeping was a bit tricky but it worked out OK (at the twelfth
hour of the experience).  A completely valid ++.

(with 120 mg) HOT-17 has an unbelievably GRIM taste Q not bitter, but
simply evil.  There is a steady and inexorable climb for three hours
to a sound and rolling plus three.  There was absolutely no body
difficulty, but there was still something going on upstairs well into
the next day.  Writing was surprisingly easy; I was completely content
with the day, and would be interested in exploring it under a variety
of circumstances.

(with 120 mg) This is my first time with this material.  It is 4:45
PM.  Small nudge at 30 minutes, but not too real.  At one hour,
threshold, quite real.  6:15 to a +1.  By 7:25, +3 about.  7:45, no
doubt +3.  Possibly still climbing; I hope so.  No body discomfort at
all, no apparent body push.  This aspect of it is similar to the easy
body of the HOT-2.  However, it's at times like these that I reflect
on just exactly how hard-headed we two are.  I mean, +3 is no longer
the out-of-body, nearly loss of center state it used to be, four years
ago.  The question intrudes: would a novice experience this as a very
scary, ego-disintegrating kind of experiment, or not?  Silly question
which answers itself.  Yes, of course.  At 3 hours, aware of some mild
time-distortion.  More a tendency to not think in terms of clock-time,
than actual distortion.  The mind lazy when attempting to keep track
of clock time.  Feel it would be quite easy and pleasant to continue
writing.  The energy could very well go in that direction.  However,
the idea of the erotic is also quite agreeable.  This is, so far, a
good-humored Buddha area of the self.

EXTENSIONS AND COMMENTARY: Two virtues sought by some users of
psychedelic drugs are high intensity and brief action.  They want a
quicky.  Something that is really effective for a short period of
time, then lets you quickly return to baseline, and presumably back to
the real world out there.

Intensity is often (but not always) regulated by dose.  The
pharmacological property of dose-dependency applies to many of these
drugs, in that the more you take, the more you get.  If you want more
intensity, take a second pill.  And often, you get a longer duration
as an added property.  But it is instructive to inquire into the
rationale that promotes brevity as a virtue.  I believe that it says
something concerning the reasons for using a psychedelic drug.  A
trade off between learning and entertainment.  Or between the
achieving of something and the appearance of achieving something.  Or,
in the concepts of the classics, between substance and image.

In a word, many people truly believe that they cannot afford the time
or energy required for a deep search into themselves.  One has to make
a living, one has to maintain a social life, one has a multitude of
obligations that truly consume the oh-so-few hours in the day.  I
simply cannot afford to take a day off just to indulge myself in
such-and-such (choose one: digging to the bottom of a complex concept,
giving my energies to those whom I can help, to search out my inner
strengths and weaknesses) so instead I shall simply do such-and-such
(choose one: read the book review, go to church on Sunday morning, use
a short-acting psychedelic).  The world is too much with us.  This may
be a bit harsh, but there is some merit to it.

HOT-17 is by no means a particularly potent compound.  The hundred
milligram area actually has been the kiss of death to several
materials, as it is often at these levels that some physical concerns
become evident.  And it certainly is not a short lived compound.  But,
as has been so often the case, the long lived materials have proven to
be the most memorable, in that once the entertainment aspect of the
experience is past you, there is time for dipping deeply into the rich
areas of the thought process, and the working through of ideas and
concepts that are easily available.  And when this access is coupled
to the capability of talking and writing, then a rewarding experience
is often the result.

As with the parent compound, 2C-T-17 itself, the presence of an
asym-metric carbon atom out there on the (s)-butyl side chain will
allow the separation of HOT-17 into two components which will be
different and distinct in their actions.  The activity of the racemic
mixture often is an amalgamation of both sets of properties, and the
separate assay of each component can often result in a fascinating and
unexpected fractionation of these properties.









From: [e-mail]
Newsgroups: sci.med,sci.chem,alt.drugs
Subject: PiHKAL: The Chemical Story.  File 4 of 6

(I'm posting this for a friend.)

This is part 4 of 6 of the second half of PiHKAL: A Chemical Love
Story, by Alexander Shulgin and Ann Shulgin.  Please forgive any typos
or misprints in this file; further, because of ASCII limitations,
many of the typographical symbols in the original book could not be
properly represented in these files.

If you are seriously interested in the chemistry contained in these
files, you should order a copy of the book PiHKAL.  The book may be
purchased for $22.95 ($18.95 + $4.00 postage and handling) from
Transform Press, Box 13675, Berkeley, CA 94701.  California residents
please add $1.38 State sales tax.

At the present time, restrictive laws are in force in the United
States and it is very difficult for researchers to abide by the
regulations which govern efforts to obtain legal approval to do work
with these compounds in human beings....  No one who is lacking legal
authorization should attempt the synthesis of any of the compounds
described in these files, with the intent to give them to man.  To do
so is to risk legal action which might lead to the tragic ruination of
a life.  It should also be noted that any person anywhere who
experiments on himself, or on another human being, with any of the
drugs described herin, without being familiar with that drug's action
and aware of the physical and/or mental disturbance or harm it might
cause, is acting irresponsibly and immorally, whether or not he is
doing so within the bounds of the law.




#90 IDNNA; 2,5-DIMETHOXY-N,N-DIMETHYL-4-IODOAMPHETAMINE

SYNTHESIS: To a stirred solution of 0.4 g
2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI) in 12 mL MeOH
containing 4 mL of a 40% formaldehyde solution there was added 1 g
sodium cyanoborohydride.  The pH was kept at about 6 by the occasional
addition of HCl.  When the pH was stable (about 48 h) the reaction
mixture was poured into 250 mL H2O and made strongly basic by the
addition of aqueous NaOH.  This was extracted with 3x75 mL CH2Cl2, the
extracts pooled, and extracted with 2x75 mL dilute H2SO4, and the
pooled acidic extracts again made basic and again extracted with
CH2Cl2.  The solvent was removed under vacuum to give 0.38 g of a
colorless oil.  This was dissolved in 2 mL IPA and treated with a
solution of 0.13 g oxalic acid dihydrate in 1.5 mL warm IPA, and then
anhydrous Et2O was added dropwise until a turbidity persisted.  Slowly
a granular white solid appeared, which was filtered off, Et2O washed,
and air dried to give 0.38 g of
2,5-dimethoxy-N,N-dimethyl-4-iodoamphetamine oxalate (IDNNA) with a mp
of 145-146 !C.  Anal. (C15H22INO6) C,H.  The hydrochloride salt of
this base proved to be hygroscopic.

DOSAGE: greater than 2.6 mg.

DURATION: unknown.

EXTENSIONS AND COMMENTARY: This base, if it were given a code name
based upon its substituents arranged in their proper alphabetical
order, would have to be called something like DNDIA, which is quite
unpronounceable.  But by a rearrangement of these terms, one can
achieve IDNNA (Iodo-Dimethoxy-N,N-dimethyl-Amphetamine) which has a
nice lilt to it.

One of the major goals of research in nuclear medicine is a drug that
can be used to demonstrate the brain blood flow pattern.  To do this
job, a drug should demonstrate four properties.  First, it must carry
a radioactive isotope that is a positron emitter (best, a fluorine or
an iodine atom, for use with the positron camera) that can be put onto
the molecule quickly, synthetically, and which will stay on the
molecule, metabolically.  Second, as to brain entry, the drug should
be rapidly and extensively taken up by brain tissue, without being
selectively absorbed or concentrated at any specific sites.  In other
words, it should go where the blood goes.  Thirdly, the absorption
should be strong enough that it will stay in the brain, and not be
washed out quickly.  This allows time to both locate and count the
radioactivity that was carried in there.  And lastly, the drug must be
without pharmacological action.

IDNNA looked like a promising candidate when tried with a radioactive
iodine label, and there was quite a flurry of interest in using it
both as an ex-perimental drug, and as a prototype material for the
synthesis of structural variants.  It went in quickly, extensively and
quite diffusely, and it stayed in for a long time.

But was it pharmacologically active?  Here one finds a tricky road to
walk.  The animal toxicity and behavioral properties can be determined
in a straightforward manner.  Inject increasing amounts into an
experimental animal and observe him closely.  IDNNA was quite inert.
But, it is a very close analogue to the extremely potent psychedelic
DOI, and it is widely admitted that animal assays are of no use in
trying to determine this specific pharmacological property.  So, a
quiet human assay was called for.  Since it did indeed go into the
brain of experimental animals, it could quite likely go into the brain
of man.  In fact, that would be a needed property if the drug were to
ever become useful as a diagnostic tool.

It was assayed up to levels where DOI would have been active, and no
activity was found.  So one could state that it had none of the
psychedelic properties of DOI at levels where DOI would be active
(this, at 2.6 milligrams orally).  But you donUt assay much higher,
because sooner or later, something might indeed show up.  So it can be
honestly said, IDNNA is less active than DOI itself, in man.  LetUs
wave our hands a bit, and make our statement with aggressive
confidence.  IDNNA has shown no activity in the human CNS at any level
that has been evaluated.  This sounds pretty good.  Just donUt go too
far up there, and donUt look too carefully.  This is not as
unscrupulous as it might sound since, in practical terms, the
extremely high specific activities of the radioactive 122I that would
be used, would dictate that only an extremely small amount of the drug
would be required.  One would be dealing, not with milligram
quantities, but with microgram quantities, or less.

Some fifteen close analogues of IDNNA were prepared, to see if any had
a better balance of biological properties.  A valuable intermediate
was an iodinated ketone that could be used either to synthesize IDNNA
itself or, if it were to be made radio-labelled, it would allow the
preparation of any desired radioactive analogue in a single synthetic
step.  The iodination of p-dimethoxybenzene with iodine monochloride
in acetic acid gave 2,5-diiodo-1,4-dimethoxybenzene as white crystals
from acetonitrile, with a mp of 167-168 !C.  Anal. (C8H8I2O2) C,H.
Treatment of this with an equivalent of butyllithium in ether,
followed with N-methyl formanilide, gave
2,5-dimethoxy-4-iodobenzaldehyde as pale yellow crystals from ethanol,
with a mp of 136-137 !C.  Anal. (C9H9IO3) C,H.  This, in solution in
nitroethane with a small amount of anhydrous ammonium acetate, gave
the nitrostyrene 1-(2,5-dimethoxy-4-iodophenyl)-2-nitropropene as
gold-colored crystals from methanol, mp 119-120 !C.  Anal.
(C11H12INO4) C,H.  This was smoothly reduced with ele-mental iron in
acetic acid to give 2,5-dimethoxy-4-iodophenylacetone as white
crystals from methylcyclopentane.  These melted at 62-63 !C and were
both spec-troscopically and analytically correct.  Anal. (C11H13IO3)
C,H.

This intermediate, when reductively aminated with dimethylamine, gives
IDNNA identical in all respects to the product from the dimethylation
of DOI above.  But it has also been reacted with 131I NaI in acetic
acid at 140 !C for 10 min, giving the radioactive compound by
exchange, and this was reductively aminated with over a dozen amines
to give radioactive products for animal assay.  There was produced in
this way, 2,5-dimethoxy-4-iodo-N-alkyl-amphetamine where the alkyl
group was methyl, isopropyl, cyclopropylmethyl, hexyl, dodecyl,
benzyl, cyanomethyl, and 3-(dimethylaminopropyl).  Several dialkyl
homologue were made, with the alkyl groups being dimethyl (IDNNA
itself), diethyl, isopropyl-methyl, and benzyl-methyl.  These specific
homologues and analogues are tallied in the index, but a number of
other things, such as hydrazine or hydroxylamine derivatives, were
either too impure or made in amounts too small to be valid, and they
are ignored.

The diethyl compound without the iodine is
2,5-dimethoxy-N,N-diethylamphetamine, which was prepared by the
reductive alkylation of DMA with acetaldehyde and sodium
cyanoborohydride.  This product, DEDMA, was a clear white oil, bp
82-92 !C at 0.15 mm/Hg which did not form a crystalline hydrochloride.
An interesting measure of just how different these N,N-dialkylated
homologues can be from the psychedelic primary amines,
pharmacologically, can be seen in the published report that the
beta-hydroxy derivative of DEDMA is an antitussive, with a potency the
same as codeine.

None of these many iodinated IDNNA analogues showed themselves to be
superior to IDNNA itself, in the rat model, and none of them have been
tasted for their psychedelic potential in man.









#91 IM; ISOMESCALINE; 2,3,4-TRIMETHOXYPHENETHYLAMINE

SYNTHESIS: A solution of 8.0 g 2,3,4-trimethoxybenzaldehyde in 125 mL
nitromethane containing 1.4 g anhydrous ammonium acetate was held at
reflux for 1.5 h.  The conversion of the aldehyde to the nitrostyrene
was optimum at this time, with a minimum development of a slow-moving
spot as seen by thin layer chromatography on silica gel plates using
CHCl3 as a developing solvent; the Rf of the aldehyde was 0.31 and the
Rf of the nitrostyrene was 0.61.  The excess nitromethane was removed
under vacuum, and the residue was dissolved in 20 mL hot MeOH.  On
cooling, the yellow crystals that formed were removed by filtration,
washed with cold MeOH and air dried yielding 4.7 g yellow crystals of
2,3,4-trimethoxy-'-nitrostyrene, with a mp of 73-74 !C.  From the
mother liquors, a second crop of 1.2 g was obtained.

A solution of 4.0 g LAH in 80 mL THF under He was cooled to 0 !C and
vigorously stirred.  There was added, dropwise, 2.7 mL of 100% H2SO4,
followed by a solution of 4.7 g 2,3,4-trimethoxy-'-nitrostyrene in 40
mL anhydrous THF.  The mixture was stirred at 0 !C for 1 h, at room
temperature for 1 h, and then brought briefly to a reflux on the steam
bath.  After cooling again, the excess hydride was destroyed with 4.7
mL H2O in THF, followed by the addition of 18.8 mL 15% NaOH which was
sufficient to convert the solids to a white and granular form.  These
were removed by filtration, the filter cake washed with THF, the
mother liquor and filtrates combined, and the solvent removed under
vacuum.  The residue was added to dilute H2SO4, and washed with 2x75
mL CH2Cl2.  The aqueous phase was made basic with 25% NaOH, and
extracted with 2x50 mL CH2Cl2.  The solvent was removed from these
pooled extracts and the amber-colored residue distilled at 95-100 !C
at 0.3 mm/Hg to provide 2.8 g of 2,3,4-trimethoxyphenethylamine as a
white oil.  This was dissolved in 20 mL IPA, neutralized with about 1
mL concentrated HCl, and diluted with 60 mL anhydrous Et2O.  After
filtering, Et2O-washing, and air drying, there was obtained 3.2 g of
2,3,4-trimethoxyphenethylamine hydrochloride (IM) as a white
crystalline product.

DOSAGE: greater than 400 mg.

DURATION: unknown.

QUALITATIVE COMMENTS: (with 300 mg) No effects whatsoever.

(with 400 mg) Maybe a slight tingle at the hour-and-a-half point.
Maybe not.  Certainly nothing an hour later.  Put this down as being
without action.

EXTENSIONS AND COMMENTARY: Some fifty years ago this material was
given the name Rreciprocal mescalineS in that it was believed to
exacerbate the clinical symptoms in schizophrenic patients.  In the
original report, one finds: RThus we have discovered an extremely
remarkable dependency of the intoxicating action upon the position of
the three methoxy groups.  Mescaline, the
3,4,5-trimethoxy-'-phenethylamine, produces in the normal subject a
much stronger over-all intoxication than in the schizophrenic patient,
whereas 2,3,4-trimethoxy-'-phenethylamine has quite the opposite
effect.  It has little action in healthy individuals, being almost
without intoxicating properties, but it is very potent in the
schizophrenic.  The metabolic conversion products of the RreciprocalS
mescaline will be further studied as soon as the study of the
metabolism of the proper mescaline is complete.

This is a pretty rich offering, and one that the present medical
community has no qualms about discarding.  At the bookkeeping level,
the promised further studies have never appeared, so all may be
forgotten as far as potential new discoveries might be concerned.

One recent related study has been reported, tying together
isomescaline and schizophrenia.  Through the use of radioactive
labelling, the extent of demethylation (the metabolic removal of the
methyl groups from the methoxyls) was determined in both schizophrenic
patients and normal subjects.  When there was a loading of the person
with methionine (an amino acid that is the principal source of the
body's methyl groups), the schizophrenics appeared to show a lesser
amount of demethylation.

But might either of these two observations lead to a diagnostic test
for schizophrenia?  At the present time, the conventional thinking is
that this probably cannot be.  The illness has such social and genetic
contributions, that no simple measure of a response to an
almost-psychedelic, or minor shift of some urinary metabolite pattern
could possibly be believed.  No independent confirmation of these
properties has been reported.  But maybe these findings are valid.  A
major problem in following these leads does not involve any complex
research protocols.  What must be addressed are the present regulatory
restrictions and the Federal law structure.  And these are formidable
obstacles.









#92 IP; ISOPROSCALINE; 3,5-DIMETHOXY-4-(i)-PROPOXYPHENETHYLAMINE

SYNTHESIS: A solution of 5.8 g of homosyringonitrile (see under
ESCALINE for its preparation) and 13.6 g isopropyl iodide in 50 mL dry
acetone was treated with 6.9 g finely powdered anhydrous K2CO3 and
held at reflux on the steam bath.  After 6 h another 5 mL of isopropyl
iodide was added, and refluxing continued for an additional 12 h.  The
mixture was filtered and the solids washed with acetone.  The mother
liquor and washes were stripped of solvent under vacuum, The residue
was taken up in dilute HCl, and extracted with 3x100 mL CH2Cl2.  The
pooled extracts (they were quite deeply yellow colored) were washed
with 2x75 mL 5% NaOH, and finally once with dilute HCl.  Removal of
the solvent under vacuum yielded 9.8 g of an amber oil, which on
distillation at 125-135 !C at 0.3 mm/Hg provided 6.0 g of
3,5-dimethoxy-4-(i)-propoxyphenylacetonitrile as a pale yellow oil.  A
pure reference sample is a white solid with a mp of 33-34 !C.  Anal.
(C13H17NO3) C,H,N.

A solution of AH was prepared by the cautious addition of 0.84 mL of
100% H2SO4 to 32 mL of 1.0 M LAH in THF, which was being vigorously
stirred under He at ice-bath temperature.  A solution of 5.93 g of
3,5-dimethoxy-4-(i)-propoxyphenylacetonitrile in 10 mL anhydrous THF
was added dropwise.  Stirring was continued for 30 min, then the
reaction mixture was brought up to reflux on the steam bath for
another 30 min.  After cooling again to room temperature, 5 mL IPA was
added to destroy the excess hydride, followed by about 10 mL of 15%
NaOH, sufficient to make the aluminum salts loose, white, and
filterable.  The reaction mixture was filtered, the filter cake washed
with IPA, the mother liquor and washes combined, and the solvent
removed under vacuum.  The residue (7.0 g of an amber oil) was
dissolved in dilute H2SO4 and washed with 3x75 mL CH2Cl2.  The aqueous
phase was made basic with aqueous NaOH, and the product extracted with
3x75 mL CH2Cl2.  The extracts were evaporated to a residue under
vacuum, and this was distilled at 125-140 !C at 0.3 mm/Hg yielding 3.7
g of a colorless oil.  This was dissolved in 15 mL IPA, neutralized
with 50 drops of concentrated HCl which allowed the deposition of a
white crystalline product.  Dilution with anhydrous Et2O and
filtration gave 3.7 g. of 3,5-dimethoxy-4-(i)-propoxyphenethylamine
hydrochloride (IP) with a mp of 163-164 !C.  Anal. (C13H22ClNO3)
C,H,N.  The catalytic hydrogenation process for reducing the nitrile
that gives rise to escaline, also works with this material.

DOSAGE: 40 - 80 mg.

DURATION: 10 - 16 h.

QUALITATIVE COMMENTS: (with 75 mg) Starts slowly.  I develop some
queasiness, turning into nausea.  Feels good to lie down and let go,
but the uneasiness remains.  Just beginning to break through in 2
hours.  But the occasional sense of relief, the breaking into the
open, were transient as new sources of discomfort were always being
dredged up.  Then for some reason I chose to dance.  Letting go to
dancing, a marvelous ecstatic experience, flowing with and being the
energy, body feeling completely free.  Noticing how this letting go
got one completely out of the feeling of unease, as though attention
simply needs to be put elsewhere.  Comedown was very slow, gentle,
euphoric; a very signicant experience.  Sleep that night was
impossible, but felt good to simply release to the feelings.  Keeping
mind still, no thinking, just allowing feelings to go where they
wished, became more and more ecstatic.  Tremendous feeling of
confidence in life and the life process.  Complete sense of
resolution.

(with 80 mg) It took about two hours for the body to settle down.
Emotions were true and well felt, a fact that is an all-important
thing to me as it probably is to everyone else I know in this kind of
exploration.  Any sense that there is a dulling of the feeling and
emotional area of the self is a negative, to be watched and noted as
are other things such as disturbed sleep, unpleasant dreams, or
irritability or depression the next day.  I was interacting with
others with a great deal of intensity.  People found themselves
wandering inside and out, listening to music, stirring soup, eating a
bit and enjoying eating, talking, laughing a great deal, and being
silent in great contentment.  It's not a very silent material, though.
Talking is too enjoyable.  There was a slight descent noted at 6-7
hours, but very gentle and smooth.  Slow and pleasant descent until
about 12th hour, when sleep was attempted.  Next day, everyone
slightly irritable but good mood anyway.  The next night I slept
deeply and well, and awoke whole and in excellent mood.

EXTENSIONS AND COMMENTARY: These two excerpts give the color and
complexity of IP.  It has proven to be a completely fascinating
phenethylamine.  And, as with all the phenethylamines, there is an
amphetamine that corresponds to it.  This would be
3,5-dimethoxy-4-isopropoxyamphetamine, or 3C-IP.  The prepa-ration of
it would require access through the O-isopropoxylation product with
syringaldehyde, followed by nitrostyrene formation with nitroethane,
followed by reduction probably with lithium aluminum hydride.  It has
not been synthesized, as far as I know, and so it has probably not
been evaluated in man.  What would be the active level?  It would
probably be more potent than IP, but I would guess not by much.  Maybe
in the 30 milligram area.

A moment's aside for a couple of the words that are so much a part of
the chemist's jargon.  Room temperature, as used above, means the
natural temperature that something comes to if it is put on the table
and is neither heated nor cooled.  The phrase, I discovered during my
year at Gif, is completely un-understandable in French.  A room has no
temperature.  Only things in rooms have temperatures.  Their
expression is more exact.  The object achieves, in the French
terminology, a temperature normale dUinterieur, or about 15 to 16 !C.
But in common laboratory parlance it has become the temperature
dUambiance.

And one finds the prefix RisoS used everywhere.  Considerable care
should be taken in the two different uses of the prefix RisoS in the
nomenclature with the mescaline analogues.  In general, the term RisoS
means the other one of two possibilities.  If you are allowed to paint
a house only with green paint or red paint, and green is the color you
actually use, then red could be called iso-green.  With isoproscaline
(here) there is a rearranging of the propyl group on the 4-oxygen of
mescaline.  It has been replaced with its branched analogue, the other
of two possibilities, the isopropyl group.  Everything is still with
the 3,4,5-orientation on the benzene ring.  However, with IM
(isomescaline) there is a rearrangement of substitution pattern on the
benzene ring, with the repositioning of the trimethoxyl substitution
pattern from the 3,4,5- arrangement to the 2,3,4- arrangement.  It has
been the side-chain that has taken the other of two possible
positions.  The term RisoS must always be interpreted in precise
context.









#93 IRIS; 5-ETHOXY-2-METHOXY-4-METHYLAMPHETAMINE

SYNTHESIS: To a solution of 9.5 g flaked KOH (10% excess) in 500 mL
95% EtOH there was added 20.4 g 4-methoxy-2-methylphenol (see under
2C-D for its preparation).  This was followed with 23.5 g ethyl
iodide, and the mixture was held at reflux overnight.  The solvent was
removed under vacuum and the residue suspended in 250 mL H2O.  This
was made strongly basic with NaOH and extracted with 3x50 mL CH2Cl2.
Removal of the solvent gave 15.75 g of 2-ethoxy-5-methoxytoluene as an
amber oil, which was used in the following step without further
purification.  Acidification of the aqueous phase followed by CH2Cl2
extraction gave, after removal of the solvent, crude recovered
starting phenol as a dark brown crystalline solid.  The reasonably
pure phenol was best isolated by sequential extractions with portions
of 80 !C H2O which, on cooling, deposited the phenol as white
crystals.

A mixture of 38 mL POCl3 and 43 mL N-methylformanilide was allowed to
incubate for 1 h and then there was added to it 15.7 g
2-ethoxy-5-methoxytoluene.  This was heated in the steam bath for 2 h,
then poured into 1 L H2O and allowed to stir overnight.  The solids
that formed were removed by filtration and H2O washed, giving 20.7 g
of a crude, amber product.  This was extracted with 2x150 mL boiling
hexane which gave crystals on cooling.  These were filtered and hexane
washed, giving 12.85 g of 5-ethoxy-2-methoxy-4-methylbenzaldehyde as
pale cream-colored solids with a mp of 75-76 !C.  Recrystallization of
an analytical sample from EtOH two times gave a product with a white
color, and a mp of 81-82 !C.

To a solution of 11.35 g 5-ethoxy-2-methoxy-4-methylbenzaldehyde in 48
mL glacial acetic acid containing 4 g anhydrous ammonium acetate there
was added 10 mL nitroethane, and the mixture heated on the steam bath
for 2 h.  Standing at room temperature overnight allowed a heavy crop
of brilliant crystals to deposit.  These were removed by filtration,
washed cautiously with acetic acid, and air dried to give 8.6 g
1-(5-ethoxy-2-methoxy-4-methylphenyl)-2-nitropropene with a mp of
118-120 !C.  Recrystallization of all from 200 mL boiling MeOH gave
8.3 g of lustrous crystals with a mp of 121-122 !C.

To a gently refluxing suspension of 6.4 g LAH in 500 mL anhydrous Et2O
under a He atmosphere, there was added 8.1 g
1-(5-ethoxy-2-methoxy-4-methylphenyl)-2-nitropropene by allowing the
condensing ether to drip into a shunted Soxhlet thimble containing the
nitrostyrene.  This effectively added a warm saturated solution of the
nitrostyrene dropwise.  Refluxing was maintained overnight, and the
cooled reaction flask stirred for several additional days.  The excess
hydride was destroyed by the cautious addition of 400 mL H2O
containing 40 g H2SO4.  When the aqueous and Et2O layers were finally
clear, they were separated, and 160 g of potassium sodium tartrate was
dissolved in the aqueous fraction.  Aqueous NaOH was then added until
the pH was >9, and this was then extracted with 3x50 mL CH2Cl2.
Evaporation of the solvent under vacuum produced an oil that was
dissolved in anhydrous Et2O and saturated with anhydrous HCl gas.
There appeared 5-ethoxy-2-methoxy-4-methylamphetamine hydrochloride
(IRIS) as fine white crystals.  These weighed, after filtration, Et2O
washing, and air drying to constant weight, 5.3 g and had a mp of
192-193 !C.  Recrystallization of an analytical sample from boiling
CH3CN gave lustrous crystals with a mp of 196-197 !C with
decomposition.

DOSAGE: greater than 9 mg.

DURATION: unknown.

QUALITATIVE COMMENTS: (with 7.5 mg) At about three hours I felt that
I was at threshold, but an hour later there was nothing.

(with 9 mg) Maybe a little light headed?  Maybe not.  Little effect
if any.

EXTENSIONS AND COMMENTARY: This is one of the ten Classic Ladies, the
ten possible homologues of DOM, which I had discussed under ARIADNE
(the first of the Ladies).  The active level is unknown, but it is
higher than 9 milligrams (the highest dose tried) and since DOM itself
would have been smashingly active at this level, it is obvious that
IRIS is a homologue with decreased potency.

This lack of activity brings up a fascinating point.  I have referred
to a drug's action on the mind, quite frequently in these notes, with
the phrase Rreasonably complex.S By that, I do not mean that a drugUs
action simply shows many facets, and if these were to be tallied, the
drug-mind interaction would become clear.  There is quite a bit of
importance intrinsically implied by the term, complex.  Simple things,
as we have come to appreciate and depend upon them in our day-to-day
living, can have simple explanations.  By this, I mean explanations
that are both completely satisfactory and satisfactorily complete.
Answers that have all the earmarks of being correct.  What is the sum
of two plus three, you ask?  Let's try five.  And for most of our
needs, five is both factual and complete.

But some years ago, a mathematician named Gdel devised a proof for a
theorem that anything that is reasonably complex cannot enjoy this
luxury (I believe he used the word RinterestingS rather than
reasonably complex).  If your collection of information is factual, it
cannot be entirely complete.  And if it is complete, it cannot be
entirely factual.  In short, we will never know, we cannot ever know,
every fact that constitutes an explanation of something.  A complete
book of knowledge must contain errors, and an error-free book of
knowledge must be incomplete.

There is a small warning light deep inside me that starts flashing any
time I hear someone begin to advance an explanation of some reasonably
complex phenomenon with an air of confidence that implies, RHere is
how it works.S What the speaker usually has is an intense familiarity
with one particular discipline or specialty and the phenomenon is
viewed through those eyes, often with the assurance that looking at it
that way, intently enough and long enough, will reveal the complete
explanation.  And be attentive to the phrase, RWe are not yet
com-pletely sure of exactly how it works.S What is really meant is,
RWe havenUt the slightest idea of how it really works.

I must admit to some guilt in this matter, certainly as much as the
next person.  I am a chemist and I suspect that the way that the
psychedelic drugs do their thing can eventually be understood through
a comparison of the structures of the molecules that are active and
those that are inactive.  I put those that have methoxyl groups in
pigeon hole #1, and those that are bicyclic into pigeon hole #2.  And
then, if pigeon hole #2 becomes more and more cluttered, I will
subdivide the contents into pigeon hole #2A for bicyclics with
heteroatoms and pigeon hole #2B for bicyclics without heteroatoms.
The more information I can accumulate, the more pigeon holes I need.

But in the adjoining lab, there is a molecular biologist who feels
that the eventual explanation for the action of the psychedelic drug
will come from the analysis and understanding of the intimate geometry
of the places in the brain where they act.  These classification
pigeon holes are called receptor sites.  But they, too, can become
more and more subdivided as they become cluttered.  One reads of a new
sub-sub type quite regularly in the literature.  The favorite
neurotransmitter of the moment, as far as the current thinking of how
these marvelous drugs work, is serotonin, or 5-HT (for
5-hydroxytryptamine).  There are 5-HT1 and 5-HT2A and 5-HT2B and (for
all I know right now) 5-HT2C and 5-HT2D receptors, and I donUt really
think that either he or I have come much closer to understanding the
mechanism of action.

And, since the mind is a reasonably complex system, Gdel has already
informed us both that neither of us will be completely successful.
Sometimes I feel that the pigeon hole approach to the classification
of knowledge might actually limit our views of the problem.  A Harvard
Professor of Medicine recently noted: RWe must recognize for what it
is, man's predilection for dividing things into tidy categories,
irrespective of whether clarity is gained or lost thereby.

No.  No one will ever have it all together.  It is like sitting down
in front of a jigsaw with a zillion zillion pieces spread all over the
kitchen table.  With diligent searching you will occasionally find a
piece that matches another, but it rarely provides any insight into
the final picture.  That will remain a mystery, unless you had the
chance to see the cover of the box in some other incarnation.  But Oh
my, what fun it is, whenever you do happen to find a new piece that
fits!

This harangue is really a lengthy prelude to the story of putting an
ethoxy group in place of a methoxy on the 2,5-dimethoxy skeleton of
these psychedelic families.  The making of IRIS was the first move in
this direction, done back in 1976.  One can have a pigeon hole that is
named REthoxy In Place of MethoxyS and toss in there the names of
perhaps twenty pairs of compounds, which differ from one another by
just this feature.  Yet when they are looked at from the potency point
of view, there are some which show a decrease in potency (which is the
case with IRIS and most of the Tweetios) and there are some which seem
to maintain their potency (such as the TMA-2/MEM pair) and there are
some where there is a distinct potency increase (the
mescaline/escaline pair, for example).

What does one do to clarify the contents of this particular pigeon
hole?  The current fad would be to subdivide it into three
subdivisions, maybe something like REthoxy in Place of Methoxy if 2-
or 5-locatedS and REthoxy in Place of Methoxy if 4-located and other
things 2,5S and REthoxy in Place of Methoxy if 4-located, and other
things 3,5.S The end point that soon becomes apparent, down the line,
will be to have as many pigeon holes as compounds!  And at the moment,
this particular piece of the jigsaw puzzle doesnUt seem to fit
anywhere at all.

Perhaps both my neighboring molecular biologist and I are asking the
wrong questions.  I am looking at the molecules and asking, RWhat are
they?S And he is following them and asking, RWhere do they go?S And
neither of us is fully attentive to the question, RWhat do they do?S
It is so easy to replace the word Rmind,S in our inquiries, with the
word Rbrain.

Yup.  The operation of the mind can certainly be classified as a
Rreasonably complexS phenomenon.  I prefer Gdel's term.  The mind is
without question an RinterestingS phenomenon.









#94 J; BDB; 2-AMINO-1-(3,4-METHYLENEDIOXYPHENYL)BUTANE;
1-(1,3-BENZODIOXOL-5-YL)-2-BUTANAMINE

SYNTHESIS: The Grignard reagent of propyl bromide was made by the
dropwise addition of 52 g 1-bromopropane to a stirred suspension of 14
g magnesium turnings in 50 mL anhydrous Et2O.  After the addition,
stirring was continued for 10 min, and then a solution of 50 g
piperonal in 200 mL anhydrous Et2O was added over the course of 30
min.  The reaction mixture was heated at reflux for 8 h, then cooled
with an external ice bath.  It was quenched with the addition of a
solution of 75 mL cold, saturated aqueous ammonium chloride.  The
formed solids were removed by filtration, and the two-phase filtrate
separated.  The organic phase was washed with 3x200 mL dilute HCl,
dried over anhydrous MgSO4, and the solvent removed under vacuum.  The
crude 62.2 g of 1-(3,4-methylenedioxyphenyl)-2-butanol, which
contained a small amount of the olefin that formed by dehydration, was
distilled at 98 !C at 0.07 mm/Hg to give an analytical sample, but the
crude isolate served well in the next reaction.  Anal. (C11H14O3) C,H.

A mixture of 65 g crude 1-(3,4-methylenedioxyphenyl)-2-butanol and 1 g
finely powdered potassium bisulfate was heated with a soft flame until
the internal temperature reached 170 !C and H2O was no longer evolved.
The entire reaction mixture was then distilled at 100-110 !C at 0.8
mm/Hg to give 55 g of 1-(3,4-methylenedioxyphenyl)-1-butene as a
colorless oil.  Anal. (C11H12O2) C,H.

To 240 mL of stirred and cooled formic acid there was added 30 mL H2O
followed, slowly, by 45 mL of 35% hydrogen peroxide.  There was then
added a solution of 48 g 1-(3,4-methylenedioxyphenyl)-1-butene in 240
mL acetone at a rate that maintained the internal temperature at less
than 40 !C.  After the addition, the reaction mixture was allowed to
stand and stir for several additional days.  The excess volatiles were
removed under vacuum with the temperature never allowed to exceed 40
!C.  The residue was dissolved in 90 mL MeOH and diluted with 450 mL
15% H2SO4.  This mixture was heated on the steam bath for 2.5 h,
cooled, and then extracted with 3x100 mL Et2O.  The extracts were
pooled, washed with 2x200 mL H2O, 2x200 mL 5% NaOH, 2x200 mL brine,
and then dried over anhydrous MgSO4.  After removal of the solvent
under vacuum, the residue was distilled at 105-135 !C at 0.3 mm/Hg to
give 28.2 g 1-(3,4-methylenedioxyphenyl)-2-butanone as an amber oil.
Redistillation gave a colorless oil, with a bp of 98 !C at 0.11 mm/Hg.
Anal.  (C11H12O3) C,H.  This intermediate ketone could be prepared by
the Wittig reaction between piperonal and the derivative of
triphenylphosphonium propyl bromide and dibutyldisulfide, followed by
hydrolysis in a HCl/acetic acid mixture, but the yields were no
better, Efforts to prepare this ketone by the iron and acid reduction
of the appropriate nitrostyrene
(1-(3,4-methylenedioxyphenyl)-2-nitro-1-butene, mp 64-65 !C) were
thwarted by the consistently unsatisfactory yield of the precursor
from the reaction between piperonal and 1-nitropropane.

A stirred solution of 20 g anhydrous ammonium acetate and 4.6 g
1-(3,4-methylenedioxyphenyl)-2-butanone in 50 mL MeOH was treated with
1.57 g sodium cyanoborohydride.  Droplets of HCl were added as needed
to maintain the pH at approximately 6.  The reaction mixture was made
basic with the addition of 250 mL dilute NaOH and extracted with 3x100
mL CH2Cl2.  The pooled organic extracts were extracted with 2x100 mL
dilute H2SO4, the pooled aqueous extracts made basic again, and
extracted again with 2x100 mL CH2Cl2.  Removal of the solvent gave a
residue which was distilled to give 2.6 g of a colorless oil which was
dissolved in 15 mL IPA, neutralized with concentrated HCl, and diluted
with an equal volume of anhydrous Et2O.  Crystals of
2-amino-1-(3,4-methylenedioxyphenyl)butane hydrochloride (J) separated
slowly.  After filtering, Et2O washing, and air drying there was
obtained 2.8 g of white crystals that melted at 159-161 !C.  Anal.
(C11H16ClNO2) C,H,N.

DOSAGE: 150 - 230 mg.

DURATION: 4 - 8 h.

QUALITATIVE COMMENTS: (with 175 mg) The first stirrings were evident
in a half hour, pleasant feelings, and without any untoward body
effects.  Within another half hour I was at a plus 2 and there it
leveled off.  I would be reluctant to drive a car, but I could were it
necessary.  There were no visual distortions, no giddiness, no
introspective urges, and no rise to a psychedelic intoxication of any
significance.  After about an hour and a half at this level, I
gradually dropped back over another two hours.  Afterwards I was quite
fatigued and languorous.

(with 200 mg and a 75 mg supplement) RA very strong climb, and a very
good, interior feeling.  It has some of the MDMA properties, but it is
difficult to concentrate on any one point.  There is a tendency to
slide off.  Excellent emotional affect; music is fine but not
gripping.  Someone had used the phrase, mental nystagmus, and there is
something valid there. The supplement was taken at the 2 hour point
when I was already aware of some dropping, and its action was noticed
in about a half hour.

(with 230 mg) Physically, there was a bit of dry mouth but no teeth
clenching, some nystagmus, maybe the slightest bit of dizziness, very
anorexic, and it is not a decongestant.  Mentally, it is extremely
benign and pleasant, funny and good-humored.  No visuals.  Peaceful.
Easy silences, easy talking.  More stoning than MDMA.

EXTENSIONS AND COMMENTARY: In general, all subjects who have explored
J have accepted it and commented favorably.  Perhaps those who have
used supplements (in an imitation of the common MDMA procedure)
achieved an additional period of effect, but also tended to drop to
baseline afterwards more rapidly.  The physical side effects, such as
teeth clench and nystagmus, were infrequent.  The consensus is that J
is a bit more RstoningS than MDMA, more like MDA, but with a
chronology that is very much the same.

Two nomenclature problems have to be faced in the naming of these
compounds.  One deals with the Chemical Abstracts terminology as
contrasted with the logical and intuitive terminology.  The other
invokes the concept of the Muni-Metro, delightfully simple, but
neither Chemical Abstracts-approved nor intuitive in form.  The first
problem is addressed here; the second is discussed where it better
belongs, under the N-methyl homologue of J (see under METHYL-J).

In short, the two-ring system of J, or of any of the MDA-MDMA family
of drugs, can be named as one ring being attached to the other, or by
a single term that encompasses both.  The first procedure, an old
friend with chemists and the one that had been used for years in the
abstracting services, calls the combination methylenedioxybenzene and,
as a prefix, it becomes methylenedioxyphenyl-something.  The benzene
or the phenyl-something is the foundation of the name, and there
happens to be a methylenedioxy-ring attached to it.  On this basis,
this compound J should be named as if it had no methylenedioxy ring
anywhere, and then simply attach the new ring as an afterthought.  So,
the one-ring parent of J is 1-phenyl-2-aminobutane, and J is
1-(3,4-methylenedioxyphenyl)-2-aminobutane (or, to be a purist, the
amino should alphabetically come first, to give
2-amino-1-(3,4-methylene-dioxyphenyl)butane).  The synthesis of the
chemical intermediates given above uses this old-fashioned
nomenclature.

But the name currently in vogue for this two-ring system is
1,3-benzodioxole.  As a prefix it becomes
1,3-benzodioxol-5-yl-something, and so J would be called
1-(1,3-benzodioxol-5-yl)-2-aminobutane.  This is the source of the
code name BDB.  And the N-methyl homologue, the alpha-ethyl analogue
of MDMA, is named MBDB, or METHYL-J, and is with its own separate
entry in this footnote.

There is a psychological nuance to this new nomenclature.  The virtues
and potential medical value of MDMA lie in its most remarkable
property of facilitating communication and introspective states
without an overlay of psychedelic action.  This property has prompted
the coining of a new pharmacological class name, Entactogen, which
comes from the Greek roots for Rtouching within.S But MDMA has been
badly smeared in both the public and the scientific view, by its wide
popular misuse, its precipitous placement into a Schedule I category
of the Federal Drug Law, and a flood of negative neurotoxicological
findings in animal studies.  There are some properties of both this
compound and its methyl-homologue that suggest this RentactogenS
world, so why not avoid the RMDS prefix that, in many eyes, is
pejorative?  Stick with the totally obscure chemical names, and call
them BDB and MBDB.  Or, even more simply, J and METHYL-J.









#95 LOPHOPHINE; 3-METHOXY-4,5-METHYLENEDIOXYPHENETHYLAMINE

SYNTHESIS: A solution of 50 g myristicinaldehyde
(3-methoxy-4,5-methylenedioxybenzaldehyde, see under MMDA for its
preparation) in 200 mL acetic acid was treated with 33 mL nitromethane
and 17.4 g anhydrous ammonium acetate and held on the steam bath for 5
h.  The reaction mixture was diluted with a little H2O and cooled in
an external ice-acetone bath.  A heavy crop of yellow crystals formed,
which were removed by filtration, washed with cold acetic acid, and
dried to constant weight.  There was thus obtained 19.3 g
3-methoxy-4,5-methylenedioxy-'-nitrostyrene with a mp of 210-212 !C.
The mother liquors were diluted with H2O, and extracted with 3x100 mL
CH2Cl2.  The pooled extracts were washed with 5% NaOH, and the solvent
removed under vacuum yielding 34 g of a dark residue that was largely
unreacted aldehyde.  This residue was reprocessed in acetic acid with
nitromethane and ammonium acetate, as described above, and provided an
additional 8.1 g of the nitrostyrene with the same mp.

A suspension of 25 g LAH in 1.5 L anhydrous Et2O in an inert
atmosphere was stirred magnetically, and brought up to a gentle
reflux.  Through a Soxhlet condenser modified to allow Et2O to return
continuously to the reaction mixture, there was added 27.0 g of
3-methoxy-4,5-methylenedioxy-'-nitrostyrene.  The addition require
many h, and when it was completed, the reaction was held at reflux for
an additional 9 days.  After cooling the reaction mixture in an
external ice bath, the excess hydride was destroyed by the cautious
addition of dilute H2SO4.  The final amount used was 1800 mL H2O
containing 133 g H2SO4.  The phases were separated, and the aqueous
phase was washed with 2x100 mL Et2O.  To it was then added 625 g
potassium sodium tartrate, and sufficient base to bring the pH to >9.
This was extracted with 3x250 mL CH2Cl2, and the pooled extracts
stripped of solvent under vacuum.  The residue was dissolved in
anhydrous Et2O and saturated with anhydrous HCl gas, giving a heavy
crystallization of salts.  These were removed by filtration, Et2O
washed, and air dried, to give 17.7 g
3-methoxy-4,5-methylenedioxyphenethylamine (LOPHOPHINE) as an
off-white solid with a mp of 160-161 !C.  This was dissolved in CH3CN
containing 5% EtOH, decolorized with activated charcoal, filtered, and
the removed charcoal washed with boiling CH3CN.  Slow cooling of the
solution provided 11.7 g of a white product which melted at 164-164.5
!C.

DOSAGE: greater than 200 mg.

DURATION: unknown.

QUALITATIVE COMMENTS: (with 150 mg) Between two and five hours, very
peaceful and euphoric mood elevation, similar to mescaline, but
without any visual distortion.  Mild enhancement of color perception,
possibly a function of mood elevation.  There was no nausea, no
eyes-closed vision.  Slept easily that evening.

(with 250 mg) Possibly something of a threshold effect from 2:30 to
4:30 of the experiment.  Intangible, and certainly there is nothing an
hour later.

EXTENSIONS AND COMMENTARY: It looks as if this compound is not active.
There is an excellent argument as to why it really should be, and the
fact that it is not active is completely unexpected.  Let me try to
explain.

Quite simply, mescaline is a major component and a centrally active
alkaloid of the Peyote plant.  It is a phenethylamine, which can
undergo a cyclization within the plant to produce a pile of
derivatives (tetrahydroisoquinolines) such as anhalonine and
O-methylanhalonidine that are marvelously complex alkaloids, all
natural components of this magical cactus.  But there is another pile
of derivatives (tetrahydroisoquinolines) such as anhalonine, and
lophophorine, and peyophorine which are the logical cyclization
products of another phenethylamine which does not exist in the cactus.
It should be there, but it is not.  If it were there it would be the
natural precursor to a host of bicyclic alkaloids, but it is absent.
This is 3-methoxy-4,5-methylenedioxyphenethylamine.  I feel that some
day it will be discovered as a plant component, and when it is it can
be given a name that reflects the generic binomial of the plant.  And
since the plant has been known as Lophophora williamsii, why not give
a name to this compound (which should be in the plant), one derived
from the Latin name, but one that has never before been used?  What
about LOPHOPHINE?  And so, I have named it, but I have not found it,
nor has anyone else.  Yet.

It is inevitable that this simple and most appealing precursor will be
found to be present in the cactus, at some future time when we will
have tools of sufficient sensitivity to detect it.  And certainly, it
would be reasonable to expect it to be an active psychedelic, and to
be as interesting in man as its close cousin, mescaline.  But, at the
present time, LOPHOPHINE is not known to be present in the plant, and
it is not known to be active in man.  I am confident that both
statuses will change in the future.









#96 M; MESCALINE; 3,4,5-TRIMETHOXYPHENETHYLAMINE

SYNTHESIS: A solution of 20 g 3,4,5-trimethoxybenzaldehyde, 40 mL
nitromethane, and 20 mL cyclohexylamine in 200 mL of acetic acid was
heated on the steam bath for 1 h.  The reaction mixture was then
diluted slowly and with good stirring, with 400 mL H2O, which allowed
the formation of a heavy yellow crystalline mass.  This was removed by
filtration, washed with H2O, and sucked as dry as possible.
Recrystallization from boiling MeOH (15 mL/g) yielded, after
filtration and air drying, '-nitro-3,4,5-trimethoxystyrene as bright
yellow crystals weighing 18.5 g.  An alternate synthesis was
effective, using an excess of nitromethane as solvent as well as
reagent, if the amount of ammonium acetate catalysis was kept small.
A solution of 20 g 3,4,5-trimethoxybenzaldehyde in 40 mL nitromethane
containing 1 g anhydrous ammonium acetate was heated on the steam bath
for 4 h.  The solvent was stripped under vacuum and the residual
yellow oil was dissolved in two volumes of hot MeOH, decanted from
some insolubles, and allowed to cool.  The crystals formed are removed
by filtration, washed with MeOH and air dried yielding 14.2 g. of
bright yellow crystals of '-nitro-3,4,5-trimethoxystyrene.  The use of
these proportions but with 3.5 g ammonium acetate gave extensive
side-reaction products even when worked up after only 1.5 h heating.
The yield of nitrostyrene was, in this latter case, unsatisfactory.

To a gently refluxing suspension of 2 g LAH in 200 mL Et2O, there was
added 2.4 g '-nitro-3,4,5-trimethoxystyrene as a saturated Et2O
solution by use of a Soxhlet extraction condenser modified to allow
the continuous return of condensed solvent through the thimble.  After
the addition was complete, the refluxing conditions were maintained
for another 48 h.  After cooling the reaction mixture, a total of 150
mL of 1.5 N H2SO4 was cautiously added, destroying the excess hydride
and untimately providing two clear phases.  These were separated, and
the aqueous phase was washed once with 50 mL Et2O.  There was then
added 50 g potassium sodium tartrate, followed by sufficient NaOH to
bring the pH >9.  This was then extracted with 3x75 mL CH2Cl2, and the
solvent from the pooled extracts was removed under vacuum.  The
residue was distilled at 120-130 !C at 0.3 mm/Hg giving a white oil
that was dissolved in 10 mL IPA and neutralized with concentrated HCl.
The white crystals that formed were diluted with 25 mL Et2O, removed
by filtration, and air dried to provide 2.1 g
3,4,5-trimethoxyphenethylamine hydrochloride (M) as glistening white
crystals.  The sulfate salt formed spectacular crystals from water,
but had a broad and uncharacteristic mp.  An alternate synthesis can
employ 3,4,5-trimethoxyphenylacetonitrile, as described under '-D.

DOSAGE: 200-400 mg (as the sulfate salt), 178-256 mg (as the
hydrochloride salt).

DURATION: 10-12 h

QUALITATIVE COMMENTS: (with 300 mg) I would have liked to, and was
expecting to, have an exciting visual day, but I seemed to be unable
to escape self-analysis.  At the peak of the experience I was quite
intoxicated and hyper with energy, so that it was not hard to move
around.  I was quite restless.  But I spent most of the day in
considerable agony, attempting to break through without success.  I
learned a great deal about myself and my inner workings.  Everything
almost was, but in the final analysis, wasnUt.  I began to become
aware of a point, a brilliant white light, that seemed to be where God
was entering, and it was inconceivably wonderful to perceive it and to
be close to it.  One wished for it to approach with all one's heart.
I could see that people would sit and meditate for hours on end just
in the hope that this little bit of light would contact them.  I
begged for it to continue and come closer but it did not.  It faded
away not to return in that particular guise the rest of the day.
Listening to Mozart's Requiem, there were magnificent heights of
beauty and glory.  The world was so far away from God, and nothing was
more important than getting back in touch with Him.  But I saw how we
created the nuclear fiasco to threaten the existence of the planet, as
if it would be only through the threat of complete annihilation that
people might wake up and begin to become concerned about each other.
And so also with the famines in Africa.  Many similar scenes of joy
and despair kept me in balance.  I ended up the experience in a very
peaceful space, feeling that though I had been through a lot, I had
accomplished a great deal.  I felt wonderful, free, and clear.

(with 350 mg) Once I got through the nausea stage, I ventured
out-of-doors and I was aware of an intensification of color and a
considerable change in the texture of the cloth of my skirt and in the
concrete of the sidewalk, and in the flowers and leaves that were
handed me by an observer.  I experienced the desire to laugh
hysterically at what I could only describe as the completely
ridiculous state of the entire world.  Although I was afraid of
motion, I was persuaded to take a ride in a car.  The driver turned on
the radio and suddenly the music 'The March of the Siamese Children'
from 'The King and I' became the most perfect background music for the
parody of real life which was indeed the normal activity of Telegraph
Avenue on any Saturday morning.  The perfectly ordinary people on
their perfectly ordinary errands were clearly the most cleverly
contrived set of characters all performing all manners of eccentric
activities for our particular hilarity and enjoyment.  I felt that I
was at the same time both observing and performing in an outrageous
moving picture.  I experienced one moment of transcendant happiness
when, while passing Epworth Hall, I looked out of the window of the
car and up at the building and I was suddenly in Italy looking up at a
gay apartment building with its shutters flung open in sunshine, and
with its window boxes with flowers.  We stopped at a spot overlooking
the bay, but I found the view uninteresting and the sun uncomfortable.
I sat there on the seat of the car looking down at the ground, and the
earth became a mosaic of beautiful stones which had been placed in an
intricate design which soon all began to move in a serpentine manner.
Then I became aware that I was looking at the skin of a beautiful
snake Q all the ground around me was this same huge creature and we
were all standing on the back of this gigantic and beautiful reptile.
The experience was very pleasing and I felt no revulsion.  Just then,
another automobile stopped to look at the view and I experienced my
first real feeling of persecution and I wanted very much to leave.

(with 400 mg) During the initial phase of the intoxication (between 2
and 3 hours) everything seemed to have a humorous interpretation.
People's faces are in caricature, small cars seem to be chasing big
cars, and all cars coming towards me seem to have faces.  This one is
a duchess moving in regal pomp, that one is a wizened old man running
away from someone.  A remarkable effect of this drug is the extreme
empathy felt for all small things; a stone, a flower, an insect.  I
believe that it would be impossible to harm anything Q to commit an
overt harmful or painful act on anyone or anything is beyond oneUs
capabilities.  One cannot pluck a flower Q and even to walk upon a
gravel path requires one to pick his footing carefully, to avoid
hurting or disturbing the stones.  I found the color perception to be
the most striking aspect of the experience.  The slightest difference
of shade could be amplified to extreme contrast.  Many subtle hues
became phosphorescent in intensity.  Saturated colors were often
unchanged, but they were surrounded by cascades of new colors tumbling
over the edges.

(with 400 mg) It took a long time to come on and I was afraid that I
had done it wrong but my concerns were soon ended.  The world soon
became transformed where objects glowed as if from an inner
illumination and my body sprang to life.  The sense of my body, being
alive in my muscles and sinews, filled me with enormous joy.  I
watched Ermina fill to brimming with animal spirit, her features
tranformed, her body cat-like in her graceful natural movement.  I was
stopped in my tracks.  The world seemed to hold its breath as the cat
changed again into the Goddess.  As she shed her clothes, she shed her
ego and when the dance began, Ermina was no more.  There was only the
dance without the slightest self-consconciousness. How can anything so
beautiful be chained and changed by other's expectations?  I became
aware of myself in her and as we looked deeply into one another my
boundaries disappeared and I became her looking at me.

EXTENSIONS AND COMMENTARY: Mescaline is one of the oldest psychedelics
known to man.  It is the major active component of the small dumpling
cactus known as Peyote.  It grows wild in the Southwestern United
States and in Northern Mexico, and has been used as an intimate
component of a number of religious traditions amongst the native
Indians of these areas.  The cactus has the botanical name of
Lophophora williamsii or Anhalonium lewinii and is immediately
recognizable by its small round shape and the appearance of tufts of
soft fuzz in place of the more conventional spines.  The dried plant
material has been classically used with anywhere from a few to a
couple of dozen of the hard tops, called buttons, being consumed in
the course of a ceremony.

Throughout the more recently published record of clinical human
studies with mescaline, it has been used in the form of the synthetic
material, and has usually been administered as the sulfate salt.
Although this form has a miserable melting point (it contains water of
crystallization, and the exact melting point depends on the rate of
heating of the sample) it nonetheless forms magnificent crystals from
water.  Long, glistening needles that are, in a sense, its signature
and its mark of purity.  The dosages associated with the above
Rqualitative commentsS are given as if measured as the sulfate,
although the actual form used was usually the hydrochloride salt.  The
conversion factor is given under RdosageS above.

Mescaline has always been the central standard against which all other
compounds are viewed.  Even the United States Chemical Warfare group,
in their human studies of a number of substituted phenethylamines,
used mescaline as the reference material for both quantitative and
qualitative comparisons.  The Edgewood Arsenal code number for it was
EA-1306.  All psychedelics are given properties that are something
like Rtwice the potency of mescalineS or Rtwice as long-lived as
mescaline.S This simple drug is truly the central prototype against
which everything else is measured.  The earliest studies with the
Rpsychotomimetic amphetaminesS had quantitative psychological numbers
attached that read as Rmescaline units.S Mescaline was cast in
concrete as being active at the 3.75 mg/kg level.  That means for a 80
kilogram person (a 170 pound person) a dose of 300 milligrams.  If a
new compound proved to be active at 30 milligrams, there was a M.U.
level of 10 put into the published literature.  The behavioral
biologists were happy, because now they had numbers to represent
psychological properties.  But in truth, none of this represented the
magic of this material, the nature of the experience itself.  That is
why, in this Book II, there is only one line given to Rdosage,S but a
full page given to Rqualitative comments.

Four simple N-modified mescaline analogues are of interest in that
they are natural and have been explored in man.

The N-acetyl analogue has been found in the peyote plant, and it is
also a major metabolite of mescaline in man.  It is made by the gentle
reaction of mescaline with acetic anhydride (a bit too much heat, and
the product N-acetyl mescaline will cyclize to a dihydroisoquinoline,
itself a fine white crystalline solid, mp 160-161 !C) and can be
recrystallized from boiling toluene.  A number of human trials with
this amide at levels in the 300 to 750 milligrams range have shown it
to be with very little activity.  At the highest levels there have
been suggestions of drowsiness.  Certainly there were none of the
classic mescaline psychedelic effects.

If free base mescaline is brought into reaction with ethyl formate (to
produce the amide, N-formylmescaline) and subsequently reduced (with
lithium aluminum hydride) it is converted to the N-methyl homologue.
This base has also been found as a trace component in the Peyote
cactus.  And the effects of N-methylation of other psychedelic drugs
have been commented upon elsewhere in these recipes, all with
consistently negative results (with the noteworthy exception of the
conversion of MDA to MDMA).  Here, too, there is no obvious activity
in man, although the levels assayed were only up to 25 milligrams.

N,N-Dimethylmescaline has been given the trivial name of Trichocerine
as it has been found as a natural product in several cacti of the
Trichocereus Genus but, interestingly, never in any Peyote variant.
It also has proven inactive in man in dosages in excess of 500
milligrams, administered parenterally.  This observation, the absence
of activity of a simple tertiary amine, has been exploited in the
development of several iodinated radiopharmaceuticals that are
mentioned elsewhere in this book.

The fourth modification is the compound with the nitrogen atom
oxidatively removed from the scene.  This is the mescaline metabolite,
3,4,5-trimethoxyphenylacetic acid, or TMPEA.  Human dosages up to 750
milligrams orally failed to produce either physiological or
psychological changes.

One additional manipulation with some of these structures has been
made and should be mentioned.  These are the analogues with an oxygen
atom inserted between the aromatic ring and the aliphatic chain.  They
are, in essence, aminoethyl phenyl ethers.  The first is related to
mescaline itself, 2-(3,4,5-trimethoxyphenoxy)ethylamine.  Human trials
were conducted over the dose range of 10 to 300 milligrams and there
were no effects observed.  The second is related to trichocerine,
N,N-dimethyl-2-(3,4,5-trimethoxyphenoxy)ethylamine.  It was inactive
in man over the range of 10 to 400 milligrams.  Mescaline, at a dose
of 420 milligrams, served as the control in these studies.









#97 4-MA; PMA; 4-METHOXYAMPHETAMINE

SYNTHESIS: A solution of 27.2 g anisaldehyde and 18.0 g nitroethane in
300 mL benzene was treated with 2.0 mL cyclohexane and refluxed using
a Dean Stark trap until H2O ceased to accumulate.  A total of 3.8 mL
was generated over about 5 days.  After the removal of the solvent
under vacuum, the viscous red oily residue was cooled and it
spontaneously crystallized.  This was ground under an equal volume of
MeOH, producing lemon-yellow crystals of
1-(4-methoxyphenyl)-2-nitropropene.  The final yield was 27.4 g of
product with a mp of 45-46 !C.  Recrystallization from 4 volumes MeOH
did not improve the mp.  An excellent alternate synthesis with a
comparable yield involved letting a solution of equimolar amounts of
the aldehyde and nitro-ethane and a tenth mole of n-amylamine stand in
the dark at room temperature for a couple of weeks.  The product
spontaneously crystal-lized, and could be recrystallized from MeOH.
The more conventional synthesis involving acetic acid as a solvent and
ammonium acetate as a catalyst, produced a poor yield of the
nitrostyrene and it was difficult to separate from the white diacetate
of the starting anisaldehyde, mp 59-60 !C.

A suspension of 32 g LAH in 1 L anhydrous Et2O was well stirred and
32.6 g 1-(4-methoxyphenyl)-2-nitropropene in Et2O was added at a rate
that maintained a reflux.  After the addition was complete, reflux was
continued for 48 h.  The reaction mixture was cooled, and the excess
hydride was destroyed by the cautious addition of dilute H2SO4.  The
Et2O was separated, and extracted with additional aqueous H2SO4.  A
solution of 700 g potassium sodium tartrate in 600 mL H2O was added,
and the pH brought to >9 with 25% NaOH.  This aqueous phase was
extracted with 3x200 mL CH2Cl2 which provided, after removal of the
solvent, 32.5 g of a clear amber oil.  This was dissolved in 100 mL
IPA, neutralized with concentrated HCl, and then diluted with 300 mL
anhydrous Et2O.  There was obtained white crystals of
4-methoxyamphetamine hydrochloride (4-MA) that weighed, after
filtering, Et2O washing and air drying, 22.2 g and had a mp of 208-209
!C.  The amphetamine metabolite, 4-hydroxyamphetamine hydrochloride
(4-HA), was prepared by heating 5.0 g 4-MA in 20 mL concentrated HCl
at 15 lbs/in.  After recrystal-lization from aqueous EtOH, the product
weighed 3.8 g and had a mp of 171-172 !C.

DOSAGE: 50 - 80 mg.

DURATION: short.

QUALITATIVE COMMENTS: (with 60 mg) At just over an hour, there was a
sudden blood pressure rise, with the systolic going up 55 mm.  This
was maintained for another hour.  I found the effects reminiscent of
DET, distinct after-images, and some parasthesia.  I was without any
residue by early evening (after 5 hours).

(with 70 mg) It hit quite suddenly.  I had a feeling of druggedness,
almost an alcohol-like intoxication, and I never was really high in
the psychedelic sense.

EXTENSIONS AND COMMENTARY: This is another of the essential
amphetamines, because of the appearance of the 4-methoxy group in two
most important essential oils.  These are the allylbenzene (estragole
or esdragol) and the propenyl isomer (anethole).  Their natural
sources have been discussed under TMA.

Two comments are warranted concerning 4-MA, one of scientific
interest, and the other about a social tragedy.

A major metabolites of amphetamine is 4-hydroxyamphetamine, from
oxidation at the 4-position.  It has been long known that with chronic
amphetamine usage there is the generation of tolerance, which
encourages ever-increasing doses to be used.  When the daily load gets
up around one or two hundred milligrams, the subject can become quite
psychotic.  The question was asked: might the chronic amphetamine user
be methylating his endogenously produced 4-hydroxyamphet-amine to
produce 4-methoxyamphetamine (4-MA), and maybe this is the agent that
promotes the psychosis?  To address this question, several studies
were done with normal subjects, about 20 years ago, to see if 4-MA
might produce a psychotic state (it didnUt at the highest levels
tried, 75 milligrams) and to see if it was excreted to some extent
unchanged in the urines of these normal subjects (it was seen even at
the lowest dosage tried, 10 milligrams).  It produced excitation and
other central effects, it produced adrenergic pressor effects, and it
consistently produced measur-able quantities of 4-MA in the urine, but
it produced no amphetamine-like crazies.  And since the administration
of up to 600 milligrams of amphetamine produced no detectable 4-MA in
the urine, this theory of psychotomimesis is not valid.

On the tragic side, a few years later, 4-MA became widely distributed
in both the US (as the sulfate salt) and in Canada (as the
hydrochloride), perhaps in-spired by some studies in rats that had
reported that it was second only to LSD in potency as a hallucinogen.
The several deaths that occurred probably followed overdose, and it
was clear that 4-MA was involved as it had been isolated from both
urine and tissue during post mortems.  It had been sold under the
names of Chicken Power and Chicken Yellow, and was promoted as being
MDA.  I could find no record of a typical street dosage, but comments
collected in association with the deaths implied that the ingested
quantites were in the hundreds of milligrams.  Rrecently, the ethoxy
homologue, 4-EA, appeared on the streets of Canada.  The dosage,
again, was not reported.  It was promptly illegalized there.

The two positional analogues of 4-MA are known; vis., 2-MA and 3-MA.
Their synthesis is straightforward, in imitation of that for 4-MA
above.  The meta-compound, 3-MA, has been metabolically explored in
man, but no central effects were noted at a 50 milligram dose (2x25
milligrams, separated by three hours).  There appears to be no report
of any human trial of 2-MA.  The N-methyl homologue of 2-MA is a
commercial adrenergic bronchodilator called Methoxyphenamine, or
Orthoxine.  It has been used in the prevention of acute asthma attacks
in doses of up to 200 milligrams, with only slight central
stimulation.  The N-methyl homologues of 3-MA and 4-MA are known, and
the latter compound is the stuff of a separate entry in this book.









#98 MADAM-6; 2,N-DIMETHYL-4,5-METHYLENEDIOXYAMPHETAMINE

SYNTHESIS: A mixture of 102 g POCl3 and 115 g N-methylformanilide was
allowed to stand for 0.5 h at room temperature during which time it
turned a deep claret color.  To this there was added 45 g
3,4-methylenedioxytoluene and the mixture was held on the steam bath
for 3 h.  It was then added to 3 L H2O.  Stirring was continued until
the oil which had separated had become quite firm.  This was removed
by filtration to give a greenish, somewhat gummy, crystalline solid,
which was finely ground under 40 mL MeOH and again filtered giving,
when air dried, 25 g of an almost white solid.  Recrystallization of a
small sample from methylcyclopentane gave ivory-colored glistening
crystals of 2-methyl-4,5-methylenedioxybenzaldehyde with a mp of
88.5-89.5 !C.  In the infra-red, the carbonyl was identical to that of
the starting piperonal (1690 cm-1) but the fingerprint was different
and unique, with bands at 868, 929, 1040 and 1052 cm-1.

A solution of 23 g 2-methyl-4,5-methylenedioxybenzaldehyde in 150 mL
nitroethane was treated with 2.0 g anhydrous ammonium acetate and
heated on the steam bath for 9 h.  The excess solvent was removed
under vacuum to give a dark yellow oil which was dissolved in 40 mL
hot MeOH and allowed to crystallize.  The solids were removed by
filtration, washed modestly with MeOH and air dried, to give 21.2 g of
1-(2-methyl-4,5-methylenedioxyphenyl)-2-nitropropene as beautiful
yellow crystals with a mp of 116-118 !C.  Recrystallization of an
analytical sample from MeOH gave lustrous bright yellow crystals with
a mp of 120-121 !C.  Anal. (C11H11NO4) C,H,N.

A suspension of 54 g electrolytic elemental iron in 240 g glacial
acetic acid was warmed on the steam bath, with frequent stirring.
When the reaction between them started, there was added, a portion at
a time, a solution of 18.2 g
1-(2-methyl-4,5-methylenedioxyphenyl)-2-nitropropene in 125 mL warm
acetic acid.  The orange color of the nitrostyrene solution became
quite reddish, white solids of iron acetate appeared, and a dark
tomato-colored crust formed which was continuously broken back into
the reaction mixture.  Heating was continued for 1.5 h, and then all
was poured into 2 L H2O.  All the insolubles were removed by
filtration, and these were washed well with CH2Cl2.  The filtrate and
washes were combined, the phases separated, and the aqueous phase
extracted with 2x100 mL additional CH2Cl2.  The combined organics were
washed with 5% NaOH, and the solvent removed under vacuum.  The
residue weighed 15.9 g, and was distilled at 90-110 !C at 0.4 mm/Hg to
give 13.9 g of 2-methyl-4,5-methylenedioxyphenylacetone that
spontaneously crystallized.  A small sample from methylcyclopentane
had a mp of 52-53 !C, another from hexane a mp of 53-54 !C, and
another from MeOH a mp of 54-55 !C.  Anal. (C11H12O3) H; C calcd,
68.73; found 67.87, 67.84.

To a stirred solution of 30 g methylamine hydrochloride in 200 mL warm
MeOH there was added 13.5 g 2-methyl-4,5-methylenedioxyphenylacetone
followed, after returning to room temperature, by 7 g sodium
cyanoborohydride.  There was added HCl as needed to maintain the pH at
approximately orange on external damp universal pH paper.  After a few
days, the reaction ceased generating base, and all was poured into 2 L
dilute H2SO4 (caution, HCN evolved).  This was washed with 3x75 mL
CH2Cl2, made basic with 25% NaOH, and the resulting mixture extracted
with 3x100 CH2Cl2.  The pooled extracts were stripped of solvent under
vacuum and the residue, 15 g of a pale amber oil, was distilled at
95-110 !C at 0.4 mm/Hg.  There was obtained 12.3 g of a white oil that
was dissolved in 60 mL IPA, neutralized with approximately 5.5 mL
concentrated HCl, and crystals of the salt formed spontaneously.
These were loosened with the addition of another 10 mL IPA, and then
all was diluted by the addition of an equal volume of anhydrous Et2O.
The white crystals were separated by filtration, Et2O washed, and air
dried to give 14.1 g of 2,N-dimethyl-4,5-methylenedioxyamphetamine
hydrochloride (MADAM-6) as a brilliant white powder with a mp of
206-207 !C.  Anal. (C12H18ClNO2) C,H.

DOSAGE: greater than 280 mg.

DURATION: unknown.

QUALITATIVE COMMENTS: (with 180 mg) There is a hint of good things
there, but nothing more than a hint.  At four hours, there is no
longer even a hint.

(with 280 mg) I took 150 milligrams, waited an hour for results,
which was niente, nada, nothing.  Took supplements of 65 milligrams
twice, an hour apart.  No effect.  Yes, we giveth up.

EXTENSIONS AND COMMENTARY: The structure of MADAM-6 was designed to be
that of MDMA, with a methyl group attached at what should be a
reasonably indifferent position.  In fact, that is the genesis of the
name.  MDMA has been called ADAM, and with a methyl group in the
6-position, MADAM-6 is quite understandable.  And the other
ortho-position is, using this nomenclature, the 2-position, and with a
methyl group there, one would have MADAM-2.  I should make a small
apology for the choice of numbers.  MDMA is a 3,4-methylenedioxy
compound, and the least ambiguous numbering scheme would be to lock
the methylenedioxy group inescapably at the 3,4-place, letting the
other ring position numbers fall where they may.  The rules of
chemistry ask that if something is really a 3,4,6-orientation it
should be renumbered as a 2,4,5-orientation.  Let's quietly ignore
that request here.

How fascinating it is, that a small methyl group, something that is
little more than one more minor bump on the surface of a molecule that
is lumpy and bumpy anyway, can so effectively change the action of a
compound.  A big activity change from a small structure change usually
implies that the bump is at a vital point, such as a target of
metabolism or a point of critical fit in some receptor site.  And
since 6-MADAM can be looked upon as 6-bump-MDMA, and since it is at
least 3x less potent than MDMA, the implication is that the action of
MDMA requires some unbumpiness at this position for its particular
action.  There are suggestions that the body may want to put a
hydroxyl group right there (a 6-hydroxy-dopamine act), and it couldnUt
if there was a methyl group right there.  The isopropylamine side
chain may want a certain degree of swing-around freedom, and this
would be restricted by a methyl bump right next to it.  And there are
all kinds of other speculations possible as to why that position
should be open.

Anyway, MADAM-6 is not active.  And the equally intriguing positional
isomer, the easily made MADAM-2, will certainly contribute to these
speculations.  A quiz for the reader!  Will
2,N-dimethyl-3,4-methylenedioxyamphetamine (MADAM-2) be: (1) Of much
reduced activity, akin to MADAM-6, or (2) Of potency and action
similar to that of MDMA, or (3) Something unexpected and
unanticipated?  I know only one way of finding out.  Make the SchiffsU
base between piperonal and cyclohexylamine, treat this with butyl
lithium in hexane with some TMEDA present, add some
N-methylformanilide, convert the formed benzaldehyde to a nitrostyrene
with nitroethane, reduce this with elemental iron to the
phenylacetone, reduce this in the presence of methylamine with sodium
cyanoborohydride, then taste the result.









#99 MAL; METHALLYLESCALINE;
3,5-DIMETHOXY-4-METHALLYLOXYPHENETHYLAMINE)

SYNTHESIS: To a solution of 5.8 g of homosyringonitrile (see under
ESCALINE for its preparation) in 50 mL of acetone containing 100 mg of
decyltriethylammonium iodide there was added 7.8 mL methallyl chloride
followed by 6.9 g of finely powdered anhydrous K2CO3.  The suspension
was kept at reflux by a heating mantle, with effective stirring.
After 6 h an additional 4.0 mL of methallyl chloride was added, and
the refluxing was continued for an additional 36 h.  The solvent and
excess methallyl chloride was removed under vacuum and the residue was
added to 400 mL H2O.  This solution was extracted with 3x75 mL CH2Cl2.
The extracts were pooled, washed with 2x50 mL 5% NaOH, and the solvent
removed to provide a dark brown oil.  This was distilled at 120-130 !C
at 0.4 mm/Hg to provide 6.1 g of
3,5-dimethoxy-4-methyallyloxyphenylacetonitrile as a lemon-colored
viscous oil.  Anal. (C14H17NO3) C,H.

A suspension of 4.2 g LAH in 160 mL anhydrous THF under He was
stirred, cooled to 0 !C, and treated with 2.95 ml of 100% H2SO4 added
dropwise.  This was followed by the addition of 6.0 g of
3,5-dimethoxy-4-methallyloxy-phenylacetonitrile dissolved in 10 mL
anhydrous THF, at a slow rate with vigorous stirring.  The reaction
mixture was held at reflux on the steam bath for 0.5 h, brought back
to room temperature, and the excess hydride destroyed with IPA.
Sufficient 15% NaOH was added to convert the formed solids to a loose,
granular texture, and the entire mixture filtered and washed with THF.
The filtrate and washings were pooled, the solvent removed under
vacuum, and the residue added to 500 mL dilute HCl.  This solution was
washed with 2x50 mL CH2Cl2, made basic with aqueous NaOH, and
extracted with 3x75 mL CH2Cl2.  The extracts were pooled, the solvent
removed under vacuum, and the residual pale amber oil distilled at
120-130 !C at 0.3 mm/Hg to provide 1.5 g of a white oil.  This was
dissolved in 8.0 mL of IPA and neutralized with 25 drops of
concentrated HCl.  The addition of 40 ml of anhydrous Et2O with
stirring produced, after a few moments delay, a spontaneous
crystallization of 3,5-dimethoxy-4-methallyloxyphenethylamine
hydrochloride (MAL) as fine white needles.  After standing overnight
these were removed by filtration, washed with an IPA/Et2O mixture,
then with Et2O, and allowed to air dry to constant weight.  The
product weighed 1.1 g, and had a mp of 153-154 !C.  Anal.
(C14H22ClNO3) C,H.

DOSAGE: 40 - 65 mg.

DURATION: 12 - 16 h.

QUALITATIVE COMMENTS: (with 45 mg) Too much overload. I am
sur-rounded with unreality.  I do not choose to repeat the
experiment.

(with 45 mg) I am basically favorably impressed.  I believe the
initial discomfort would be alleviated by taking two 30 milligram
doses separated by an hour.

(with 45 mg) Much too much too much.  There are shades of what might
become amnesia.  I am losing immediate contact.  I will not repeat.

(with 50 mg) A good level.  I found myself totally caught up in the
visual theater.  Although I had trouble sleeping, I would willingly
repeat the experiment at the same level.

(with 60 mg) Extremely restless.  Am very impressed with all the
activity.  But if I repeated it would be at a lower dose.

(with 60 mg) Friendly territory.  There is much kaleidoscopic TneonU
colors.  Eyes closed very active.  Eyes open there is considerable
visual distortions seen in melted wax.  Faces are distorted (friendly)
but the sinister is not far away.

(with 65 mg) Completely involved Q good psychedelic state Q visual
entertainment with alternation (i.e., depth and movement) at the
retinal level Q detail in watercolors.  Later in the experience (the 8
hour point) easy childhood memory recall.

(with 65 mg) Beautiful.  To a +2 by the 1st hr and continued
climbing.  Intense +3 within 2 hrs.  Quite strong body.  Diuretic.
Fantasy, imagery, erotic.  Way up, good connections between parts of
self.  Slight slowing of pulse in 7th to 8th hour.  Excellent solid
sleep with strong, clear, balancing dreams.  But not until after 12
hrs.

EXTENSIONS AND COMMENTARY: This testimony can be accurately described
as a mixed bag!

This base, MAL, lies as a hybrid of two other compounds, AL and CPM.
It is an olefin (as is AL) which means that it has a place of
unsaturation in its structure.  And it is an isostere of CPM which
means that the carbon atoms are all in the same location, but just the
connecting electrons (called the chemical bonds) are in different
places.  Actually there is yet a third compound in this same picture,
called PROPYNYL.  And yet, although all of them have extremely close
structural similarities, there are such great differences in action
that one does not dare to generalize.  CPM leads largely to fantasy,
MAL largely to visual imagery, AL is twice as potent as either of
these but it doesnUt show either effect, and PROPYNYL is almost
without any action at all.

Speaking of generalization, I am glad that there are always
exceptions.  Some years ago, I had a most difficult experience with a
strain of marijuana that was known by the name of DRED.  The only word
that I can use to describe my response to it is to say that I felt I
had been poisoned.  From this I warned myself to beware (and to
believe in) whatever common name a drug might have been given.
Fortunately, MAL did not live up to its name (at least for me),
although some of the experimental subjects might disagree!

One additional compound was suggested by these parallels.  Each of
these three drugs can be viewed as having a negative something hanging
out a-ways from the molecular center.  With AL and MAL, this is the
olefin double bond.  With CPM this is a very strained three-member
ring.  What about an oxygen?  The reaction between homosyringonitrile
and methoxyethyl chloride produced the precursor to such a product
(3,5-dimethoxy-4-(2-methoxyethoxy)-phenethylamine) but the yield was
so bad that the project was abandoned.  This same grouping has
successfully been put into the 4-position of the sulfur-containing
analog, and the result (2C-T-13) has proved to be quite a potent and
interesting material.  Maybe someday hang a sulfur atom out there at
the end of that chain.

The name methallylescaline actually is completely unsound.  There is
no union of a methallyl with an escaline.  What is really there is not
an escaline at all, but rather a mescaline with a 2-propene attached
to the methyl of the methoxy on the 4-position.  There is no way of
naming the thing in that manner, so the only logical solution is to
take off the methyl entirely, and then put the methallyl on in its
place.  The name of this would then be
4-methylallyldesmethylmescaline.  That would have received the
abbreviation MAD which would have been even more difficult to deal
with.  MAL is preferable.









#100 MDA; 3,4-METHYLENEDIOXYAMPHETAMINE

SYNTHESIS: (from piperonal) To a solution of 15.0 g piperonal in 80 mL
glacial acetic acid there was added 15 mL nitroethane followed by 10 g
cyclohexylamine.  The mixture was held at steam-bath temperature for 6
h, diluted with 10 mL H2O, seeded with a crystal of product, and
cooled overnight at 10 !C.  The bright yellow crystals were removed by
filtration, and air dried to yield 10.7 g of
1-(3,4-methylenedioxyphenyl)-2-nitropropene with a mp of 93-94 !C.
This was raised to 97-98 !C by recrystallization from acetic acid.
The more conventional efforts of nitrostyrene synthesis using an
excess of nitroethane as a solvent and anhydrous ammonium acetate as
the base, gives impure product in very poor yields.  The nitrostyrene
has been successfully made from the components in cold MeOH, with
aqueous NaOH as the base.

A suspension of 20 g LAH in 250 mL anhydrous THF was placed under an
inert atmosphere and stirred magnetically.  There was added, dropwise,
18 g of 1-(3,4-methylenedioxyphenyl)-2-nitropropene in solution in THF
and the reaction mixture was maintained at reflux for 36 h.  After
being brought back to room temperature, the excess hydride was
destroyed with 15 mL IPA, followed by 15 mL of 15% NaOH.  An
additional 50 mL H2O was added to complete the conversion of the
aluminum salts to a loose, white, easily filtered solid.  This was
removed by filtration, and the filter cake washed with additional THF.
The combined filtrate and washes were stripped of solvent under
vacuum, and the residue dissolved in dilute H2SO4.  Washing with 3x75
mL CH2Cl2 removed much of the color, and the aqueous phase was made
basic and reextracted with 3x100 mL CH2Cl2.  Removal of the solvent
yielded 13.0 g of a yellow-colored oil that was distilled.  The
fraction boiling at 80-90 !C at 0.2 mm weighed 10.2 g and was
water-white.  It was dissolved in 60 mL of IPA, neutralization with
concentrated HCl, and diluted with 120 mL of anhydrous Et2O which
produced a lasting turbidity.  Crystals formed spontaneously which
were removed by filtration, washed with Et2O, and air dried to provide
10.4 g of 3,4-methylenedioxyamphetamine hydrochloride (MDA) with a mp
of 187-188 !C.

(from 3,4-methylenedioxyphenylacetone) To a solution of 32.5 g
anhydrous ammonium acetate in 120 mL MeOH, there was added 7.12 g
3,4-methylenedioxyphenylacetone (see under MDMA for its preparation)
followed by 2.0 g sodium cyanoborohydride.  The resulting yellow
solution was vigorously stirred, and concentrated HCl was added
periodically to keep the pH of the reaction mixture between 6 and 7 as
determined by external damp universal pH paper.  After several days,
undissolved solids remained in the reaction mixture and no more acid
was required.  The reaction mixture was added to 600 mL of dilute HCl,
and this was washed with 3x100 mL CH2Cl2.  The combined washes were
back-extracted with a small amount of dilute HCl, the aqueous phases
combined, and made basic with 25% NaOH.  This was then extracted with
3x100 mL CH2Cl2, these extracts combined, and the solvent removed
under vacuum to provide 3.8 g of a red-colored residue.  This was
distilled at 80-90 !C at 0.2 mm/Hg to provide 2.2 g of an absolutely
water-white oil.  There was no obvious formation of a carbonate salt
when exposed to air.  This was dissolved in 15 mL IPA, neutralized
with 25 drops of concentrated HCl, and diluted with 30 mL anhydrous
Et2O.  Slowly there was the deposition of white crystals of
3,4-methylenedioxyamphetamine hydrochloride (MDA) which weighed 2.2 g
and had a mp of 187-188 !C.  The preparation of the formamide (a
precursor to MDMA) and the acetamide (a precursor to MDE) are
described under those entries.

DOSAGE: 80 - 160 mg.

DURATION: 8 - 12 h.

QUALITATIVE COMMENTS: (with 100 mg) The coming on was gradual and
pleasant, taking from an hour to an hour and one half to do so.  The
trip was euphoric and intense despite my having been naturally
depleted from a working day and having started so late.  One thing
that impressed itself upon me was the feeling I got of seeing the play
of events, of what I thought to be the significance of certain people
coming into my life, and why my TdanceU, like everyone elseUs, is
unique.  I saw that every encounter or event is a potential for
growth, and an opportunity for me to realize my completeness at where
I am, here and now, not at some future where I must lug the pieces of
the past for a final assemblage Tthere.U I was reminded of living the
moment to its fullest and I felt that seeing this was indicative that
I was on the right track.

(with 128 mg) Forty-five minutes after the second dosage, when I was
seated in a room by myself, not smoking, and where there was no
possible source of smoke rings, an abundance of curling gray smoke
rings was readily observed in the environment whenever a relaxed
approach to subjective observation was used.  Visually these had
complete reality and it seemed quite unneccessary to test their
properties because it was surely known and fully appreciated that the
source of the visual phenomena could not be external to the body.
When I concentrated my attention on the details of the curling gray
forms by trying to note how they would be affected by passing a finger
through their apparent field, they melted away.  Then, when I relaxed
again, the smoke rings were there.  I was as certain that they were
really there as I am now sure that my head is on top of my body.

(with 140 mg) I vomited quite abruptly, and then everything was OK.
I had been drinking probably excessively the last two days, and maybe
the body needed to unpoison itself.  The tactile sense is beautiful,
but there seems to be some numbness as well, and I feel that nothing
erotic would be do-able.  Intimacy, yes, but no performance IUm pretty
sure.  I saw the experience start drifting away only four hours into
it, and I was sad to see it go.  It was an all around delightful day.

(with 200 mg, 2x100 mg spaced 1 h) RThe first portion was apparent at
one-half hour.  There was microscopic nausea shortly after the second
portion was taken, and in an hour there was a complete +++ developed.
The relaxation was extreme.  And there seemed to be time distortion,
in that time seemed to pass slowly.  There was a occasional LSD-like
moment of profoundness, but by and large it was a simple intoxication
with most things seeming quite hilarious.  The intoxication was also
quite extreme.  Some food was tried later in the experiment, and it
tasted good, but there was absolutely no appetite.  None at all.

(with 60 mg of the RRS isomer) There was a light and not too gentle
development of a somewhat brittle wound-up state, a + or even a ++.
Chills, and I had to get under an electric blanket to be comfortable.
The effects smoothed out at the fourth hour, when things started to
return to baseline.  Not too entertaining.

(with 100 mg of the RRS isomer) Rapid development from the 40 minute
point to an hour and a quarter; largely a pleasant intoxication, but
there is something serious there too.  No great insights, and not too
much interference with the day's goings-on.  Completely clear at the 8
hour point.

(with 120 mg of the RRS isomer) This is a stoning intoxicant.  I
would not choose to drive, because of possible judgement problems, but
my handwriting seems to be clear and normal.  The mental excitement
dropped rapidly but I was aware of physical residues for several
additional hours.

(with 80 mg of the RSS isomer) A very thin, light threshold, which is
quite delightful.  I am quite willing to push this a bit higher.

(with 120 mg of the RSS isomer) Perhaps to a one +.  Very light, and
very much like MDMA, but perhaps shorter lived.  I am pretty much
baseline in three hours.

(with 160 mg of the RSS isomer) The development is very rapid, and
there is both muscular tremor and some nausea.  The physicals are
quite bothersome.  With eyes closed, there are no effects noticeable,
but with eyes open, things are quite bright and sparkling.  The
muscular spasms persist, and there is considerable teeth clenching.  I
feel that the mental is not worth the physical.

EXTENSIONS AND COMMENTARY: There are about twenty different synthetic
routes in the literature for the preparation of MDA.  Many start with
piperonal, and employ it to make methylenedioxyphenylacetone or a
methylenedioxydihydro-cinnamic acid amide instead of the nitrostyrene.
The phenylacetone can be reduced in several ways other than the
cyanoborohydride method mentioned here, and the amide can be
rearranged directly to MDA.  And there are additional methods for the
reduction of the nitrostyrene that use no lithium aluminum hydride.
Also there are procedures that have safrole or isosafrole as starting
points.  There is even one in the underground literature that starts
with sassafras root bark.  In fact, it is because safrole is one of
the ten essential oils that MDA can humorously be referred to as one
of the Ten Essential Amphetamines.  See the comments under TMA.

There is a broad and checkered history concerning the use and abuse of
MDA, and it is not the case that all the use was medical and all the
abuse was social.  One of the compulsive drives of both the military
and the intelligence groups, just after World War II, was to discover
and develop chemical agents which might serve as Rtruth serumsS or as
incapacitating agents.  These government agencies considered the area
of the psychedelics to be a fertile field for searching.  The giving
of relatively unexplored drugs in a cavalier manner to knowing and
unknowing subjects was commonplace.  There was one case in 1953,
involving MDA and a psychiatric patient named Howard Blauer that
proved fatal.  The army had contracted with several physicians at the
New York State Psychiatric Institute to explore new chemicals from the
Edgewood Arsenal and one of these, with a chemical warfare code number
of EA-1298, was MDA.  The last and lethal injection into Blauer was an
intravenous dose of 500 milligrams.

There have been a number of medical explorations.  Under the code
SKF-5 (and trade name of Amphedoxamine) it was explored as an anorexic
agent.  It has been found promising in the treatment of psychoneurotic
depression.  There are several medical reports, and one book (Claudio
Naranjo's The Healing Journey), that describe its values in
psychotherapy.

MDA was also one of the major drugs that was being popularly used in
the late 1960's when the psychedelic concept exploded on the public
scene.  MDA was called the Rhug-drugS and was said to stand for Mellow
Drug of America.  There was no difficulty in obtaining unending
quantities of it, as it was available as a research chemical from
several scientific supply houses (as were mescaline and LSD) and was
sold inexpensively under its chemical name.

A few experimental trials with the pure optical isomers show a
consistency with all the other psychedelic compounds that have been
studied in their separated forms, the higher potency with the RRS
isomer.  The less potent RSS isomer seemed to be more peaceful and
MDMA-like at lower doses, but there were worrisome toxic signs at
higher levels.

The structure of MDA can be viewed as an aromatic ring (the
3,4-methylenedioxyphenyl ring) with a three carbon chain sticking out
from it.  The amine group is on the second of the three carbon atoms.
The isomers, with the amine function moved to the first of these
carbons atoms (a benzylamine) and with the amine function moved to the
third (furthest out atom) of these carbon atoms (a (n)-propylamine),
are known and both have been assayed.

The benzylamine counterpart (as if one were to move the amine function
from the beta-carbon to the alpha-carbon of the three carbon chain of
the amphetamine molecule) is alpha-ethyl-3,4-methylenedioxybenzylamine
or 1-amino-1-(3,4-methylenedioxyphenyl)propane, ALPHA.  The
hydrochloride salt has a mp of 199-201 !C.  At low threshold levels
(10 milligram area) there were eyes-closed RdreamsS with some body
tingling.  The compound was not anorexic at any dose (up to 140
milligrams) and was reported to produce a pleasant, positive feeling.
It is very short-lived (about 3 hours).  The N-methyl homologue is
alpha-ethyl-N-methyl-3,4-methylenedioxybenzylamine or
1-methylamino-1-(3,4-methylenedioxy-phenyl)propane, M-ALPHA.  It is
similar in action, but is perhaps twice as potent (a plus one or plus
two dose is 60 milligrams) and of twice the duration.

The (n)-propylamine counterpart (as if one were to move the amine
function the other direction, from the beta-carbon to the gamma-carbon
of the three carbon chain of the amphetamine molecule) is
gamma-3,4-methylenedioxyphenylpropylamine or
1-amino-3-(3,4-methylenedioxyphenyl)propane, GAMMA.  The hydrochloride
salt has a mp of 204-205 !C.  At oral levels of 200 milligrams there
was some physical ill-at-ease, possible time distortion, and a feeling
of being keenly aware of one's surroundings.  The duration of effects
was 4 hrs.

The phenethylamine that corresponds to MDA (removing the alpha-methyl
group) is 3,4-methylenedioxyphenethylamine, or homopiperonylamine, or
MDPEA, or simply H in the vocabulary of the Muni-Metro world.  This
compound is an entry in its own rights.  The adding of another carbon
atom to the alpha-methyl group of MDA gives compound J, and leads to
the rest of the Muni-Metro series (K, L etc).  All of this is
explained under METHYL-J.  The bending of this alpha-methyl group back
to the aromatic ring gives an aminoindane, and with J one gets an
aminotetralin.  Both compounds react in animal discrimination studies
identically to MDMA, and they appear to be free of neurochemical
toxicity.

The two possible homologues, with either one or two methyl groups on
the methylene carbon of the methylenedioxy group of MDA, are also
known.  The ethylidene compound (the acetaldehyde addition to the
catechol group) has been encoded as EDA, and the acetone
(isopropylidine addition to the catechol group) is called IDA.  In
animal discrimination studies, and in in vitro neurotransmitter
studies, they both seem to be of decreased potency.  EDA is down two
to three-fold from MDA, and IDA is down by a factor of two to
three-fold again.  Human trials of up to 150 milligrams of the
hydrochloride salt of EDA producd at best a threshold
light-headedness.  IDA remains untested as of the present time.  The
homologue of MDA (actually of MDMA) with the added carbon atom in,
rather than on, the methylenedioxy ring, is a separate entry; see
MDMC.

A final isomer to be mentioned is a positional isomer.  The
3,4-methylene-dioxy group could be at the 2,3-position of the
amphetamine skeleton, giving 2,3-methylenedioxyamphetamine, or
ORTHO-MDA.  It appears to be a stimulant rather than another MDA.  At
50 milligrams, one person was awake and alert all night, but reported
no MDA-like effects.









#101 MDAL; N-ALLYL-MDA; 3,4-METHYLENEDIOXY-N- ALLYLAMPHETAMINE

SYNTHESIS: A total of about 20 mL allylamine was introduced under the
surface of 20 mL concentrated HCl, and the mixture stripped of
volatiles under vacuum The resulting 24 g of wet material did not
yield any crystals with either acetone or Et2O.  This was dissolved in
75 mL MeOH, treated with 4.45 g 3,4-methylenedioxy-phenylacetone (see
under MDMA for its preparation), and finally with 1.1 g sodium
cyanoborohydride.  Concentrated HCl was added as needed over the
course of 5 days to keep the pH constant at about 6.  The reaction
mixture was then added to a large amount of H2O, acidified with HCl,
and extracted with 3x100 mL CH2Cl2.  The aqueous phase was made basic
with 25% NaOH, and extracted with 3x100 mL CH2Cl2.  Evaporation of the
solvent from these extracts yielded 3.6 g of an amber oil which, on
distillation at 90-95 !C at 0.2 mm/Hg, yielded 2.6 g of an off-white
oil.  This was dissolved in 10 mL IPA, neutralized with about 25 drops
of concentrated HCl, and the resulting clear but viscous solution was
diluted with Et2O until crystals formed.  These were removed by
filtration, washed with IPA/Et2O (1:1), then with Et2O, and air dried
to constant weight.  There was thus obtained 2.5 g of
3,4-methylenedioxy-N-allylamphetamine hydrochloride (MDAL) with a mp
of 174-176 !C and a proton NMR spectrum that showed that the allyl
group was intact.  Anal. (C13H18ClNO2) N.

DOSAGE: greater than 180 mg.

DURATION: unknown.

EXTENSIONS AND COMMENTARY: Here is another inactive probe, like MDPR,
that could possibly serve as a primer to LSD.  The three carbon chain
on the nitrogen seen with MDPR is almost identical to the three carbon
chain on the nitrogen atom of MDAL.  And yet, where an RinactiveS
level of 180 milligrams of MDPR is a rather fantastic enhancer of LSD
action, the same weight of this compound not only does not enhance,
but actually seems to somewhat antagonize the action of LSD.  All this
difference from just a couple of hydrogen atoms.  Identical carbon
atoms, identical oxygen atoms, and an identical nitrogen atom.  And
all in identical places.  Simply C13H18ClNO2 rather than C13H20ClNO2.

So, apparently, almost identical is not good enough!









#102 MDBU; N-BUTYL-MDA; 3,4-METHYLENEDIOXY-N-BUTYLAMPHETAMINE

SYNTHESIS: A total of 30 mL butylamine was introduced under the
surface of 33 mL concentrated HCl, and the mixture stripped of
volatiles under vacuum.  The resulting glassy solid was dissolved in
160 mL MeOH and treated with 7.2 g 3,4-methylenedioxyphenylacetone
(see under MDMA for its preparation).  To this there was added 50%
NaOH dropwise until the pH was at about 6 as determined by the use of
external dampened universal pH paper.  The solution was vigorously
stirred and 2.8 g sodium cyanoborohydride was added.  Concentrated HCl
was added as needed, to keep the pH constant at about 6.  The addition
required about two days, during which time the reaction mixture first
became quite cottage-cheese like, and then finally thinned out again.
All was dumped into 1 L H2O acidified with HCl, and extracted with
3x100 mL CH2Cl2.  These extracts were combined, extracted with 2x100
mL dilute H2SO4, which was combined with the aqueous fraction above.
This latter mixture was made basic with 25% NaOH, and extracted with
3x150 mL CH2Cl2.  Evaporation of the solvent yielded 4.0 g of an amber
oil which, on distillation at 90-100 !C at 0.15 mm/Hg, yielded 3.2 g
of a white clear oil.  This was dissolved in 20 mL IPA, neutralized
with 30 drops of concentrated HCl, and the spontaneously formed
crystals were diluted with sufficient anhydrous Et2O to allow easy
filtration.  After Et2O washing and air drying, there was obtained 2.8
g of 3,4-methylenedioxy-N-butylamphetamine hydrochloride (MDBU) as
white crystals with a mp of 200-200.5 !C.  Anal. (C14H22ClNO2) N.

DOSAGE: greater than 40 mg.

DURATION: unknown.

EXTENSIONS AND COMMENTARY: Straight chain homologues on the nitrogen
atom of MDA longer than two carbons are probably not active.  This
butyl compound provoked no interest, and although the longer chain
counterparts were made by the general sodium cyanoborohydride method
(see under MDBZ), they were not tasted.  All mouse assays that
compared this homologous series showed a consistent decrease in action
(anesthetic potency and motor activity) as the alkyl chain on the
nitrogen atoms was lengthened.

This synthetic procedure, using the hydrochloride salt of the amine
and sodium cyanoborohydride in methanol, seems to be quite general for
ketone compounds related to 3,4-methylenedioxyphenylacetone.  Not only
were most of the MD-group of compounds discussed here made in this
manner, but the use of phenylacetone (phenyl-2-propanone, P-2-P)
itself appears to be equally effective.  The reaction of butylamine
hydrochloride in methanol, with phenyl-2-propanone and sodium
cyanoborohydride at pH of 6, after distillation at 70-75 !C at 0.3
mm/Hg, produced N-butylamphetamine hydrochloride (23.4 g from 16.3 g
P-2-P).  And, in the same manner with ethylamine hydrochloride there
was produced N-ethylamphetamine (22.4 g from 22.1 g P-2-P) and with
methylamine hydrochloride there was produced N-methylamphetamine
hydrochloride (24.6 g from 26.8 g P-2-P). The reaction with simple
ammonia (as ammonium acetate) gives consistently poor yields in these
reactions.









#103 MDBZ; N-BENZYL-MDA; 3,4-METHYLENEDIOXY-N-BENZYLAMPHETAMINE

SYNTHESIS: To a suspension of 18.6 g benzylamine hydrochloride in 50
mL warm MeOH there was added 2.4 g of 3,4-methylenedioxyphenylacetone
(see under MDMA for its preparation) followed by 1.0 g sodium
cyanoborohydride.  Concentrated HCl in MeOH was added over several
days as required to maintain the pH at about 6 as determined with
external, dampened universal paper.  When the demand for acid ceased,
the reaction mixture was added to 400 mL H2O and made strongly acidic
with an excess of HCl.  This was extracted with 3x150 mL CH2Cl2 (these
extracts must be saved as they contain the product) and the residual
aqueous phase made basic with 25% NaOH and again extracted with 4x100
mL CH2Cl2.  Removal of the solvent under vacuum and distillation of
the 8.7 g pale yellow residue at slightly reduced pressure provided a
colorless oil that was pure, recovered benzylamine.  It was best
characterized as its HCl salt (2 g in 10 mL IPA neutralized with about
25 drops concentrated HCl, and dilution with anhydrous Et2O gave
beautiful white crystals, mp 267-268 !C).  The saved CH2Cl2 fractions
above were extracted with 3x100 mL dillute H2SO4.  These pooled
extracts were back-washed once with CH2Cl2, made basic with 25% NaOH,
and extracted with 3x50 mL CH2Cl2.  The solvent was removed from the
pooled extracts under vacuum, leaving a residue of about 0.5 g of an
amber oil.  This was dissolved in 10 mL IPA, neutralized with
concentrated HCl (about 5 drops) and diluted with 80 mL anhydrous
Et2O.  After a few min, 3,4-methylenedioxy-N-benzylamphetamine
hydrochloride (MDBZ) began to appear as a fine white crystalline
product.  After removal by filtration, Et2O washing and air drying,
this weighed 0.55 g, and had a mp of 170-171 !C with prior shrinking
at 165 !C.  Anal. (C17H20ClNO2) N.

DOSAGE: greater than 150 mg.

DURATION: unknown.

EXTENSIONS AND COMMENTARY: The benzyl group is a good ally in the
synthetic world of the organic chemist, in that it can be easily
removed by catalytic hydrogenation.  This is a trick often used to
protect (for a step or series of steps) a position on the molecule,
and allowing it to become free and available at a later part in a
synthetic scheme.  In pharmacology, however, it is often a
disappointment.  With most centrally active alkaloids, there is a
two-carbon separation between the weak base that is called the
aromatic ring, and the strong base that is called the nitrogen.  This
is what makes phenethylamines what they are.  The phen- is the
aromatic ring (this is a shortened form of prefix phenyl which is a
word which came, in turn, from the simplest aromatic alcohol, phenol);
the ethyl is the two carbon chain, and the amine is the basic
nitrogen.  If one carbon is removed, one has a benzylamine, and it is
usually identified with an entirely different pharmacology, or is most
often simply not active.  A vivid example is the narcotic drug,
Fentanyl.  The replacement of the phenethyl group, attached to the
nitrogen atom with a benzyl group, virtually eliminates its analgesic
potency.

Here too, there appears to be little if any activity in the N-benzyl
analogue of MDA.  A number of other variations had been synthesized,
and none of them ever put into clinical trial.  With many of them
there was an ongoing problem in the separation of the starting amine
from the product amine.  Sometimes the difference in boiling points
could serve, and sometimes their relative polarities could be
exploited. Sometimes, ion-pair extraction would work wonders.  But
occasionally, nothing really worked well, and the final product had to
be purified by careful crystallization.

Several additional N-homologues and analogues of MDA are noted here.
The highest alkyl group on the nitrogen of MDA to give a compound that
had been assayed, was the straight-chain butyl homologue, MDBU.  Six
other N-alkyls were made, or attempted.  Isobutylamine hydrochloride
and 3,4-methylenedioxyphenylacetone were reduced with sodium
cyanoborohydride in methanol to give
3,4-methylenedioxy-N-(i)-butylamphetamine boiling at 95-105 !C at 0.15
mm/Hg and giving a hydrochloride salt (MDIB) with a mp of 179-180 !C.
Anal. (C14H22ClNO2) N.  The reduction with sodium cyanoborohydride of
a mixture of (t)-butylamine hydrochloride and
3,4-methylenedioxyphenylacetone in methanol produced
3,4-methylenedioxy-N-(t)-butylamphetamine (MDTB) but the yield was
miniscule.  The amyl analog was similarly prepared from (n)-amylamine
hydrochloride and 3,4-methylenedioxyphenylacetone in methanol to give
3,4-methylenedioxy-N-amylamphetamine which distilled at 110-120 !C at
0.2 mm/Hg and formed a hydrochloride salt (MDAM) with a mp of 164-166
!C.  Anal. (C15H24ClNO2) N.  A similar reaction with (n)-hexylamine
hydrochloride and 3,4-methylenedioxyphenylacetone in methanol, with
sodium cyanoborohydride, produced after acidification with dilute
sulfuric acid copious white crystals that were water and ether
insoluble, but soluble in methylene chloride!  This sulfate salt in
methylene chloride was extracted with aqueous sodium hydroxide and the
remaining organic solvent removed to give a residue that distilled at
110-115 !C at 0.2 mm/Hg to give
3,4-methylenedioxy-N-(n)-hexylamphetamine which, as the hydrochloride
salt (MDHE) had a mp of 188-189 !C.  Anal. (C16H26ClNO2) N.  An
attempt to make the 4-amino-heptane analogue from the primary amine,
3,4-methylenedioxyphenylacetone, and sodiumcyanoborohydride in
methanol seemed to progress smoothly, but none of the desired product
3,4-methylenedioxy-N-(4-heptyl)-amphetamine could be isolated.  This
base has been named MDSE, with a SE for septyl rather than HE for
heptyl, to resolve any ambiguities about the use of HE for hexyl.  In
retrospect, it had been assumed that the sulfate salt would have
extracted into methylene chloride, and the extraordinary partitioning
of the sulfate salt of MDHE mentioned above makes it likely that the
sulfate salt of MDSE went down the sink with the organic extracts of
the sulfuric acid acidified crude product.  Next time maybe ether as a
solvent, or citric acid as an acid.  With (n)-octylamine hydrochloride
and 3,4-methylenedioxyphenylacetone in methanol, with sodium
cyanoborohydride, there was obtained
3,4-methylenedioxy-N-(n)-octylamphetamine as a water-insoluble,
ether-insoluble sulfate salt.  This salt was, however, easily soluble
in methylene chloride, and with base washing of this solution, removal
of the solvent, and distillation of the residue (130-135 !C at 0.2
mm/Hg) there was eventually gotten a fine hydrochloride salt (MDOC) as
white crystals with a mp of 206-208 !C.  Anal. (C18H30ClNO2) N.

As to N,N-dialkylhomologues of MDA, the N,N-dimethyl has been
separately entered in the recipe for MDDM.  Two efforts were made to
prepare the N,N-diethyl homologue of MDA.  The reasonable approach of
reducing a mixture of diethylamine hydrochloride and
3,4-methylenedioxyphenylacetone in methanol with sodium
cyanoborohydride was hopelessly slow and gave little product.  The
reversal of the functionality was successful.  Treatment of MDA (as
the amine) and an excess of acetaldehyde (as the carbonyl source) with
sodium borohydride in a cooled acidic medium gave, after acid-base
workup, a fluid oil that distilled at 85-90 !C at 0.15 mm/Hg and was
converted in isopropanol with concentrated hydrochloric acid to
3,4-methylenedioxy-N,N-diethylamphetamine (MDDE) with a mp of 177-178
!C.  Anal. (C14H22ClNO2) N.

And two weird N-substituted things were made.  Aminoacetonitrile
sulfate and 3,4-methylenedioxyphenylacetone were reduced in methanol
with sodium cyanoborohydride to form
3,4-methylenedioxy-N-cyanomethylamphetamine which distilled at about
160 !C at 0.3 mm/Hg and formed a hydrochloride salt (MDCM) with a mp
of 156-158 !C after recrystallization from boiling isopropanol. Anal.
(C12H15ClN2O2) N.  During the synthesis of MDCM, there appeared to
have been generated appreciable ammonia, and the distillation provided
a fore-run that contained MDA.  The desired product had an acceptable
NMR, with the N-cyanomethylene protons as a singlet at 4.38 ppm.  A
solution of t-butylhydrazine hydrochloride and
3,4-methylenedioxyphenylacetone in methanol was reduced with sodium
cyanoborohydride and gave, after acid-basing and distillation at
95-105 !C at 0.10 mm/Hg, a viscous amber oil which was neutralized in
isopropanol with concentrated hydrochloric acid to provide
3,4-methylenedioxy-N-(t)-butylaminoamphetamine hydrochloride (MDBA)
with a mp of 220-222 !C with decomposition.  Anal. (C14H23ClN2O2); N:
calcd, 9.77; found, 10.67, 10.84.









#104 MDCPM; CYCLOPROPYLMETHYL-MDA;
3,4-METHYLENEDIOXY-N-CYCLOPROPYLMETHYLAMPHETAMINE

SYNTHESIS: A solution of 9.4 g cyclopropylmethylamine hydrochloride in
30 mL MeOH was treated with 1.8 g 3,4-methylenedioxyphenylacetone (see
under MDMA for its preparation) followed by 0.5 g sodium
cyanoborohydride.  Concentrated HCl was added as needed to keep the pH
constant at about 6.  After several days stirring, the reaction
mixture was added to H2O, acidified with HCl, and washed with 2x100 mL
CH2Cl2.  The aqueous phase was made basic with 25% NaOH, and extracted
with 3x150 mL CH2Cl2.  Removal of the solvent from these extracts
under vacuum yielded 2.8 g of a crude product which, on distillation
at 90-100 !C at 0.1 mm/Hg, yielded 0.4 g of a clear white oil.  This
was dissolved in a small amount of IPA, neutralized with a few drops
of concentrated HCl, and diluted with anhydrous Et2O to the point of
turbidity.  There was obtained a small yield of crystalline
3,4-methylenedioxy-N-cyclopropylmethylamphetamine hydrochloride
(MDCPM) which was filtered off, Et2O washed and air dried.  The mp was
218-220 !C, with extensive darkening just prior to melting.  Anal.
(C14H20ClNO2) N.

DOSAGE: greater than 10 mg.

DURATION: unknown.

EXTENSIONS AND COMMENTARY: The record of the tasting assay of this
compound is pretty embarrassing.  The highest level tried was 10
milligrams, which showed no hint of activity.  But in light of the
rather colorful activities of other cyclopropylmethyl things such as
CPM and 2C-T-8 , this compound might someday warrant reinvestigation.
It is a certainty that the yield could only be improved with a careful
resynthesis.









#105 MDDM; N,N-DIMETHYL-MDA;
3,4-METHYLENEDIOXY-N,N-DIMETHYLAMPHETAMINE

SYNTHESIS: To a well stirred solution of 9.7 g dimethylamine
hydrochloride in 50 mL MeOH there was added 3.56 g of
3,4-methylenedioxyphenylacetone (see under MDMA for its preparation)
followed by 0.88 g sodium cyanoborohydride.  A 1:1 mixture of
concentrated HCl and MeOH was added as required to maintain the pH at
about 6 as determined with external, dampened universal paper.  Twenty
drops were called for over the first four h, and a total of 60 drops
were added over the course of two days at which time the reduction was
complete.  After the evaporation of most of the MeOH solvent, the
reaction mixture was added to 250 mL H2O and made strongly acidic with
an excess of HCl.  After washing with 2x100 mL CH2Cl2 the aqueous
phase was made basic with 25% NaOH, and extracted with 3x100 mL
CH2Cl2.  Removal of the solvent under vacuum yielded a nearly
colorless oil that was distilled at 85-90 !C at 0.3 mm/Hg.  There was
obtained 1.5 g of a water-white oil that was dissolved in 8 mL IPA,
neutralized with concentrated HCl and then diluted with 10 mL
anhydrous Et2O.  The slightly turbid solution deposited a light lower
oily layer which slowly crystallized on scratching.  With patience, an
additional 75 mL of Et2O was added, allowing the formation of a white
crystalline mass.  This was removed by filtration and washed with
additional Et2O.  After air drying there was obtained 1.3 g of
3,4-methylenedioxy-N,N-dimethylamphetamine hydrochloride (MDDM) with a
mp of 172-173 !C.  The NMR spectrum (60 mH) of the hydrochloride salt
(in D2O and with external TMS) was completely compatible with the
expected structure.  The signals were: 1.25, 1.37 (d) CCH3, 3H; ArCH2
under the N(CH3)2, 2.96, 8H; CH (m) 3.65; CH2O2 (s) 6.03 2H; ArH 6.93
(3H).  Anal: (C12H18ClNO2) N.

DOSAGE: greater than 150 mg.

DURATION: unknown.

QUALITATIVE COMMENTS: (with 150 mg)  No effects whatsoever.

(with 150 mg) The effects, if any, were so-so.  Perhaps a threshold.
But my libido was non-existent for three days.

(with 550 mg) I took 550 milligrams of it Saturday night and I had a
pretty bad trip.  On a scale of positive 10 to negative 10 it was
about a negative 6.  It really downed me.  Two other friends took 200
milligrams.  They found it very pleasant after about 20 minutes.  It
was a plus 3 [on the -10 to +10 scale].  Then it wore off a little
bit; and then, 4 hours later, it hit them even stronger and was about
a plus 5.

(with 1000 mg) I took up to a gram of it and absolutely nothing.

EXTENSIONS AND COMMENTARY: I cannot attest for the actual drug that
had been used in the two larger-dose reports above.  These are from an
anonymous source associated with clandestine syntheses.  If this
material does eventually prove to be active, it is going to require a
pretty hefty dose.  But it may well have some activity, as there have
been reports in the forensic literature of its preparation, or at
least its intended preparation, in illicit laboratories.  It seems
unlikely that much effort would be directed towards the synthesis of a
completely inactive compound.

The reduced potency of MDDM has been exploited in an unexpected way.
Based on the premise that the dialkylation of the amine group of
amphetamine makes the parent compound intrinsically less active but
without interfering with its ability to enter the brain, a large
number of materials have been explored to take advantage of this very
property.  There is a need in medical diagnosis for agents that can
allow various organs of the body to be visualized.  One of the most
powerful modalities for this work is the positron camera, and the use
of the unusual properties of the positron that allow it to work.  In
the art of positron emission tomography (PET), an emitted positron
(from a radioactive and thus unstable atom) will quickly interact with
a nearby electron and all mass disappears with the complete conversion
to energy.  The detection of the produced pair of annihilation gamma
rays will establish with great exactness the line along which this
interaction occurred.  So if one were to put an unstable atom into a
compound that went to the tissue of the brain, and this atom were to
decay there, the resulting gamma rays would allow a RphotographS to be
made of the brain tissue.  One could in this way visualize brain
tissue, and observe abnormalities.

But what is needed is a molecule that carries the unstable atom (and
specifically one that emits positrons) and one which goes to the brain
as well.  One of the very best unstable atoms for the formation of
positrons is iodine, where there is an isotope of mass 122 which is
perfect for these needs.  And, of course, the world of the psychedelic
drugs is tailor-made to provide compounds that go to the brain.  But,
the last thing that the physician wants, with the diagnostic use of
such tools, would be to have the patient bouncing around in some
turned-on altered state of consciousness.

So the completely logical union of these requirements is to take a
compound such as DOI (carrying the needed atom and certainly going to
the brain) and put two methyl groups on the nitrogen (which should
reduce the chances for conspicuous biological activity).  This
compound was made, and it does label the brain, and it has shown
promise as a flow indicator in the brain, and it and several of its
close relatives are discussed in their own separate recipe, called
IDNNA.









#106 MDE; MDEA; EVE; N-ETHYL-MDA;
3,4-METHYLENEDIOXY-N-ETHYLAMPHETAMINE

SYNTHESIS: (from MDA) To a solution of 3.6 g of the free base of
3,4-methylenedioxyamphetamine (MDA) in 20 g pyridine, there was added
2.3 g acetic anhydride, and the mixture stirred at room temperature
for 0.5 h.  This was then poured into 250 mL H2O and acidified with
HCl.  This aqueous phase was extracted with 3x75 mL CH2Cl2, the
extracts pooled and washed with dilute HCl, and the solvent removed
under vacuum.  The pale amber residue of
N-acetyl-3,4-methylenedioxyamphetamine weighed 5.2 g as the crude
product, and it was reduced without purification.  On standing it
slowly formed crystals.  Recrystallization from a mixture of
EtOAc/hexane (1:1) gave white crystals with a mp of 92-93 !C.

A stirred suspension of 4.8 g LAH in 400 mL anhydrous THF was brought
up to a reflux, and then treated with a solution of 5.0 g of the
impure N-acetyl-3,4-methylenedioxyamphetamine in 20 mL anhydrous THF.
Reflux conditions were maintained for 3 days, and then after cooling
in an ice bath, the excess hydride was destroyed with the careful
addition of H2O.  The 4.8 mL H2O (in a little THF) was followed with
4.8 mL of 15% NaOH, and finally an additional 15 mL H2O.  The white,
granular, basic mass of inorganic salts was removed by filtration, the
filter cake washed with additional THF, and the combined filtrate and
washings stripped of solvent under vacuum.  The residue was dissolved
in 20 mL IPA, made acidic with 40 drops of concentrated HCl, and
diluted with 150 mL anhydrous Et2O.  The crystalline product was
removed by filtration, washed with 80% Et2O (containing IPA) followed
by Et2O itself, and then air dried to provide 3.0 g of
3,4-methylenedioxy-N-ethylamphetamine hydrochloride (MDE) as fine
white crystals with a mp of 198-199 !C.

(from 3,4-methylenedioxyphenylacetone with aluminum amalgam) To 40 g
of thin aluminum foil cut in 1 inch squares (in a 2 L wide mouth
Erlenmeyer flask) there was added 1400 mL H2O containing 1 g mercuric
chloride.  Amalgamation was allowed to proceed until there was the
evolution of fine bubbles, the formation of a light grey precipitate,
and the appearance of occasional silvery spots on the surface of the
aluminum. This takes between 15 and 30 min depending on the freshness
of the surfaces and the temperature of the H2O.  The H2O was removed
by decantation, and the aluminum was washed with 2x1400 mL of fresh
H2O.  The residual H2O was removed as thoroughly as possible by
shaking, and there was added, in succession and with swirling, 72.5 g
ethylamine hydrochloride dissolved in 60 mL warm H2O, 180 mL IPA, 145
mL 25% NaOH, 53 g 3,4-methylenedioxy-phenylacetone (see under MDMA for
its preparation), and finally 350 mL IPA.  The exothermic reaction was
kept below 60 !C with occasional immersion into cold water and, when
it was thermally stable, it was allowed to stand until it had returned
to room temperature and all the insolubles settled to the bottom as a
grey sludge.  The clear yellow overhead was decanted and the sludge
removed by filtration and washed with MeOH.  The combined decantation,
mother liquors, and washes, were stripped of solvent under vacuum, the
residue suspended in 1500 ml of H2O, and sufficient HCl added to make
the phase distinctly acidic.  This was then washed with 2x100 mL
CH2Cl2, made basic with 25% NaOH, and extracted with 3x100 mL of
CH2Cl2.  After removal of the solvent from the combined extracts,
there remained 59.5 g of an amber oil which was distilled at 145-150
!C at 0.5 mm/Hg, producing 40.3 g of an off-white oil.  This was
dissolved in 600 mL IPA, neutralized with about 20 mL of concentrated
HCl and then treated with 300 mL anhydrous Et2O.  After filtering off
the white crystals, washing with a IPA/Et2O (2:1) mixture, with Et2O
and air drying, the final 3,4-methylenedioxy-N-ethylamphetamine
hydrochloride (MDE) weighed 37.4 g.

(from 3,4-methylenedioxyphenylacetone with NaBH3CN) To a well stirred
solution of 31.0 g ethylamine hydrochloride in 110 mL MeOH there was
added 6.6 g of 3,4-methylenedioxyphenylacetone (see under MDMA for its
preparation) followed by 3.0 g sodium cyanoborohydride.  Concentrated
HCl in MeOH was added as required to maintain the pH at about 6 as
determined with external, dampened universal pH paper.  About 2 days
were required for the reduction to be complete as determined by the
final stabilization of the pH.  The reaction mixture was added to 1 L
H2O and made strongly acidic with an excess of HCl.  After washing
with 2x100 mL CH2Cl2 the aqueous phase was made basic with 25% NaOH,
and extracted with 3x100 mL CH2Cl2.  Removal of the solvent under
vacuum yielded 8.3 g of a pale amber oil that was distilled at 85-100
!C at 0.2 mm/Hg.  There was obtained 6.0 g of a water-white oil that
was dissolved in 65 mL IPA and neutralized with 75 drops of
concentrated HCl which produced crystals spontaneously.  These were
diluted with some 20 mL of anhydrous Et2O removed by filtration,
washed first with IPA/Et2O (2:1), and then with Et2O.  After air
drying there was obtained 6.1 g of
3,4-methylenedioxy-N-ethylamphetamine hydrochloride (MDE) with a mp of
201-202 !C.  Anal. (C12H18ClNO2) N.

DOSAGE: 100 - 200 mg.

DURATION: 3 - 5 h.

QUALITATIVE COMMENTS: (with 100 mg) There was a warm light all about
me.  And a gentle, almost alcohol-like, intoxication.  The drug seems
to change my state of awareness, but it does nothing else.  The world
is as intense or as dull as I choose to make it.  At the 1.5 hour
point I was clearly dropping, and an hour later yet, completely
without residue.

(with 160 mg) The first effects were felt in forty minutes and I
seemed to be completely there by the end of that first hour.  There
was an initial slightly dizzy intoxication, and then I felt very nice.
A good intoxication, with maybe a little motor incoordination.  There
was absolutely no appetite at all.  The next morning there was still
some feeling of elation but I was still very relaxed.  High marks for
the quality of the experience.

(with 160 mg) Overall this was a wonderful experience.  I felt that
the effect was stronger and smoother than MDMA, but perhaps the group
enhancement may be partly responsible.  I felt definitely fewer
physiological side-effects than with MDMA, particularly the urinating
problem; although there was dehydration, there was less burning
annoyance.

(with 160 mg) I was hard hit, to the extent that there was difficulty
in verbalizing and following other people's thoughts.  I entered the
experience with some cold symptoms, and my sore throat disappeared.  I
felt quite intoxicated and tranquilized.

(with 200 mg) Very stoned.  There was some nausea in the beginning of
the experience.  As it developed I found it very difficult to
concentrate on what I was thinking or saying simply due to the
extraordinary nature of coming on to this material.  There is
noticeable jaw-clenching and rice crispies in the ears.  This is a
meditative material not unlike MDMA except there are more difficulties
in forming words.  And there is a problem in focusing the eyes, what I
want to call Teye-romp.U My anorexia was extremely long-lived Q
perhaps a total of 72 hours.  This may have been too high a dosage.

EXTENSIONS AND COMMENTARY: This immediate homologue of MDMA has a very
similar chronology but requires a slightly larger dose.  Another
similarity is the occasional report of teeth clenching, especially
following the use of supplemental dosages intended to extend the
effects of the drug.  These supplements have been explored in the 50
to 75 milligram range, usually at the two hour point.  In one
unpublished clinical experiment with MDMA, an extension was attempted
at the 1 hour 45 minute point with MDE rather than with MDMA, to see
if there was any change in the qualitative character of the
experience.  The effective time of intoxication was extended, but the
group fell surprisingly quiet, with a drop in the usual urge to
converse and interact.

The effects of MDE are similar in many ways to those of MDMA, but
there are believable differences.  The particular magic, and affective
transference, does not appear to be there.  There is a stoning
intoxication, as there is with MDA, and there is a seemingly
unrewarding aspect to the upping of the dosages, again similar to MDA,
and the properties of unusually easy communication and positive
self-viewing of MDMA seem to be absent.  Maybe the RSS isomer would
have these properties, and they are lost in the racemate due to
something coming from a more potent RintoxicatingS RRS isomer.  The
optical isomers have never been evaluated separately in man.

There are only two ways in which two drugs can interact to produce a
result that is not obvious from the summing of their individual
actions.  One is the process of synergism, where two active materials
are allowed to interact within a single individual and at one time,
and the consequence of this interaction is different than that which
would have been expected.  The other is the process of potentiation,
where only one drug is active, but the presence of the second (and
inactive) drug enhances the observed action of the first.  MDE seems
to fall in the first category.

The Rpiggy-backS or Rwindow exploitationS studes were first discovered
and explored with MDE, and have subsequently been extended most
successfully with MDMA.  The earliest procedure used was to assay
modest quantities of active materials at the drop-off period of MDE,
to exploit the open and benign state that was present.  Usually, only
a fraction of the standard dosage of the following drug was necessary
to evoke a full experience.  In psychotherapy applications, this
sequence has been frequently used with MDMA followed by a second
material that has been chosen to modify and expand the opening that
the MDMA produced.

With the placement of MDMA under legal control in 1985, MDE
occasionally appeared in the illicit street trade.  It had been called
EVE, which carries some perverse logic in light of the nickname used
occasionally for MDMA, which was ADAM.  The term INTELLECT has been
used for it as well, but there has been no apparent reason advanced
for this.  And a final note on nomenclature.  An old literature use of
the code MDE was for the compound 3,4-methylenedioxyethanol-amine.
See the discussion on this under the recipe for DME.

I have been told of an analogue of MDE that has been synthesized, and
explored by the researcher who synthesized it.  It contains the
N-trifluoroethyl group common to several pharmaceuticals such as
Quazepam.  The analogue is
3,4-methylenedioxy-N-(2,2,2-trifluoroethyl)amphetamine hydrochloride
(mp 207-209 !C) which was made from 2,2,2-trifluoroethylamine and
3,4-methylenedioxyphenylacetone and sodium cyanoborohydride in
methanol.  The best final line for this compound is that it is
Rpossibly active.S The most heroic dosage schedule mentioned was a
total of 500 milligrams, taken in three approximately equal portions
over the course of five or six hours, with only a very mild
intoxication and little or no sympathomimetic effects.  And what
little there might have been was quickly gone.  A collection of
totally unexplored N-substituted homologues and analogues of MDE is
gathered at the end of the recipe for MDBZ.

Another direction that has been used to homologate the MDMA and MDE
structure is with the length of the aliphatic chain that carries the
phenyl ring and the amine function.  RHS shows the two-carbon chain,
RIS shows the amphetamine chain length, and MDE can be called ETHYL-I.
The four-carbon chain is the RJS group, and this entire Muni-Metro
concept is explained under METHYL-J.









#107 MDHOET; HYDROXYETHYL-MDA;
3,4-METHYLENEDIOXY-N-(2-HYDROXYETHYL)AMPHETAMINE

SYNTHESIS: To a well stirred solution of 25 g ethanolamine
hydrochloride in 75 mL MeOH there was added 4.45 g of
3,4-methylenedioxyphenylacetone (see under MDMA for its preparation)
followed by 1.1 g sodium cyanoborohydride.  Concentrated HCl in MeOH
was added as required, over the next few days, to maintain the pH at
about 6 as determined with external, dampened universal pH paper.  The
reaction mixture was added to 300 mL H2O and made strongly acidic with
an excess of HCl.  After washing with 3x100 mL CH2Cl2 the aqueous
phase was made basic with 25% NaOH, and extracted with 4x100 mL
CH2Cl2.  Removal of the solvent under vacuum yielded 3.5 g of a
viscous off-white oil that was distilled at 160 !C at 1.3 mm/Hg to
give 2.0 g of a white viscous oil.  The pot residue remained fluid,
but was discarded.  This distillate was dissolved in 8.0 mL IPA to
give, eventually, a clear solution.  This was neutralized with
concentrated HCl and diluted with 100 mL anhydrous Et2O.  The loose
white crystals of 3,4-methylenedioxy-N-(2-hydroxy-ethyl)amphetamine
hydrochloride (MDHOET) that formed were removed by filtration, washed
with Et2O, and air dried.  These weighed 2.3 g, and had a mp of
147-148 !C.  Anal. (C12H18ClNO3) N.

DOSAGE: greater than 50 mg.

DURATION: unknown.

EXTENSIONS AND COMMENTARY: Most compounds with bare, exposed polar
groups like hydroxyls are not centrally active, as they simply do not
have any way of getting into the brain.  MDHOET is certainly not very
active, if it is active at all.

There was one report that at very high doses some central effects were
indeed observed.  With quantities in the several hundreds of
milligrams a picture emerged of changes in perceived color and depth
perception, but without euphoria.  It was said to resemble a mild dose
of ketamine.  This is an interesting comment, in that ketamine has
found its major medical use as an anesthetic, and MDHOET is among the
most effective of all the N-substituted MDA derivatives assayed in
several animal analgesia models.









#108 MDIP; N-ISOPROPYL-MDA;
(3,4-METHYLENEDIOXY-N-ISOPROPYLAMPHETAMINE)

SYNTHESIS: To a well stirred and cooled solution of 14.75 g
isopropylamine in 100 mL MeOH there was added 4.45 g of
3,4-methylenedioxyphenylacetone (see under MDMA for its preparation)
followed by a 1:1 mixture of concentrated HCL and MeOH, sufficient to
bring the pH to about 4.  This was followed with 1.1 g sodium
cyanoborohydride, and stirring was continued overnight.  When the pH
increased to over 6 there was added an additional 0.5 g of the
borohydride, and additional methanolic HCl was added as needed to
maintain the pH there.  When the pH became stable, the reaction
mixture was brought soundly acid with the addition of yet additional
HCl, and all solvents were removed under vacuum.  The residues were
added to 500 mL H2O and washed with 3x100 mL CH2Cl2.  The aqueous
phase was made basic with 25% NaOH, and extracted with 4x100 mL
CH2Cl2.  Removal of the solvent under vacuum yielded 2.8 g of an amber
liquid that was distilled at 95-110 !C at 0.3 mm/Hg.  There was
obtained about 2 mL of a white oil that was dissolved in 10 mL of IPA,
neutralized with about 20 drops of concentrated HCl producing
spontaneous crystals.  These were diluted with some 40 mL of anhydrous
Et2O, removed by filtration, washed with Et2O, and then air dried.
There was obtained 1.6 g of 3,4-methylenedioxy-N-isopropylamphetamine
hydrochloride (MDIP) with a mp of 186-186.5 !C with prior sintering at
185 !C.  Anal. (C13H20ClNO2) N.

DOSAGE: greater than 250 mg.

DURATION: unknown.

QUALITATIVE COMMENTS: (with 250 mg) At 35 minutes there was an
extremely slight head disturbance which increased over the next few
minutes.  I would have missed it if there had been any sensory input
at all.  At the one hour point there was a slight physical malaise,
but no 'open window' of any kind, either like MDMA or like LSD.  At
the most, this was a threshold, and in another half hour, I was
completely baseline.

EXTENSIONS AND COMMENTARY: The structure of MDIP can be looked at as
exactly that of MDE but with an additional methyl group (one carbon)
hanging off the ethyl that is on the nitrogen.  And with that slight
additional weight, the activity has disappeared.  On those occasions
where research has shown a compound to be inactive, there has been
some study made that could be called a RprimerS experiment.  Why not
take advantage of the fact that an RinactiveS compound might well be
sitting in some receptor site in the brain without doing anything?
Might its presence, wherever it might be, have some effect if only a
person were to explore it in the correct way?  Might it augment or
interfere with the action of another compound?  Many experiments of
this kind have been performed, geared to milk additional information
out of a new trial of a new material.

Here is an example of a primer experiment that involved MDIP.  Some
five hours following an inactive trial with 120 milligrams of MDIP
(maybe a slight disturbance at one hour, nothing at two hours) a
calibration dose of 80 milligrams of MDMA was taken.  The effects of
the MDMA were noted at the 33 minute point, and an honest plus one was
achieved at one hour.  At this point a second 80 milligrams was added
to the inventory that was already on board, and the general
intoxication and the eye effects that followed were completely
explained by the MDMA alone.  It was obvious that the two drugs did
not see one-another.

Sometimes an experiment can involve the assay of an unknown material
at the supplement time of an active drug.  This has been called
Rpiggybacking.S Here is an example.  At the five hour point of an
experiment with 140 milligrams of MDE (this had been a light
experience, a plus one which had not laster more than two hours) a
dosage of 200 milligrams of MDIP rekindled a +1 experience, a pleasant
intoxication of the MDE sort, but one that was quite invested with
tremor and some feelings of eye-popping.  It was almost as if the
physical toxic effects outweighed the mental virtues.  Imagine an
iceberg, with the bulk of its mass underwater.  The MDE had had its
own modest effects, and had submerged into invisibility, and the
response to a little bit of an otherwise inactive MDIP was to refloat
a bit of the otherwise unseeable MDE.









#109 MDMA; MDM; ADAM; ECSTASY; 3,4-METHYLENEDIOXY-N-METHYLAMPHETAMINE

SYNTHESIS: (from MDA) A solution of 6.55 g of
3,4-methylenedioxyamphetamine (MDA) as the free base and 2.8 mL formic
acid in 150 mL benzene was held at reflux under a Dean Stark trap
until no further H2O was generated (about 20 h was sufficient, and 1.4
mL H2O was collected).  Removal of the solvent gave an 8.8 g of an
amber oil which was dissolved in 100 mL CH2Cl2, washed first with
dilute HCl, then with dilute NaOH, and finally once again with dilute
acid.  The solvent was removed under vacuum giving 7.7 g of an amber
oil that, on standing, formed crystals of
N-formyl-3,4-methylenedioxyamphetamine.  An alternate process for the
synthesis of this amide involved holding at reflux for 16 h a solution
of 10 g of MDA as the free base in 20 mL fresh ethyl formate.  Removal
of the volatiles yielded an oil that set up to white crystals,
weighing 7.8 g.

A solution of 7.7 g N-formyl-3,4-methylenedioxyamphetamine in 25 mL
anhydrous THF was added dropwise to a well stirred and refluxing
solution of 7.4 g LAH in 600 mL anhydrous THF under an inert
atmosphere.  The reaction mixture was held at reflux for 4 days.
After being brought to room temperature, the excess hydride was
destroyed with 7.4 mL H2O in an equal volume of THF, followed by 7.4
mL of 15% NaOH and then another 22 mL H2O.  The solids were removed by
filtration, and the filter cake washed with additional THF.  The
combined filtrate and washes were stripped of solvent under vacuum,
and the residue dissolved in 200 mL CH2Cl2.  This solution was
extracted with 3x100 mL dilute HCl, and these extracts pooled and made
basic with 25% NaOH.  Extraction with 3x75 mL CH2Cl2 removed the
product, and the pooled extracts were stripped of solvent under
vacuum.  There was obtained 6.5 g of a nearly white residue which was
distilled at 100-110 !C at 0.4 mm/Hg to give 5.0 g of a colorless oil.
This was dissolved in 25 mL IPA, neutralized with concentrated HCl,
followed by the addition of sufficient anhydrous Et2O to produce a
lasting turbidity.  On continued stirring, there was the deposition of
fine white crystals of 3,4-methylenedioxy-N-methylamphetamine
hydrochloride (MDMA) which were removed by filtration, washed with
Et2O, and air dried, giving a final weight of 4.8 g.

(from 3,4-methylenedioxyphenylacetone) This key intermediate to all of
the MD-series can be made from either isosafrole, or from piperonal
via 1-(3,4-methylenedioxyphenyl)-2-nitropropene.  To a well stirred
solution of 34 g of 30% hydrogen peroxide in 150 g 80% formic acid
there was added, dropwise, a solution of 32.4 g isosafrole in 120 mL
acetone at a rate that kept the reaction mixture from exceeding 40 !C.
This required a bit over 1 h, and external cooling was used as
necessary.  Stirring was continued for 16 h, and care was taken that
the slow exothermic reaction did not cause excess heating.  An
external bath with running water worked well.  During this time the
solution progressed from an orange color to a deep red.  All volatile
components were removed under vacuum which yielded some 60 g of a very
deep red residue.  This was dissolved in 60 mL of MeOH, treated with
360 mL of 15% H2SO4, and heated for 3 h on the steam bath.  After
cooling, the reaction mixture was extracted with 3x75 mL Et2O, the
pooled extracts washed first with H2O and then with dilute NaOH, and
the solvent removed under vacuum The residue was distilled (at 2.0
mm/108-112 !C, or at about 160 !C at the water pump) to provide 20.6 g
of 3,4-methylenedioxyphenylacetone as a pale yellow oil.  The oxime
(from hydroxylamine) had a mp of 85-88 !C.  The semicarbazone had a mp
of 162-163 !C.

An alternate synthesis of 3,4-methylenedioxyphenylacetone starts
originally from piperonal.  A suspension of 32 g electrolytic iron in
140 mL glacial acetic acid was gradually warmed on the steam bath.
When quite hot but not yet with any white salts apparent, there was
added, a bit at a time, a solution of 10.0 g of
1-(3,4-methylenedioxyphenyl)-2-nitropropene in 75 mL acetic acid (see
the synthesis of MDA for the preparation of this nitrostyrene
intermediate from piperonal and nitroethane).  This addition was
conducted at a rate that permitted a vigorous reaction free from
excessive frothing.  The orange color of the reaction mixture became
very reddish with the formation of white salts and a dark crust.
After the addition was complete, the heating was continued for an
additional 1.5 h during which time the body of the reaction mixture
became quite white with the product appeared as a black oil climbing
the sides of the beaker.  This mixture was added to 2 L H2O, extracted
with 3x100 mL CH2Cl2, and the pooled extracts washed with several
portions of dilute NaOH.  After the removal of the solvent under
vacuum, the residue was distilled at reduced pressure (see above) to
provide 8.0 g of 3,4-methylenedioxyphenylacetone as a pale yellow oil.

To 40 g of thin aluminum foil cut in 1 inch squares (in a 2 L wide
mouth Erlenmeyer flask) there was added 1400 mL H2O containing 1 g
mercuric chloride.  Amalgamation was allowed to proceed until there
was the evolution of fine bubbles, the formation of a light grey
precipitate, and the appearance of occasional silvery spots on the
surface of the aluminum. This takes between 15 and 30 min depending on
the freshness of the surfaces, the temperature of the H2O, and the
thickness of the aluminum foil.  (Aluminum foil thickness varies from
country to country.)  The H2O was removed by decantation, and the
aluminum was washed with 2x1400 mL of fresh H2O.  The residual H2O
from the final washing was removed as thoroughly as possible by
shaking, and there was added, in succession and with swirling, 60 g
methylamine hydrochloride dissolved in 60 mL warm H2O, 180 mL IPA, 145
mL 25% NaOH, 53 g 3,4-methylenedioxyphenylacetone, and finally 350 mL
IPA.  If the available form of methylamine is the aqueous solution of
the free base, the following sequence can be substituted: add, in
succession, 76 mL 40% aqueous methylamine, 180 mL IPA, a suspension of
50 g NaCl in 140 mL H2O that contains 25 mL 25% NaOH, 53 g
3,4-methylenedioxyphenylacetone, and finally 350 mL IPA.  The
exothermic reaction was kept below 60 !C with occasional immersion
into cold water and, when it was thermally stable, it was allowed to
stand until it had returned to room temperature with all the
insolubles settled to the bottom as a grey sludge.  The clear yellow
overhead was decanted and the sludge removed by filtration and washed
with MeOH.  The combined decantation, mother liquors and washes, were
stripped of solvent under vacuum, the residue suspended in 2400 ml of
H2O, and sufficient HCl added to make the phase distinctly acidic.
This was then washed with 3x75 mL CH2Cl2, made basic with 25% NaOH,
and extracted with 3x100 mL of CH2Cl2.  After removal of the solvent
from the combined extracts, there remained 55 g of an amber oil which
was distilled at 100-110 !C at 0.4 mm/Hg producing 41 g of an
off-white liquid.  This was dissolved in 200 mL IPA, neutralized with
about 17 mL of concentrated HCl, and then treated with 400 mL
anhydrous Et2O.  After filtering off the white crystals, washing with
an IPA/Et2O mixture, (2:1), with Et2O, and final air drying, there was
obtained 42.0 g of 3,4-methylenedioxy-N-methylamphetamine (MDMA) as a
fine white crystal.  The actual form that the final salt takes depends
upon the temperature and concentration at the moment of the initial
crystallization.  It can be anhydrous, or it can be any of several
hydrated forms.  Only the anhydrous form has a sharp mp; the published
reports describe all possible one degree melting point values over the
range from 148-153 !C.  The variously hydrated polymorphs have
distinct infrared spectra, but have broad mps that depend on the rate
of heating.

DOSAGE: 80 - 150 mg.

DURATION: 4 - 6 h.

QUALITATIVE COMMENTS: (with 100 mg) MDMA intrigued me because
everyone I asked, who had used it, answered the question, 'What's it
like?' in the same way: 'I donUt know.'  'What happened?'  'Nothing.'
And now I understand those answers.  I too think nothing happened.
But something seemed changed.  Before the 'window' opened completely,
I had some somatic effects, a tingling sensation in the fingers and
temples Q a pleasant sensation, not distracting.  However, just after
that there was a slight nausea and dizziness similar to a little too
much alcohol.  All these details disappeared as I walked outside.  My
mood was light, happy, but with an underlying conviction that
something significant was about to happen.  There was a change in
perspective both in the near visual field and in the distance.  My
usually poor vision was sharpened.  I saw details in the distance that
I could not normally see.  After the peak experience had passed, my
major state was one of deep relaxation.  I felt that I could talk
about deep or personal subjects with special clarity, and I
experienced some of the feeling one has after the second martini, that
one is discoursing brilliantly and with particularly acute analytical
powers.

(with 100 mg) Beforehand, I was aware of a dull, uncaring tiredness
that might have reflected too little sleep, and I took a modest level
of MDMA to see if it might serve me as a stimulant.  I napped for a
half hour or so, and woke up definitely not improved.  The feeling of
insufficient energy and lack of spark that IUd felt before had become
something quite strong, and might be characterized as a firm feeling
of negativity about everything that had to be done and everything I
had been looking forward to.  So I set about my several tasks with no
pleasure or enjoyment and I hummed a little tune to myself during
these activities which had words that went: 'I shouldnUt have done
that, oh yes, I shouldnUt have done that, oh no, I shouldnUt have done
that; it was a mistake.'  Then I would start over again from the
beginning.  I was stuck in a gray space for quite a while, and there
was nothing to do but keep doing what I had to do.  After about 6
hours, I could see the whole mental state disintegrating and my
pleasant feelings were coming back.  But so was my plain, ornery
tiredness.  MDMA does not work like Dexedrine.

(with 120 mg) I feel absolutely clean inside, and there is nothing
but pure euphoria.  I have never felt so great, or believed this to be
possible.  The cleanliness, clarity, and marvelous feeling of solid
inner strength continued throughout the rest of the day, and evening,
and through the next day.  I am overcome by the profundity of the
experience, and how much more powerful it was than previous
experiences, for no apparent reason, other than a continually
improving state of being.  All the next day I felt like 'a citizen of
the universe' rather than a citizen of the planet, completely
disconnecting time and flowing easily from one activity to the next.

(with 120 mg) As the material came on I felt that I was being
enveloped, and my attention had to be directed to it.  I became quite
fearful, and my face felt cold and ashen.  I felt that I wanted to go
back, but I knew there was no turning back.  Then the fear started to
leave me, and I could try taking little baby steps, like taking first
steps after being reborn.  The woodpile is so beautiful, about all the
joy and beauty that I can stand.  I am afraid to turn around and face
the mountains, for fear they will overpower me.  But I did look, and I
am astounded.  Everyone must get to experience a profound state like
this.  I feel totally peaceful.  I have lived all my life to get here,
and I feel I have come home.  I am complete.

(with 100 mg of the RRS isomer) There were the slightest of effects
noted at about an hour (a couple of paresthetic twinges) and then
nothing at all.

(with 160 mg of the RRS isomer) A disturbance of baseline at about
forty minutes and this lasts for about another hour.  Everything is
clear by the third hour.

(with 200 mg of the RRS isomer) A progression from an alert at thirty
minutes to a soft and light intoxication that did not persist.  This
was a modest +, and I was at baseline in another hour.

(with 60 mg of the RSS isomer) The effects began developing in a
smooth, friendly way at about a half-hour.  My handwriting is OK but I
am writing faster than usual.  At the one hour point, I am quite
certain that I could not drive, time is slowing down a bit, but I am
mentally very active.  My pupils are considerably dilated.  The
dropping is evident at two hours, and complete by the third hour.  All
afternoon I am peaceful and relaxed, but clear and alert, with no
trace of physical residue at all.  A very successful ++.

(with 100 mg of the RSS isomer) I feel the onset is slower than with
the racemate.  Physically, I am excited, and my pulse and blood
pressure are quite elevated.  This does not have the 'fire' of the
racemate, nor the rush of the development in getting to the plateau.

(with 120 mg of the RSS isomer) A rapid development, and both writing
and typing are impossible before the end of the first hour.  Lying
down with eyes closed eliminates all effects; the visual process is
needed for any awareness of the drug's effects.  Some teeth clenching,
but no nystagmus.  Excellent sleep in the evening.

EXTENSIONS AND COMMENTARY: In clinical use, largely in
psychotherapeutic sessions of which there were many in the early years
of MDMA study, it became a common procedure to provide a supplemental
dosage of the drug at about the one and a half hour point of the
session.  This supplement, characteristically 40 milligrams following
an initial 120 milligrams, would extend the expected effects for about
an additional hour, with only a modest exacerbation of the usual
physical side-effects, namely, teeth clenching and eye twitching.  A
second supplement (as, for instance, a second 40 milligrams at the two
and a half hour point) was rarely felt to be warranted.  There are,
more often than not, reports of tiredness and lethargy on the day
following the use of MDMA, and this factor should be considered in the
planning of clinical sessions.

With MDMA, the usual assignments of activity to optical isomers is
reversed from all of the known psychedelic drugs.  The more potent
isomer is the RSS isomer, which is the more potent form of amphetamine
and methamphetamine.  This was one of the first clear distinctions
that was apparent between MDMA and the structurally related
psychedelics (where the RRS isomers are the more active).  Tolerance
studies also support differences in mechanisms of action.  In one
study, MDMA was consumed at 9:00 AM each day for almost a week (120
milligrams the first day and 160 milligrams each subsequent day) and
by the fifth day there were no effects from the drug except for some
mydriasis.  And even this appeared to be lost on the sixth day.  At
this point of total tolerance, there was consumed (on day #7, at 9:00
AM) 120 milligrams of MDA and the response to it was substantially
normal with proper chronology, teeth clench, and at most only a slight
decrease in mental change.  A complete holiday from any drug for
another 6 days led to the reversal of this tolerance, in that 120
milligrams of MDMA had substantially the full expected effects.  The
fact that MDMA and MDA are not cross-tolerant strengthens the argument
that they act in different ways, and at different sites in the brain.

A wide popularization of the social use of MDMA occurred in 1984-1985
and, with the reported observation of serotonin nerve changes in
animal models resulting from the administration of the structurally
similar drug MDA, an administrative move was launched to place it
under legal control.  The placement of MDMA into the most restrictive
category of the Federal Controlled Substances Act has effectively
removed it from the area of clinical experimentation and human
research.  The medical potential of this material will probably have
to be developed through studies overseas.

A word of caution is in order concerning the intermediate
3,4-methylene-dioxyphenylacetone, which has also been called
piperonylacetone.  A devilish ambiguity appeared in the commercial
market for this compound, centered about its name.  The controversy
focused on the meaning of the prefix, piperonyl, which has two
separate chemical definitions.  Let me try to explain this fascinating
chaos in non-chemical terms.  Piperonyl is a term that has been used
for a two-ring system (the methylenedioxyphenyl group) either without,
or with, an extra carbon atom sticking off of the side of it.  Thus,
piperonylacetone can be piperonyl (the two-ring thing without the
extra carbon atom attached) plus acetone (a three carbon chain thing);
the total number of carbons sticking out, three.  Or, piperonylacetone
can be piperonyl (the two-ring thing but with the extra carbon atom
attached) plus acetone (a three carbon chain thing); the total number
of carbons sticking out, four.

Does this make sense?

The three carbon sticking out job gives rise to MDA and to MDMA and to
many homologues that are interesting materials discussed at length in
these Book II comments.  This is the usual item of commerce, available
from both domestic and foreign suppliers.  But the four-carbon
sticking out job will produce totally weird stuff without any apparent
relationship to psychedelics, psychoactives or psychotropics
whatsoever.  I know of one chemical supply house which supplied the
weird compound, and they never did acknowledge their unusual use of
the term piperonyl.  There is a simple difference of properties which
might be of value.  The three carbon (correct) ketone is an oil with a
sassafras smell that is always yellow colored.  The four carbon
(incorrect) ketone has a weak terpene smell and is white and
crystalline.  There should be no difficulties in distinguishing these
two compounds.  But unprincipled charlatans can always add mineral oil
and butter yellow to otherwise white solids to make them into yellow
oils.  Caveat emptor.









#110 MDMC; EDMA; 3,4-ETHYLENEDIOXY-N-METHYLAMPHETAMINE

SYNTHESIS: To a solution of 27.6 g protocatechualdehyde
(3,4-dihydroxybenzaldehyde) in 250 mL acetone there was added 57 g
finely powdered anhydrous K2CO3 and 43 g 1,2-dibromoethane.  The
mixture was held at reflux for 16 h, and then the acetone removed by
evaporation.  The remaining tar-like goo was distributed between equal
volumes of H2O and CH2Cl2, and the phases separated by centrifugation.
The organic phase was washed with 2x50 mL 5% NaOH, and the solvent
removed under vacuum.  The residue (22.0 g with the smell of the
starting halide) was distilled to give a fraction that boiled at 110
!C at 0.25 mm/Hg to yield 3,4-ethylenedioxybenzaldehyde
(1,4-benzodioxane-6-carboxaldehyde) as a white oil weighing 6.88 g.
This spontaneously crystallized to give white solids that melted at
50-51 !C.

A solution of 6.64 g 3,4-ethylenedioxybenzaldehyde in 40 mL
nitroethane was treated with 0.26 g anhydrous ammonium acetate and
held at reflux for 3 days.  TLC analysis showed that there was much
aldehyde remaining unreacted, so an additional 0.7 g ammonium acetate
was added, and the mixture held at reflux for an additional 6 h.  The
excess nitroethane was removed under vacuum.  The residue was
dissolved in 30 mL hot MeOH which, with patience and slow cooling,
finally deposited a heavy yellow-gold powder.  This product
1-(3,4-ethylenedioxyphenyl)-2-nitro-propene melted at 95-96 !C and
weighed 6.03 g when air dried to constant weight.  Recrystallization
from either MeOH or EtOAc gave the product as a yellow solid, but
without any improvement in mp.

A solution of 4.0 g of 1-(3,4-ethylenedioxyphenyl)-2-nitropropene was
made in 30 mL warm acetic acid.  This was added to a suspension of 16
g elemental electrolytic iron in 75 mL acetic acid.  The mixture was
heated on the steam bath, and an exothermic reaction set in at about
70 !C.  Heating was continued and the reaction allowed to proceed
until the mass was a thick gray color and a dirty scum had been formed
on the surface.  After about 2 h, the entire mix was poured into 2 L
H2O and filtered free of a little residual unreacted iron which was
washed with CH2Cl2.  The filtrate and washes were extracted with 3x100
mL CH2Cl2 and the pooled organic extracts washed with 2x50 mL 5% NaOH.
Removal of the solvent gave 3.38 g of an amber oil which was
distilled.  The product 1-(3,4-ethylenedioxyphenyl)-2-propanone
distilled as a white oil, at 105-110 !C at 0.2 mm/Hg.  It weighed 2.74
g.

To 2.0 g. of 1 inch squares of light-weight aluminum foil there was
added a solution of 50 mg mercuric chloride in 70 mL water.  After
standing at room temperature for 30 min, the H2O was drained away, and
the amalgamated aluminum washed twice with H2O, and shaken as dry as
possible.  There was then added, promptly and in immediate sequence, a
solution of 3 g methylamine hydrochloride in 3 mL H2O, 9 mL IPA, 7.25
mL 25% NaOH, 2.70 g of 1-(3,4-ethylenedioxyphenyl)-2-propanone, and 18
mL IPA.  The mixture was heated on the steam bath until an exothermic
reaction set in, and then it was continuously swirled as the reaction
proceeded.  When the aluminum was consumed, there was a colorless gray
sludge, and this was filtered and washed with 2x10 mL MeOH.  The
combined mother liquors and washes were stripped of solvent under
vacuum.  The two phase residue was suspended in 400 mL H2O containing
sufficient H2SO4 to make the resulting water solution acidic to pH
paper. This was washed with 3x50 mL CH2Cl2, made basic with 25% NaOH,
and the product extracted with 3x50 mL CH2Cl2.  The resulting 3.01 g
slightly amber residue oil was distilled at 110-120 !C at 0.25 mm/Hg
to give 2.53 g of a white oil, which did not appear to absorb carbon
dioxide.  This was dissolved in 12 mL IPA, neutralized with 1 mL
concentrated HCl and diluted with anhydrous Et2O to the point of
initial turbidity.  There separated white crystals of
3,4-ethylenedioxy-N-methylamphetamine hydrochloride (MDMC) which
weighed, when air dried to constant weight, 2.53 g.

DOSAGE: 200 or more mg.

DURATION: 3 - 5 h.

QUALITATIVE COMMENTS: (with 150 mg) A flood of paresthesia at the 30
minute point, and then nothing.  There was the development of a plus
one-and-a half effect over the next hour with the tendency to drift
into a dozing state with hypnogogic imagery.  There were colored
letters in the periphery of my visual field.  There was no appetite
loss nor was there any blood pressure rise.  And no eye jiggle or
teeth clenching.  I was out of the experience in 4 to 5 hours.  A
repeat of this level a few days later gave a bare possible threshold
with no other effects.

(with 200 mg) There was something unmistakable at 45 minutes, with
hints of nystagmus.  Possibly MDMA-like, with no indicators of
anything psychedelic.  Subtle return to baseline, and there were no
after-effects.

(with 250 mg) Alert at 40 minutes, and to a clear ++ at an hour.
Slight something in the eye muscles.  Dropping thirty minutes later,
and baseline at three hours.

(with 250 mg) I am at a bare threshold at best.

EXTENSIONS AND COMMENTARY: What a strange and completely
unsatisfactory compound!  In the original run-up from low levels to
increasing higher levels, there never was a dosage that was a minus,
that had no effect.  At every level, something was thought to be
there, usually at a level of a single plus or thereabouts.  But with
different people, different responses.  There is no way of guessing
what an active level might be, or how consistent that level might be
between different people, or for that matter what the responses are
that might be expected at that level.

This was yet one more effort to find an MDMA-like substitute by the
miniscule manipulation of the MDMA molecule.  Perhaps a small
molecular change might leave the particular magic of the MDMA action
alone, but eliminate the serotonin neuron problem in test animals.
Maybe the serotonin neuron change is essential for MDMA to have the
action it has.  Who can tell?

The original name that this compound got, during the several
explorations of MDMA analogues, was based on the nickname for MDMA
which was Adam.  HADUEM was mentioned with the hydroxy compound, MADAM
with the 6-methyl homologue, and FLADAM with the 6-fluoro analogue.
This compound got the sobriquet MACADAM from that horrible black gooey
mess generated at the aldehyde stage.  This was shortened to RCS and
eventually the RCS was added to the MDMA parent name.  Thus, MDMC.  It
doesnUt really make sense; EDMA is more reasonable.  But then there is
no reason why MDMC should make sense.









#111 MDMEO; N-METHOXY-MDA; 3,4-METHYLENEDIOXY-N-METHYOXYAMPHETAMINE

SYNTHESIS: To a solution of 20.9 g methoxyamine hydrochloride in 75 mL
MeOH (a strongly acidic solution) there was added 4.45 g
3,4-methylenedioxyphenylacetone (see under MDMA for its preparation)
followed by 1.10 g sodium cyanoborohydride.  There was the immediate
formation of a solid phase, and the evolution of what appeared to be
hydrogen cyanide.  To this there were added about 4 mL 5% NaOH which
brought the pH to the vicinity of 3 or 4.  Another 1.0 g of sodium
cyanoborohydride was added (no gas evolution this time) and stirring
was continued at ambient temperature for 6 days.  All was added to 500
mL H2O, acidified with 10 mL HCl, and extraction with 3x100 mL CH2Cl2
removed almost all the color.  The aqueous phase was made basic with
25% NaOH, and extracted with 4x100 mL CH2Cl2.  Evaporation of the
solvent from these extracts yielded 1.8 g of a pale yellow oil which,
on distillation at 90-95 !C at 0.5 mm/Hg, gave a 1.6 g fraction of an
absolutely white, viscous, clear oil.  This was dissolved in 8 mL IPA
and neutralized with concentrated HCl.  The product was an
exceptionally weak base, and appropriate end points must be respected
on the external pH paper (yellow to red, rather than purple to
orange).  Anhydrous Et2O was added to the point of turbidity, and as
soon as crystallization had actually started, more Et2O was added with
stirring, for a net total of 200 mL.  After a couple of h standing,
the fine white crystalline 3,4-methylenedioxy-N-methoxyamphetamine
hydrochloride (MDMEO) was removed by filtration, Et2O washed, and air
dried to constant weight.  There was obtained 1.7 g of a product with
a mp of 143-146 !C.  The proton NMR was excellent with the N-methoxyl
group a sharp singlet at 4.06 ppm.  Anal. (C11H16ClNO3) N.

DOSAGE: greater than 180 mgs.

DURATION: unknown

EXTENSIONS AND COMMENTARY: Why the interest in the N-methoxy analogue
of MDA?  There are several reasons.  One, this is an isostere of MDE
and it would be interesting to see if it might serve as a primer to
the promotion of the effectiveness of other drugs (see primer
discussion under MDPR).  In one experiment, wherein a 60 microgram
dosage of LSD was used an hour and a half after a 180 milligram load
of MDMEO, there was no augmentation of effects.  Thus, it would appear
not to be a primer.  Another reason for interest was that the
material, although having an extremely similar overall structure to
most of the active MD-series compounds, is very much a weaker base.
And MDOH, which is also a very much weaker base than MDA, still shows
the action and potency of MDA.  And, as this compound appears to be
inactive, base strength is not a sole predictor of activity.

The ultimate reason for making MDMEO was, of course, that it could be
made.  That reason is totally sufficient all by itself.









#112 MDMEOET; N-METHOXYETHYL-MDA;
3,4-METHYLENEDIOXY-N-(2-METHOXYETHYL)AMPHETAMINE

SYNTHESIS: A crude solution of methoxyethylamine hydrochloride was
prepared from 17.7 g methoxyethylamine and 20 mL concentrated HCl with
all volatiles removed under vacuum. This was dissolved in 75 mL MeOH
and there was added 4.45 g of 3,4-methylenedioxyphenylacetone (see
under MDMA for its preparation) followed by 1.3 g sodium
cyanoborohydride.  Concentrated HCl in MeOH was added as required to
maintain the pH at about 6 as determined with external, dampened
universal pH paper.  About 4.5 mL were added over the course of 5
days, at which time the pH had stabilized.  The reaction mixture was
added to 400 mL H2O and made strongly acidic with an excess of HCl.
After washing with 2x100 mL CH2Cl2 the aqueous phase was made basic
with 25% NaOH, and extracted with 4x75 mL CH2Cl2.  Removal of the
solvent under vacuum yielded 6.0 g of an amber oil that was distilled
at 110-120 !C at 0.2 mm/Hg.  There was obtained 4.7 g of a
crystal-clear white oil that was dissolved in 30 mL IPA and
neutralized with 45 drops of concentrated HCl producing a heavy mass
of spontaneous crystals that had to be further diluted with IPA just
to be stirred with a glass rod.  These were diluted with 200 mL of
anhydrous Et2O, removed by filtration, and washed with additional
Et2O.  After air drying there was obtained 4.9 g of
3,4-methylenedioxy-N-(2-methoxyethyl)amphetamine hydrochloride
(MDMEOET) with a mp of 182.5-183 !C.  Anal. (C13H20ClNO3) N.

DOSAGE: greater than 180 mg.

DURATION: unknown.

EXTENSIONS AND COMMENTARY: This is another example of the replacement
of a neutral atom out near the end of a chain, with a more basic and a
more polar one.  MDMEOET would be called an isostere of MDBU in that
it has the same shape, with a methylene unit (the CH2) replaced by an
oxygen atom.  No activity turned up with either compound, so nothing
can be learned from this particular example of change of polarity.









#113 MDMP; a,a,N-TRIMETHYL-3,4-METHYLENEDIOXY-PHENETHYLAMINE;
METHYLENEDIOXYMEPHENTERMINE

SYNTHESIS: To a well stirred solution of 1.64 g of
1-(N-(benzyloxycarbonyl)amino)-1,1-dimethyl-2-(3,4-methylenedioxyphenyl)ethane
(see under MDPH for its preparation) in 10 mL anhydrous THF there was
added a suspension of 0.38 g LAH in 25 mL THF.  All was held at reflux
for 24 h, the excess hydride was destroyed by the addition of 1.5 mL
H2O, and sufficient aqueous NaOH was added to make the reaction
mixture basic and flocculant enough to be filterable.  The inorganic
solids were removed by filtration and, following washing with THF, the
combined filtrate and washings were stripped of organic solvent under
vacuum.  The residue was dissolved in 100 mL Et2O and washed with 2x50
mL saturated aqueous NaHCO3.  After drying the organic phase with
anhydrous MgSO4, the solvent was removed under vacuum to give a yellow
oil.  This was dissolved in 50 mL absolute EtOH and neutralized with
concentrated HCl.  Removal of the solvent under vacuum yielded an
off-white solid that was recrystallized from an EtOH/EtOAc mixture to
provide 0.84 g of a,a,N-trimethyl-3,4-methylenedioxyphenethylamine
hydrochloride (MDMP) with a mp of 206-208 !C.  The NMR spectrum showed
the a,a-dimethyl pair as a singlet at 1.38 ppm.  Anal. (C12H18ClNO2)
C,H,N.

DOSAGE: above 110 mg.

DURATION: perhaps 6 hours.

QUALITATIVE COMMENTS: (with 60 mg) There was a faint, dull alerting
at just over a half hour.  The time sense was out of order, and an
absence of visuals but a generalized attentiveness to my surroundings
was suggestive of MDMA.  Nothing remained at the six hour point.

(with 110 mg) There was a light-headedness, and a complete absence of
libido.  Nothing in any way psychedelic, but there are hints of
discomfort (jaw tension) that will bear close watching at higher
dosages.  It might evolve at higher levels into something like MDMA.

EXTENSIONS AND COMMENTARY: This is one of several candidates for
clinical use as a substitute for MDMA, but there will have to be a
much broader study of its qualitative action in man.  It is clearly
not psychedelic at these modest levels, and in in vitro animal studies
it was apparently inactive as a serotonin releaser.  The warped logic
for looking at phentermine analogs was discussed in the comments that
concerned MDPH.  The initials used here have been chosen with care.
MDM should not be used as it has found some currency as an
abbreviation for MDMA (Methylene-Dioxy-Methamphetamine).  MDMP fits
neatly with Methylene-Dioxy-Me-Phentermine.









#114 MDOH; N-HYDROXY-MDA; 3,4-METHYLENEDIOXY-N-HYDROXYAMPHETAMINE

SYNTHESIS: To a well stirred solution of 14.8 g hydroxylamine
hydrochloride in 120 mL MeOH there was added 3.6 g of
3,4-methylenedioxyphenylacetone (see under MDMA for its preparation)
followed by 1.0 g sodium cyanoborohydride.  The oxime, prepared from
the ketone and hydroxylamine in MeOH with pyridine, may be substituted
for these two components.  Concentrated HCl was added over the course
of a couple of days, to keep the pH near neutrality.  When the
reaction was complete, it was added to H2O, made strongly acidic with
HCl, and washed with 3x100 mL CH2Cl2.  The aqueous phase was made
basic with 25% NaOH, and reextracted with 3x100 mL of CH2Cl2.  The
extracts were pooled, and the solvent removed under vacuum to give 1.7
g of an oily residue which, with pumping under a hard vacuum for a few
minutes, changed to a white solid.  This can be Kugelrohred if the
vacuum is sufficiently good to keep the temperature during the
distillation below 100 !C.  The extremely viscous distillate formed
crystals immediately upon wetting with IPA.  It was dissolved in 20 mL
of warm IPA and neutralized with concentrated HCl, with the titration
end-point being red rather than orange on universal pH paper.  Modest
addition of Et2O allowed the formation of
3,4-methylenedioxy-N-hydroxyamphetamine hydrochloride (MDOH) as white
crystals, which weighed 1.4 g when air dried.  If the temperature of
distillation exceeded 100 !C, there was extensive decomposition during
distillation, with the formation of 3,4-methylenedioxyamphetamine
(MDA) and the oxime of the ketone.  Under these circumstances, the
only base isolated was MDA.  The surest isolation procedure was to
obtain MDOH as the free base, as a crystalline solid which could be
recrystallized from 5 volumes of boiling IPA.  The free base had a mp
of 94-95 !C (and should not be confused with the oxime of
3,4-methylenedioxyphenylacetone which has a mp of 86-88 !C since the
mixed mp is depressed, mp 56-62 !C, or with the free base of MDA which
is an oil).  Anal. (C10H13NO3) N.  The hydrochloride salt had a mp of
149-150 !C (and should not be confused with the hydrochloride of MDA
which has a mp of 185-186 !C since the mixed mp is depressed, mp
128-138 !C).  Anal. (C10H14ClNO3) N.  Acetic anhydride can serve as a
useful tool for distinguishing these materials.  MDA gives an N-acetyl
derivative with an mp of 92-93 !C.  MDOH gives an N,O-diacetyl
derivative with a mp of 72-74 !C.  Methylenedioxyphenylacetone oxime
gives an O-acetyl derivative that is an oil.

DOSAGE: 100 - 160 mg.

DURATION: 3 - 6 h.

QUALITATIVE COMMENTS: (with 100 mg) I felt hampered the first hour by
some internal barrier, which prevented total enjoyment.  However, this
began to break through in a wonderful way just before the supplement
was offered.  Since I felt I was beginning to move through the
barrier, I declined the supplement, particularly since I was anxious
to compare the after-effects with my first experience.  I had found
the first time very remarkable, but felt unusually tired for several
days following.  I feel it is important to know whether this is a
specific drug-induced effect, or the result of psychological
phenomena.  The experience continued in a rich, meaningful way.  There
was a marvelous inner glow, the warmth from all the other participants
was wonderful to feel, nature was most beautiful.  There were no
dramatic breakthroughs, or rushes of insight or energy, but just a
wonderful contemplative space where things gently unfolded as you put
your attention on them.

(with 100 mg) The material came on fairly rapidly.  In about 30
minutes, I was intensely intoxicated, and more deeply than with MDMA.
It was a glorious feeling, and beauty was everywhere enhanced.  With
eyes closed it felt marvelous, and it was appealing to pursue the
inner experience.  I did notice an internal dryness which was
characteristic of MDMA, and I had similar difficulty in urinating, but
not as intense as with MDMA.

(with 120 mg) The colors of the market-place, of all the fresh foods,
constituted a beautiful mosaic.  Nothing practical, simply a real
treasure to be used with individual intention and enjoyment.
Everything was seen with new eyes, new meanings, faces, figures, the
colors of the rainbow subconsciously individually applied.  A
'soul-scape'.  The following day very exhausted, tired, back-pain.

EXTENSIONS AND COMMENTARY: The first time that MDOH was synthesized,
it had inadvertently and unknowingly been converted to MDA.  And the
search for proper dosage and characterization of effects of this
product was, of course, the rediscovery of the dosage and the effects
of MDA.  It is one of the world's most remarkable coincidences that
after the second synthesis of MDOH, when MDOH had really and truly
been actually prepared, the brand new search for proper dosage and
characterization of effects revealed that they were almost identical
to the earlier observations for (the inadvertently produced) MDA.

This reminds me of my speculations in the discussion of both FLEA and
the HOT compound where they also showed paired molecular structures
with their prototypes that differ only by a single oxygen atom.
Again, might there be some metabolic interconversion within the body?
The immediate thought would be that the oxygen atom (the hydroxy
group) might be metabolically removed, and the effects of either drug
are due to the action of MDA.  But the opposite direction is in many
ways more appealing, the in vivo conversion of MDA to MDOH.  Why more
appealing?  For one thing, oxidative changes are much more common in
the body than reductive changes.  For another, the conversion of
amphetamine to N-hydroxyamphetamine is an intermediate in the
conversion of amphetamine to phenylacetone, a known metabolic process
in several animal species.  And that intermediate,
N-hydroxyamphetamine, is a material that gives the famous cytochrome
P-450 complex that has fascinated biochemists studying the so-called
NADPH-dependent metabolism.

I would put my money on the likelihood of MDA going to MDOH if it
should turn out that the two drugs interconvert in the body.  And in
that case, it would be MDOH, or another metabolite on down the line
that is common to both MDA and MDOH, that is the factor intrinsic to
the intoxication that is produced.  Human metabolic studies are
needed, and they have not yet been done.









#115 MDPEA; 3,4-METHYLENEDIOXYPHENETHYLAMINE; HOMOPIPERONYLAMINE

SYNTHESIS: A suspension of 4.0 g LAH in 300 mL anhydrous Et2O was
stirred and heated to a gentle reflux in an inert atmosphere.  There
was added 3.9 g 3,4-methylenedioxy-'-nitrostyrene (see under BOH for
its preparation) by allowing the condensing Et2O to leach it out from
a Soxhlet thimble.  After the addition was complete, the reaction
mixture was held at reflux for an additional 48 h.  It was then cooled
and the excess hydride was destroyed by the cautious addition of 300
mL of 1.5 N H2SO4.  When both phases were completely clear, they were
separated, and the aqueous phase washed once with 50 mL Et2O.  There
was then added 100 g potassium sodium tartrate, followed by sufficient
base to bring the pH >9.  This was extracted with 3x75 mL CH2Cl2, and
the solvent from these pooled extracts was removed under vacuum.  The
residue was dissolved in 150 mL anhydrous Et2O and saturated with
anhydrous HCl gas.  There was a heavy crystallization of
3,4-methylenedioxyphenethylamine hydrochloride (MDPEA) which weighed
3.0 g and had a mp of 212-213 !C.

DOSAGE: greater than 300 mg.

DURATION: unknown.

QUALITATIVE COMMENTS: (with 200 mg) It was taken twice at different
times in a dosage of 200 milligrams each time, without the slightest
peripheral or central effects.

(with 300 mg) My tinnitus had disappeared.  Probably nothing.

EXTENSIONS AND COMMENTARY: How strange.  Even more than DMPEA, this
cyclic analogue MDPEA is a potential prodrug to dopamine, and would be
a prime candidate for central activity.  So why is this drug not
active?  The usual reason advanced by the pharmacologists is that the
body is full of potent enzymes known as monoamine oxidases, and this
is a monoamine, and so the body simply chews away on it in an
oxidative manner, inactivating it before it ever makes it to some
target receptor.

That is the pitch given in the textbooks.  Phenethylamines are subject
to easy enzymatic oxidation, hence they are not active.  The presence
of an alpha-methyl group (the corresponding amphetamines) blocks the
compound from easy access to the enzyme, and since that protects them
from oxidative destruction, they are active.  The oft-quoted exception
is mescaline, and even it is largely destroyed, as evidenced by the
large amount needed for activity (a fraction of a gram).  Sorry, I
canUt buy it.  This entire book is peppered with phenethylamines that
are active at the few-milligram area.  Why arenUt they also destroyed
as well?  The textbooks simply are not right.

MDPEA was one of the seven compounds evaluated as to toxicity and
animal behavior at the University of Michigan under contract from the
Army Chemical Center.  Its Edgewood Arsenal code number was EA-1297.
The number for MDA itself was EA-1298.

The beta-hydroxy analogue of MDPEA is the ethanolamine MDE, standing
for methylenedioxyethanolamine.  This is an old term, and in the more
recent literature, since 1975 certainly, MDE has been used to
represent methylenedioxyethylamphetamine.  The ethanolamine compound
is discussed in the recipe for DME.

There is a family of compounds, to be discussed elsewhere, that is
called the Muni-Metro (see under METHYL-J).  The simplest member is
this compound, MDPEA, and under its chemically acceptable synonym,
homopiperonylamine, it can be called RHS.  Following that code, then,
the N-methyl homologue of MDPEA is METHYL-H, and it has been looked
at, clinically, as an antitussive agent.  N-METHYL-MDPEA, or METHYL-H,
or N-methyl-3,4-methylenedioxyphenethylamine is effective in this role
at dosages of about 30 milligrams, but I have read nothing that would
suggest that there were any central effects.  I have tried it at this
level and have found a little tightness of the facial muscles, but
there was nothing at all in the mental area.









#116 MDPH; a,a-DIMETHYL-3,4-METHYLENEDIOXY-

PHENETHYLAMINE; 3,4-METHYLENEDIOXYPHENTERMINE

SYNTHESIS: To 150 mL of THF, under an atmosphere of nitrogen, there
was added 11.2 g diisopropylamine, and the solution was cooled with
external dry ice/IPA.  There was then added 48 mL of a 2.3 M solution
of butyllithium in hexane, dropwise, with good stirring.  This was
warmed to room temperature, stirred for a few min, and then all was
cooled again in the dry ice bath.  Following the dropwise addition of
4.4 g of isobutyric acid there was added 10.5 mL
hexamethylphosphoramide.  Again, the stirred reaction mixture was
brought to room temperature for about 0.5 h.  There was then added,
drop-wise, 8.5 g 3,4-methylenedioxybenzyl chloride and the mixture
allowed to stir overnight at room temperature.  The reaction mixture
was poured into 100 mL 10% HCl, and the excess THF was removed under
vacuum.  The acidic aqueous residue was extracted with 2x150 mL Et2O.
These extracts were pooled, washed with 10% HCl, and then extracted
with 3x75 mL of 4 N Na2CO3.  These extracts were pooled, made acidic
with HCl, and again extracted with Et2O.  After drying the pooled
extracts with anhydrous MgSO4, the solvent was removed under vacuum to
give a residue that spontaneously crystallized.  Recrystallization
from hexane yielded 6.5 g of
2,2-dimethyl-3-(3,4-methylenedioxyphenyl)propionic acid as white
crystals with a mp of 71-73 !C.  The NMR spectrum in CDCl3 showed the
alpha-dimethyl groups as a sharp singlet at 1.18 ppm.  Anal.
(C12H14O4) C,H.

The triethylamine salt of
2,2-dimethyl-3-(3,4-methylenedioxyphenyl)propionic acid (5.4 g amine,
11.4 g acid) was dissolved in 10 mL H2O and diluted with sufficient
acetone to maintain a clear solution at ice-bath temperature.  A
solution of 6.4 g ethyl chloroformate in 40 mL acetone was added to
the 0 !C solution over the course of 30 min, followed by the addition
of a solution of 4.1 g sodium azide in 30 mL H2O.  Stirring was
continued for 45 min while the reaction returned to room temperature.
The aqueous phase was extracted with 100 mL toluene which was washed
once with H2O and then dried with anhydrous MgSO4.  This organic
solution of the azide was heated on a steam bath until nitrogen
evolution had ceased, which required about 30 min.  The solvent was
removed under vacuum and the residue was dissolved in 30 mL benzyl
alcohol.  This solution was heated on the steam bath overnight.
Removal of the excess benzyl alcohol under vacuum left a residue 13.5
g of
1-(N-(benzyloxycarbonyl)amino)-1,1-dimethyl-2-(3,4-methylenedioxyphenyl)ethane
as an amber oil.  The dimethyl group showed, in the NMR, a sharp
singlet at 1.30 ppm in CDCH3.  Anal. (C19H21NO4) C,H.  This carbamate
was reduced to the primary amine (below) or to the methylamine (see
under MDMP).

A solution of 3.27 g of
1-[N-(benzyloxycarbonyl)amino]-1,1-dimethyl-2-(3,4-methylenedioxyphenyl)ethane
in 250 mL absolute ethanol was treated with 0.5 g 10% palladium on
carbon.  This mixture was shaken under hydrogen at 35 pounds pressure
for 24 h.  The carbon was removed by filtration through Celite, and
the filtrate titrated with HCl.  The solvent was removed under vacuum,
and the residue allowed to crystallize.  This produce was
recrystallized from an EtOH/EtOAc mixture to provide
a,a-dimethyl-3,4-methylenedioxyphenethylamine hydrochloride (MDPH).
The white crystals weighed 1.63 g and had a mp of 180-181 !C.  Anal.
(C11H16ClNO2) C,H,N.

DOSAGE: 160 - 240 mg.

DURATION: 3 - 5 h.

QUALITATIVE COMMENTS: (with 120 mg) The alert was felt in forty
minutes and I was pretty much there at an hour and twenty.  Quite like
MDA, simple, with no lines, no colors, no motion, no fantasy.  I am
pleasantly stoned.  The anorexia is real, as is the impotency.  The
drop from the 4th to the 6th hour was softened by a modest amount of
wine, and this proved to be extremely intoxicating.  My speech was
slurred, and there was later amnesia for the rather aggressive and
uninhibited behavior that occurred.  I felt that there was more drug
than alcohol contributing to this episode.  My dream patterns were
disturbingly unreal.

(with 160 mg) A very quiet development. There was no body load
whatsoever.  And no visual, and I saw it fading away all too soon.
This might be a good promoter, like MDPR.  I felt refreshed and
relaxed on the following morning.

(with 200 mg) This has an inordinately foul taste.  I felt slightly
queasy.  There were short daydreams which were quickly forgotten.  I
see no values that are worth the hints of physical problems, a little
eye mismanagement and some clenching of teeth, and a tendency to
sweat.  I was able to sleep at only five hours into it, but there were
a couple of darts.  This is not as rewarding (stoning) as MDA, and has
none of the magic of MDMA.  It was a short-lived plus two.

EXTENSIONS AND COMMENTARY: What is the train of thought that leads
from the structure of a known compound (which is active) to the
structure of an unknown one (which may or may not be active)?
Certainly the extrapolations involve many what-if's and maybeUs.  The
path can be humorous, it certainly can be tortuous, and it often calls
for special things such as faith, insight, and intuition.  But can one
say that it is logical?

    Logic is a tricky thing to evaluate.  One of the earliest
approaches was laid down by Aristotle, in the form of the syllogism.
In it there are three lines consisting of two premises and a
conclusion, a form that is called a Rmood.S All are statements of
relationships and, if the premises are true, there are only certain
conclusions that may logically follow.  For example:

Every man is a lover.

Every chemist is a man.

Therefore, every chemist is a lover.

Letting lover be the major term RaS and letting chemist be the minor
term RbS and letting man be the middle term RmS, this reduces to:

Every m is a,

Every b is m.

Therefore, every b is a

and it is a valid mood called Barbara.

Of the 256 possible combinations of all's and someUs and noneUs and
are's and are-notUs, only 24 moods are valid.  The reasoning here with
MDPH goes:

Some stimulants when given a methylenedioxy ring are
MDMA-like.

Some ring-unsubstituted 1,1-dimethylphenylethylamines are
stimulants.

Therefore, some ring-unsubstituted
1,1-dimethylphenylethyl        amines when given a methylenedioxy
ring are         MDMA-like.

In symbolic form this is:

Some m is a, and

Some b is m, then

Some b is a

and this is not one of the 24 valid moods.  Given the first premise as
some m is a, there is only one valid syllogism form that can follow,
and this is known as Disamis, or:

Some m is a, and

Every m is b, then

Some b is a

which translates as:

Some stimulants when given a methylenedioxy group are
MDMA-like.

Every stimulant is a ring-unsubstituted
1,1-dimethylphenyl        ethylamine.

Therefore, some ring-unsubstituted
1,1-dimethylphenylethyl        amines when given a methylenedioxy
group are         MDMA-like.

The conclusion is the same.  But the second premise is false so the
entire reasoning is illogical.  What is the false second premise?  It
is not a fact that every stimulant is a phentermine.  There are lots
of stimulants that are not phentermines.

So much for applying syllogistics to pharmacology.









#117 MDPL; N-PROPARGYL-MDA; N-PROPYNYL-MDA;
3,4-METHYLENEDIOXY-N-PROPARGYLAMPHETAMINE)

SYNTHESIS: A solution of 10.5 g propargylamine hydrochloride in 40 mL
MeOH was treated with 2.0 g 3,4-methylenedioxyphenylacetone (see under
MDMA for its preparation) followed by 0.55 g sodium cyanoborohydride.
Concentrated HCl was added as needed, to keep the pH constant at about
6.  The reaction seemed to progress very slowly.  After about five
days, the reaction mixture was added to 400 of H2O, acidified with
HCl, and extracted with 3x100 mL CH2Cl2.  The aqueous phase was made
basic with 25% NaOH, and extracted with 3x100 mL CH2Cl2.  Evaporation
of the solvent from these extracts yielded 1.6 g of a clear amber,
strong smelling oil which, on distillation at 105-110 !C at 0.2 mm/Hg,
yielded 1.0 g of an almost colorless oil.  This was dissolved in 20 mL
IPA, neutralized with about 10 drops of concentrated HCl, and the
spontaneously formed crystals were diluted with 50 mL anhydrous Et2O.
After filtration, Et2O washing and air drying, there was obtained 1.1
g white crystals of 3,4-methylenedioxy-N-propargylamphetamine
hydrochloride (MDPL) with a mp of 189-190 !C.  Anal. (C13H16ClNO2) N.

DOSAGE: greater than 150 mg.

DURATION: unknown.

EXTENSIONS AND COMMENTARY: There is a continuing uncertainty about the
name for the three-carbon radical that contains a triple bond.  The
hydrocarbon is propyne, although it has been referred to as
methylacetylene in the older literature.  The adjective, going from
the triple bond out to the point of attachment, is called propargyl,
as in propargyl chloride.  When the adjective must be built on the
parent hydrocarbon, the double bond is on the outside and one reads
away from it, as in 2-propynyl something.  However, when the
hydrocarbon is essentially the entire structure, then things get named
going towards the triple bond, as in 3-chloro-1-propyne.  Wait.  IUm
not done yet!  When the actual hydrocarbon name becomes distorted into
the derivative, then the triple bond is again at the high end of the
numbering scheme.  Propynol is 2-propyn-1-ol, which is, of course, the
same as 3-hydroxypropyne, or propargyl alcohol.  The code MDPL takes
the first and last letter of the two of them, both propargyl and
propynyl.









#118 MDPR; N-PROPYL-MDA; 3,4-METHYLENEDIOXY-N-PROPYLAMPHETAMINE

SYNTHESIS: A total of 20 mL concentrated HCl was added beneath the
surface of 20 mL propylamine, and when the addition was complete, the
mixture was stripped of volatiles under vacuum.  The slightly yellow
residual oil weighed 20.7 g and set up to crystals on cooling.  It was
dissolved in 75 mL MeOH, and there was added 4.45 g of
3,4-methylenedioxyphenylacetone (see under MDMA for its preparation)
followed by 1.1 g sodium cyanoborohydride.  Concentrated HCl in MeOH
was added as required to maintain the pH at about 6 as determined with
external, dampened universal pH paper.  When the generation of base
had stopped, the MeOH was allowed to evaporate and the residue was
suspended in 1 L water.  This was made strongly acidic with an excess
of HCl.  After washing with CH2Cl2, the aqueous phase was made basic
with 25% NaOH, and extracted with 3x100 mL CH2Cl2.  Removal of the
solvent from the pooled extracts under vacuum yielded 3.3 g of a pale
amber oil that was distilled at 85-90 !C at 0.2 mm/Hg.  This fraction
was water-white and weighed 2.3 g.  It was dissolved in 10 mL IPA and
neutralized with 25 drops concentrated HCl which produced crystals
spontaneously. These were diluted with anhydrous Et2O, removed by
filtration, washed with additional Et2O, and air dried.  In this way
there was obtained 2.3 g of 3,4-methylenedioxy-N-propylamphetamine
hydrochloride (MDPR) with a mp of 190-192 !C.  Recrystallization from
IPA gave a mp of 194-195 !C.  The NMR spectrum was completely
consistent with the assigned chemical structure.  Anal. (C13H20ClNO2)
N.

DOSAGE: greater than 200 mg.

DURATION: unknown.

QUALITATIVE COMMENTS: (with 200 mg) There are the slightest hints of
physical response, maybe a smidgin of a lightheadedness at the one
hour point.  Perhaps a slight teeth clench.  Certainly there is no
central mental effect.

EXTENSIONS AND COMMENTARY: This particular drug, considering that it
was without activity, has proven one of the richest veins of
pharmacological raw material.  Two clues suggested its potential
value.  A number of reports in the 150 to 200 milligram area suggested
that something was taking place in the periphery even without any
clear central effects.  The term Rbody windowS was used occasionally
by experimenters, an outgrowth of the term RwindowS that was used (at
that time, the mid-1970Us) to describe the mental effects of MDMA.  It
was as if the body was opened up and made receptive, instead of the
mind.  The second clue came from many anecdotal reports that
methedrine (a potent central nervous system stimulant) would augment
the effects of an LSD dosage which followed it.  The putting of a drug
on top of an inactive drug is the RprimerS concept.  It turned out
that MDPR was an extraordinary primer to some following psychedelic,
especially LSD, even at modest doses.  The putting of a drug on top of
an active drug, usually during the latter part of its effectiveness
is, as previously stated, called Rpiggy-backing.S A third drug-drug
interaction has also been studied; the simultaneous administration of
two active drugs, to study synergism.  There may be an enhancement, or
an inhibition, of one with the other.  Let's now re-enter the
subsection RQualitative CommentsS again, with this primer concept in
mind.

QUALITATIVE COMMENTS: (with 160 mg followed at 2 h by 60 5gs LSD) RThe
visual phenomena were extraordinary.  We were at the beach just south
of Mendocino.  In anything that had ever been living, there was an
endlessly deep microcosm of detail.  Endless, and forever more
microscopic in intricacy.  A sea urchin shell, a bit of driftwood, a
scrap of dried seaweed, each was a treasure of jewels.  I have never
had such wealth of visual eroticism and bliss before.  Later, we
visited the pygmy forest, but these living fossils were not as
magical.

(with 160 mg followed at 2 h by 60 5gs LSD) RWe both felt the first
effects at about 30 minutes, and an hour later we found ourselves in a
startling folie-a-deux, involved in reliving the origins of manUs
arrival on earth.  We were deep in a tropic environment, defending
ourselves against the nasties of nature (insects, threatening things,
blistering heat) and determining that man could indeed live here and
perhaps survive.  A shared eyes-closed fantasy that seemed to be the
same script for both of us.

(with 160 mg followed at 2 h by100 5gs LSD) RThis proved to be almost
too intoxicating, and a problem arose that had to have a solution.
The entire research group was here, and all were following this same
regimen.  Two hours into the second half of the experiment a telephone
call came that reminded me of a promise I had made to perform in a
social afternoon with the viola in a string quartet.  Why did I answer
the phone?  My entire experience was, over the course of about 20
minutes, pushed down to a fragile threshold, and I drove about 10
minutes to attend a swank afternoon event and played an early
Beethoven and a middle Mozart with an untouched glass of expensive
Merlot in front of me.  I could always blame the booze.  I declined
the magnificent food spread, split, and returned to my own party.
Safely home, and given 20 more minutes, I was back into a rolling +++
and I now know that the mind has a remarkable ability to control the
particular place the psyche is in.

(with 200 mg followed at 2 h by 60 5gs LSD) RThere was a steady climb
from the half-hour point to about 2 hours.  There was not the
slightest trace of anything sinister.  There was simply a super
tactile person-to-person window.  I had an overpowering urge to go out
and interact with other people.  To see, to talk, to be with others.
There are unending fantasies of things erotic.  Perhaps being with
others should be circumspect.  By evening the effects had largely worn
off, but this was an incredible day, beautiful and unexpectedly
relaxing.

EXTENSIONS AND COMMENTARY: There is need for more commentary.  It must
be noted that all of the above comments used rather modest dosages of
LSD.  The notes of this period, some two years of exploring
interactions of the MD series of compounds as preludes to true
psychedelics, are difficult to distill into a simple pattern.  Most of
these studies used LSD in the 60-100 microgram range which is
fundamentally a modest level.  Many trials were made where the
challenge of acid plopped right on top of an active residue of another
drug was more in keeping with the RpiggybackS argument.  An
illustration of this is a trial in which the primer was MDMA followed
at 5 hours (this is at a time of almost no effect) with a larger dose
of LSD (250 micrograms).  The LSD overwhelmed the residual numbing of
the MDMA, and the generated state was overwhelmingly erotic and out of
body.  There can be no way of analytically organizing such a gemisch
of drug-drug interactions with any logic that would allow a definitive
interpretation.  And LSD is not the only agent that can be used to
challenge the Rbody windowS such as that produced by MDPR.  2C-B,
2C-T-2 and 2C-T-7 have all been used with fine success as well.

In general, the use of an MD compound (looking at it as a stimulant
and primer) followed by a psychedelic, brings about an exaggeration
and enhancement of the latter compound.  Much work must be done in
this area to make sense of it all.



#119 ME; METAESCALINE; 3,4-DIMETHOXY-5-ETHOXYPHENETHYLAMINE

SYNTHESIS: To a vigorously stirred suspension of 18.6 g of
5-bromobourbonal in 100 mL CH2Cl2 there was added 14.2 g methyl
iodide, 1.0 g decyltriethylammonium iodide, and 120 mL 5% NaOH.  The
color was a deep amber, and within 1 min the top phase set up to a
solid.  This was largely dispersed with the addition of another 50 mL
of water.  The reaction was allowed to stir for 2 days.  The lower
phase was washed with H2O, and saved.  The upper phase was treated
with another 100 mL CH2Cl2, 50 mL of 25% NaOH, another g of
decyltriethylammonium iodide, and an additional 50 mL of methyl
iodide.  The formed solids dispersed by themselves in a few h to
produce two relatively clear layers.  Stirring was continued for an
additional 3 days.  The lower phase was separated, washed with H2O,
and combined with the earlier extract.  The solvent was removed under
vacuum to give 20.3 g of an amber oil that was distilled at 120-133 !C
at 0.4 mm/Hg to yield 15.6 g of 3-bromo-4-methoxy-5-ethoxybenzaldehyde
as a white crystalline solid with a mp of 52-53 !C.

A mixture of 15.6 g 3-bromo-4-methoxy-5-ethoxybenzaldehyde and 10 mL
cyclohexylamine was heated with an open flame until it appeared free
of H2O.  The residue was put under a vacuum (0.5 mm/Hg) and distilled
at 148-155 !C yielding 19.2 g
3-bromo-N-cyclohexyl-4-methoxy-5-ethoxybenzylidenimine as an off-white
crystalline solid with a melting point 66-68.5 !C.  Recrystallization
from 100 mL boiling MeOH gave a mp of 67-68.5 !C.  The C=N stretch in
the infra-red was at 1640 cm-1.  Anal. (C16H22BrNO2) C,H.

A solution of 17 g
3-bromo-N-cyclohexyl-4-methoxy-5-ethoxybenzyl-idenimine in 200 mL
anhydrous Et2O was placed in an atmosphere of He, stirred
magnetically, and cooled with an external dry-ice acetone bath.  Then
38 mL of a 1.55 M solution of butyllithium in hexane was added over 2
min, producing a clear yellow solution.  There was then added 25 mL of
butyl borate at one time, and the stirred solution allowed to return
to room temperature.  This was followed with 100 mL of saturated
aqueous ammonium sulfate.  The Et2O layer was separated, washed with
additional saturated ammonium sulfate solution, and evaporated under
vacuum The residue was dissolved in 200 mL of 50% MeOH and treated
with 12 mL of 30% hydrogen peroxide.  This reaction was mildly
exothermic, and was allowed to stir for 15 min, then added to an
aqueous solution of 50 g ammonium sulfate.  This was extracted with
2x100 mL CH2Cl2, the pooled extracts washed once with H2O, and the
solvent removed under vacuum.  The residue was suspended in dilute
HCl, and heated on the steam bath for 0.5 h.  Stirring was continued
until the reaction was again at room temperature and then it was
extracted with 2x100 mL CH2Cl2.  These extracts were pooled and in
turn extracted with 2x100 mL dilute NaOH.  The aqueous extracts were
reacidified with HCl, and reextracted with 2x100 mL CH2Cl2.  After
pooling, the solvent was removed under vacuum to yield an oily
residue.  This was distilled at 118-130 !C at 0.2 mm/Hg to yield 7.5 g
of 3-ethoxy-5-hydroxy-4-methoxybenzaldehyde as a distillate that set
to white crystals.  Recrystallization from cyclohexane gives a product
with a mp of 77-78 !C.  Anal. (C10H12O4) C,H.

A solution of 7.3 g of 3-ethoxy-5-hydroxy-4-methoxybenzaldehyde in 100
mL acetone was treated with 5 mL methyl iodide and 8.0 g finely
powdered anhydrous K2CO3, and held at reflux on a steam bath for 6 h.
The solvent was removed under vacuum, and the residue was suspended in
H2O.  After making this strongly basic, it was extracted with 3x50 mL
CH2Cl2, the extracts were pooled, and the solvent removed under
vacuum.  The residual amber oil was distilled at 110-120 !C at 0.4
mm/Hg to yield 7.3 g of a white oil.  This spontaneously set to white
crystals of 3,4-dimethoxy-5-ethoxybenzaldehyde which had a mp of
49-49.5 !C.  Anal. (C11H14O4) C,H.  This same aldehyde can be
obtained, but in a less satisfactory yield, by the ethylation of
3,4-dimethoxy-5-hydroxybenzaldehyde described under the preparation of
metaproscaline (MP).

A solution of 7.2 g 3,4-dimethoxy-5-ethoxybenzaldehyde in 100 mL
nitromethane containing 0.1 g anhydrous ammonium acetate was held at
reflux for 50 min.  The excess nitromethane was removed under vacuum
producing 6.8 g of a red oil which was decanted from some insoluble
material.  Addition of 10 mL hot MeOH to the decantings, gave a
homogeneous solution that spontaneously crystallized on cooling.  The
yellow crystals were removed by filtration, washed sparingly with MeOH
and air dried yielding 3.5 g yellow crystals of
3,4-dimethoxy-5-ethoxy-'-nitrostyrene, with a mp of 89.5-90 !C after
recrystallization from MeOH.  Anal. (C12H15NO5) C,H.

A solution of 2.0 g LAH in 100 mL anhydrous THF under He was cooled to
0 !C and vigorously stirred.  There was added, dropwise, 1.3 mL of
100% H2SO4, followed by the dropwise addition of a solution of 3.1 g
3,4-dimethoxy-5-ethoxy-'-nitrostyrene in 50 mL anhydrous THF, over the
course of 10 min.  The mixture was stirred at 0 !C for a while, and
then brought to a reflux on the steam bath for 30 min.  After cooling
again, the excess hydride was destroyed with IPA in THF, followed by
the addition of 20 mL 10% NaOH which was sufficient to convert the
solids to a white and granular form.  These were removed by
filtration, the filter cake washed with IPA, the mother liquor and
filtrates combined, and the solvents removed under vacuum.  The
residue was added to 150 mL dilute H2SO4, and the cloudy suspension
washed with 2x75 mL CH2Cl2 which removed much of the color.  The
aqueous phase was made basic with 25% NaOH, and extracted with 3x50 mL
CH2Cl2.  The solvent was removed from these pooled extracts and the
residue distilled at 103-116 !C at 0.25 mm/Hg to provide 2.3 g of a
colorless viscous liquid.  This was dissolved in 10 mL IPA,
neutralized with about 25 drops of concentrated HCl, which produced an
insoluble white solid.  This was diluted with 40 mL anhydrous Et2O
added slowly with continuous stirring.  The white crystalline
3,4-dimethoxy-5-ethoxyphenethylamine hydrochloride (ME) was isolated
by filtration, washed with Et2O, and air dried, and weighed 2.4 g.  It
had a mp of 202-203 !C which increased by one degree upon
recrystallization from boiling IPA.  Anal. (C12H20ClNO3) C,H.

DOSAGE: 200 - 350 mg.

DURATION: 8 - 12 h.

QUALITATIVE COMMENTS: (with 200 mg) It tasted pretty strong.
However, the taste was soon gone, and an energetic feeling began to
take over me.  It continued to grow.  The feeling was one of great
camaraderie, and it was very easy to talk to people.  Everyone was
talking to everyone else.  I found it most pleasant, energetic and at
the same time relaxing, with my defenses down.  This material did not
seem to lead to introspection; however, it might if one took it
without other people around.  Heightened visual awareness was mild,
but the audio awareness was quite heightened.  The feeling of being
with everyone was intense.

(with 250 mg) Initially I took 200 milligrams of metaescaline, and
the experience developed for me very gradually at first, and very
pleasantly.  After about one half hour I became aware of a wall that
seemed to shut me in, not unpleasantly.  The wall slowly dissolved,
but I was afraid I might get into a negative experience.  I felt
immediate relief (from this isolation) upon taking the additional 50
mg (at 2:23 into the experiment) as though glad of the decision.  I
lay down outside on a blanket.  There was a marvelous feeling inside,
although no imagery.  I felt the wall dissolve completely, and I
desired to join the group.  From this point on the experience was most
enjoyable, euphoric.  Although not dramatic like some psychedelics, it
was most rewarding for me personally.  I felt a marvelous bond with
everyone present, with clear-headed, excellent thinking, and excellent
communication.  All in all, a most rewarding and enjoyable experience.
Afterwards I felt much strengthened, with good energy and good
insight.  I have a strong feeling that the group tailored the nature
of the experience, and that I and others were most desirous of group
interaction.  I feel that one could do a lot of other things with it
if one turned one's attention to it.

(with 275 mg) Onset of both physical and mental change was slow
relative to other psychochemicals.  Very gradual internal stirrings
were felt at about the hour-and-a-half point. These were mostly
feelingful rather than cognitive, and were quite pleasurable.  At
about the two-and-a-half hour point I grew quite thirsty, and drank a
pint of beer.  Almost immediately, and quite unexpectedly, I tomsoed
to a much higher level and remained there for another three hours
until the whole experience waned.  [The verb, to tomso, means a sudden
rekindling of the drug-induced altered state with a small amount of
alcohol. It is explained in the recipe for TOMSO.]  During the
experience heights, and in fact before it reached its height, talking
was easy and unimpeded.  The transference feelings so characteristic
of MDMA were basically not there.  But for purposes of psychotherapy,
there were some advantages: fluent associations, undefended positions,
and general bonaise.

(with 400 mg) Ingested 300 milligrams at about 1:30 in the afternoon.
Very quiet climb.  Occasional yawns.  Matter-of-fact view of the
world.  No rosy glow.  At the end of the second hour, I seem to be
stuck at a ++.  Take another 100 milligrams at 3:45 PM.  Still tastes
awful.  Feel a small head-rush fifteen minutes after taking the
supplement, and within a half hour I am completely +3.  For a while
this was a sterner mescaline.  Saw the eternal, continual making of
choices, all opposites continually in motion with each other.  Yin and
yang everywhere, giving life to every molecule.  The universe itself
keeps alive by the action-reaction, the yes-no, the black-white,
male-female, plus-minus.  All life is a continual making of choices on
all levels.  Then I closed my eyes, and I found myself floating up to
the very top of a temple, where there was radiant light and a sense of
homecoming.  Making love is a clear stream over and through rocks and
canyons Q the earth and sky make love, and the rocks make love to
other rocks, and the water is the teasing, fondling, living and moving
actions of loving.  To realize that, on some level, all existence
makes love to all other existence.  The Japanese Garden: a structured
way of laying out a small glimpse into cosmic love-making, so that it
can be read by other human souls.  All loving, when direct and free
and undemanding, is a touching of the Source.  The hardest lesson, of
course, is how to love yourself that same way.  And it remains both
the first lesson of Kindergarten and the Ph.D. final.  I was able to
drift into sleep at about 4:00 AM.

EXTENSIONS AND COMMENTARY: The reorientation of the single ethyl group
of escaline (E) to the meta-position produces metaescaline (ME).  In
cats, in studies of over 50 years ago, the two compounds produced
similar effects at similar dosages.  In man, ME also appears to be
similar to mescaline in potency.  However, a subtle difference is
apparent between ME and Peyote, the natural source of mescaline.  With
Peyote itself, the initial taste of the crude cactus is more than just
foul; it might better be described as unbelievably foul.  But in the
middle of a Peyote experience, the taste of the cactus is truly
friendly.  When ME was retasted in the middle of an experience, the
taste was still foul.

There are other distinctions from mescaline.  Unlike mescaline or
Peyote, there is rarely any body discomfort during the early phase of
intoxication, no nausea and only an occasional comment suggesting
hyperreflexia.  And, also unlike mescaline, most subjective reports on
ME claim that music produces little imagery, and the exaggeration of
color perception is more reserved.  Appetite is normal, the tastes and
textures of food are unusually rewarding.  No subject has ever
expressed a reluctance to repeat the experience.  Sleep is easy,
refreshing, and the following day seems free from residue.









From: [e-mail]
Newsgroups: sci.med,sci.chem,alt.drugs
Subject: PiHKAL: The Chemical Story.  File 5 of 6

(I'm posting this for a friend.)

This is part 5 of 6 of the second half of PiHKAL: A Chemical Love
Story, by Alexander Shulgin and Ann Shulgin.  Please forgive any typos
or misprints in this file; further, because of ASCII limitations,
many of the typographical symbols in the original book could not be
properly represented in these files.

If you are seriously interested in the chemistry contained in these
files, you should order a copy of the book PiHKAL.  The book may be
purchased for $22.95 ($18.95 + $4.00 postage and handling) from
Transform Press, Box 13675, Berkeley, CA 94701.  California residents
please add $1.38 State sales tax.

At the present time, restrictive laws are in force in the United
States and it is very difficult for researchers to abide by the
regulations which govern efforts to obtain legal approval to do work
with these compounds in human beings....  No one who is lacking legal
authorization should attempt the synthesis of any of the compounds
described in these files, with the intent to give them to man.  To do
so is to risk legal action which might lead to the tragic ruination of
a life.  It should also be noted that any person anywhere who
experiments on himself, or on another human being, with any of the
drugs described herin, without being familiar with that drug's action
and aware of the physical and/or mental disturbance or harm it might
cause, is acting irresponsibly and immorally, whether or not he is
doing so within the bounds of the law.





#120 MEDA; 3-METHOXY-4,5-ETHYLENEDIOXYAMPHETAMINE

SYNTHESIS: To a solution of 50 g 3,4-dihydroxy-5-methoxybenzaldehyde
in 100 mL distilled acetone there was added 70 g ethylene bromide and
58 g finely powdered anhydrous K2CO3.  The mixture was held at reflux
for 5 days.  This was then poured into 1.5 L H2O and extracted with
4x100 mL CH2Cl2.  Removal of the solvent from the pooled extracts gave
a residue which was distilled at 19 mm/Hg.  Several of the fractions
taken in the 203-210 !C range spontaneously crystallized, and they
were pooled to give 18.3 g of 3-methoxy-4,5-ethylenedioxybenzaldehyde
as white solids with a mp of 80-81 !C.  A small sample with an equal
weight of malononitrile in EtOH treated with a few drops of
triethylamine gave 3-methoxy-4,5-ethylenedioxybenzalmalononitrile as
pale yellow crystals from EtOH with a mp of 153-154 !C.

A solution of 1.50 g 3-methoxy-4,5-ethylenedioxybenzaldehyde in 6 mL
acetic acid was treated with 1 mL nitroethane and 0.50 g anhydrous
ammonium acetate, and held on the steam bath for 1.5 h.  To the cooled
mixture H2O was cautiously added until the first permanent turbidity
was observed, and once crystal-lization had set in, more H2O was added
at a rate that would allow the generation of additional crystals.
When there was a residual turbidity from additional H2O, the addition
was stopped, and the beaker held at ice temperature for several h.
The product was removed by filtration and washed with a little 50%
acetic acid, providing 0.93 g
1-(3-methoxy-4,5-ethylenedioxyphenyl)-2-nitropropene as dull yellow
crystals with a mp of 116-119 !C.  Recrystallization of an analytical
sample from MeOH gave a mp of 119-121 !C.

A stirred suspension of 6.8 g LAH in 500 mL anhydrous Et2O under an
inert atmosphere was brought up to a gentle reflux.  A total of 9.4 g
1-(3-methoxy-4,5-ethylenedioxyphenyl)-2-nitropropene in warm Et2O was
added over the course of 0.5 h.  Refluxing was maintained for 6 h, and
then the reaction mixture was cooled and the excess hydride destroyed
by the cautious addition of 400 mL 1.5 N H2SO4.  The two clear phases
were separated, and the aqueous phase was brought to pH of 6 by the
addition of a saturated Na2CO3 solution.  This was filtered free of a
small amount of insolubles, and the clear filtrate was heated to 80
!C.  To this there was added a solution of 9.2 g picric acid (90%
material) in 100 mL boiling EtOH, and the clear mixture allowed to
cool in an ice bath.  Scratching generated yellow crystals of the
picrate salt.  This salt was filtered free of the aqueous environment,
treated with 50 mL of 5% NaOH, and stirred until the picric acid was
totally in the form of the soluble sodium salt.  This was then
extracted with 3x100 mL CH2Cl2, the extracts pooled, and the solvent
removed under vacuum.  The residue weighed 6.0 g, and was dissolved in
100 mL anhydrous Et2O, and saturated with dry HCl gas.  The white
solids that formed were filtered free of the Et2O, and ground up under
50 mL of slightly moist acetone, providing 4.92 g of
3-methoxy-4,5-ethylenedioxyamphetamine hydrochloride monohydrate
(MEDA) as white crystals.

DOSAGE: greater than 200 mg.

DURATION: unknown.

EXTENSIONS AND COMMENTARY: There are times when the Gods smile in
unexpectedly nice ways.  Having found the activity of MMDA, the
RscientificS thing to do would be to compare it against the other
RpsychotomimeticS amphetamine that was known at that time (this was
1962), namely TMA.  Comparing their structures, the only difference of
any kind was that two of the adjacent methoxyl groups of TMA were
replaced with a 5-membered ring, called the methylenedioxy ring.

Where does one go next?  Some perverse inspiration suggested
increasing the size of this ring to a 6-membered ring, the
ethylenedioxy (or dioxene) homologue.  Well, if you thought that
getting myristicinaldehyde was a difficulty, it was nothing compared
to getting this 6-membered counterpart.  But I huffed and I puffed,
and I did make enough to taste and to evaluate.  And it was here that
I got the divine message!  No activity!!  So, rather than being
condemned forever a la Sisyphus to push ever larger rings up my
psyche, I gave myself permission to pursue another path.  The message
was: RDonUt change the groups.  Leave them as they are, but relocate
them instead.S And that led directly to TMA-2 and its story.

A couple of diversions may be mentioned here.  Before the blessed
inactivity of MEDA was established, the 7-membered ring counterpart,
3-methoxy-4,5-trimethylenedioxyamphetamine (MTMA) was prepared by
essentially the same procedure.  The above
3-methoxy-4,5-dihydroxybenzaldehyde with trimethylene bromide gave
3-methoxy-4,5-trimethylenedioxybenzaldehyde, white solids, with a
malononitrile derivative with a mp of 134-135 !C; the aldehyde with
nitroethane gave the nitropropene with a mp of 86-87 !C; and this with
LAH gave MTDA as the hydrochloride (mp 160-161 !C) again isolated
first as the picrate.  It had been tasted at up to an 8 milligram
dosage (no activity, but none expected) before being abandoned.  And,
an initial effort was made to synthesize a five-member ring
(methylenedioxy) with a methyl sticking out from it.  This ethylidine
homologue got as far as the aldehyde stage.  The reaction between
3,4-dihydroxy-5-methoxybenzaldehyde and 1,1-dibromoethane in acetone
containing anhydrous potassium carbonate gave a minuscule amount of a
product that was a two-component mixture.  This was resolved by dozens
of separate injections into a preparatory gas chromatography system,
allowing the isolation of the second of the two components in a
quantity sufficient to demonstrate (by NMR spectroscopy) that it was
the desired 3-methoxy-4,5-ethylidinedioxybenzaldehyde.  Starting with
the pre-prepared dipotassium salt or the lead salt of the
catecholaldehyde gave nothing.  With no activity being found with
MEDA, all was abandoned.

There are some comments made under MDA for successful chemistry (using
a different approach) alo#ng these lines when there is no methoxyl
group present.  These are the compounds EDA and IDA.  But the
pharmacology was still not that exciting.









#121 MEE; 4,5-DIETHOXY-2-METHOXYAMPHETAMINE

SYNTHESIS: To a solution of 166 g bourbonal in 1 L MeOH there was
added a solution of 66 g KOH pellets in 300 mL H2O.  There was then
added 120 g ethyl bromide, and the mixture was held at reflux on the
steam bath for 3 h.  The reaction was quenched with three volumes of
H2O, and made strongly basic by the addition of 25% NaOH.  This was
extracted with 3x300 mL CH2Cl2, and the pooled extracts stripped of
solvent under vacuum.  There remained 155 g of
3,4-diethoxybenzaldehyde as a fluid oil that had an infra-red spectrum
identical (except for being slightly wet) to that of a commercial
sample from the Eastman Kodak Company.

A solution of 194 g 3,4-diethoxybenzaldehyde in 600 g glacial acetic
acid was arranged in a flask that could be magnetically stirred, yet
cooled as needed with an external ice bath.  A total of 210 g of 40%
peracetic acid in acetic acid was added at a rate such that, with ice
cooling, the exothermic reaction never raised the internal temperature
above 26 !C.  The reaction developed a deep red color during the 2 h
needed for the addition.  At the end of the reaction the mixture was
quenched by the addition of three volumes of H2O, and the remaining
acidity was neutralized by the addition of solid Na2CO3 (700 g was
required).  This aqueous phase was extracted several times with
CH2Cl2, and the solvent was removed from the pooled extracts under
vacuum.  The residue was a mixture of the intermediate formate ester
and the end product phenol.  This was suspended in 800 mL 10% NaOH,
and held on the steam bath for 1.5 h.  After cooling, this was washed
once with CH2Cl2 (discarded) and then acidified with HCl.  There was
the formation of an intensely hydrated complex of the product phenol,
reminiscent of the problem encountered with 3-ethoxy-4-methoxyphenol.
This was worked up in three parts.  The entire acidified aqueous phase
was extracted with Et2O (3x200 mL) which on evaporation gave 80 g of
an oil.  The hydrated glob was separately ground up under boiling
CH2Cl2 which, on evaporation, gave an additional 30 g of oil, and the
aqueous mother liquor from the glob was extracted with 2x200 mL CH2Cl2
which provided, after removal of the solvent, an additional 10 g.
These crude phenol fractions were combined and distilled at 1.5 mm/Hg.
Following a sizeable forerun, a fraction boiling at 158-160 !C was the
anhydrous product, 3,4-diethoxyphenol.  It was a clear, amber oil, and
weighed 70.0 g.  The slightest exposure to H2O, even moist air, give a
solid hydrate, with mp of 63-64 !C.  This phenol can be used for the
synthesis of MEE (this recipe) or for the preparation of EEE (see the
separate recipe).  A solution of 2.0 g of this phenol in 5 mL CH2Cl2
was diluted with 15 mL hexane.  This was treated with 2 g methyl
isocyanate followed by a few drops of triethylamine.  After about 5
min, white crystals formed of 3,4-diethoxyphenyl-N-methyl carbamate,
with a mp of 90-91 !C.

A solution of 26.6 g 3,4-diethoxyphenol in 50 mL MeOH was mixed with
another containing 9.6 g KOH pellets dissolved in 200 mL hot MeOH.
There was then added 21.4 g methyl iodide, and the mixture was held at
reflux for 2 h on the steam bath.  This was then quenched in 3 volumes
of water, made strongly basic with 25% NaOH, and extracted with 3x150
mL CH2Cl2.  Evaporation of the solvent from the pooled extracts gave
19.3 g of 1,2-diethoxy-4-methoxybenzene (3,4-diethoxyanisole) as a
clear, pale amber oil that solidified when cooled.  The mp was 20-21
!C.

A mixture of 32.0 g N-methyl formanilide and 36.2 g POCl3 was allowed
to stand until it was a deep red color (about 0.5 h).  To this there
was added 18.3 g 1,2-diethoxy-4-methoxybenzene and the exothermic
reaction was heated on the steam bath for 2.5 h.  This was then poured
over 600 mL chipped ice, and the dark oily material slowly began
lightening in color and texture.  A light oil was formed which, on
continued stirring, became crystalline.  After the conversion was
complete, the solids were removed by filtration producing, after
removal of as much H2O as possible by suction, 26.9 g of crude
aldehyde.  A small sample pressed on a porous plate had a mp of
87.5-88.5 !C.  Recrystallization of the entire damp crop from 50 mL
boiling MeOH gave, after cooling, filtering, and air drying, 17.7 g of
4,5-diethoxy-2-methoxybenzaldehyde as fluffy, off-white crystals with
a mp of 88-88.5 !C.  A solution of 1.0 g of this aldehyde and 0.5 g of
malononitrile dissolved in warm absolute EtOH was treated with 3 drops
triethylamine.  There was the immediate formation of crystals which
were filtered and air dried to constant weight.  The product,
4,5-diethoxy-2-methoxybenzalmalononitrile, was a bright yellow
crystalline material, which weighed 1.0 g and had a mp of 156-157 !C.

To a solution of 14.7 g 4,5-diethoxy-2-methoxybenzaldehyde in 46 g
glacial acetic acid, there was added 8.0 g nitroethane and 5.0 g
anhydrous ammonium acetate.  The mixture was heated on the steam bath
for 2 h, becoming progressively deeper red in color.  The addition of
a small amount of H2O to the hot, clear solution produced a slight
turbidity, and all was allowed to stand overnight at room temperature.
There was deposited a crop of orange crystals that was removed by
filtration and air dried.  There was obtained 7.0 g
1-(4,5-diethoxy-2-methoxyphenyl)-2-nitropropene as brilliant orange
crystals that had a mp of 89-90.5 !C.  This was tightened up, but not
improved, by trial recrystallization from acetic acid, mp 89-90 !C,
and from hexane, mp 90-90.5 !C.  Anal. (C14H19NO5) C,H.

To a gently refluxing suspension of 5.0 g LAH in 400 mL anhydrous Et2O
under a He atmosphere, there was added 6.5 g
1-(4,5-diethoxy-2-methoxyphenyl)-2-nitropropene by allowing the
condensing Et2O to drip into a shunted Soxhlet thimble containing the
nitrostyrene.  This effectively added a warm saturated solution of the
nitrostyrene dropwise.  Refluxing was maintained for 5 h, and the
reaction mixture was cooled with an external ice bath.  The excess
hydride was destroyed by the cautious addition of 400 mL of 1.5 N
H2SO4.  When the aqueous and Et2O layers were finally clear, they were
separated, and 100 g of potassium sodium tartrate was dissolved in the
aqueous fraction.  Aqueous NaOH was then added until the pH was >9,
and this was extracted with 3x200 mL CH2Cl2.  Removal of the solvent
under vacuum produced an off-white oil that was dissolved in anhydrous
Et2O and saturated with anhydrous HCl gas.  The crystals of
4,5-diethoxy-2-methoxyamphetamine hydrochloride (MEE) that formed were
very fine and slow to filter, but finally were isolated as a white
powder weighing 5.4 g and melting at 178.5-180 !C.  Anal.
(C14H24ClNO3) C,H,N.

DOSAGE: greater than 4.6 mg.

DURATION: unknown.

EXTENSIONS AND COMMENTARY: There were early trials made with MEE,
before it became known what direction the ethoxy substitution results
would take.  A number of progressive trials, up to a dosage of 4.6
milligrams, were without any central effects at all.

There is an instinct in structure-activity studies to think of a
change as a success or a failure, depending on whether there is an
increase or a decrease in the desired activity.  But if one were to
look at the effects of putting an ethoxy group onto TMA-2 in place of
a methoxy group as a way of decreasing the effectiveness, then the
4-position becomes the worst position (MEM is equipotent to TMA-2),
and the 5-position is perhaps a little less bad (MME is almost as
potent) and the 2-position is the best by far (EMM is out of it,
potency-wise).  In other words, in the comparison of the 2- and the
5-positions, the lengthening of the 5-position gives modest loss of
activity, and the lengthening of the whatever in the 2-position is the
most disruptive.  With this as a basis for prediction, then MEE (which
differs from MEM only by a lengthening of the 5-position substituent)
might be only a little less active than MEM and, as MEM is about the
same as TMA-2, it is distinctly possible that MEE may show activity in
the area at dosages that are not much above the 25 to 50 milligram
area.  Of all the diethoxy homologues, it would be the most promising
one to explore.

Which brings to mind a quotation of a hero of mine, Mark Twain.  RI
like science because it gives one such a wholesome return of
conjecture from such a trifling investment of fact.









#122 MEM; 2,5-DIMETHOXY-4-ETHOXYAMPHETAMINE

SYNTHESIS: A solution of 83 g bourbonal (also called ethyl vanillin,
or vanillal, or simply 3-ethoxy-4-hydroxybenzaldehyde) in 500 mL MeOH
was treated with a solution of 31.5 g KOH pellets (85% material)
dissolved in 250 mL H2O.  There was then added 71 g methyl iodide, and
the mixture was held under reflux conditions for 3 h.  All was added
to 3 volumes of H2O, and this was made basic with the addition of 25%
NaOH.  The aqueous phase was extracted with 5x200 mL CH2Cl2.  The
pooling of these extracts and removal of the solvent under vacuum gave
a residue of 85.5 g of the product 3-ethoxy-4-methoxybenzaldehyde,
with a mp of 52-53 !C.  When this product was recrystallized from
hexane, its mp was 49-50 !C.  When the reaction was run with the same
reactants in a reasonably anhydrous environment, with methanolic KOH,
the major product was the acetal, 3-ethoxy-a,a,4-trimethoxytoluene.
This was a white glistening product which crystallized readily from
hexane, and had a mp of 44-45 !C.  Acid hydrolysis converted it to the
correct aldehyde above.  The addition of sufficient H2O in the
methylation completely circumvents this by-product.  A solution of 1.0
g of this aldehyde and 0.7 g malononitrile in 20 mL warm absolute
EtOH, when treated with a few drops of triethylamine, gave immediate
yellow color followed, in a few min by the formation of crystals.
Filtration, and washing with EtOH, gave bright yellow crystals of
3-ethoxy-4-methoxybenzalmalononitrile with a mp of 141-142 !C.

A well stirred solution of 125.4 g 3-ethoxy-4-methoxybenzaldehyde in
445 mL acetic acid was treated with 158 g 40% peracetic acid (in
acetic acid) at a rate at which, with ice cooling, the internal
temperature did not exceed 27 !C.  The addition required about 45 min.
The reaction mixture was then quenched in some 3 L H2O.  There was the
generation of some crystals which were removed by filtration.  The
mother liquor was saved.  The solid material weighed, while still wet,
70 g and was crude formate ester.  A small quantity was recrystallized
from cyclohexane twice, to provide a reference sample of
3-ethoxy-4-methoxyphenyl formate with a mp of 63-64 !C.  The bulk of
this crude formate ester was dissolved in 200 mL concentrated HCl
which gave a deep purple solution.  This was quenched with water which
precipitated a fluffy tan solid, which was hydrated phenolic product
that weighed about 35 g, and melted in the 80-90 !C. range.  The
mother liquors of the above filtration were neutralized with Na2CO3,
then extracted with 3x100 ml Et2O.  Removal of the solvent gave a
residue of about 80 g that was impure formate (containing some
unoxidized aldehyde).  To this there was added 500 mL 10% NaOH, and
the dark mixture heated on the steam bath for several h.  After
cooling, the strongly basic solution was washed with CH2Cl2, and then
treated with 200 mL Et2O, which knocked out a heavy semi-solid mass
that was substantially insoluble in either phase.  This was, again,
the crude hydrated phenol.  The Et2O phase, on evaporation, gave a
third crop of solids.  These could actually be recrystallized from
MeOH/H2O, but the mp always remained broad.  When subjected to
distillation conditions, the H2O was finally driven out of the
hydrate, and the product 3-ethoxy-4-methoxyphenol distilled as a clear
oil at 180-190 !C at 0.8 mm/Hg.  This product, 45.1 g, gave a fine NMR
spectrum, and in dilute CCl4 showed a single OH band at 3620 cm-1,
supporting the freedom of the OH group on the aromatic ring from
adjacent oxygen.  Efforts to obtain an NMR spectrum in D2O immediately
formed an insoluble hydrate.  This phenol can serve as the starting
material for either MEM (see below) or EEM (see separate recipe).

To a solution of 12.3 g 3-ethoxy-4-methoxyphenol in 20 mL MeOH, there
was added a solution of 4.8 g flaked KOH in 100 mL heated MeOH.  To
this clear solution there was then added 10.7 g methyl iodide, and the
mixture held at reflux on the steam bath for 2 h.  This was then
quenched in 3 volumes H2O, made strongly basic with 10% NaOH, and
extracted with 3x100 mL CH2Cl2.  Removal of the solvent from the
pooled extracts under vacuum gave 9.4 g of an amber oil which
spontaneously crystallized.  The mp of 1,4-dimethoxy-2-ethoxybenzene
was 42-43.5 !C, and was used, with no further purification, in the
following step.

A mixture of 17.3 g N-methylformanilide and 19.6 g POCl3 was allowed
to stand for 0.5 h, producing a deep claret color.  To this there was
added 9.2 g 1,4-dimethoxy-2-ethoxybenzene, and the mixture was held on
the steam bath for 2 h.  It was then poured into chipped ice and, with
mechanical stirring, the dark oily phase slowly became increasingly
crystalline.  This was finally removed by filtration, providing a
brown solid mat which showed a mp of 103.5-106.5 !C.  All was
dissolved in 75 mL boiling MeOH which, on cooling, deposited fine
crystals of 2,5-dimethoxy-4-ethoxybenzaldehyde that were colored a
light tan and which, after air drying to constant weight, weighed 8.5
g and had a mp of 108-109.5 !C.  Search was made by gas chromatography
for evidence of the other two theoretically possible positional
isomers, but none could be found.  The NMR spectrum showed the two
para-protons as clean singlets, with no noise suggesting other
isomers.  There was a single peak by GC (for the recrystallized
product) but the mother liquors showed a contamination that proved to
be N-methylformanilide.  A 0.3 g sample, along with 0.3 g
malononitrile, was dissolved in 10 mL warm absolute EtOH, and treated
with a drop of triethylamine.  There was the immediate formation of a
yellow color followed, in 1 min, by the deposition of fine yellow
needles.  Filtering and air drying gave 0.25 g of
2,5-dimethoxy-4-ethoxybenzalmalononitrile, with a mp of 171-172 !C.

A solution of 7.3 g 2,5-dimethoxy-4-ethoxybenzaldehyde in 25 g glacial
acetic acid was treated with 3.6 g nitroethane and 2.25 g anhydrous
ammonium acetate, and heated on the steam bath.  After two h, the
clear solution was diluted with an equal volume of H2O, and cooled in
an ice bucket.  There was the formation of a heavy crop of orange
crystals which were removed by filtration.  The dry weight of
1-(2,5-dimethoxy-4-ethoxyphenyl)-2-nitropropene was 4.8 g and the mp
was 120-124 !C.  Recrystallization of an analytical sample from MeOH
gave a mp of 128-129 !C.  Anal. (C13H17NO5) C,H.

To a gently refluxing suspension of 3.3 g LAH in 400 mL anhydrous Et2O
under a He atmosphere, there was added 4.3 g
1-(2,5-dimethoxy-4-ethoxy)-2-nitropropene by allowing the condensing
Et2O to drip into a shunted Soxhlet thimble apparatus containing the
nitrostyrene, thus effectively adding a warm saturated ether solution
of it to the hydride mixture.  The addition took 2 h.  Refluxing was
maintained for 5 h, and then the reaction mixture was cooled to 0 !C
with an external ice bath.  The excess hydride was destroyed by the
cautious addition of 300 mL of 1.5 N H2SO4.  When the aqueous and Et2O
layers were finally clear, they were separated, and 100 g of potassium
sodium tartrate was dissolved in the aqueous fraction.  Aqueous NaOH
was then added until the pH was >9, and this was then extracted with
3x100 mL CH2Cl2.  Evaporation of the solvent from the pooled extracts
produced an almost white oil that was dissolved in 100 mL anhydrous
Et2O and saturated with anhydrous HCl gas.  There was deposited a
white crystalline solid of 2,5-dimethoxy-4-ethoxyamphetamine
hydrochloride (MEM) which weighed 3.1 g and had a mp of 171-172.5 !C.
Anal. (C13H22ClNO3) C,H,N.

DOSAGE: 20 - 50 mg.

DURATION: 10 - 14 h.

QUALITATIVE COMMENTS: (with 20 mg) I experienced some physical
discomfort, but doesnUt that tell us about the work to be done, rather
than the property of the material?  The breakthrough I had was the
following day (and this seems to be the way MEM operates, i.e., first
the energy and expansion, next day insight) was of the highest value
and importance for me.  I was given a methodology for dealing with my
shadow parts.  No small gift.  And I did it all alone and the results
were immediate.  I am so grateful.

(with 20 mg, at 1.5 h following 120 mg MDMA) RThe transition was very
smooth, with no obvious loss of the MDMA experience.  I felt less of a
need to talk, but the intimate closeness with the others was
maintained.  The experience continues to grow more profound and
euphoric and I prayed, in the latter part of the afternoon, that it
wouldnUt stop.  It continued until midnight with marvelous feelings,
good energy, and much hilarity.  And it abated very little over the
next several days leaving me with the feeling of lasting change with
important insights still coming to mind one week later.

(with 25 mg, at 2 h following 120 mg MDMA) RI found that sounds in
general were distracting.  No, they were out-and-out annoying.  I may
have been in an introspective mood, but I really wanted to be alone.
No body problems at all.  Felt good.  I developed some color changes
and some pattern movement.  Not much, but then I didnUt explore it
much.  The wine party afterwards was certainly most pleasant.  The
soup was a great pleasure.  And that hard bread was good.  The
material was clearly not anorexic, or at least I overcame whatever
anorexia there might have been.

(with 30 mg) I was aware of this in thirty minutes and it slowly
developed from there to an almost +++ in the following hour.  There
were visual phenomena, with some color enhancement and especially a
considerable enhancement of brights and darks.  The first signs of
decline were at about six hours, but there was something still working
there after another six hours had passed.  A slow decline, certainly.

(with 50 mg) I came into the experience knowing that yesterday had
been a very fatiguing and tense day.  I felt this material within the
first ten minutes which is the fastest that I have ever felt anything.
The ascent was rapid and for the first hour I tended to an inward
fantasying with a distinct sensual tinge.  There was a persistent
queasiness that never left me, and it contrasted oddly with a good
feeling of outward articulation and lucidity which succeeded in coming
to the fore after the introverted first hour.  Sleep was difficult,
but the next day was calm and clear.

(with 50 mg) Lots of energy, best directed into activity.  Clear
imaging, thinking.  Intense yet serene.  Good feeling of pleasantness
and some euphoria.  I felt the need to keep moving.  Hard to stay
still.

(with 70 mg, in two parts) RThe effects of the 40 milligrams were
muted by another drug experiment yesterday morning, and I never got
much over a plus 1.  There is an erotic nature, tactile sensitivity
perhaps not as delicate as with 2C-B, but it is there.  At the 2 hour
point, an additional 30 milligrams increased the body impact (a
distinct tremor and sensitivity) but somehow not a lot more mental.  I
have been compromised by yesterday.

EXTENSIONS AND COMMENTARY: MEM was both a valuable and dramatic
compound, as well as a drug that played a watershed role.  The
completion of all the possible trimethoxyamphetamines (the TMAUs)
showed that only two of them combined the values of dependability of
positive psychedelic effects with a reasonably high potency.  Both
TMA-2 and TMA-6 are treasures, both active in similar dosages, and
both offer methoxyl groups that are begging to be replaced by other
things.  The first focus was on TMA-2, partly because the needed
synthetic chemistry was better known, and partly because I had
discovered its activity earlier.  But there were three entirely
different and distinct methoxyl groups to work on, in TMA-2.  There is
one at the 2-position, one at the 4-position, and one at the
5-position.  The most obvious thing to do, it seemed, was to make each
of them one carbon longer.  Replace a methoxy with an ethoxy.  And a
logical naming pattern could follow the use of M for methoxy, and E
for ethoxy, in sequence right around the ring from the 2- to the 4- to
the 5-positions.  The first group to be compared, then, would be EMM,
MEM, and MME.  And of these three, it was only MEM that was right up
there in drama and in potency.  But, by the time that became apparent,
I had already completed the diethoxy possibilities (EEM, EME, and MEE)
as well as the triethoxy homologue, EEE.  With the discovery that the
4-position was the magic leverage point, and that the homologues at
positions 2- and 5- were clearly less interesting, all emphasis was
directed at this target, and this has led to the many 4-substituted
families that are now known to be highly potent and felt by many to be
personally valuable.

Why put such emphasis on potency, I am frequently asked? Why should it
matter how much of a compound you take, as long as the effective level
is much lower than its toxic level?  Well, in a sense, that is the
very reason.  There are no guides as to what the toxic levels of any
of these many compounds might really be in man.  There is simply no
way of determining this.  Only a few have been explored in animals in
the pursuit of an LD-50 level.  Most of them are similar to
one-another, in that they are, in mice, of relatively low toxicity
and, in rat, of relatively high toxicity.  But this toxicity appears
not to be related to potency in man.  So, if one might extrapolate
that they are of more or less the same risk to man (from the toxic
point of view) then the lower the dosage, the greater the safety.
Maybe.  In the absence of anything factual, it makes a reasonable
operating hypothesis.

Many of the reports of MEM effects have been with experiments in which
an effective dose of MDMA had been taken shortly earlier.  There has
developed a concept, embraced by a number of researchers, that the
ease and quietness usually seen with the development of the MDMA
experience can mitigate some of the physically disturbing symptoms
sometimes seen with other psychedelics.  This may be partly due to a
familiar entry into a altered place, and partly due to a lessening of
dosage usually required for full effects.  MEM seems to have had more
trials using this combination than many of the other psychedelic
drugs.









#123 MEPEA; 3-METHOXY-4-ETHOXYPHENETHYLAMINE

SYNTHESIS: A solution of 10.0 g 3-methoxy-4-ethoxybenzaldehyde in 150
mL nitromethane was treated with 1.7 g anhydrous ammonium acetate, and
heated on the steam bath for 1 h.  The excess nitromethane was removed
under vacuum, yielding a loose, yellow crystalline mass that was
filtered and modestly washed with cold MeOH.  The 8.0 g of damp yellow
crystals thus obtained were dissolved in 50 mL of vigorously boiling
CH3CN, decanted from a small amount of insolubles (probably ammonium
acetate residues) and cooled in an ice bath.  The crystals so obtained
were removed by filtration, washed with 2x5 mL cold CH3CN, and air
dried to constant weight.  The yield of
4-ethoxy-3-methoxy-'-nitrostyrene was 6.3 g of beautiful yellow
crystals.

A solution of 2.3 g LAH in 70 mL anhydrous THF was cooled, under He to
0 !C with an external ice bath.  With good stirring there was added
2.3 mL 100% H2SO4 dropwise, to minimize charring.  This was followed
by the addition of 6.2 g 3-ethoxy-4-methoxy-'-nitrostyrene in
anhydrous THF.  After a few min further stirring, the temperature was
brought up to a gentle reflux on the steam bath, and then all was
cooled again to 0 !C.  The excess hydride was destroyed by the
cautious addition of IPA followed by sufficent 10% NaOH to give a
white granular character to the oxides, and to assure that the
reaction mixture was basic.  The reaction mixture was filtered and the
filter cake well washed with THF.  The filtrate and washes were
combined and stripped of solvent under vacuum.  The residue was
dissolved in dilute H2SO4.  This was washed with 2x75 mL CH2Cl2, which
removed the residual yellow color.  The remaining aqueous phase was
made basic with NaOH, and extracted with 3x75 mL CH2Cl2.  These
extracts were combined and the solvent removed under vacuum.  The
residue was distilled at 108-115 !C at 0.4 mm/Hg to give 4.2 g of a
mobile, colorless liquid.  This was dissolved in 12 mL IPA,
neutralized with 60 drops concentrated HCl, and diluted with 100 mL
anhydrous Et2O.  There was deposited a fine white crystalline product
which, after removal by filtration, ether washing, and air drying,
yielded 3.8 g of 3-methoxy-4-ethoxyphenethylamine hydrochloride
(MEPEA).

DOSAGE: 300 mg or greater.

DURATION: short.

QUALITATIVE COMMENTS: (with 120 mg) I am at perhaps a +1, a very
slight effect of lightness, without any body awareness at all.  And
then in another hour, I was completely baseline again.

(with 300 mg) Whatever changes took place were complete at the end of
an hour.  The effects were very quiet, very pleasant, and very light.
There was nothing psychedelic here, but rather a gentle lifting of
spirits.  No sensory enhancement or other expected changes.

EXTENSIONS AND COMMENTARY: This is one of the very few phenethylamines
with only two substituents that shows even a hint of central activity.
And there is an interesting story attached.  I got a call out of
absolutely nowhere, from a Stanislov Wistupkin, that he had discovered
a number of new psychedelic drugs which he would like to share with
me.  Two of them were simple phenethylamines, one with an ethoxy group
at the 4-position, and one with an allyloxy group there.  Both, he
said, were mood elevators active between 100 and 300 milligrams.  One
of them was this material, here called MEPEA, and the other one was
3-methoxy-4-allyloxyphenethylamine, or MAPEA.  When I did meet him in
person, he gave me a most remarkable publication which had been
authored some ten years earlier, by a person named Leminger, now dead.
It was all in Czech, but quite unmistakably, right there on the third
page, were the structures of MEPEA and MAPEA, and the statement that
they were active at between 100 and 300 milligrams.  I have not yet
made the allyloxy compound, but I feel that it too might be a gentle
mood elevator similar to the ethoxy.

A most appealing extension of these materials would be the amphetamine
derivatives, things with a 3-methoxy group, and something small and
terse on the 4-position.  The immediate analogies of MEPEA and MAPEA
would be 3-methoxy-4-ethoxy- (and 3-methoxy-4-allyloxy)-amphetamine.
And equally interesting would be the 4-hydroxy analogue.  This would
be an easily made compound from vanillin, one of our most enjoyable
spices in the kitchen cabinet, and it would be directly related to the
essential oils, eugenol and isoeugenol.  This amphetamine compound has
already been synthesized, but it is still unexplored in man.

Some years ago a report appeared in the forensic literature of Italy,
of the seizure of a small semitransparent capsule containing 141
milligrams of a white powder that was stated to be a new
hallucinogenic drug.  This was shown to contain an analogue of DOM,
3-methoxy-4-methylamphetamine, or MMA.  The Italian authorities made
no mention of the net weight contained in each dosage unit, but it has
been found that the active level of MMA in man is in the area of 40-60
milligrams.  The compound can apparently be quite dysphoric, and long
lived.

In the Czechoslovakian publication that presented MEPEA and MAPEA.
there were descriptions of escaline (E), proscaline (P), and the
allyloxy analogue (AL).  These are all active in man, and have been
entered elsewhere.  This is the only published material dealing with
psychedelic drugs I have ever been able to find, from the laboratory
of Otakar Leminger.  What sort of man was this chemist?  He worked for
years in industry, and only at the time of his retirement did he
publish this little gem.  He lived at Usti, directly north of Praha,
on the Labe river (which is called by the better known name, the Elbe,
as soon as it enters Germany).  Might there be other treasures that he
had discovered, and never published?  Was young Wistupkin a student of
his?  Are there unrecognized notes of Otakar Leminger sitting in some
farm house attic in Northern Czechoslovakia?  I extend my heartfelt
salute to an almost unknown explorer in the psychedelic drug area.









#124 META-DOB; 5-BROMO-2,4-DIMETHOXYAMPHETAMINE

SYNTHESIS: The reaction of 2,4-dimethoxyamphetamine (2,4-DMA) with
elemental bromine proceeded directly to the formation of
5-bromo-2,4-dimethoxyamphetamine which was isolated as the
hydrobromide salt with a melting point of 204.5-205.5 !C and in a 67%
yield.  A mp of 180-181 !C has also been published.

DOSAGE: 50 - 100 mg.

DURATION: 5 - 6 h.

EXTENSIONS AND COMMENTARY: There is very little synthetic information
available, and some of it is contradictory.  The initial human report
in the medical literature says only that a dosage of about 100
milligrams produced effects that were similar to those produced by
MDA.  Both the quality of the experience and the potency of the
compound have been modified in more recent publications by the
originators of this compound.  A 40 milligram dose, after an induction
period of an hour, produced a vague uneasiness that was interpreted
originally as a threshold psychedelic effect.  At doses in the 60 to
90 milligram range, there were produced feelings of anxiety and
paranoid fantasies, and distinct toxic signs such as flushing,
palpitations, and occasional nausea, vomiting and diarrhea.  Any
psychedelic effects seem to have been blurred by the more obvious
toxic actions of the drug.  I have been told that their final
conclusion was that the drug appears toxic in the 50 to 60 milligram
range.  I have not personally explored this positional isomer of DOB.

The positional isomer of DOB with the bromine in the ortho-position is
4,5-dimethoxy-2-bromoamphetamine and is called, not surprisingly,
ORTHO-DOB.  It has been made by the condensation of
2-bromo-4,5-dimethoxybenzaldehyde with nitroethane to give
1-(2-bromo-4,5-dimethoxyphenyl)-2-nitropropene with a mp of 105-106
!C.  Reduction to the amphetamine had to be conducted at a low
temperature and using only an equimolar amount of lithium aluminum
hydride, to minimize reductive removal of the bromo group.  The
hydrochloride salt of 2-bromo-4,5-dimethoxyamphetamine (ORTHO-DOB) had
a mp of 214-215.5 !C, and the hydrobromide salt a melting point of
196-197 !C or of 210 !C.  Both have been reported.  The yield from the
direct bromination of 3,4-DMA was apparently very bad.  I do not think
that the compound has ever gone into man.

There are three other dimethoxyamphetamine isomers known, and each has
been explored chemically as to its reactivity with elemental bromine.
With 2,3-DMA, a mixture of the 5-Br-2,3-DMA and 6-Br-2,3-DMA was
formed; with 2,6-DMA, 3-Br-2,6-DMA was formed; and with 3,5-DMA, a
mixture of 2-Br-3,5-DMA and the 2,6-dibromo product was produced.  The
bromination of 2,5-DMA is, of course, the preferred procedure for the
synthesis of 4-Br-2,5- DMA, or DOB, q.v.  None of these positional
isomers has evear been put into man, but 3-Br-2,6-DMA and the
iodo-counterpart have been explored as potential radio-fluorine
carriers into the brain.  This is all discussed in the 3,4-DMA recipe.









#125 META-DOT; 2,4-DIMETHOXY-5-METHYLTHIOAMPHETAMINE

SYNTHESIS: To 27 g 1,3-dimethoxybenzene that was being well stirred,
there was added, dropwise, 29 g concentrated H2SO4 over a period of 15
min.  Stirring was continued for 1 hour, and then the mixture was
poured slowly into 250 mL of saturated aqueous K2CO3.  The precipitate
that formed was removed by filtration, and dried at 125 !C to give
59.6 g crude potassium 2,4-dimethoxybenzenesulfonate.  This was finely
ground, and 30 g of it was treated with 35 g of POCl3 and the mixture
heated on the steam bath for 2 h.  This was cooled to room
temperature, and then poured over 300 mL crushed ice.  When all had
thawed, this was extracted with 2x150 mL Et2O.  The extracts were
pooled, washed with saturated brine, and the solvent removed under
vacuum to give a residue which solidified.  There was thus obtained
14.2 g 2,4-dimethoxybenzenesulfonyl chloride as white solids with a mp
of 69-72 !C.  Heating of a small portion with concentrated ammonium
hydroxide gave the corresponding sulfonamide which, on
recrystallization from EtOH, produced white needles with a mp of
165.5-166.5 !C.

To a stirred and gently refluxing suspension of 11 g LAH in 750 mL
anhydrous Et2O, there was added 13.2 g 2,4-dimethoxybenzenesulfonyl
chloride in an Et2O solution.  The refluxing was maintained for 48 h
then, after cooling externally with ice water, the excess hydride was
destroyed by the slow addition of 600 mL of 10% H2SO4.  The phases
were separated, and the aqueous phase extracted with 2x200 Et2O.  The
organics were pooled, washed once with 200 mL H2O, and the solvent
removed under vacuum.  The residue was dried azeotropically through
the addition and subsequent removal of CH2Cl2.  Distillation of the
residue provided 8.0 g 2,4-dimethoxythiophenol as a colorless oil,
boiling at 89-92 !C at 0.5 mm/Hg.

To a solution of 7.8 g 2,4-dimethoxythiophenol in 40 mL absolute EtOH
there was added a solution of 4 g 85% KOH in 65 mL EtOH.  This was
followed by the addition of 5 mL methyl iodide, and the mixture was
held at reflux for 30 min.  This was poured into 200 mL H2O, and
extracted with 3x50 mL Et2O.  The pooled extracts were washed once
with aqueous sodium hydrosulfite, then the organic solvent was removed
under vacuum.  The residue was distilled to give 8.0 g of
2,4-dimethoxythioanisole as a colorless oil with a bp of 100-103 !C at
0.6 mm/Hg.

To a mixture of 15 g POCl3 and 14 g N-methylformanilide that had been
warmed briefly on the steam bath there was added 7.8 g of
2,4-dimethoxythioanisole.  The reaction was heated on the steam bath
for an additional 20 min and then poured into 200 mL H2O.  Stirring
was continued until the insolubles had become completely loose and
granular.  These were removed by filtration, washed with H2O, sucked
as dry as possible, and then recrystallized from boiling MeOH.  The
product, 2,4-dimethoxy-5-(methylthio)benzaldehyde, was an off-white
solid weighing 8.6 g.  It could be obtained in either of two
polymorphic forms, depending on the concentration of aldehyde in MeOH
at the time of crystal appearance.  One melted at 109-110 !C and had a
fingerprint IR spectrum including peaks at 691, 734, 819 and 994 cm-1.
The other melted at 124.5-125.5 !C and had major fingerprint peaks at
694, 731, 839 and 897 cm-1.  Anal. (C10H12O3S) C,H.

A solution of 8.2 g 2,4-dimethoxy-5-(methylthio)benzaldehyde in 30 mL
nitroethane was treated with 1.8 g anhydrous ammonium acetate and
heated on the steam bath for 4 h.  Removal of the excess nitroethane
under vacuum gave a colored residue which crystallized when diluted
with MeOH.  Recrystallization of the crude product from boiling EtOH
gave, after filtration, washing and air drying to constant weight, 8.3
g 1-(2,4-dimethoxy-5-methylthiophenyl)-2-nitropropene with a mp of
112-113 !C.  Anal. (C12H15NO4S) C,H,N.

A suspension of 6.5 g LAH in 250 mL anhydrous THF was placed under a
N2 atmosphere and stirred magnetically and brought to reflux.  There
was added, dropwise, 8.0 g of
1-(2,4-dimethoxy-5-methylthiophenyl)-2-nitropropene in 50 mL THF.  The
reaction mixture was maintained at reflux for 18 h.  After being
brought to room temperature, the excess hydride was destroyed by the
addition of 6.5 mL H2O in 30 mL THF.  There was then added 6.5 mL of
3N NaOH, followed by an additional 20 mL H2O.  The loose, white,
inorganic salts were removed by filtration, and the filter cake washed
with an additional 50 mL THF.  The combined filtrate and washes were
stripped of solvent under vacuum yielding a residue that was
distilled.  The free base boiled at 125-128 !C at 0.1 mm/Hg and was a
white oil which solidified on standing.  It weighed 5.1 g and had a mp
of 47-48.5 !C.  This was dissolved in 50 mL IPA, neutralized with
concentrated HCl (until dampened universal pH paper showed a deep red
color) and diluted with anhydrous Et2O to the point of turbidity.
There was a spontaneous crystallization providing, after filtering,
washing with Et2O, and air drying,
2,4-dimethoxy-5-methylthioamphetamine hydrochloride (META-DOT) with a
mp of 140.5-142 !C.  Anal. (C12H20ClNO2S) C,H,N.

DOSAGE: greater than 35 mg.

DURATION: unknown.

QUALITATIVE COMMENTS: (with 35 mg) There was a vague awareness of
something all afternoon, something that might be called a thinness.
Possibly some brief cardiovascular stimulation, but nothing completely
believable.  This is a threshold level at the very most.

EXTENSIONS AND COMMENTARY: Again, as with the studies with ORTHO-DOT,
it is apparent that the activity of META-DOT is going to be way down
from the most interesting of these isomers, PARA-DOT (ALEPH-1, or just
ALEPH).  In the rectal hyperthermia assay (which calculates the
psychedelic potential of compounds by seeing how they influence the
body temperature of experimental animals in comparison to known
psychedelics) the three DOT's were compared with DOM.  And the results
fell into line in keeping with the activities (or loss of activities)
found in man.  PARA-DOT was about half as active as DOM, but both
ORTHO-DOT and the compound described here, META-DOT, were down by
factors of 50x and 30x respectively.  These animal studies certainly
seem to give results that are reasonable with a view to other known
psychedelic drugs, in that mescaline was down from DOM by a factor of
more than 1000x, and LSD was some 33x more potent than DOM.

I have a somewhat jaundiced view of this rabbit rectal hyperthermia
business.  One is presumably able to tell whether a compound is a
stimulant or a psychedelic drug by the profile of the temperature
rise, and how potent it will be by the extent of the temperature rise.
But the concept of pushing thermocouples into the rear ends of
restrained rabbits somehow does not appeal to me.  I would rather
determine both of these parameters from human studies.









#126 METHYL-DMA; DMMA; 2,5-DIMETHOXY-N-METHYLAMPHETAMINE

SYNTHESIS: To a stirred solution of 28.6 g methylamine hydrochloride
in 120 mL MeOH there was added 7.8 g 2,5-dimethoxyphenylacetone
followed by 2.6 g sodium cyanoborohydride.  HCL was added as needed to
maintain the pH at about 6.  The reaction was complete in 24 h, but
was allowed to stir for another 3 days.  The reaction mixture was
poured into 600 mL H2O, acidified with HCl (HCN evolution, caution)
and washed with 3x100 mL CH2Cl2.  Aqueous NaOH was added, making the
solution strongly alkaline, and this was then extracted with 3x100 mL
CH2Cl2.  Removal of the solvent from the pooled extracts under vacuum
gave 8.3 g of a clear, off-white oil that distilled at 95-105 !C. at
0.25 mm/Hg.  The 6.5 g of colorless distillate was dissolved in 25 mL
IPA, neutralized with concentrated HCl, and then diluted with
anhydrous Et2O to the point of cloudiness.  As crystals formed,
additional Et2O was added in small increments, allowing clearing
crystallization between each addition.  In all, 200 mL Et2O was used.
After filtering,Et2O washing, and air drying, there was obtained 6.2 g
of 2,5-dimethoxy-N-methylamphetamine hydrochloride (METHYL-DMA) as
fine white crystals with a mp of 117-118 !C.  The mixed mp with
2,5-DMA (114-116 !C) was depressed to 96-105 !C.  An alternate
synthesis gave the same overall yield of an identical product, but
started with 2,5-DMA.  It required two synthetic steps.  The free base
amine was converted to the crystalline formamide with formic acid in
benzene using a Dean Stark trap, and this intermediate was reduced to
METHYL-MDA with LAH.

DOSAGE: above 250 mg.

DURATION: unknown.

QUALITATIVE COMMENTS: (with 250 mg) There is a slight paresthesia at
about 45 minutes, an awareness on the surface of the skin as if I had
been touched by a cold draft of air.  But nothing more.  At three
hours, I am completely out, if I was ever in.  In the evening I
assayed 120 milligrams of MDMA, and it barely produced a threshold
effect, so the two materials might be seeing one another.

EXTENSIONS AND COMMENTARY: This is a difficult compound to pin down in
the anthology of drugs.  For some reason it has intrigued several
independent, quiet researchers, and I have accumulated a number of
interesting reports over the years.  One person told me that he had
felt nothing at up to 60 milligrams.  Another had found a threshold at
50 milligrams, and had complete and thorough experiences at both 150
and 200 milligrams.  Yet another person described two incidents
involving separate individuals, with intravenous administrations of
0.2 mg/Kg, which would be maybe 15 or 20 milligrams.  Both claimed a
real awareness in a matter of minutes, one with a tingling in the
genitalia and the other with a strange presence in the spine.  Both
subjects reported increases in body temperature and in blood pressure.
Apparently the effects were felt to persist for many hours.

There is an interesting, and potentially informative, convergence of
the metabolite of one drug with the structure of another.  Under 4-MA,
mention was made of a bronchodilator that has been widely used in the
treatment of asthma and other allergenic conditions.  This compound,
2-methoxy-N-methylamphetamine is known by the generic name of
methoxyphenamine, and a variety of trade names with Orthoxine (Upjohn)
being the best known.  The typical dosage of methoxyphenamine is
perhaps 100 milligrams, and it may be used several times a day.  It
apparently produces no changes in blood pressure and only a slight
cardiac stimulation.  And one of the major metabolites of it in man is
the analogue with a hydroxyl group at the 5-position of the molecule.
This phenolic amine, 5-hydroxy-2-methoxy-N-methylamphetamine is just a
methyl group away from METHYL-DMA; it could either be methylated to
complete the synthesis, or METHYL-DMA could be demethylated to form
this phenol.  There is plentiful precedent for both of these reactions
occuring in the body.  It is always intriguing when drugs which show
distinctly different actions can, in principle, intersect
metabolically at a single structure.  One wonders just what the
pharmacology of that common intermediate might be.

Three additional N-methylated homologues of known psychedelics warrant
mention, but do not really deserve separate recipes.  This is because
they have had only the most cursory assaying, which I have learned
about by personal correspondence.  All three were synthesized by the
reduction of the formamide of the parent primary amine with LAH.
METHYL-TMA (or N-methyl-3,4,5-trimethoxyamphetamine) had been run up
in several trials to a maximum of 240 milligrams, with some mental
disturbances mentioned only at this highest level.  METHYL-TMA-2 (or
N-methyl-2,4,5-trimethoxyamphetamine) had been tried at up to 120
milligrams without any effects.  METHYL-TMA-6 (or N-methyl-2,4,6-
trimethoxyamphetamine) had been tried at up to 30 milligrams and it,
too, was apparently without effects.  These are reports that I have
heard from others, but I have had no personal experience with them.
Those that I can describe from personal experience are entered
separately as recipes of their own.  And there are many, many other
N-methyl homologues which have been prepared and characterized in the
literature, and have yet to be tasted.  So far, however, the only
consistent thing seen is that, with N-methylation, the potency of the
psychedelics is decreased, but the potency of the stimulants appears
to be pretty much maintained.









#127 METHYL-DOB; 4-BROMO-2,5-DIMETHOXY-N-METHYLAMPHETAMINE

SYNTHESIS: To a solution of 6.0 g of the free base of
2,5-dimethoxy-N-methyl-amphetamine (see recipe under METHYL-DMA) in 30
mL glacial acetic acid there was added, dropwise and with good
stirring, a solution of 5.5 g bromine in 15 mL acetic acid.  The
reaction became quite warm, and turned very dark.  After stirring an
additional 45 min, the mixture was poured into 200 mL H2O and treated
with a little sodium hydrosulfite which lightened the color of the
reaction.  There was added 20 mL concentrated HCl, and the reaction
mixture was washed with 2x100 mL CH2Cl2 which removed most of the
color.  The aqueous. phase was made basic with 25% NaOH, and extracted
with 3x100 mL CH2Cl2.  The removal of the solvent from the pooled
extracts under vacuum gave 1.8 g of an oil which was dissolved in 10
mL IPA, neutralized with concentrated HCl, and diluted with 100 mL
anhydrous Et2O.  No crystals were obtained, but rather an oily and
somewhat granular insoluble lower phase.  The Et2O was decanted, and
the residue washed by grinding up under 3x100 mL Et2O.  The original
decanted material was combined with the three washes, and allowed to
stand for several h.  The product
4-bromo-2,5-dimethoxy-N-methylamphetamine hydrochloride (METHYL-DOB)
separated as fine white crystals which weighed, after filtering and
air drying, 0.3 g and had a mp of 149-150 !C.  The Et2O-insoluble
residue finally set up to a pale pink mass which was finely ground
under a few mL acetone.  Filtration and air drying gave a second crop
of product as 0.9 g of pale lavender solids, with a mp of 143-145 !C.

DOSAGE: greater than 8 mg.

DURATION: probably rather long.

QUALITATIVE COMMENTS: (with 8.0 mg) At an hour and twenty minutes, I
was suddenly quite light headed.  An hour later I must say that the
effects are real, and generally good.  I am spacey Q nothing tangible.
And a couple of hours yet later I am still aware.  My teeth are
somewhat rubby, and as things have been pretty steady for the last
three hours, this will prove to be long lasting.  There are a lot of
physical effects that may be kidding me into providing myself some of
the mental.  At the sixth hour, I find that this is almost entirely
physical.  My teeth are tight, there is a general physical tenseness,
my reflexes seem exaggerated, and my eyes are quite dilated.  All of
these signs are lessened by the eighth hour, and do not interfere with
sleep at the twelfth hour.  There is no desire to proceed any further,
at least at the present time.  Mental (+) physical (++).  Next day,
slight impression of persistence of toxicity.

(with 10 mg) Nothing psychedelic, but awfully hard on the bod.  The
next day (24 hours later) I had a severe response to 5 milligrams of
psilocybin.

EXTENSIONS AND COMMENTARY: The mention above, of the 10 milligrams of
METHYL-DOB followed by 5 milligrams of psilocybin, leads to some
interesting speculation.  The usual pattern that is seen when two
psychedelic drugs are taken too closely together is that the second
experience is less effective than would have been expected.  This is
the property that is called tolerance, and it is frequently seen in
pharmacology.  The two exposures may be to a single drug, or they may
be to two different drugs which usually have some properties in
common.  It is as if the spirit of the receptor site had become a
little tired and needed a while to rest up and recuperate.  When there
is a demand for a repeat of full effectiveness, the user will
customarily increase the dosage of the drug that is used.  It is one
of the built-in protections, in the area of psychedelics that, after
one experience, you must wait for a period of time to lose the
refractoriness that has set in.

The measure of the degree of tolerance that can be shared between
different drugs, called cross-tolerance, can be used as an estimate of
the similarities of their mechanisms of action.  In other words, if A
and B are somehow seen by the body as being similar, then a normally
effective dose of A will make a next-day's normally effective dose of
B weaker than expected.  Or not active at all.  And B will do the same
job on A.  If two drugs are different in their ways of doing things in
the body, there is most often no cross-tolerance seen.  This was
described for MDMA and MDA, and is the basis of the argument that they
act by distinctly separate mechanisms.  A person who used what would
be held as an active dose of MDMA for several days lost all response
to the drug.  He was tolerant to its effects.  But an exposure to an
effective dose of MDA at the time that tolerance to MDMA was complete,
provided a normal response to the MDA.  The drugs are not
cross-tolerant and the body recognizes them as distinct individuals.

But for one drug to promote, or to exaggerate, the effect of another
is called potentiation, and can be a clue to the dynamics going on in
the brain or body.  Here, admittedly in only a single report,
METHYL-DOB had somehow sensitized the subject to a rather light dosage
of psilocybin.  But there have been other reports like this that I
have heard of, from here and there.  I have been told of an experiment
with the dextro-isomer of DOM (this is the inactive optical isomer) at
a level that was, not surprisingly, without any effects.  The
researcher had a severe reaction the following day with what was
referred to as RpoorS hashish.  A similar form of potentiation has
been commented upon under the recipe for TOMSO, where an inactive
drug, and a most modest amount of alcohol, add together to create an
unexpectedly intense intoxication.  But note that in each of these
cases, it is a phenethylamine interacting with a non-phenethylamine
(psilocybin is an indole, hashish is a non-alkaloid terpene thing, and
alcohol is, well, alcohol).

The bottom line with METHYL-DOB is, as with the other N-methylated
psychedelics, that it is way down in potency, and probably not worth
pursuing.









#128 METHYL-J; MBDB; EDEN;
2-METHYLAMINO-1-(3,4-METHYLENEDIOXYPHENYL)BUTANE;
N-METHYL-1-(1,3-BENZODIOXOL-5-YL)-2-BUTANAMINE

SYNTHESIS: A solution of 0.12 g mercuric chloride in 180 mL H2O was
added to 5 g aluminum foil that had been cut into 1 inch squares, and
amalgamation allowed to proceed for 0.5 h.  The gray cloudy aqueous
phase was decanted, and the resulting aluminum washed with 2x200 mL
H2O.  After shaking as dry as possible, there was added, in sequence,
a solution of 7.6 g methylamine hydrochloride in an equal weight H2O,
23 mL IPA, 18.3 mL 25% NaOH, 6.72 g
1-(3,4-methylenedioxyphenyl)-2-butanone (see under the recipe of J for
its preparation), and finally 44 mL additional IPA.  The mixture was
occasional swirled, and cooled externally as needed to keep the
temperature below 50 !C.  After the reduction was completed (no
metallic aluminum remaining, only gray sludge), it was filtered and
the residues washed with MeOH.  The combined filtrate and washes were
stripped of organic volatiles under vacuum, the residue treated with
100 mL Et2O, and this was extracted with 2x50 mL 3 N HCl.  After
washing the pooled aqueous extracts with 3x100 mL CH2Cl2, they were
made basic with an excess of 25% NaOH and extracted with 5x50 mL
CH2Cl2.  Drying of these extracts with anhydrous MgSO4 and removal of
the solvent gave a residue that was distilled at 88 !C at 0.08 mm/Hg
to give a colorless oil that was dissolved in IPA and neutralized with
concentrated HCl.  The solids that separated were removed by
filtration, Et2O washed, and air dried to provide 6.07 g
2-methylamino-1-(3,4-methylenedioxyphenyl)butane hydrochloride
(METHYL-J or MBDB) as white crystals with a mp of 156 !C.  Anal.
(C12H18ClNO2) C,H,N.  Reductive amination of the butanone with
methylamine hydrochloride in MeOH, employing sodium cyano-borohydride,
gave an identical product but in a smaller yield.

DOSAGE: 180 - 210 mg.

DURATION: 4 - 6 h.

QUALITATIVE COMMENTS: (with 210 mg) Generally very, very friendly,
very quiet effect.  I can read easily, but looking at pictures in most
books is relatively meaningless.  Distinct de-stressing effect, to the
point where it's too much trouble to set out to do anything at all,
really.  There is just no drive, and it isnUt even bothersome to be
missing it.  Do I like it?  Yes, very much.  Feel that IUve just begun
to explore it, though.  Would I consider this material in therapy?
Well, sure, it's worth trying.  Destressing would be excellent, and
better than MDMA in some ways, but the empathy and intuition levels
have yet to be explored in a therapy setting.  I feel that they may be
somehow lower.

(with 210 mg) Onset rapid.  Alert 20 minutes, and to a +2.5 at 30 to
35 minutes.  No physical symptoms, i.e., teeth clench, no stomach
problems.  Good visual enhancement; eyes open Q bright colors Q no
visuals with eyes closed.  No 'cone of silence' that I get with MDMA
(and enjoy), otherwise IUm not sure I could tell which was which if I
took them blind.

(with 210 mg and a 50 mg supplement) RTasted perfectly rotten.
Suspect I was getting some type of alert in 5 minutes (I often get one
quickly with MDMA) and at 30 minutes, a full blown high developed
rather abruptly.  It would be difficult to describe the high.  I
suspect it is the lack of language for the phenomenon.  I would
describe it somewhat like an alcohol high without the disabling side
effects of confusion, slurring, staggering and etc.  The high never
got any more intense than at that 30 minute point and with a
noticeable drop in another hour, I took a 50 mg supplement.  I enjoyed
the high.  I relaxed with the material.  However, it did not seem to
have the same qualities as MDMA, in that it was not as stimulating,
and it had very little visual activity.  I talked with others, but
found it easy to lie down and relax.  There was some jaw-clenching
towards the end, and I had considerable nystagmus at the peak which I
could control.  After the experience, I did not want to drink alcohol
very much (sell it as a substitute for EtOH!).

(with 210 mg and a 70 mg supplement) RI begin to feel the rush at 20
minutes, increasing rapidly.  Very much like MDMA, only more intense
intoxication.  Otherwise same symptoms: intense euphoria that I call a
feeling of grace, soft skin, voices, youthful appearance, animated
discussions, feelings of great closeness to others.  I start to drop
noticeably at less than an hour and a half into it, but I delayed a
supplement until the hour and fifty minute point.  It does not get me
back to the original intoxication.  However, it is very nice, very
much like MDMA.  Only difference is that there seems to be more
quietness, less inclination to talk than with an MDMA supplement.  My
conclusion: Seems an excellent substitute for MDMA, Next time may try
somewhat lower amount, supplement sooner.

EXTENSIONS AND COMMENTARY: An observer who was familiar with the
outwardly apparent effects with groups experimenting with MDMA felt
that, although most subjects commented favorably in their comparisons
of METHYL-J with MDMA, there was lacking some of the spontaneity, the
warmth, and the clear intimacy of the latter drug.  The dosage range
explored is remarkably tight, attesting to a consistency of response.
The typical supplement used, if any, was 70 milligrams or less, just
before the two hour point.  This indicates a chronology similar to
that of MDMA, and about two thirds the potency.

The arguments that weigh the use of the code name of MBDB against the
use of METHYL-J are present in the recipe for BDB (or J).  But what is
the source of this H, I, J, K naming thing that I have called the Muni
Metro?

First, a little bit of local color.  In San Francisco, there is a
public transportation called the S.F. Municipal Metropolitan System
complex that has integrated an underground street-car system that
emerges above ground and connects with a bus network.  A number of the
street-car lines fan across the city to the outer reaches which are
called the Avenues.  These lines are named by sequential letters.
There is the J Church Street line, the K Ingelside line, the L Taraval
line, the M Ocean line, and the N Judah.  And in the pharmacological
complex that involved the lengthening of the aliphatic chain, there
were two coincidental benchmarks in the names that were proposed.
Those without an alpha-substituent (no carbon atoms at the position
alpha to the amine group, the phenethylamines) were originally called
the H compounds.  H stood for Rhomopiperonylamine.S And the first of
those with the alpha-ethyl group there (two carbon atoms at the
position alpha to the amine group) was familiarly called RJacobamineS
in recognition of a famous chemist who had set the synthetic wheels in
motion.

It is quite obvious, that with one carbon atom lying on that
alpha-position, you are precisely half-way between no carbons and two
carbons.  And there was one letter of the alphabet that lies precisely
half-way between an H and a J.  So, an natural naming pattern
developed.  The I compounds were already pretty well known by names
such as MDA and MDMA and MDE, so I, and METHYL-I, and ETHYL-I, didnUt
have any appeal.  But for the new, the alpha-ethyl compounds, why not
call them the J-compounds?  If it has a methyl on the nitrogen it will
be METHYL-J and if it has an ethyl group it will be ETHYL-J.  And in
the next longer group, the 3-carbon propyl group on the alpha-position
becomes the K family, and the 4-carbon butyl group located there, the
L family.  Each with its METHYL and ETHYL prefixes, if the nitrogen
atoms are substituted with a methyl or and ethyl group.  VUla, comme
on dit en Fran

ais.  Le systme Muni Metro.  Plus simple.









#129 METHYL-K; 2-METHYLAMINO-1-(3,4-METHYLENEDIOXYPHENYL)PENTANE;
N-METHYL-1-(1,3-BENZODIOXOL-5-YL)-2-PENTYLAMINE

SYNTHESIS: The Grignard reagent of butyl bromide was prepared in
anhydrous Et2O by the dropwise addition of 68 g n-butyl bromide to a
well-stirred suspension of 14 g magnesium turnings in 500 mL anhydrous
Et2O.  When the exothermic reaction had stopped, there was added a
solution of 60 g piperonal in about 100 mL Et2O, over the course of 1
h.  After the exothermic addition was complete, the reaction mixture
was held at reflux for several h, then cooled and decomposed by the
addition of dilute HCl.  The phases were separated, and the aqueous
phase extracted with 2x75 mL CH2Cl2.  The organics were combined and
gave, after the removal of the solvents under vacuum, 84 g of
1-hydroxy-1-(3,4-methylenedioxyphenyl)pentane as a yellow liquid.
This was used in the following dehydration step without further
purification.

A mixture of 52 g of the crude
1-hydroxy-1-(3,4-methylenedioxyphenyl)pentane and 2 g powdered KHSO4
was heated with a flame until there was no more apparent generation of
H2O.  The resulting dark, fluid oil was distilled at 100-110 !C at 0.3
mm/Hg to give 29.5 g of 1-(3,4-methylenedioxyphenyl)-1-pentene as a
light yellow liquid.  This was employed in the following oxidation
step without further purification.

To 120 mL of 90% formic acid there was added, with good stirring, 15
mL H2O, followed by 23 mL of 35% H2O2 To this mixture, cooled with an
external ice bath, there was added a solution of 24 g crude
1-(3,4-methylenedioxyphenyl)-1-pentene in 120 mL acetone at a rate
slow enough to keep the internal temperature from exceeding 35 !C.  At
the end of the addition, the temperature was brought up to 45 !C by
heating briefly on the steam bath, and then the reaction mixture was
allowed to stand and stir at ambient temperature for several h.  All
volatiles were removed under vacuum, with a bath temperature
maintained at 45 !C.  The residue was dissolved in 30 mL MeOH, then
there was added 200 mL 15% H2SO4 and the mixture held on the steam
bath for 1.5 h.  There was then added an additional 300 mL H2O, and
this was extracted with 2x250 mL of a petroleum ether/EtOAc (5:1)
mixture.  The extracts were pooled, and the solvents removed under
vacuum to give a residue that was distilled at 115-120 !C at 0.3
mm/Hg.  This light yellow liquid weighed 13.5 g and was substantially
pure 1-(3,4-methylenedioxyphenyl)-2-pentanone by TLC.

To 5.0 g of aluminum foil cut into 1 inch squares, there was added a
solution of 150 mg HgCl2 in 200 mL H2O.  The mixture was heated
briefly until there were clear signs of active amalgamation, such as
fine bubbling for the aluminum surfaces and the beginning of the
formation of a gray, amorphous solid phase.  The HgCl2 solution was
decanted off and the aluminum was washed with 2x200 mL additional H2O.
After shaking as dry as possible, there was added, in sequence and
with good swirling agitation between each addition, 10 g methylamine
hydrochloride in 10 mL H2O, 27 mL IPA, 22 mL of 25% NaOH, 5.0 g
1-(3,4-methylenedioxyphenyl)-2-pentanone, and finally an additional 50
mL IPA.  The mixture was heated on the steam bath periodically to
maintain the reaction rate at a vigorous boil.  When all of the
aluminum had been consumed, the cooled mixture was filtered and the
solids washed with MeOH.  The combined filtrate and washings were
stripped of solvent under vacuum.  The residue was dissolved in dilute
H2SO4 and washed with 2x75 mL CH2Cl2.  After making basic again with
25% NaOH, this was extracted with 2x100 mL CH2Cl2, and the pooled
extracts were stripped of solvent under vacuum.  The residue was
distilled at 105-110 !C at 0.3 mm/Hg to give 2.7 g of a colorless
liquid.  This was dissolved in 15 mL IPA, neutralized with
concentrated HCl, and diluted with 75 mL anhydrous Et2O which allowed
a delayed appearance of a fine white crystal.  This was removed by
filtration, Et2O washed, and air dried to give 2.45 g
2-aminomethyl-1-(3,4-methylenedioxyphenyl)pentane hydrochloride
(METHYL-K) as a white product with a mp of 155-156 !C.  Anal.
(C13H20ClNO2) C,H.

DOSAGE: greater than 100 mg.

DURATION: unknown.

QUALITATIVE COMMENTS: (with 100 mg) There were no effects.  I was
busy and totally wound up and didnUt sleep until 3 AM, but this was
probably unrelated to the Me-K.

EXTENSIONS AND COMMENTARY: The well appears to be running dry, with a
pentane chain as a basic skeleton.  METHYL-J, at this level, was
already showing a number of hints and clues, largely physical such as
coldness in the feet and a slight mastoidal pressure, that activity
was right around the corner.  But METHYL-K gave no such hints.  The
unmethylated homologue, 2-amino-1-(3,4-methylenedioxyphenyl)pentane
(K), was also made, by the reductive amination of
1-(3,4-methylene-dioxyphenyl)-2-pentanone with ammonium acetate and
sodium cyanoborohydride in methanol.  It was a white crystalline
solid, mp 202-203 !C, but is given here in the comments only, as its
human assaying had never even been initiated.  Anal. (C12H18ClNO2)
C,H.  The N-ethyl homologue,
2-ethylamino-1-(3,4-methylene-dioxyphenyl)pentane (ETHYL-K), is
entered with its own recipe, on the other hand, since testing had been
started with it.

And the longest chain that has been explored in this Muni Metro series
is the six-carbon hexyl chain which is, quite logically, the L-series,
sort of the end of the Taraval line (see under METHYL-J for an
explanation).  The central compound for all the L-compounds was the
ketone 1-(3,4-methylenedioxyphenyl)-2-hexanone, which was prepared by
the Grignard reagent of (n)-amyl bromide with piperonal to give
1-hydroxy-1-(3,4-methylenedioxyphenyl)hexane, dehydration of this with
potassium bisulfate to the olefin, and oxidation of this with hydrogen
peroxide and formic acid to the L-ketone which was an orange-colored
liquid with a bp of 125-135 !C at 0.3 mm/Hg.  This ketone was
reductively aminated with ammonium acetate and sodium cyanoborohydride
in methanol to produce 2-amino-1-(3,4-methylenedioxyphenyl)hexane
hydrochloride (L) as a white crystalline product with a mp of 157-158
!C.  Anal. (C13H20ClNO2) C,H.  And this ketone was reductively
aminated with methylamine hydrochloride and amalgamated aluminum in
isopropanol to produce
2-methylamino-1-(3,4-methylenedioxyphenyl)hexane hydrochloride
(METHYL-L) as a white crystalline product with a mp of 139-141 !C.
Anal. (C14H22ClNO2) C,H.  The reduction of this ketone in a similar
manner with ethylamine hydrochloride produced
2-ethylamino-1-(3,4-methylenedioxyphenyl)hexane (ETHYL-L).  None of
this series has yet been explored either as psychedelic or
entactogenic materials.









#130 METHYL-MA; PMMA; DOONE; 4-MMA; 4-METHOXY-N-METHYLAMPHETAMINE

SYNTHESIS: A solution of 20 g methylamine hydrochloride in 150 mL hot
MeOH was treated with 10.0 g 4-methoxyphenylacetone and stirred
magnetically.  After returning to room temperature, there was added
5.0 g sodium cyanoborohydride, followed by cautious addition of HCl as
required to maintain the pH at about 6.  The reaction was complete
after a few days, and the mixture was poured into 800 mL H2O.  This
was acidified with HCl (HCN evolution!) and washed with 3x75 mL
CH2Cl2, which removed most of the yellow color.  There was 25% NaOH
added to make the reaction mixture strongly basic, and this was
extracted with 3x75 mL CH2Cl2.  The solvent was removed from the
pooled extracts under vacuum, and the 10.3 g of residue distilled at
0.3 mm/Hg.  The 9.7 g of colorless oil that distilled at 75-90 !C was
dissolved in 50 mL IPA, neutralized with 4.5 mL concentrated HCl, and
then diluted with 100 mL anhydrous Et2O.  There were generated
glistening crystals of 4-methoxy-N-methylamphetamine hydrochloride
(METHYL-MA or DOONE) that weighed, after washing with Et2O and air
drying to constant weight, 11.0 g and which had a mp of 177-178 !C.
The same base can be made by the action of ethyl chloroformate on 4-MA
in the presence of triethylamine to make the carbamate, or the action
of formic acid to make the formamide.  These can then be reduced with
LAH to this same end product.

DOSAGE: greater than 100 mg.

DURATION: short.

QUALITATIVE COMMENTS: (with 110 mg) One hour into it, my pulse was up
over 100, and I was compulsively yawning.  There was some eye muscle
disturbance, a little like the physical side of MDMA, but there was
none of its central effects.  But all the hints of the cardiovascular
are there.  By the fourth hour, I am pretty much back to baseline, but
the yawning is still very much part of it.  I might repeat this, at
the same level, but with continuous close monitoring of the body.

EXTENSIONS AND COMMENTARY: Why would there be interest in this
particular compound?  The track record from the comparison of active
compounds that are primary amines, and their N-methyl homologues, has
shown that, in general, the stimulant component might be maintained,
but the RpsychedelicS contribution is generally much reduced.  MDMA
is, of course, an exception, but then, that particular compound is a
one-of-a-kind thing which simply defies all the rules anyway, and I
drop it from this kind of reasoning.  And as 4-MA is a pretty pushy
stimulant with little if any sensory sparkle, why bother with the
N-methyl compound at all?

For a completely silly and romantic reason.  When the MDMA story
became front-page news back in mid-1985, the cartoonist-author of
Doonesbury, Gary Trudeau, did a two-week feature on it, playing it
humorous, and almost (but not quite) straight, in a hilarious sequence
of twelve strips.  On August 19, 1985 he had Duke, president of Baby
Doc College, introduce the drug design team from USC in the form of
two brilliant twins, Drs. Albie and Bunny Gorp.  They vividly
demonstrated to the enthusiastic conference that their new drug
RIntensityS was simply MDMA with one of the two oxygens removed.
RVoila,S said one of them, with a molecular model in his hands, RLegal
as sea salt.S And what is MDMA with one oxygen atom removed?  It is
4-methoxy-N-methylamphetamine or METHYL-MA which, according to the
twins, should give the illusion of substance to one's alter ego.  So,
I called it Doonesamine, or simply RDOONES for short.  Maybe that was
also a homonym for Frank Herbert's science fiction book, RDune,S
wherein the magical drug RspiceS provided a most remarkable alteration
of the user's state of consciousness.

This comic strip presentation was the first nationally distributed
allusion to the term Rdesigner drugs,S and perhaps it lent unexpected
support for the passage, just a year later, of the Controlled
Substances Analogue Enforcement Act of 1986.  This intentionally vague
piece of legislation makes the giving of, or the taking of, or even
the possession with the intent to take, any drug that in any way
alters your state of consciousness, a felony.  A shameful and
desperate effort by the governmental authorities to maintain the image
of control in a lost situation.

Enough editorial.  Back to historic technicalities.  In truth,
METHYL-MA is a well studied drug, at least in animals.  In both mice
and rats, it is an exceptionally potent agent in creating the state of
catatonia.  Animal studies, prompted by the clandestine synthesis of
METHYL-MA, have shown that there is indeed locomotor stimulation and
some central effects, but these effects are somehow different than
those of a simple amphetamine-like agent.  The experimenterUs
conclusions, based on its structural resemblance to 4-MA and its
proclivity to produce catatonia in some animal species and the
ever-present possibility that there might be unsuspected neurochemical
changes to be seen with its use, are that human experimentation should
be discouraged.  I have come to the same conclusion, but in my case
this is based on a much more succinct observation: I tried it and I
didnUt like it.

A brief comment on two of the N,N-dimethylhomologues of
methoxyamphetamine.  One was 4-methoxy-N,N-dimethylamphetamine,
4-MNNA.  This material, made by the reductive amination of
4-methoxyphenylacetone with dimethylamine, was a colorless oil, which
distilled at 70-85 !C at 0.3 mm/Hg.  The corresponding
2-methoxy-N,N-dimethylamphetamine was similarly made.  2-MNNA was also
a colorless oil and had the same bp.  Both of them were fluorinated
with 18F labelled acetyl hypofluorite (3% and 6% yields respectively)
but neither of them was pursued any further in the search for a brain
blood flow indicator.









#131 METHYL-MMDA-2; 2-METHOXY-N-METHYL-4,5-METHYLENEDIOXYAMPHETAMINE

SYNTHESIS: A suspension of 17.4 g electrolytic elemental iron in 100 g
glacial acetic acid was heated on the steam-bath until there were the
first signs of bubbling and reaction, about 60 !C.  There was then
added, in small portions, a suspension of 9.2 g
1-(2-methoxy-4,5-methylenedioxyphenyl)-2-nitropropene (see under
MMDA-2 for its preparation) in 40 g warm glacial acetic acid.  The
reaction was extremely exothermic.  After the color had lightened as
much as possible, there was added an additional quantity of iron
sufficient to completely discharge the residual yellow color.
Mechanical stirring was maintained as the reaction mixture was allowed
to return to room temperature.  All was poured into 800 mL H2O, and
the insolubles were removed by filtration.  These were washed
alternately with H2O and with CH2Cl2, the combined filtrate and washes
were separated, and the aqueous phase extracted with 3x100 mL CH2Cl2.
All organics were combined, washed with 2x75 mL 5% NaOH (which removed
most of the color) and the solvent removed under vacuum.  The 8.7 g
residue was distilled at 90-105 !C at 0.2 mm/Hg to give 6.7 g of
2-methoxy-4,5-methylenedioxyphenylacetone as a pale yellow oil.

To a magnetically stirred solution of 30 g methylamine hydrochloride
in 150 mL warm MeOH, there was added 6.5 g
2-methoxy-4,5-methylenedioxyphenylacetone followed by 3.0 g sodium
cyano-borohydride.  Concentrated HCl was added as was required to keep
the mixture at a pH of about 6.  When the reaction was complete, it
was added to 1 L H2O and made strongly basic with 25% NaOH.  This was
extracted with 3x100 mL CH2Cl2, and the pooled extracts were, in turn,
extracted with 2x100 mL dilute H2SO4.  This aqueous phase was washed
with CH2Cl2, made basic with NaOH, and extracted with 3x100 mL CH2Cl2.
Removal of the solvent from these pooled extracts under vacuum gave
8.7 g of an amber oil.  This was distilled at 110-125 !C at 0.25 mm/Hg
to give 5.1 g of a colorless oil.  This was dissolved in 30 mL IPA,
neutralized with about 3 mL concentrated HCl, and diluted with 60 mL
anhydrous Et2O.  The clear solution slowly deposited white crystals
which were removed by filtration and air dried to give 4.2 g
2-methoxy-N-methyl-4,5-methylenedioxyamphetamine hydrochloride
(METHYL-MMDA-2) with a mp of 168-169 !C.  Anal. (C12H18ClNO3) C,H.

DOSAGE: greater than 70 mg.

DURATION: unknown.

QUALITATIVE COMMENTS: (with 70 mg) Maybe a threshold Q pleasant but
not possible to characterize it.

EXTENSIONS AND COMMENTARY: With the effective dosage of the
unmethylated homologue being the range of 25 to 50 milligrams, this
N-methyl compound is, as with the other N-methylated materials
discussed here, again of reduced activity.  The highest dose yet
reported was 70 milligrams, and there is no way of estimating what
miight be an active level nor, once there, what the quality of the
effects might be.

This is the only MMDA analogue that has been explored as an N-methyl
derivative.  A more highly substituted analogue has also been made,
the N-methyl derivative of DMMDA.  Isoapiole (see its preparation
under DMMDA) was oxidized with formic acid and hydrogen peroxide to
the ketone (2,5-dimethoxy-3,4-methylenedioxyphenylacetone, a solid
with a mp of 75-76 !C from methanol) which was reductively aminated
with methylamine and amalgamated aluminum to give
2,5-dimethoxy-N-methyl-3,4-methylenedioxyamphetamine hydrobromide
monohydrate (METHYL-DMMDA, or DMMDMA) as a white crystalline solid
with a mp of 91-92 !C.  The hydrochloride salt was a hygroscopic
solid.  Anal. (C13H22BrNO5) C,H.  The above ketone has also been used
in the synthesis of another methylated DMMDA, on the beta-carbon.
This is described under DMMDA itself.  DMMDMA has not yet been
launched into an evaluation program, and I wouldnUt be surprised if
the needed dosage might be up there somewhere over 100 milligrams.  I
feel quite sure that the answers may be known in the near future.
There is a surprisingly large number of inconspicuous chemical
explorers out there all over the world, doing their synthetic thing in
their private laboratories.  They are truly the astronauts of inner
space.









#132 MMDA; 3-METHOXY-4,5-METHYLENEDIOXYAMPHETAMINE

SYNTHESIS: (from protocatechualdehyde) A solution of 18 g commercial
protocatechualdehyde (3,4-dihydroxybenzaldehyde) in 200 mL warm acetic
acid was filtered free of any insolubles, to provide a very dark but
clear solution.  With good stirring there was then added 20 g
elemental bromine.  The reaction spontaneously heated to about 30 !C
and solids appeared in about 5 min.  Stirring was continued for 1 h,
and then the light gray solids that had formed were removed by
filtration and lightly washed with acetic acid.  These were air dried
on the steam bath until free of acetic acid smell.  The product,
3-bromo-4,5-dihydroxybenzaldehde, weighed 11.7 g and had a mp of 222
!C.

To a solution of 11.7 g 3-bromo-4,5-dihydroxybenzaldehyde in 36 mL
DMSO there was added 29 g methylene iodide followed by 20.8 g
anhydrous K2CO3.  This was heated on the steam bath for 3 h, added to
1 L H2O, made strongly basic with NaOH, then extracted with 3x100 mL
CH2Cl2.  These extracts were pooled, washed with H2O, and the solvent
removed under vacuum.  The dark brown semi-solid residue was distilled
with the major fraction (6.0 g) coming over at 120-130 !C at 0.3
mm/Hg.  This, upon recrystallization from 35 g boiling MeOH, gave 1.3
g of 3-bromo-4,5-methylenedioxybenzaldehyde as an off white
crystalline solid with a mp of 123-124 !C.

A mixture of 2.2 g 3-bromo-4,5-methylenedioxybenzaldehyde and 3.6 mL
cyclohexylamine in a distillation flask was heated to 100 !C to effect
solution, and then with an open flame until the signs of H2O evolution
were evident.  This was then placed under a hard vacuum to remove the
generated water and excess cyclohexylamine, and the product distilled
at 120-125 !C at 0.2 mm/Hg.  There was obtained 2.4 g of the Schiff
base of the aldehyde and the amine, melting at 86-96 !C.
Recrystallization of an analytical sample from 5 volumes of MeOH gave
3-bromo-4,5-methylenedioxybenzylidine-N-cyclohexylamine as a white
solid with a mp of 97.5-98.5 !C.  Anal. (C14H16BrNO2) H; C: calcd,
54.20; found, 53.78.

A solution of 2.2 g
3-bromo-4,5-methylenedioxybenzylidine-N-cyclohexylamine (the above
Schiff base) in 50 mL anhydrous Et2O was placed in a He atmosphere,
stirred magnetically, and cooled with a dry ice/acetone bath.  A white
fine crystalline phase appeared.  There was then added 5.2 mL 1.55 M
butyllithium in hexane (the fine solids dissolved) followed by 4.0 mL
of tributyl borate.  After returning to room temperature, the reaction
was quenched with 20 mL of saturated aqueous ammonium sulfate.  The
Et2O/hexane layer was separated, washed with additional ammonium
sulfate solution, and then stripped of volatiles under vacuum.  The
residue was dissolved in 100 mL 50% MeOH, treated with 2 mL of 30%
hydrogen peroxide and, after 15 min swirling, quenched with a solution
of 10 g ammonium sulfate in 50 mL H2O.  This aqueous phase (pH about
8) was extracted with 2x50 mL CH2Cl2, the extract pooled and stripped
of solvent under vacuum, and the residue dissolved in warm, dilute
HCl.  After all the residue had dissolved (a few min heating was
sufficient), the solution was cooled to room temperature and extracted
with 2x50 mL CH2Cl2.  These organics were pooled and extracted in turn
with 2x50 mL 5% NaOH.  Acidification of the pooled aqueous fractions
with HCl, followed by extraction with 2x50 mL CH2Cl2 gave, after
evaporation of the solvent, a residue that was distilled at 140-150 !C
at 0.25 mm/Hg to give 3-hydroxy-4,5-methylenedioxybenzaldehyde.  This
was recrystallized from toluene (40 mL/g) to give 0.46 g of an
off-white product with a mp of 134-134.5 !C.  Anal. (C8H6O4) C,H.

A solution of 0.44 g 3-hydroxy-4,5-methylenedioxybenzaldehyde in 10 mL
dry acetone was treated with 0.5 g methyl iodide and 0.5 g powdered
anhydrous K2CO3, and was held at reflux for 6 h.  All volatiles were
stripped under vacuum, the residue dissolved in water, made strongly
basic with NaOH, and extracted with 3x50 mL CH2Cl2.  Removal of the
solvent gave myristicinaldehyde (mp 133-134 !C) which, on
recrystallization from hexane, gave a final yield of 0.42 g with a mp
of 134-135 !C.  Care must be taken with two sequential products that
have identical mps.  A mixed mp with the unmethylated phenol above is
strong depressed, whereas that with an authentic sample is not.

A solution of 9.8 g myristicinaldehyde in 35 mL glacial acetic acid
was treated with 5.3 mL nitroethane and 3.2 g anhydrous ammonium
acetate, and heated on the steam bath for 1.5 h.  It was removed,
treated with H2O with good stirring to just short of turbidity, seeded
with product nitrostyrene, and allowed to come slowly to room
temperature.  The bright yellow solids that formed were removed by
filtration, washed with a small amount of aqueous acetic acid, and
sucked as free of solvent as possible.  This material, pressed on a
porous plate, had a mp of 107-110 !C.  Recrystallization from 60 mL
boiling EtOH gave, after filtering and air drying, 5.1 g of
1-(3-methoxy-4,5-methylenedioxyphenyl)-2-nitropropene as light yellow
solids with a mp of 109-110 !C.

A suspension of 7.5 g LAH in 500 mL anhydrous Et2O was magnetically
stirred, and heated in an inert atmosphere to a gentle reflux.  The
condensing Et2O leached out a total of 9.8 g
1-(3-methoxy-4,5-methylenedioxyphenyl)-2-nitropropene from a Soxhlet
thimble in a shunted reflux condenser.  This, in effect, added the
nitrostyrene to the reaction medium as a warm saturated Et2O solution.
When the addition was completed, the refluxing was maintained for an
additional 5 h, then the reaction mixture was cooled and the excess
hydride destroyed by the addition of 400 mL 1.5 N H2SO4 (the first 20
mL a drop at a time and with very good stirring).  The phases were
separated, and sufficient saturated aqueous Na2CO3 was added to the
aqueous phase to bring the pH up to about 6.0.  This was heated to 80
!C and filtered through a coarse sintered glass funnel to remove some
insoluble fines.  The clear filtrate was brought up almost to a boil,
and treated with a solution of 10.2 g of 90% picric acid in 110 mL
boiling EtOH.  Crystals of the picrate formed immediately at the
edges, and as the reaction flask was cooled in an ice tub, the entire
reaction set to a yellow mass of crystals.  These were removed by
filtration, washed sparingly with 80% EtOH, and air dried to give 14.0
g of the picrate salt of MMDA, with a mp of 182-184 !C.
Recrystallization of a small sample from EtOH dropped this to 179-181
!C.  This salt was treated with 30 mL 5% NaOH, and the red solution
decanted from some insolubles.  Additional H2O and NaOH effectively
dissolved everything, and the resulting basic aqueous phase was
extracted with 3x50 mL CH2Cl2.  The pooled extracts were stripped of
solvent under vacuum, and the residue dissolved in 200 mL anhydrous
Et2O and saturated with anhydrous HCl gas.  There was a heavy
precipitation of white crystals, which were removed by filtration,
Et2O washed, and air dried to give 6.37 g
3-methoxy-4,5-methylenedioxyamphetamine hydrochloride (MMDA) with a mp
of 190-191 !C.  Anal. (C11H16ClNO3) Cl.

(from Oil of Nutmeg) The careful distillation of Oil of Nutmeg (or the
Oil of Mace) allowed the isolation of a number of compounds in varying
degrees of purity.  The fraction that boiled in the 110-115 !C range
at about 1.0 mm/Hg was myristicin
(3-methoxy-4,5-methylenedioxyallylbenzene).  It constituted some 7% of
the original oil of commerce and, in its original isolated form, was
obtained with a purity of 87%.  The major contaminant was elemicin
(3,4,5-trimethoxyallylbenzene).  A solution of 100 g myristicin in 100
g absolute EtOH was treated with 200 g solid KOH and heated on a steam
bath overnight.  Removal of the volatiles under vacuum, flooding the
residue with H2O, and extraction with 3x100 mL CH2Cl2 gave, after
removal of the solvent from the combined extracts, a residue of crude
isomyristicin (a mixture of the cis- and trans-isomers).  This product
was distilled, and the fraction boiling at 125-130 !C at 1 mm/Hg gave
63 g of isomyristicin as a pale yellow oil that spontaneously
crystallized.  The mp was 41.5-42.5 !C.  Part of the losses associated
with the purification of these solids was due to formation of the
cis-isomer of isomyristicin, which was an oil.

A solution of 50 g isomyristicin in 300 mL dry acetone containing 24 g
pyridine was vigorously stirred and cooled to 0 !C with an ice bath.
To this there was added 54 g tetranitromethane which had been
pre-cooled to 0 !C.  Stirring was continued for exactly 2 min, and
then the reaction was quenched by the addition of a cold solution of
16.8 g KOH in 300 mL H2O.  Stirring was continued until the
temperature had again been lowered to near 0 !C.  The product was
removed by filtration.  Extraction of the filtrate with CH2Cl2 and
removal of the solvent provided additional nitrostryrene, for a
combined yield of 50.7 g with a mp of 103 !C due to the presence of a
small amount of free myristicinaldehyde.  A recrystallization from
MeOH produced 1-(3-methoxy-4,5-methylenedioxyphenyl)-2-nitropropene
with a mp of 109-110 !C.  This material was completely adequate for
the above-described reduction to MMDA.  The conversion of this
nitropropene to myristicinaldehyde is an alternative to the lengthy
synthesis given above), and can be used in the preparation of
LOPHOPHINE.

A mixture of 50 g
1-(3-methoxy-4,5-methylenedioxyphenyl)-2-nitropropene and 26 g racemic
a-methylbenzylamine was heated on the steam bath.  The mixture
gradually formed a clear solution with the steady evolution of
nitroethane.  When the reaction became quiet, there was added a
mixture of 20 mL concentrated HCl in 100 mL H2O.  The reaction mixture
dissolved completely, and as the temperature continued to rise there
was the abrupt solidification as the formed myristicinaldehyde
crystallized out.  This product was removed by filtration and, when
combined with a second crop obtained by the hexane extraction of the
filtrate, gave 36.9 g of myristicinaldehyde.  The mp of 128-129 !C was
raised to 133-134 !C by recrystallization from hexane.

DOSAGE: 100 - 250 mg.

DURATION: moderate.

QUALITATIVE COMMENTS: (with 100 mg) I felt completely relaxed at one
hour.  Almost as if I was floating.  There were no obvious effects on
taste, and the relaxation and composed feeling is much like a small
dose, maybe 20 mikes, of LSD.  There was some dilation, and in the
evening I was a little restless and slightly tired.  I slept well, and
awoke refreshed and happy.

(with 100 mg) It seemed to take 45 minutes to work and then it came
on very suddenly, as if my eyeballs were being pulled out and my whole
head expanding.  Soon a cold feeling set in with shivering Q this was
not unpleasant.  My state in about two hours seemed to be one of
empathy and passivity, compassion of an impersonal sort.  The music
sounded artificial and canned and tinny, in contrast to the voices,
which sounded rich and full and finely articulated and melodious.

(with 150 mg) We are on the beach at the river mouth drying seaweed,
on split redwood.  There is a slight nausea, slight cramps, and then
my visual field starts to light up.  Still vertigo but only with my
eyes open, and heaviness and time stretches out; numbness in the chest
as when an opiate is taken.  There are geometric patterns, but the
excess light on my closed eyelids interferes with this.  A dance of
the glittering diamond studded sea waves, increasing motion and
beauty.  More landscapes appear inside.  This is a good introductory
drug to the drugs of this class, to become familiar with the drug
state in as gentle a fashion as possible.  This substance seems to
have a much gentler action than others of this class; perhaps more
like cannabis or psilocybin.  There is very little paranoia.  I note
hallucinations of two types: those which are strictly retinal and more
minute and small and influenced by light and focused on the light
ahead on the retina or lids; and the other, those deep in the visual
tract and occiput which are larger and more global and dream-like and,
when solid, are quite dramatic and unforgettable as in meditation.

(with 210 mg) MMDA tastes awful.  The bitter alkaloid taste is
followed by a distinctively chemical laboratory flavor as if from old
rubber tubing.  Nothing seems to happen for about 45 minutes when
rather suddenly an anvil seems to lower itself over your head; you
feel disoriented, and tend to withdraw from social contact a little.
The drug gives less feeling of being ill than mescaline.  The effect
definitely reaches a climax with a pleasant afterglow following.
Apparently there are no profound motor coordination problems.  MMDA
yields that 'Sunday afternoon' feeling of desiring to lie down and
enjoy life; a luxurious feeling of 'layback.'  No enhancement of
colors in visual scene (except for some greenish tinges in faces) but
upon closing eyes hallucinations appear to be quite real in 3-D, like
watching a movie.  First these dreams appear in black and white, but
later colors start appearing.  Chartreuse and magenta first appear,
then blue and finally red.  First I had visions of large numbers on
gaming tables, then people.  MMDA appears to bring dreams to the
conscious level; is a link between the subconscious and the
conscious.

(with 225 mg) I had a strange awareness of my hands in about 20
minutes Q not a feeling in them as just that I was attracted to them
somehow.  Then I began to get fearful, an acute experience of
aloneness.  I lay face down (a depressed position for me).  Next I was
talking to the kids at school (an image) or to other teachers.  This
was very vivid.  The scenes at school were more vivid that the real
scenes around me here.  Those people were much more real.  I am
actually very sleepy right now during the experiment.  Of any
experience I have had, this was most like a series of dreams easily
remembered.  When it was over, I felt as if I had had a long period of
sleeping Q I had gone to bed and had a series of dream-like states
very vivid and colorful and real.

EXTENSIONS AND COMMENTARY: The phrase that had been used by several of
the subjects in the early trials with MMDA, again and again, was
Rbrain movies.S Apparently the richest of the effects were to be had
with the eyes closed.  This is the compound that I had first completed
in 1962, and had named it MMDA, and had begun the exploring of it when
I heard that Dr. Gordon A. Alles, a professor of pharmacology at U. C.
L. A. who had his own private laboratory in Los Angeles, had also
synthesized it in 1962, had also named it MMDA, and had also begun
exploring it.  We made a date to meet and share ideas, and then he
died, at the age of 62, in 1963.

This is a material that might be a contributing factor to the
pharmacology of nutmeg.  The major essential oil from that spice is
myristicin, and it is the easiest source of MMDA.  It has been
reported that the passage of this oil through the liver of a rabbit
will generate MMDA in that animal.  The only difference between the
two molecules, structurally, are the elements of ammonia.  Myristicin
plus ammonia gives MMDA.  Another natural source of myristicin is Oil
of Parsley, which is also an excellent source of apiole, mentioned
under DMMDA.  A rumor that had currency in the 1960Us, that parsley
could get you high, probably had its origins in the reports of
myristicin being present, coupled with myristicin being the principal
source of MMDA.  The relationship to myristicin (an essential oil) led
to the classifying of MMDA as a Essential Amphetamine.  These
relationships are expanded upon, under TMA.

At the time that the FDA issued its proclamation of dangerous drugs
(in the mid-1960Us), MMDA was being talked about, and in fact it had
just become available commercially in England through the Koch Light
Industries.  But to my knowledge it had never appeared on the street,
so its having being swept into the listings of evil drugs was simply a
coincidence of bad timing.  The close resemblance of initials between
MMDA, and the currently notorious MDMA, has led to no small amount of
confusion in the popular press.  They remain totally separate and
completely different drugs.









#133 MMDA-2; 2-METHOXY-4,5-METHYLENEDIOXYAMPHETAMINE

SYNTHESIS: A solution of 11.5 g pellet KOH (85%) in 75 mL EtOH was
treated with 25 g sesamol followed by 27 g methyl iodide.  This was
brought to reflux on the steam bath.  Salt formation was apparent in
20 min, and refluxing was main-tained for a total of 4 h.  The solvent
was removed under vacuum, and residue poured into 400 mL H2O.  This
was acidified with HCl and extracted with 3x150 mL CH2Cl2.  The pooled
extracts were washed with 3x100 mL 5% NaOH, which removed most of the
color.  The solvent was removed under vacuum to provide 24.0 g of
3,4-methylenedioxyanisole as a pale amber oil.

A mixture of 56.4 g POCl3 and 49.1 g N-methylformanilide was allowed
to stand for 40 min and then it was poured into a beaker containing 64
g 3,4-methylenedioxyanisole.  There was an immediate exothermic
reaction with darkening and the generation of bubbles.  This was
heated on the steam bath for 1 h, then poured into 1 L H2O with
extremely vigorous stirring.  The dark brown phase was quite opaque,
and then there was a sudden lightening of color with the generation of
a fine pale yellow solid.  Stirring was continued for 2 h, then these
crystals were removed by filtration. This crude product was
recrystallized from 400 mL boiling MeOH yielding, after filtering,
washing, and air drying to constant weight, 44.1 g
2-methoxy-4,5-methylenedioxybenzaldehyde with a mp of 110-111 !C.
Only one positional isomer was visible in the final product by GC, but
extraction of the original mother liquors with CH2Cl2 produced, after
evaporation of the solvent under vacuum, 2 g of a red oil that showed
two earlier peaks on OV-17.  These were consistent with about 1% of
each of the two alternate positional isomers that could result from
the Vilsmeier formylation reaction.

A solution of 43 g 2-methoxy-4,5-methylenedioxybenzaldehyde in 185 g
nitroethane was treated with 9.3 g anhydrous ammonium acetate and
heated on the steam bath for 4.5 h.  The excess nitroethane was
removed under vacuum to give a residue that spontaneously
crystallized.  These solids were washed out mechanically with the aid
of 200 mL cold MeOH, and the brilliant orange crystals recovered by
filtering and air drying to constant weight.  There was obtained 35.7
g 1-(2-methoxy-4,5-methylenedioxyphenyl)-2-nitropropene with a mp of
166-167 !C.  This was not improved by recrystallization from IPA.
Evaporation of solvent from the methanolic washes gave yellow solids
(4.6 g melting at 184-186 !C) which, on recrystallization from
THF/hexane, melted at 188-190 !C.  This showed a molecular weight of
416 by chemical ionization mass spectroscopy (isobutane at 0.5 torr)
and is the C20H20N2O8 adduct of one molecule each of nitrostyrene,
aldehyde, and ammonia that frequently appears as a very insoluble
impurity in aldehyde-nitroethane condensations that are catalyzed by
ammonium acetate.

To a refluxing suspension of 36 g LAH in 1 L anhydrous THF under an
inert atmosphere, there was added 44.3 g
1-(2-methoxy-4,5-methylenedioxyphenyl)-2-nitropropene in hot THF.  The
solubility was very low, so that it was necessary to use a heat lamp
on the dropping funnel to maintain a clear solution for addition.  The
addition required 2 h and the reflux was maintained for 36 h.  The
reaction mixture was then cooled in an ice bath and there was added,
in sequence and commensurate with heat evolution, 36 mL H2O, 36 mL 15%
NaOH, and finally 108 mL H2O.  The granular solids were removed by
filtration and washed with THF.  The combined filtrate and washes were
stripped of solvent under vacuum yielding 58.8 g of a pale amber oil.
This was dissolved in 100 mL IPA, neutralized with con-centrated HCl
(20 mL was needed) and diluted with 500 mL anhydrous Et2O.  More IPA
was required to keep an oil phase from appearing.  After the
crystalline product was completely formed, it was removed by
filtration, washed with IPA/Et2O, and finally with Et2O.  Air drying
gave 31.1 g of 2-methoxy-4,5-methylenedioxyamphetamine hydrochloride
(MMDA-2) with a mp of 186-187 !C.

DOSAGE: 25 - 50 mg.

DURATION: 8 - 12 h.

QUALITATIVE COMMENTS: (with 25 mg) Had some not-too-pleasant jangly
effects Q this is not the smoothest of drugs.  Duration: onset at 1
1/2 hours (dose after lunch), acute 3 to 4 hours, seconal at 11 hours
to stop residual effects so I could sleep.  Occasionally from 5 to 10
hours acute abdominal distress, resembling gas pains but unable to
defecate.  Abdominal muscles tight and hard.  This occurred for about
15 minutes every hour or so.  Rather unpleasant.

(with 30 mg) There was the first subtle note at 45 minutes, and the
slow development makes the changes easy to assimilate, but difficult
to quantitate.  My awareness is truly enhanced.  Nothing is distorted,
so there can be no misrepresentation as a result.  This would be a
good material to introduce someone to the slow-on slow-off type of
experience.  It would be impossible for any person, at this level, on
this drug, to have a bad experience.  This is very much like a slow
MDA, perhaps 80 milligrams of it, and fully as controllable.  The
N-methyl of this is a must.

(with 40 mg) The chemical is primarily a visual enhancer with only an
extremely modest amount of visual distortion.  The retinal activity
was of a minor and non-threatening nature.  The chemical seemed to
facilitate empathic communication and the emotions felt strong and
clean.  Conversation flowed easily, without inhibitions or
defensiveness.  Anorexia accompanied experience.  There was no
impotence.  There was some restless movement which dissipated with
exercise (walking and playing frisbee).  Next day woke feeling
energetic, no muscular stiffness, alert.  I would repeat this
experience.

(with 50 mg) I was coming on within 40-60 minutes, easy and slow, but
the body was +3 before the mind.  The mental was strange for the first
2-3 hours Q I called it 'High Sierras' Q realistic, dispassionate, not
kind.  Some dark areas are persistent.  Watched last half of Circus of
Dr. Lao and the whole feeling changed from pornographic to erotic.
Delightful.  Some fantasy.  On coming down, sleep was difficult.  The
body feels unexpectedly depleted.  Rubber legs and handwriting jerky.

EXTENSIONS AND COMMENTARY: A comparison of this material to MDA was
often made by subjects who were familiar with both.  But it is hard to
separate that which is intellectualized from that which is felt.  An
awareness of the chemical structure immediately shows, of course, the
close resemblance.  There is the complete MDA molecule, with the
addition of a methoxy group.  And for the non-chemist, the name itself
(MMDA-2) represents the second possible methoxy-MDA.  Certainly one
property that is shared with MDA is the broad variety of opinions as
to the quality of its action.  Some like it much, and some like it not
at all.  The N-methyl homologue was indeed made, for direct evaluation
in comparison to N-methyl MDA (which is MDMA).

The phenethylamine analog of MMDA-2 has been prepared by the
condensation of the above benzaldehyde with nitromethane (in acetic
acid with ammonium acetate catalyst, giving an equal weight of the
nitrostyrene as deep orange crystals with a mp of 166-167 !C from
ethyl acetate) followed by lithium aluminum hydride reduction (in
ether).  The product, 2-methoxy-4,5-methylenedioxyphenethylamine
hydrochloride (2C-2) melted at 218-219 !C.  There were no effects
observed at up to 2.6 milligrams, but no higher trials were made.  The
4-carbon homologue was made similarly (from the aldehyde and
nitropropane but using tert-butylammonium acetate as a reagent in 100%
excess and isopropanol as solvent, giving orange crystals melting at
98-99 !C from methanol) followed by reduction (with lithium aluminum
hydride in ether) to give
1-(2-methoxy-4,5-methylenedioxyphenyl)-2-aminobutane hydrochloride
(4C-2) with a mp of 172-174 !C.  This material has never even been
tasted.

The Tweetio homologue of MMDA-2 has been tasted, however.  This is
2-ethoxy-4,5-methylenedioxyamphetamine, or EMDA-2.  The allyl ether of
sesamol (3,4-methylenedioxy-allyloxybenzene) was rearranged to the
2-allyl phenol which was, in turn, converted to the ethyl ether.
Reaction with tetranitromethane gave the nitrostyrene intermediate
which had a mp of 120-121 !C.  The final hydrochloride salt of EMDA-2
had a mp of 188-188.5 !C.  At 135 milligrams, there have been reported
eyes-closed visual phenomena, with intense colors.  The overall
duration is similar to MMDA-2 (some 10 hours) and there are reported
sleep disturbances.  At 185 milligrams, the feelings were intensified,
there were Rmarvelous eyes-closed visuals (the colors were
incredible), good concentration, but distinct body-tingles and
rushes.S The time span was about 12 hours from start to finish, but it
proved to be impossible to sleep afterwards.  This homologue is thus
about a third the potency of MMDA-2.









#134 MMDA-3a; 2-METHOXY-3,4-METHYLENEDIOXYAMPHETAMINE

SYNTHESIS: To a solution of 100 g of 2,3-dihydroxyanisole in 1 L dry
acetone there was added 110 g of powdered anhydrous K2CO3 followed by
210 g of methylene iodide.  This was brought up to a reflux on the
steam bath.  There was a sudden appearance of a solid phase, and then
a gentle reflux was maintained for three days, during which time much
of the heavy solid that initially formed had redissolved.  The
reaction mixture was filtered to remove the insoluble salts, and these
were washed with hot acetone.  The combined mother liquor and washes
were stripped of solvent under vacuum, leaving a solid residue.  This
was leached with several portions of boiling hexane.  These were
pooled, and removal of the solvent under vacuum provided 53.6 g of
2,3-methylenedioxyanisole as white crystals with a sharp spicy smell.

A mixture of 120 g N-methylformanilide and 137 g POCl3 was allowed to
incubate at ambient temperature for 0.5 h, then there was added 53 g
of crude 2,3-methylenedioxyanisole.  The dark reaction mixture was
heated on the steam bath for 2 h and then poured into a beaker filled
with shaved ice.  This was stirred until hydrolysis was complete, and
the black, almost crystalline gunk that separated was removed by
filtration.  The 53.6 g of crude product was analyzed by GC using an
ethylene glycol succinate column at 190 !C.  Three peaks were apparent
and had baseline separation.  The major peak at 7.8 min constituted
82% of the product and was 2-methoxy-3,4-methylenedioxybenzaldehyde.
A minor peak at 12.0 min represented 16% of the product and was the
positional isomer 4-methoxy-2,3-methylenedioxybenzaldehyde.  A trace
component (2%) lay intermediate (at 9.5 min) and was
myristicinaldehyde.  The mps of the two major benzaldehydes were
sufficiently different that they could serve as means of
identification.  The major product was obtained directly from the
black gunk by repeated extraction with boiling cyclohexane which, upon
removal of the solvent, gave 33.1 g of a yellow-colored product.
This, upon one additional recrystallization from boiling cyclohexane,
gave 24.4 g of 2-methoxy-3,4-methylenedioxybenzaldehyde as pale yellow
crystals with a mp of 103-105 !C.  The mother liquors were pooled and,
after removal of all volatiles under vacuum, yielded an amber-colored
solid that upon recrystallization provided a yellowish crystals.
These, after yet another crystallization from cyclohexane, gave 4.1 g
of 4-methoxy-2,3-methylenedioxybenzaldehyde with a mp of 85-86 !C.
This latter isomer was used in the synthesis of MMDA-3b.

To a solution of 3.5 g 2-methoxy-3,4-methylenedioxybenzaldehyde in 14
g acetic acid there was added 1.4 g anhydrous ammonium acetate and 2.3
mL of nitroethane.  The mixture was brought to reflux and held there
for 35 min.  It was then quenched by the addition of 40 mL H2O,
knocking out an orange, gummy solid.  This was removed by filtration,
and recrystallized from 50 mL boiling MeOH.  After cooling for a few h
in an ice bath, the bright yellow crystals were removed by filtration,
washed with MeOH and air dried to constant weight, yielding 2.15 g
1-(2-methoxy-3,4-methylenedioxyphenyl)-2-nitropropene.  The mp was
106-107 !C. Recrystallization from EtOH raised this mp to 109.5-110.5
!C.

A suspension of 2.2 g LAH in 300 mL anhydrous Et2O under an inert
atmosphere was brought to a gentle reflux.  The reflux condensate was
passed through a modified Soxhlet thimble containing 1.95 g
1-(2-methoxy-3,4-methylenedioxyphenyl)-2-nitropropene effectively
adding it, over the course of 0.5 h, to the reaction mixture as a
saturated Et2O solution.  The mixture was maintained at reflux for 16
h.  After cooling to 0 !C with an ice bath, the excess hydride was
destroyed by the addition of 1.5 N H2SO4.  The phases were separated,
and the aqueous phase washed with 2x100 mL Et2O.  To the aqueous phase
there was added 50 g potassium sodium tartrate followed by sufficient
25% NaOH to raise the pH >9.  This was then extracted with 3x100 mL
CH2Cl2, and the solvent from the pooled extracts removed under vavuum.
The residual white oil was dissolved in 250 mL anhydrous Et2O, and
saturated with anhydrous HCl gas.  There was produced a crop of white
microcrystals of 2-methoxy-3,4-methylenedioxyamphetamine hydrochloride
(MMDA-3a) which was removed by filtration, washed with Et2O, and air
dried to a constant weight of 1.2 g.  The mp was 154-155 !C.

DOSAGE: 20 - 80 mg.

DURATION: 10 - 16 h.

QUALITATIVE COMMENTS: (with 20 mg) I became aware at about an hour,
and an hour later I found myself suddenly caught up in the marvelous
world of insects.  Right alongside a pile of bricks I saw a measuring
worm, and with great tenderness and patience I picked him up, observed
his fore and aft 'feet' and finally replaced him and watched him
acclimate himself.  There was also a spider on the bricks, and I was
compelled to watch him in action.  I was grateful that I was not being
observed.  Time was moving slowly, and I felt I should intentionally
move slowly, so as not to exhaust myself.

(with 40 mg) This developed between one and two hours into it, and
there were considerable body tremors.  Talking directed the energy
outwards, and I became aware of a visually sparkling world about me.
I started dropping way too soon; it would have been interesting to
have gone higher.  By early evening I was left only with an awareness
of some residual physical hypersensitivity, and there was light
diarrhea.  I am not at all sure just what to compare this drug to.  It
is gentle.

(with 60 mg) There were visuals of a soft sort Q things moved with
eyes open, and with eyes closed the music was great.  There seemed to
be some lasting stimulation, but it didnUt get in the way of sleeping.
The next morning, however, I was still on.  A good compound.

EXTENSIONS AND COMMENTARY: The term MMDA-3a has the feel of being
complicated, but there is a reason for the code.  As had been
mentioned, MMDA was the initials for methoxy (the M) methylenedioxy
(the MD) amphetamine (the A).  And with a molecule of amphetamine
there are six ways of sticking these two groupings on the aromatic
ring.  The numbers 1-6 had already been assigned to the six ways of
sticking three methoxyl groups onto an amphetamine molecule (with the
trimethoxyamphetamines, the TMAUs) and I decided to hew to the same
convention with the methylenedioxy counterparts.  However, there are
two #3's (the methoxy and the methylenedioxy can go onto the three
oxygen atoms in a row in two different ways, whereas the three
methoxys can go on in just one way) and there can be no #6 (since a
methylenedioxy must, perforce, have two oxygens that are adjacent, and
there are none to be so found in the 2,4,6-orientation of TMA-6).  So,
with two possible MMDA-3's it becomes reasonable, in fact essential,
to name one of them RaS and the other RbS.  The RaS orientation occurs
in nature as the essential oil croweacin, or
1-allyl-2-methoxy-3,4-methylenedioxybenzene.  It thus can allow
MMDA-3a to be classified as an Essential Amphetamine, since it can
arise, in principle, by amination in the liver in vivo.  But in the
laboratory, croweacin is certainly not a practical starting material
in this synthesis.

I have been told of a number of clinical trials that have explored
MMDA-3a at considerably higher levels, but I have no explicit
quotations to give, and the details are quite sketchy.  Three trials
at 80 milligrams, and one at 100 milligrams, all made comparisons, in
both quantity and quality of the experience, to 100 micrograms of LSD.
However, two events occurred that may or may not be related to these
trials; one subject had a spontaneous peak experience five days after
the experiment, and another made a symbolic suicide attempt.

And, as with MMDA-2, both the 2-carbon RphenethylamineS analogue and
the 4-carbon RARIADNES analogue of MMDA-3a have been made.  The
phenethylamine analog was prepared by the condensation of 7.6 g of the
above benzaldehyde with nitromethane (in acetic acid with ammonium
acetate catalyst, giving 5.4 g of the nitrostyrene with a mp of
115.5-116.5 !C from methanol) followed by lithium aluminum hydride
reduction (in ether).  The product,
2-methoxy-3,4-methylenedioxyphenethylamine hydrochloride (2C-3a)
melted at 143-145 !C.  A series of subjective evaluations were made,
and there are reports of marginal effects in the 40 to 120 milligram
range.  At 40 milligrams, perhaps the hint of a psychic energizer; at
65 milligrams, there was a pleasant mood elevation; at 80 milligrams,
there was a brief paresthetic twinge noted at about the hour and a
half point, and at 120 milligrams, about the same at one hour, and
then nothing.  The fact that there can be such a modest change of
effect over a three-fold range of dosage suggests that this compound
might have some merit as an anti-depressant.  It would be interesting
to know if it blocks serotonin reuptake!

The 4-carbon analog was made similarly (from the aldehyde and
nitropropane but using tert-butylammonium acetate as a reagent in 100%
excess and isopropanol as solvent, giving bright yellow crystals
melting at 105.5-106.5 !C from 25 volumes of boiling methanol)
followed by reduction (with lithium aluminum hydride in ether) to give
1-(2-methoxy-3,4-methylenedioxyphenyl)-2-aminobutane hydrochloride
(4C-3a) with a mp of 183-185 !C with prior sintering at 173 !C.  This
material has been tasted at up to 3.5 milligrams with nothing noted.
There have been no trials at any higher dose.









#135 MMDA-3b; 4-METHOXY-2,3-METHYLENEDIOXYAMPHETAMINE

SYNTHESIS: A solution of 7.0 g of 98% pure (by GC)
4-methoxy-2,3-methylenedioxybenzaldehyde (see under MMDA-3a for its
preparation) in 30 mL glacial acetic acid was treated with 5 mL
nitroethane and 3 g anhydrous ammonium acetate, and heated on the
steam bath for 3.5 h.  H2Owas added to the hot solution to the point
of turbidity, then it was allowed to cool to room temperature with
occasional stirring.  A modest crop of yellow crystals formed which
were removed by filtration, washed with aqueous acetic acid and air
dried to constant weight.  There was obtauned 4.6 g of
1-(4-methoxy-2,3-methylenedioxphenyl)-2-nitropropene, with a mp of
95-102 !C.  Recrystallization from EtOH tightened this to 97-101.5 !C.
The infra-red spectrum is completely different from that of its
positional isomer
1-(2-methoxy-3,4-methylenedioxyphenyl)-2-nitropropene.

A suspension of 7.0 g LAH in 1 L anhydrous Et2O under an inert
atmosphere was brought to a gentle reflux.  The reflux condensate was
passed through a Soxhlet thimble containing 6.15 g
1-(4-methoxy-2,3-methylenedioxyphenyl)-2-nitropropene which was
effectively adding the nitropropene as a saturated solution.  The
mixture was maintained at reflux for 16 h.  After cooling to 0 !C with
an ice bath, the excess hydride was destroyed by the addition of 800
mL of 1.5 N H2SO4.  The phases were separated, and the aqueous phase
washed with 2x100 mL Et2O.  To this phase there was added 175 g
potassium sodium tartrate followed by sufficient 25% NaOH to raise the
pH >9.  This was then extracted with 3x100 mL CH2Cl2, and the solvent
from the pooled extracts removed under vacuum.  The residual off-white
oil weighed 5.4 g and was dissolved in 250 mL anhydrous Et2O and
saturated with anhydrous HCl gas.  There was produced a crop of
slightly sticky white solids that finally became granular and loose.
These were removed by filtration, washed with Et2O, and air dried to
give 5.56 g of 4-methoxy-2,3-methylenedioxyamphetamine hydrochloride
(MMDA-3b) with a mp of 196-199 !C.  A small sample from propanol had a
mp of 199-200 !C, and a sample from nitromethane/MeOH (5:1) had a mp
of 201-202 !C.

DOSAGE: greater than 80 mg.

DURATION: unknown.

QUALITATIVE COMMENTS: (with 60 mg) Definitely active.  Qualitatively
like MDA; quantitatively perhaps less.

(with 80 mg) No more effective than 60 mg.

EXTENSIONS AND COMMENTARY: And that's all there is known as to the
activity of MMDA-3b in man.  Very, very little.  Nothing has ever been
tried in excess of 80 milligrams that I know of, and the above trials
were made over 20 years ago.  There can be little argument that the 3b
is less effective than the 3a, but no one can say by how much.  The
literature statement is that it is threefold less, but that was based
on the relative responses at just-above-threshold levels.  The effects
here are hand-wavingly similar to those reported for MMDA-3a at 20
milligrams, but these are difficult to compare accurately as they were
reported by different people.  There have been absolutely no animal
studies reported with MMDA-3b in the scientific literature.  And
neither the 2-carbon nor the 4-carbon analogues of MMDA-3b has even
been prepared.

The remaining MMDA-analogue that has been prepared, is the
2,3,6-isomer.  The flow diagram started with sesamol
(3,4-methylenedioxyphenol) which was methylated with methyl iodide,
converted to the aldehyde using butyllithium and N-methylformanilide
(putting the new group directly between the two oxygen atoms, giving
2,3-methylenedioxy-6-methoxybenzaldehyde), reaction with nitroethane
to the nitrostyrene, and its reduction with lithium aluminum hydride
in ether.  The product, 6-methoxy-2,3-methylenedioxyamphetamine
hydrochloride (MMDA-5) is practically unexplored in man.  I have heard
one report that 30 milligrams was modestly active, but not a
particularly pleasant experience.  Another person told me that he had
tried 15 milligrams, but he neglected to mention if there had been any
effects.  I have not tried it myself.  But, I have succumbed to the
pressure of the experimental pharmacologists to give a number for the
RY-axisS of their animal behavior studies.  So I said to myself, if
this is active at 30 milligrams, and mescaline is active at 300
milligrams, why not say that it is 10x the activity of mescaline?  So
I did.  But I have absolutely no confidence in that number.

And if the information on MMDA-5 is sparse, look at the positional
isomer, MMDA-4, which I have discussed under its analogue TMA-4.  Here
nothing is known at all, since the compound itself is unknown.  No one
has yet found a way of making it.









#136 MME; 2,4-DIMETHOXY-5-ETHOXYAMPHETAMINE

SYNTHESIS: A solution was made of 166 g ethylvanillin
(4-ethoxy-3-methoxybenzaldehyde) in 600 mL glacial acetic acid and
arranged so that it can be stirred continuously, magnetically, and
cooled as needed with an external ice bath.  There was then added a
total of 218 g of 40% peracetic acid in acetic acid, at a rate that
permitted the temperature to stay at 25 !C with the continuous
application of the ice bath.  The temperature should not drop below 23
!C (the reaction stops) but it absolutely cannot be allowed to exceed
29 !C (the reaction can no longer be controlled).  The addition takes
about 1.5 h.  At the end of the reaction, there was added 3 volumes of
H2O, and all acids were neutralized with solid K2CO3.  The 3 or so L
of black, gooey mess was extracted with 2x400 mL boiling Et2O which,
on pooling and evaporation, provided 60 g of a black oil which was a
mixture containing mainly the intermediate formate and the product
phenol.  This was treated with 300 mL 10% NaOH, and heated on the
steam bath for 1 h.  After cooling, this was washed with 2x150 mL
CH2Cl2 (discarded), acidified with HCl, and extracted with 3x200 mL
Et2O.  The pooled extracts were washed with 2x200 mL saturated NaHCO3,
and then the Et2O was removed under vacuum.  The residual black oil,
41.3 g, was distilled at 1.0 mm/Hg to give a fraction boiling at
140-145 !C as a pale amber oil that set up as crystals.  The weight of
the isolated 4-ethoxy-3-methoxyphenol was 29.1 g.  An analytical
sample had a mp of 45.5-46 !C.  This product can be used either for
the synthesis of MME (see below) or for the synthesis of EME (see
separate recipe).  A solution of 0.5 g of this phenol, and 0.5 g
methyl isocyanate in 10 mL hexane containing 1 mL CH2Cl2 was treated
with three drops of triethylamine.  In about 1 h, there was the
spontaneous formation of white crystals of 4-ethoxy-3-methoxyphenyl
N-methyl carbamate, with a mp of 104-105 !C.

A solution of 14 g of the distilled, solid 4-ethoxy-3-methoxyphenol in
20 mL MeOH was treated with a solution of 5.3 g KOH in 100 mL hot
MeOH.  There was then added 11.9 g methyl iodide, and the mixture was
held at reflux temperature for 2 h.  The reaction was quenched with 3
volumes H2O, made strongly basic by the addition of 1 volume of 5%
NaOH, and extracted with 2x150 mL Et2O.  Pooling the extracts and
removal of the solvent under vacuum gave 9.7 g of
2,4-dimethoxy-1-ethoxybenzene as a clear, off-white oil that showed a
single peak by GC.  An acceptable alternate synthesis of this ether is
the ethylation of 2,4-dimethoxyphenol, which is described in the
recipe for TMA-4.  The index of refraction was nD25 = 1.5210.

A mixture of 17.3 g N-methylformanilide and 19.6 g POCl3 was allowed
to stand at room temperature until a strong red color had been
generated (about 0.5 h).  There was then added 9.2 g
2,4-dimethoxy-1-ethoxybenzene and the mixture was heated on the steam
bath for 2 h.  The black, viscous product was poured onto 800 mL
cracked ice, and mechanically stirred.  The deep color gradually faded
to a yellow solution, and then yellow crystals began to form.  After
standing overnight, these were removed by filtration and sucked as dry
as possible, yielding 16 g of a wet, crude product.  This was
dissolved in 100 mL boiling MeOH which, on cooling, deposited fluffy,
white crystals of 2,4-dimethoxy-5-ethoxybenzaldehyde.  The dry weight
was 8.8 g and the mp was 107-108 !C.  The mother liquor showed no
isomeric aldehydes by GC, but there were small suggestions of isomers
seen in the CH2Cl2 extracts of the original water filtration.  A
sample of 0.7 g of the aldehyde obtained as a second crop from the
methanolic mother liquors was dissolved, along with 0.5 g
malononitrile, in 20 mL hot EtOH.  The addition of 3 drops of
triethylamine generated the almost immediate formation of brilliant
yellow crystals, 1.4 g after filtration and EtOH washing, with a mp of
134-135.5 !C.  Recrystallization from toluene gave an analytical
sample of 2,4-dimethoxy-5-ethoxybenzalmalononintrile with a mp of
135-136 !C.

A solution of 6.7 g 2,4-dimethoxy-5-ethoxybenzaldehyde in 23 g glacial
acetic acid was treated with 3.3 g nitroethane and 2.05 g anhydrous
ammonium acetate.  The mixture was heated on the steam bath for 2.5 h.
The addition of a little water to the cooled solution produced a gel
which was a mixture of starting aldehyde and product nitrostyrene.
The solvent was decanted from it, and it was triturated under MeOH, to
provide a yellow solid with a mp of 76-84 !C.  Recrystallization from
30 mL boiling MeOH gave, after filtering and air drying, 4.3 g of a
yellow solid with a mp of 90-92 !C.  There was still appreciable
aldehyde present, and this was finally removed by yet another
recrystallization from toluene.  The product,
1-(2,4-dimethoxy-5-ethoxyphenyl)-2-nitropropene, was obtained as
bright yellow crystals with a mp of 96-97 !C.  The analytical sample
was dried in vacuum for 24 h to completely dispel the tenacious
residual traces of toluene.  Anal. (C13H17NO5) C,H.

To a gently refluxing suspension of 1.6 g LAH in 120 mL anhydrous Et2O
under a He atmosphere, there was added 2.1 g
1-(2,4-dimethoxy-5-ethoxyphenyl)-2-nitropropene by allowing the
condensing ether to drip into a shunted Soxhlet thimble containing the
nitrostyrene.  This effectively added, dropwise, a warm saturated
solution of the nitrostyrene to the reaction mixture.  Refluxing was
continued for 6 h, and after cooling the reaction flask to 0 !C the
excess hydride was destroyed by the cautious addition of 1.5 N H2SO4.
When the aqueous and Et2O layers were finally clear, they were
separated, and 40 g of potassium sodium tartrate was dissolved in the
aqueous fraction.  Aqueous NaOH was then added until the pH was >9,
and this was then extracted with 3x200 mL CH2Cl2.  Evaporation of the
solvent under vacuum produced 1.6 g of an amber oil that was dissolved
in 300 mL anhydrous Et2O and saturated with anhydrous HCl gas.  There
was an immediate white blush, then there was the generation of an oily
solid that upon further administration of HCl became a fine, loose
white powder.  This was removed by filtration, Et2O washed, and air
dried to give 1.6 g 2,4-dimethoxy-5-ethoxyamphetamine hydrochloride
(MME) with a mp of 171-172 !C.  Anal. (C13H22ClNO3) C,H,N.

DOSAGE: 40 mg and above.

DURATION : probably 6 - 10 h.

QUALITATIVE COMMENTS: (with 40 mg) At the one hour point there was a
real threshold, and at the second hour, while I was walking down 24th
Street, there was an honest 1+.  By the third hour it was at, or just
under a ++, with the earmarks of a possibly interesting collection of
effects, were it just a bit more intense.  I had unexpected diarrhea
at hour #5, and by #6 I was mending, and by #8 I was largely down.
The day was very encouraging, and this must be re-tried at 50 or 60
milligrams.

EXTENSIONS AND COMMENTARY: This is one of the very few compounds with
which I actually risked (and took) the lives of experimental animals.
I was still impressed by the scientific myth that pharmacological
research wasnUt really acceptable without animal support data.  And I
had access to an experimental mouse colony at the University.  I
injected one mouse with a dose of 300 mg/Kg., i.p.  That sounds pretty
scientific.  But what it really means is that I picked up a mouse by
the scruff of the back with my left hand, then turned my hand over so
that the mouse was belly-up.  I put the ring finger over a hind leg to
keep things relatively immobile.  Usually at this point there is a
little urine evident where there had been none before.  And I took a
syringe equipped with a very fine needle and containing about 8
milligrams of MME in a fraction of a mL of a water solution and pushed
that needle into the mouse at about where the navel would be if one
could see the mouse's navel, and then I pulled the needle back just a
little so that there should be nothing at the business end but the
loose folds of the peritoneum.  Then I pushed the syringe plunger
home, effectively squirting the water solution into the area that
surrounds the intestines.  I dropped the mouse back into his cage, and
watched.  In this case, the mouse went into a twitching series of
convulsions (known as clonic in the trade) and in five minutes he was
dead.

Fired with the lust for killing, I grabbed another mouse, and nailed
him with 175 mg/Kg.  Dead in 6 minutes.  Another one at 107 mg/Kg.
Dead in 5 minutes.  Another at 75 mg/Kg.  Well, he looked pretty sick
there for a while, and had some shakes, and then he seemed to be
pretty much OK.  One final orgy of murder.  I injected 5 mice at 100
mg/Kg i.p., and watched four of them die within 20 minutes.  I took in
my hands the sole survivor, and I went outside the laboratory and let
him loose on the hillside.  He scampered away and I never saw him
again.

And what did I learn, at the cost of seven precious lives which I can
never replace?  Not a damned thing.  Maybe there is an LD-50 somewhere
around 60 or 80 mg/Kg.  This is for mice, not for men.  I was
intending to take an initial trial dose of 300 micrograms of this
completely untested compound, and it would have made no difference to
me if the LD-50 had been 600 mg/Kg or 6 mg/Kg.  I still took my trial
dose, and had absolutely no effects, and I never killed another mouse
again.  No, that is simply out-and-out dishonest.  I had an invasion
of field mice last winter coming up through a hole in the floor behind
the garbage holder under the kitchen sink, and I blocked the hole, but
I also set some mouse traps.  And I caught a couple.  But never again
for the simple and stupid reasons of being able to say that RThis
compound has an LD-50 in the mouse of 70 mg/Kg.S Who cares?  Why kill?

But there are two very valuable things that have come out of this
simple study with MME.  One is, of course, that it is an active
compound and as such warrants additional attention.  And the other,
and even more important, is that as one of the three possible ethoxy
homologues of TMA-2, it is less active than MEM.  The third possible
ethoxy compound is EMM and, as will be found elsewhere in this book,
it is even less active.  Thus it is MEM, only, that maintains the
potency of TMA-2, and this was the initial observation that really
focused my attention on the importance of the 4-position.









#137 MP; METAPROSCALINE; 3,4-DIMETHOXY-5-(n)-PROPOXYPHENETHYLAMINE

SYNTHESIS: There was mixed 96 g of 5-bromovanillin and 90 mL 25% NaOH.
The solution was almost complete, when there was a sudden deposition
of a heavy precipitate.  This was diluted with 200 mL water.  There
was then added 300 mL methylene chloride, 85 g methyl iodide, and 3 g
decyltriethylammonium chloride.  The heterogenous mixture was
vigorously stirred for 2 days.  The organic phase was separated, and
the aqueous phase extracted once with 100 mL CH2Cl2.  The organic
phase and extract were pooled, washed with water and the solvent
removed under vacuum The residue weighed 46.3 g and spontaneously
crystallized.  It was recrystallized from 40 mL of MeOH to yield 34 g
of 3-bromo-4,5-dimethoxybenzaldehyde as white crystals with a mp of
60.5-61 !C.  An additional 4 g product was obtained from the mother
liquor.  Acidification of the aqueous phase above produced, after
recrystalization from IPA/acetone, 13.2 g of recovered
5-bromo-vanillin, with a mp of 166-169 !C.

A mixture of 38.7 g 3-bromo-4,5-dimethoxybenzaldehyde and 17.2 g
cyclohexylamine was heated with an open flame at about 120 !C until it
appeared to be free of H2O.  The residue was put under a vacuum (0.2
mm/Hg) and distilled at 146-160 !C yielding 44.6 g
3-bromo-N-cyclohexyl-4,5-dimethoxybenzylidenimine as a clear oil which
did not crystallize.  The imine stretch in the infra-red was at 1640
cm-1.  Anal. (C15H20BrNO2) C,H.

A solution of 31.6 g 3-bromo-N-cyclohexyl-4,5-dimethoxybenzylidenimine
in 300 mL anhydrous Et2O was placed in an atmosphere of He, stirred
magnetically, and cooled with an dry ice/acetone bath.  Then 71 mL of
a 1.55 M solution of butyllithium in hexane was added over a 2 min
period.  The reaction mixture turned cloudy and a light precipitate
formed which seemed heaviest at the half-way point.  Stirring remained
easy and was continued for 10 min.  There was then added 35 mL of
butyl borate at one time.  The precipitate dissolved, and the stirred
solution allowed to return to room temperature.  There was then added
200 mL of an aqueous solution containing 20 g ammonium sulfate.  The
Et2O layer was separated, washed with saturated ammonium sulfate
solution, and the organic solvents removed under vacuum.  The residue
was dissolved in 250 mL of 70% MeOH and 14 mL of 30% hydrogen peroxide
added in small portions.  This reaction was very exothermic, and
stirring was continued for 1 h.  The reaction mixture was then added
to 500 mL H2O, which knocked out white solids.  A small sample of this
intermediate, N-cyclohexyl-3,4-dimethoxy-5-hydroxybenzylidineimine was
recrystallized from MeOH to a white crystal with a mp of 148-149 !C
and which showed the C=N bond as a doublet at 1635 and 1645 cm-1 in
the infra-red.  These wet solids were suspended in 200 mL 5% HCl and
heated on the steam bath for 1 h.  Stirring was continued until the
reaction was again at room temperature and then it was extracted with
2x100 mL CH2Cl2.  These extracts were pooled and in turn extracted
with 2x75 mL dilute NaOH.  The aqueous extracts were reacidified with
HCl, and reextracted with 2x100 mL CH2Cl2.  These extracts were
pooled, and the solvent removed under vacuum to yield a brown viscous
oil as a residue.  This was distilled at 105-120 !C at 0.2 mm/Hg to
yield 8.8 g of 3,4-dimethoxy-5-hydroxybenzaldehyde as a distillate
that set to white crystals.  Recrystallization from toluene/hexane
gave a sample with the mp 64-65 !C.  The literature mps are several,
ranging from at about 60 !C to about 70 !C.

A solution of 4.7 g of 3,4-dimethoxy-5-hydroxybenzaldehyde in 75 mL
acetone was treated with 6.0 g powdered KI, 16 mL (21 g) propyl
bromide, and 7.0 g finely powdered anhydrous K2CO3, and this mixture
was held at reflux on a steam bath for 15 h.  The reaction mixture was
added to 1 L H2O, made strongly basic, and extracted with 3x100 mL
CH2Cl2.  The extracts were pooled, washed with 5% NaOH, and the
solvent removed under vacuum yielding 8.8 g of a yellow oil,
undoubtedly containing propyl iodide.  This residue was distilled at
133-145 !C at 0.15 mm/Hg to yield 4.5 g of
3,4-dimethoxy-5-(n)-propoxybenzaldehyde as a white oil which did not
crystallize.  There was an appreciable pot residue.  This product was
clearly impure, having a minor, slower moving component not the
starting phenol, as seen by TLC (on silica gel, with CH2Cl2 as a
developing solvent).  Fusion of a small amount of impure aldehyde with
p-anisidine produced a crystalline anil which, on hydrolysis with
dilute acid, produced an aldehyde sample free of this impurity.  But
as this sample also remained as an oil, the above crude product was
used in the following preparation.

To a solution of 3.8 g 3,4-dimethoxy-5-(n)-propoxybenzaldehyde in 50
mL nitromethane, there was added 0.5 g anhydrous ammonium acetate.
This was held at reflux for 50 min.  The excess nitromethane was
removed under vacuum and 2 volumes of boiling MeOH were added to the
residue.  The hot solution was decanted from some residual insolubles,
and on cooling spontaneously crystallized.  These solids were removed
by filtration, washed sparingly with MeOH and air dried yielding 3.3 g
yellow crystals of 3,4-dimethoxy-'-nitro-5-(n)-propoxynitrostyrene as
yellow crystals melting at 79-81 !C.  Recrystallization from MeOH or
cyclohexane neither improved the mp nor freed the product from a
residual opalescenceseen in the melt.  Anal. (C13H17NO5) C,H.

A solution of 1.5 g LAH in 30 mL anhydrous THF under He was cooled to
0 !C and vigorously stirred.  There was added, dropwise, 1.0 mL of
100% H2SO4, followed by the dropwise addition of a solution of 2.3 g
3,4-dimethoxy-'-nitro-5-(n)-propoxynitrostyrene in 10 mL anhydrous
THF, over the course of 5 min.  The mixture was stirred at 0 !C for a
while, and then brought to a reflux on the steam bath.  After cooling
again, the excess hydride was destroyed with IPA added dropwise,
followed by the addition of about 10 mL of 10% NaOH which was
sufficient to covert the solids to a white, granular form.  These were
removed by filtration, the filter cake washed with IPA, the mother
liquor and filtrates were combined, and the solvents were removed
under vacuum to yield an amber oil.  This residue was added to 75 mL
dilute H2SO4 which produced a gummy insoluble phase which was
physically removed with a spatula.  The aqueous phase was washed with
3x50 mL CH2Cl2.  It was then made basic with 25% NaOH, and extracted
with 2x75 mL CH2Cl2.  The solvent was removed from these pooled
extracts and the residue distilled at 106-116 !C at 0.2 mm/Hg to
provide 1.3 g of the product as a colorless liquid.  This was
dissolved in 4 mL IPA, neutralized with about 20 drops of concentrated
HCl, and diluted with 4 volumes of anhydrous Et2O added slowly with
continuous stirring.  A white crystalline salt crystallized out
spontaneously and was isolated by filtration, washed first with IPA,
then with Et2O, and air dried giving 1.3 g
3,4-dimethoxy-5-(n)-propoxyphenethylamine hydrochloride (MP) with a mp
of 170-171 !C. Anal. (C13H22ClNO3) C,H.

DOSAGE: greater than 240 mg.

DURATION: unknown.

QUALITATIVE COMMENTS: (with 160 mg) There might have been some
disturbance at the three to four hour point, but it was extremely
light if at all.

(with 240 mg) No effects whatsoever.

EXTENSIONS AND EXTRAPOLATIONS: The loss of activity on lengthening the
carbon chain on the meta-oxygen from two to three (from metaescaline
to metaproscaline) discouraged any further exploration at this
specific point of the molecule.  The isopropyl analog
(3,4-dimethoxy-5-(i)-propoxyphenethylamine, metaisoproscaline, MIP)
was started and carried along as far as the aldehyde, and abandoned
with the discovery that metaproscaline was without activity.  There
were other fish to fry.









#138 MPM; 2,5-DIMETHOXY-4-(n)-PROPOXYAMPHETAMINE

SYNTHESIS: To a solution of 68 g 2,5-dimethoxybenzaldehyde in 250 mL
glacial acetic acid that had been warmed to 25 !C and well stirred,
there was added, dropwise, 86 g of a 40% peracetic acid solution (in
acetic acid).  The reaction was exothermic, and the rate of addition
was dictated by the need to maintain the internal temperature within a
few degrees of 28 !C.  External cooling was used as needed.  The
addition took 1 h, and when the reaction had clearly been completed
(there was no further temperature rise) the entire reaction mixture
was added to 3 volumes of H2O.  The excess acid was neutralized with
solid K2CO3.  The dark solution was extracted with 3x100 mL Et2O, the
extracts pooled, and stripped of solvent under vacuum to give 59 g of
crude 2,4-dimethoxyphenyl formate.  This was suspended in 200 mL 10%
NaOH, and the mixture heated on the steam bath for 1 h.  On cooling,
the reaction mixture was washed with 2x200 mL methylene chloride,
acidified with HCl, and extracted with 3x200 mL CH2Cl2.  The extracts
were pooled and the solvent removed under vacuum.  There remained as
residue, 47.4 g 2,5-dimethoxyphenol which was deep amber in color, but
clear and fluid.  It was homogenous by GC and completely correct by
NMR.  It was used without further purification.

To a solution of 3.08 g 2,5-dimethoxyphenol in 20 g MeOH, there was
added a solution of 1.26 g flaked KOH in 20 g hot MeOH.  There was
then added 2.46 g n-propyl bromide, and the mixture held at reflux for
2 h on the steam bath.  This was quenched in 5 volumes H2O, made
strongly basic with 10% NaOH, and extracted with 3x100 mL CH2Cl2.
Removal of the solvent from the pooled extracts left 2.0 g of
1,4-dimethoxy-2-(n)-propoxybenzene as a clear, amber oil.  The IR
spectrum was appropriate, no phenol was present, and this residue was
used in the following reaction without further purification or
characterization.

A mixture of 3.5 g N-methylformanilide and 4.0 g POCl3 was held at
room temperature for 0.5 h producing a deep red color.  To this there
was added 2.0 g 1,4-dimethoxy-2-(n)-propoxybenzene, and the mixture
was held on the steam bath for 1.75 h.  It was then poured over 400 mL
shaved ice, and vigorous stirring was maintained until the dark
complex had completely broken up.  This aqueous mixture was allowed to
stand overnight, and the crude aldehyde solids that had formed were
removed by filtration, water washed, and sucked as dry as possible.
This 2.0 g damp material was crystallized from 20 mL boiling MeOH
giving, after filtering and drying to constant weight, 1.4 g
2,5-dimethoxy-4-(n)-propoxybenzaldehyde as reddish-tan solids, with a
mp of 97-98 !C.  To the methanolic mother liquors of this
crystallization there was added a gram of malononitrile and a few
drops of triethylamine.  The eventual addition of a little H2O
encouraged the separation of crystals which were removed, and had a mp
of 150-152 !C.  Recrystallization from toluene gave gold-colored
crystals of the benzalmalononitrile with a mp of 153.5-155 !C, but the
melt remained slightly cloudy.

To a solution of 1.4 g 2,5-dimethoxy-4-(n)-propoxybenzaldehyde and
0.65 g nitroethane in 4.4 g glacial acetic acid there was added 0.4 g
anhydrous ammonium acetate, and the mixture was heated on the steam
bath for 5 h.  The addition of a modest amount of H2O and scratching
with a glass rod produced crystal seed.  The reaction was diluted with
about 5 mL H2O, seeded, and allowed to stand at room temperature
overnight.  There was generated a crystalline product which was
removed by filtration and air dried.  There was thus obtained 0.6 g
1-(2,5-dimethoxy-4-(n)-propoxyphenyl)-2-nitropropene as yellow-orange
crystals, with a mp of 83-84 !C.  The addition of H2O to the mother
liquors provided an additional 0.3 g of an orange solid which proved
to be largely unreacted starting aldehyde.

To a stirred, warm suspension of 0.5 g LAH in 20 mL anhydrous Et2O
under a He atmosphere, there was added 0.6 g
1-(2,5-dimethoxy-4-(n)-propoxyphenyl)-2-nitropropene dissolved in a
little anhydrous Et2O.  The mixture was heated and stirred for a few
h, and the excess hydride decomposed with 30 mL 1.5 N H2SO4.  The two
layers were separated, and 15 g potassium sodium tartrate was
dissolved in the aqueous fraction.  Aqueous NaOH was then added until
the pH was >9, and this was then extracted with 3x50 mL CH2Cl2.
Removal of the solvent under vacuum gave 0.7 g of an amber oil that
was dissolved in anhydrous Et2O and saturated with anhydrous HCl gas.
No crystals formed, and so the ether was removed under vacuum, leaving
a residue that set up to crystals that were then no longer soluble in
ether.  They were, however, very soluble in chloroform.  These were
ground under dry Et2O, removed by filtration, and air dried giving
0.35 g 2,5-dimethoxy-4-(n)-propoxyamphetamine hydrochloride (MPM) with
a mp of 123 - 125 !C.

DOSAGE: 30 mg or more.

DURATION: probably short.

QUALITATIVE COMMENTS: (with 15 mg) This is just barely threshold.  A
marginal intoxication at best.  This level is producing less response
that the 11 mg. trial of MEM, so the propoxy is off in potency.  At
four and a half hours I am out of whatever little there was.

(with 30 mg) By the mid-second hour, I am at a valid plus one.  I
cannot identify the nature Q with eyes closed it would be lost, as it
would also be if I were watching a play or movie.  It would have been
interesting to see where it could have gone.  Seventh hour, completely
clear.

EXTENSIONS AND COMMENTARY: The 4-propoxy homologue of TMA-2 and MEM is
clearly less active, and this has discouraged me from putting too much
more effort in this direction.  Three additional materials of this
pattern were prepared and either shown to be even less active, or
simply were not assayed at all.  These are the 4-isopropoxy isomer
(MIPM), the (n)-butoxy homologue (MBM), and the (n)-amyl homologue
(MAM).  They scarcely warrant separate recipes as they were all made
in a manner similar to this one describing MPM.

For the preparation of MIPM, the above phenol, 2,5-dimethoxyphenol was
isopropylated with isopropyl bromide in methanolic KOH giving
2,5-dimethoxy-1-(i)-propoxybenzene as an oil.  This formed the
benzaldehyde with the standard Vilsmeier conditions, which melted at
77-78 !C from hexane and which gave a yellow malononitrile derivative
melting at 171.5-173 !C.  The nitrostyrene, from nitroethane in acetic
acid was orange colored and melted at 100-101 !C from either methanol
or hexane.  This was reduced with lithium aluminum hydride in ether to
give 2,5-dimethoxy-4-(i)-propoxyamphetamine hydrochloride (MIPM).  The
properties of the isolated salt were strange (soluble in acetone but
not in water) and the microanalysis was low in the carbon value.  The
molecular structure had a pleasant appeal to it, with a complete
reflection symmetry shown by the atoms of the amphetamine side chain
and the isopropoxy side chain.  But the nature of the actual product
in hand had no appeal at all, and no assay was ever started.

For the preparation of MBM, the starting phenol was alkylated to
2-(n)-butoxy-1,4-dimethoxybenzene in methanolic KOH with n-butyl
bromide.  The benzaldehyde melted at 79.5-81 !C from methanol, and
formed a malononitrile derivative that had a melting point of
134.5-135 C.  The nitrostyrene from the aldehyde and nitroethane in
acetic acid crystallized from methanol with a mp of 71-72 !C.  Lithium
aluminum hydride reduction in ether gave the ether-insoluble
chloroform-soluble product 4-(n)-butoxy-2,5-dimethoxyamphetamine
hydrochloride (MBM) with a melting point of 128-130 !C.  This product
met all tests for structural integrity, and assays were started.  At
levels of up to 12.0 milligrams, there were no effects noted.

As to the preparation of MAM, the exact same sequence was used, except
for the employment of n-amyl bromide.  The benzaldehyde crystallized
from methanol with a mp of 79-80 !C, and formed a malononitrile
derivative which was bright yellow and melted at 103-104 !C.  The
nitrostyrene, when pure, melted at 57-58.5 !C but proved very
difficult to separate from the aldehyde.  The final product,
4-(n)-amyl-2,5-dimethoxyamphetamine hydrochloride (MAM) was obtained
by lithium aluminum hydride reduction in ether and melted at 125-127
!C.  It was assayed at up to 16 milligrams, at which level there was
noted a heaviness in the chest and head at the 2-hour point, but no
cardiovascular disturbance and no mydriasis.  This was called an
inactive level, and no higher one has yet been tried.









#139 ORTHO-DOT; 4,5-DIMETHOXY-2-METHYLTHIOAMPHETAMINE

SYNTHESIS: To 26.4 g veratrol that was being magnetically stirred
without any solvent, there was added 50 g chlorosulfonic acid a bit at
a time over the course of 20 min.  The reaction was exothermic, and
evolved considerable HCl.  The deeply colored mixture that resulted
was poured over 400 mL crushed ice and when all had thawed, it was
extracted with 2x150 mL CH2Cl2.  Removal of the solvent under vacuum
gave a residue that set up as a crystalline mass.  The weight of the
crude 3,4-dimethoxybenzenesulfonyl chloride was 37.1 g and it had a mp
of 63-66 !C.  Recrystallization raised this to 72-73 !C.  Reaction
with ammonium hydroxide gave the sulfonamide as colorless needles from
EtOH, with a mp of 132-133 !C.

The finely pulverized 3,4-dimethoxybenzenesulfonyl chloride (33 g) was
added to 900 mL of crushed ice in a 2 L round-bottomed flask equipped
with a heating mantle and reflux condenser.  There was then added 55
mL concentrated H2SO4 and, with vigorous mechanical stirring, there
was added 50 g of zinc dust in small portions.  This mixture was
heated until a vigorous reaction ensued and refluxing was continued
for 1.5 h.  After cooling to room temperature and decantation from
unreacted metallic zinc, the aqueous phase was extracted with 3x150 mL
Et2O.  The pooled extracts were washed once with saturated brine and
the solvent was removed under vacuum.  The residue was distilled to
give 20.8 g of 3,4-dimethoxythiophenol boiling at 86-88 !C at 0.4
mm/Hg.

A solution of 10 g 3,4-dimethoxythiophenol in 50 mL absolute EtOH was
protected from the air by an atmosphere of N2.  There was added a
solution of 5 g 85% KOH in 80 mL EtOH.  This was followed by the
addition of 6 mL methyl iodide, and the mixture was held at reflux for
30 min.  This was poured into 200 mL H2O and extracted with 3x50 mL
Et2O.  The pooled extracts were washed once with aqueous sodium
hydrosulfite, then the organic solvent was removed under vacuum.  The
residue was distilled to give 10.3 g of 3,4-dimethoxythioanisole with
a bp of 94-95 !C at 0.4 mm/Hg.  The product was a colorless oil that
crystallized on standing.  Its mp was 31-32 !C.

To a mixture of 15 g POCl3 and 14 g N-methylformanilide that had been
warmed briefly on the steam bath there was added 8.2 g of
3,4-dimethoxythioanisole, the exothermic reaction was heated on the
steam bath for an additional 20 min, and then poured into 200 mL H2O.
Stirring was continued until the insolubles had become completely
loose and granular.  These were removed by filtration, washed with
H2O, sucked as dry as possible, and then recrystallized from 100 mL
boiling EtOH.  The product, 4,5-dimethoxy-2-(methylthio)benzaldehyde,
was an off-white solid, weighing 8.05 g and having a mp of 112-113 !C.
Anal. (C10H12O3S) C,H.

A solution of 2.0 g 4,5-dimethoxy-2-(methylthio)benzaldehyde in 8 mL
nitroethane was treated with 0.45 g anhydrous ammonium acetate and
heated on the steam bath for 4.5 h.  Removal of the excess solvent
under vacuum gave a red residue which was dissolved in 5 mL boiling
MeOH.  There was the spontaneous formation of a crystalline product
which was recrystallized from 25 mL boiling MeOH to give, after
cooling, filtering and air drying, 1.85 g of
1-(4,5-dimethoxy-2-methylthiophenyl)-2-nitropropene as bright orange
crystals with a mp of 104-105 !C.  Anal. (C12H15NO4S) C,H,N.

A suspension of 1.3 g LAH in 50 mL anhydrous THF was placed under an
inert atmosphere and stirred magnetically.  When this had been brought
to reflux conditions, there was added, dropwise, 1.65 g of
1-(4,5-dimethoxy-2-methylthiophenyl)-2-nitropropene in 20 mL THF.  The
reaction mixture was maintained at reflux for 18 h.  After being
brought back to room temperature, the excess hydride was destroyed by
the addition of 1.3 mL H2O in 10 mL THF.  There was then added 1.3 mL
of 3N NaOH followed by an additional 3.9 mL H2O.  The loose, inorganic
salts were removed by filtration, and the filter cake washed with
additional 20 mL THF.  The combined filtrate and washes were stripped
of solvent under vacuum yielding a light yellow oil as a residue.
This was dissolved in 20 mL IPA, neutralized with 0.9 mL concentrated
HCl, and diluted with 200 mL anhydrous Et2O.  There was thus formed
1.20 g of 4,5-dimethoxy-2-methylthioamphetamine hydrochloride
(ORTHO-DOT) as a pale yellow crystalline product.  This melted at
218-219.5 !C, and recrystallization from EtOH yielded a white product
and increased the mp to 222-223 !C with decomposition Anal.
(C12H20ClNO2S) C,H,N.

DOSAGE: greater than 25 mg.

DURATION: unknown.

QUALITATIVE COMMENTS: (with 25 mg) Vague awareness, with the feeling
of an impending something.  Light food sat uncomfortably.  By the late
afternoon there was absolutely nothing.  Threshold at best.

EXTENSIONS AND COMMENTARY: This material, ORTHO-DOT, can be looked at
as the sulfur homologue of TMA-2 with the sulfur atom located in place
of the oxygen at the 2-position of the molecule.  At what level this
compound might show activity is completely unknown, but wherever that
might be, it is at a dosage greater than that for the PARA-DOT isomer,
ALEPH-1 (or ALEPH), which was fully active at 10 milligrams (ALEPH can
be looked at as TMA-2 with the sulfur atom located in place of the
oxygen at the 4-position of the molecule).  A lot of variations are
easily makable based on this structure, but why bother?  ALEPH is the
much more appealing candidate for structural manipulation.









#140 P; PROSCALINE; 3,5-DIMETHOXY-4-(n)-PROPOXYPHENETHYLAMINE

SYNTHESIS: A solution of 5.8 g of homosyringonitrile (see under E for
its synthesis), 100 mg decyltriethylammonium iodide, and 10 g n-propyl
bromide in 50 mL anhydrous acetone was treated with 6.9 g finely
powdered anhydrous K2CO3 and held at reflux for 10 h.  An additional 5
g of n-propyl bromide was added to the mixture, and the refluxing
continued for another 48 h.  The mixture was filtered, the solids
washed with acetone, and the combined filtrate and washes stripped of
solvent under vacuum.  The residue was suspended in acidified H2O, and
extracted 3x175 mL CH2Cl2.  The pooled extracts were washed with 2x50
mL 5% NaOH, once with dilute HCl (which lightened the color of the
extract) and then stripped of solvent under vacuum giving 9.0 g of a
deep yellow oil.  This was distilled at 132-142 !C at 0.3 mm/Hg to
yield 4.8 g of 3,5-dimethoxy-4-(n)-propoxyphenylacetonitrile as a
clear yellow oil.  Anal. (C13H17NO3) C H N.

A solution of 4.7 g 3,5-dimethoxy-4-(n)-propoxyphenylacetonitrile in
20 mL THF was treated with 2.4 g powdered sodium borohydride.  To this
well-stirred suspension there was added, dropwise, 1.5 mL
trifluoroacetic acid.  There was a vigorous gas evolution from the
exothermic reaction.  Stirring was continued for 1 h, then all was
poured into 300 mL H2O.  This was acidified cautiously with dilute
H2SO4, and washed with 2x75 mL CH2Cl2.  The aqueous phase was made
basic with dilute NaOH, extracted with 2x75 mL CH2Cl2, the extracts
pooled, and the solvent removed under vacuum.  The residue was
distilled at 115-125 !C at 0.3 mm/Hg to give 1.5 mL of a colorless oil
which upon dissolving in 5 mL IPA, neutralizing with 27 drops
concentrated HCl, and dilution with 25 mL anhydrous Et2O yielded 1.5 g
3,5-dimethoxy-4-(n)-propoxyphenethylamine hydrochloride (P) as
spectacular white crystals.  The catalytic hydrogenation process for
reducing the nitrile (see under E) also succeeded with this material.
The mp was 170-172 !C.  Anal. (C13H22ClNO3) C,H,N.

DOSAGE: 30 - 60 mg.

DURATION: 8 - 12 h.

QUALITATIVE COMMENTS: (with 30 mg) Proscaline dulled my sense of pain
and made the other senses really sharp.  Everything felt really soft,
and clean and clear.  I could feel every hair my hand was touching.  I
felt so relaxed and at ease.  I know that under the appropriate
circumstances, this material would lead to uninhibited eroticism.

(with 35 mg) The whole experiment was very quiet.  There was no
nystagmus, no anorexia, and insignificant visuals with the eyes
closed.  I was restless with a bit of tremor for the first couple of
hours, and then became drowsy.  Would I do this again?  Probably not.
It doesnUt seem to offer anything except speculation about the nature
of the high.  The high was pleasant, but quite uneventful.

(with 40 mg) For me there was a deep feeling of peace and
contentment.  The euphoria grows in intensity for several hours and
remains for the rest of the day making this one of the most enjoyable
experiences I have ever had.  It was marvel-ous talking and joking
with the others.  However, I was a little disappointed that there was
no enhanced clarity and no deep realizations.  There was not a problem
to be found.  There were no motivations to discuss anything serious.
If I had any objection, it would be with the name, not the
pharmacology.

(with 60 mg) The development of the intoxication was complete in a
couple of hours.  I feel that there is more physical effect than
mental, in that there is considerable irritability.  This should
probably be the maximum dose.  Despite feeling quite drunk, my
thinking seems straight.  The effects were already waning by the fifth
hour, but sleep was not possible until after the twelth hour.  There
was no hangover the next day.

EXTENSIONS AND COMMENTARY: There is a very early report describing the
human use of proscaline tucked away in the Czechoslovakian literature
that describes experiments at up to 80 milligrams.  At these dosages,
there were reported some difficulty with dreams, and the residual
effects were still apparent even after 12 hours.

The amphetamine homologue of proscaline,
3,5-dimethoxy-4-(n)-propoxy-amphetamine is an unexplored compound.
Its synthesis could not be achieved in parallel to the description
given for P.  Rather, the propylation of syringaldehyde to give
3,5-dimethoxy-4-(n)-propoxybenzaldehyde, followed by coupling with
nitroethane and the reduction of the formed nitrostyrene with lithium
aluminum hydride would be the logical process.  Following the
reasoning given under E, the initials for this base would be 3C-P, and
I would guess it would be active, and a psychedelic, in the 20 to 40
milligram range.









#141 PE; PHENESCALINE; 3,5-DIMETHOXY-4-PHENETHYLOXYPHENETHYLAMINE

SYNTHESIS: To a solution of 5.8 g homosyringonitrile (see under E for
its preparation) in 50 mL of acetone containing 100 mg
decyltriethylammonium iodide, there was added 14.8 g
'-phenethylbromide and 6.9 g of finely powdered anhydrous K2CO3.  The
greenish mixture was refluxed for 3 days, with two additional 4 g
batches of anhydrous K2CO3 being added at 24 h intervals.  After
addition to aqueous base, the product was extracted with CH2Cl2, the
pooled extracts were washed with dilute base (the organic phase
remained a deep purple color) and then finally with dilute HCl (the
organic phase became a pale yellow).  The solvent was removed giving
15.6 g crude 3,5-dimethoxy-4-phenethyloxyphenylacetonitrile which
distilled at 165-185 !C at 0.3 mm/Hg to yield
3,5-dimethoxy-4-phenethyloxyphenylacetonitrile as a reddish viscous
oil weighing 8.1 g.  Anal. (C18H19NO3) C,H.

A solution of 7.9 g of distilled
3,5-dimethoxy-4-phenethyloxyphenylacetonitrile in 15 mL dry THF was
added to a 0 !C solution of AH prepared from a vigorously stirred
solution of 4.6 g LAH in 160 ml THF which had been treated, at 0 !C
with 3.6 mL 100% H2SO4 under an atmosphere of He.  The gelatinaceous
reaction mixture was brought to a brief reflux on the steam bath, then
cooled again.  It was treated with 5 mL IPA which destroyed the
unreacted hydride, followed by sufficient 15% NaOH to give loose,
white filterable solids.  These were removed by filtration and washed
with THF.  The filtrate and the washes were combined and, after
removal of the solvent under vacuum, there remained 7.8 g of the
product as a crude base which crystallized spontaneously.
Distillation of this product at 170-180 !C at 0.35 mm/Hg gave 5.1 g
white solids, with a mp of 85-86 !C from hexane.  This base was
dissolved in 20 mL warm IPA and treated with 1.6 mL concentrated HCl.
To the resulting clear solution, there was added 75 mL anhydrous Et2O
which gave, after a few moments of stirring, a spontaneous
crystallization of 3,5-di-methoxy-4-phenethyloxyphenethylamine
hydrochloride (PE) as beautiful white crystals.  The weight was 5.4 g
after air drying, and the mp was 151-152 !C.  Anal. (C18H24ClNO3) C,H.

DOSAGE: greater than 150 mg.

DURATION: unknown.

QUALITATIVE COMMENTS: (with 150 mg) At most, there was a bare
threshold over the course of the afternoon.  A vague unreal feeling,
as if I had not had quite enough sleep last night.  By late afternoon,
even this had disappeared and I was left with an uncertainty that
anything at all had occurred.

EXTENSIONS AND COMMENTARY: There is not much there, so there is not
much to make commentary on.  This response is called a RthreshholdS
effect, and cannot be used to predict with any confidence just what
level (if any) would produce psychological effects.

A similar chain on the 4-position, but with one less carbon atom,
deserves special comment.  Rather than a phenethyloxy group, this
would be benzyloxy group (which in this day and age of Chemical
Abstracts purity should probably be called a phenylmethoxy group).  If
one were to follow the naming philosophy of Rproscaline equals P and
buscaline equals BS convention, one would call it 4-benzescaline, and
give it the code name BZ.  The nomenclature purist would probably call
the compound PM (for phenylmescaline or, more likely
phenylmethoxydimethoxyphenethylamine), since the term BZ is awkward
and misleading.  It is a code name that has been given to a potent CNS
agent known as quinuclidin-3-yl benzilate, which is a chemical and
biological warfare (CBW) incapacitating agent currently being stored
by the military to the extent of 20,000 pounds.  And, BZ has also
recently become the jargon name given to benzodiazepine receptors.
They have been called the BZ-receptors.

However, let's be awkward and misleading, and call this benzyloxy-base
BZ.  For one thing, the three-carbon analogue 3C-BZ has already been
described in its own recipe using this code.  And the 4-fluoroanalogue
of it, 3C-FBZ, is also mentioned there.  And BZ has already been
described synthetically, having been made in exactly the procedure
given for escaline, except that the reduction of the nitrile was not
done by catalytic hydrogenation but rather by sodium borohydride in
the presence of cobalt chloride.  It has been shown to be a effective
serotonin agonist, and may warrant human experimentation.  The
serotonin activity suggests that it might be active at the same levels
found for proscaline.

All of this says very little about PE.  But then, there is very little
to say about PE except that it may be active at very high levels, and
I am not sure just how to get there safely.









#142 PEA; PHENETHYLAMINE

SYNTHESIS: This compound has been made industrially by a number of
routes, the motant being the reduction of benzyl cyanide and the
decarboxylation of phenylanaline.  It is offered in the catalogs of
all the major chemical supply houses for a few pennies per gram.  It
is a very strong base with a fishy smell, and rapidly forms a solid
carbonate salt upon exposure to the air.  It is a natural biochemical
in both plants and animals.

DOSAGE: greater than 1600 mg.

DURATION: unknown.

QUALITATIVE COMMENTS: (with 200, 400, 800 and 1600 mg) No effects.

(with 500 mg) No effects.

(with 800 and 1600 mg) No effects.

(with 25 and 50 mg i.v.)  RNo effects.

EXTENSIONS AND COMMENTARY: Here is the chemical that is central to
this entire book.  This is the structural point of departure for every
compound that is discussed here.  It is the RPS in PIHKAL.  It is
without activity in man!  Certainly not for the lack of trying, as
some of the dosage trials that are tucked away in the literature (as
abstracted in the RQualitative CommentsS given above) are pretty heavy
duty.  Actually, I truly doubt that all of the experimenters used
exactly that phrase, RNo effects,S but it is patently obvious that no
effects were found.  It happened to be the phrase I had used in my own
notes.

This, the simplest of all phenethylamines, has always been the darling
of the psychopharmacologists in that it is structurally clean, it is
naturally present in various human fluids and tissues, and because of
its close chemical relationship to amphetamine and to the
neurotransmitters.  These facts continuously encourage theories that
involve PEA in mental illness.  Its levels in urine may be decreased
in people diagnosed as being depressed.  Its levels may be increased
in people diagnosed as being paranoid schizophrenics.  Maybe it is
also increased in people under extreme stress.  The human trials were
initially an attempt to provoke some psychological change, and indeed
some clinicians have reported intense headaches generated in
depressives following PEA administration.  But then, others have seen
nothing.  The studies evolved into searches for metabolic difference
that might be of some diagnostic value.  And even here, the jury is
still out.

Phenethylamine is found throughout nature, in both plants and animals.
It is the end product of phenylalanine in the putrefaction of tissue.
One of its most popularized occurrences has been as a major component
of chocolate, and it has hit the Sunday Supplements as the
love-sickness chemical.  Those falling out of love are compulsive
chocolate eaters, trying to replenish and repair the body's loss of
this compound Q or so the myth goes.  But this amine is voraciously
metabolized to the apparently inactive compound phenylacetic acid, and
to some tyramine as well.  Both of these products are also normal
components in the body.  And, as a wry side-comment, phenylacetic acid
is a major precursor in the illicit synthesis of amphetamine and
methamphetamine.

Phenethylamine is intrinsically a stimulant, although it doesnUt last
long enough to express this property.  In other words, it is rapidly
and completely destroyed in the human body.  It is only when a number
of substituent groups are placed here or there on the molecule that
this metabolic fate is avoided and pharmacological activity becomes
apparent.

    To a large measure, this book has emphasized the RphenylS end
of the phenethylamine molecule, and the Rwhat,S the where,S and the
Rhow manyS of the substituent groups involved.  There is a broad
variety of chemical groups that can be attached to the benzene ring,
at one or more of the five available positions, and in an unending
number of combinations.  And, in any given molecule, the greater the
number of substituents on the benzene ring, the greater the likelihood
that there will be psychedelic action rather that stimulant action.

    But what can be said about the RethylamineS end of the
phenethylamine molecule?  This is the veritable backbone that holds
everything together, and simple changes here can produce new
prototypes that can serve as starting points for the substituent game
on the benzene ring.  Thus, just as there is a RfamilyS of compounds
based on the foundation of phenethylamine itself, there is an equally
varied and rich RfamiliesS of other compounds that might be based on
some phenethylamine with a small modification to its backbone.

    So, for the moment, leave the aromatic ring alone, and let us
explore simple changes in the ethylamine chain itself.  And the
simplest structural unit of change is a single carbon atom, called the
methyl group.  Where can it be placed?

The adding of a methyl group adjacent to the amine produces
phenylisopropylamine, or amphetamine.  This has been exploited already
as one of the richest families of psychedelic drugs; and over half of
the recipes in Book II are specifically for amphetamine analogues with
various substituents on the aromatic ring.  The further methylation of
amphetamine with yet another methyl group, this time on the nitrogen
atom, yields methamphetamine.  Here the track record with various
substituents on the aromatic ring is not nearly as good.  Many have
been explored and, with one exception, the quality and potency of
human activity is down.  But the one exception, the N-methyl analogue
of MDA, proved to be the most remarkable MDMA.

The placement of the methyl group between the two carbons (so to
speak) produces a cyclopropyl system.  The simplest example is
2-phenylcyclopropylamine, a drug with the generic name of
tranylcypromine and the trade name Parnate.  It is a mono-amine
oxidase inhibitor and has been marketed as an antidepressant, but the
compound is also a mild stimulant causing insomnia, restlessness and
photophobia.  Substitutions on the benzene ring of this system have
not been too promising.  The DOM analogue,
2,5-dimethoxy-4-methyltranylcypromine is active in man, and is
discussed in its own recipe under DMCPA.  The inactive mescaline
analogue TMT is also mentioned there.

The dropping of one carbon from the phenethylamine chain gives a
benzyl amine, basically an inactive nucleus.  Two families deserve
mention, however.  The phencylidine area, phenylcyclohexylpiperidine
or PCP, is represented by a number of benzyl amines.  Ketamine is also
a benzyl amine.  These are all analgesics and anesthetics with central
properties far removed from the stimulant area, and are not really
part of this book.  There is a benzyl amine that is a pure stimulant,
which has been closely compared to amphetamine in its action This is
benzylpiperazine, a base that is active in the 20 to 100 milligram
range, but which has an acceptability similar to amphetamine.  If this
is a valid stimulant, I think that much magic might be found in and
around compounds such as (1) the MDMA analogue,
N-(3,4-methylenedioxybenzyl)piperazine (or its N-methyl-counterpart
N-(3,4-methylenedioxybenzyl)-NU-methylpiperazine) or (2) the DOM
analogue, 2,5-dimethoxy-4-methylbenzylpiperazine.  The benzyl amine
that results by the relocation of the amine group of MDA from the
beta-carbon atom to the alpha-carbon atom is known, and is active.
It, and its N-methyl homologue, are described and discussed in the
commentary under MDA.  Dropping another carbon atom gives a yet
shorter chain (no carbons at all!) and this is to be found in the
phenylpiperazine analogue 3-trifluoromethylphenylpiperazine.  I have
been told that this base is an active hallucinogen as the
dihydrobromide salt at 50 milligrams sublingually, or at 15 milligrams
intravenously in man.  The corresponding 3-chloro analogue at 20 to 40
milligrams orally in man or at 8 milligrams intravenously, led to
panic attacks in some 10% of the experimental subjects, but not to any
observed psychedelic or stimulant responses.

What happens if you extend the chain to a third carbon?  The parent
system is called the phenyl-(n)-propylamine, and the parent chain
structure, either as the primary amine or as its alpha-methyl
counterpart, represents compounds that are inactive as stimulants.
The DOM-analogues have been made and are, at least in the rabbit
rectal hyperthermia assay, uninteresting.  A commercially available
fine chemical known as piperonylacetone has been offered as either of
two materials.  One, correctly called 3,4-methylenedioxyphenylacetone
or 3,4-methylenedioxybenzyl methyl ketone, gives rise upon reductive
amination to MDA (using ammonia) or MDMA (using methylamine).  This is
an aromatic compound with a three-carbon side-chain and the
amine-nitrogen on the beta-carbon.  The other so-called
piperonylacetone is really 3,4-methylenedioxybenzylacetone, an
aromatic compound with a four-carbon side-chain.  It produces, on
reductive amination with ammonia or methylamine, the corresponding
alpha-methyl-(n)-propylamines, with a four-carbon side-chain and the
amine-nitrogen on the gamma-carbon.  They are completely unexplored in
man and so it is not known whether they are or are not psychedelic.
As possible mis-synthesized products, they may appear quite
unintentionally and must be evaluated as totally new materials.  The
gamma-amine analogue of MDA, a methylenedioxy substituted three carbon
side-chain with the amine-nitrogen on the gamma carbon, has indeed
been made and evaluated, and is discussed under MDA.  The extension of
the chain of mescaline to three atoms, by the inclusion of an oxygen
atom, has produced two compounds that have also been assayed.  They
are mentioned in the recipe for mescaline.

The chain that reaches out to the amine group can be tied back in
again to the ring, with a second chain.  There are 2-aminobenzoindanes
which are phenethylamines with a one-carbon link tying the
alpha-position of the chain back to the aromatic ring.  And there are
2-aminotetralines which are phenethylamines which have a two-carbon
link tying the alpha-position of the chain back to the aromatic ring.
Both unsubstituted ring systems are known and both are fair
stimulants.  Both systems have been modified with the DOM substituent
patterns (called DOM-AI and DOM-AT respectively), but neither of these
has been tried in man.  And the analogues with the MDA substitution
pattern are discussed elsewhere in this book.

And there is one more obvious remaining methylation pattern.  What
about phenethylamine or amphetamine compounds with two methyl groups
on the nitrogen?  The parent amphetamine example,
N,N-dimethylamphetamine, has received much notoriety lately in that it
has become a scheduled drug in the United States.  Ephedrine is a
major precursor in the illicit synthesis of methamphetamine, and with
the increased law-enforcement attention being paid to this process,
there has been increasing promotion of the unrestricted homologue,
N-methylephedrine, to the methamphetamine chemist.  This starting
material gives rise to N,N-dimethylamphetamine which is a material of
dubious stimulant properties.  A number of N,N-dimethylamphetamine
derivatives, with RpsychedelicS ring substituents, have been explored
as iodinated brain-flow indicators, and they are explicitly named
within the appropriate recipes.  But none of them have shown any
psychedelic action.

This is as good a place as any to discuss two or three simple
compounds, phenethylamines, with only one substituent on the benzene
ring.  The 2-carbon analog of 4-MA, is 4-methoxyphenethylamine, or
MPEA.  This is a kissing cousin to DMPEA, of such fame in the search
for a urine factor that could be related to schizophrenia.  And the
end results of the search for this compound in the urine of mentally
ill patients are as controversial as they were for DMPEA.  There has
been no confirmed relationship to the diagnosis.  And efforts to see
if it is centrally active were failures Q at dosages of up to 400
milligrams in man, there was no activity.  The 4-chloro-analogue is
4-chlorophenethylamine (4-Cl-PEA) and it has actually been pushed up
to even higher levels (to 500 milligrams dosage, orally) and it is
also without activity.  A passing bit of charming trivia.  A
positional isomer of MPEA is 3-methoxyphenethylamine (3-MPEA) and,
although there are no reported human trials with this, it has been
graced with an Edgewood Arsenal code number, vis., EA-1302.









#143 PROPYNYL; 3,5-DIMETHOXY-4-(2-PROPYNYLOXY)PHENETHYLAMINE

SYNTHESIS: To a solution of 5.8 g homosyringonitrile (see under E for
its preparation) in 50 mL acetone containing 100 mg
decyltriethylammonium iodide, there was added 12 g of an 80% solution
of propargyl bromide in toluene and 6.9 g of finely powdered anhydrous
K2CO3.  This mixture was held at reflux on the steam bath for 12 h,
after which the solvent was removed under vacuum.  The residues were
added to 0.5 L H2O, acidified, and extracted with 3x75 mL CH2Cl2.  The
extracts were pooled, washed with 5% NaOH, and then with dilute HCl
which discharged the deep color.  Removal of the organic solvent under
vacuum yielded 6.6 g of crude product.  This was distilled at 138-148
!C at 0.25 mm/Hg, yielding 4.3 g
3,5-dimethoxy-4-(2-propynyloxy)phenylacetonitrile which spontaneously
crystallized.  A small sample from MeOH had a mp of 94-95 !C. Anal.
(C13H13NO3) C,H.

A suspension of 2.8 g LAH in 70 mL anhydrous THF was cooled to 0 !C
with good stirring under He, and treated with 2.0 g 100% H2SO4.  To
this, a solution of 4.2 g
3,5-dimethoxy-4-(2-propynyloxy)phenylacetonitrile in 30 mL anhydrous
THF was added very slowly.  After the addition had been completed, the
reaction mixture was held at reflux on the steam bath for 0.5 h,
cooled to room temperature, treated with IPA to decompose the excess
hydride, and finally with 15% NaOH to convert the solids to a white
filterable mass.  The solids were separated by filtration, the filter
cake was washed with THF, and the filtrate and washes were pooled.
After removal of the solvent, the residue was added to 100 mL dilute
H2SO4, and washed with 3x75 mL CH2Cl2.  The aqueous phase was made
basic with dilute NaOH, and the product extracted with 2x75 mL CH2Cl2.
After removal of the solvent under vacuum, the residue was distilled
at 125-155 !C at 0.3 mm/Hg to provide 2.4 g of a light amber viscous
liquid.  This was dissolved in 10 mL IPA, acidified with concentrated
HCl until a droplet produced a red color on dampened, external
universal pH paper, and then diluted with 40 mL anhydrous Et2O with
good stirring.  After a short delay,
3,5-dimethoxy-4-(2-propynyloxy)phenethylamine hydrochloride (PROPYNYL)
spontaneously crystallized.  The product was removed by filtration,
washed first with an IPA/Et2O mixture, and finally with Et2O.  The
yield was 3.0 g of white needles.

DOSAGE: 80 mg or more.

DURATION: 8 - 12 h.

QUALITATIVE COMMENTS: (with 55 mg) I have cold feet Q literally Q I
donUt mean that in the spiritual or adventurous sense.  But also I am
somewhat physically fuzzy.  I feel that if I were in public my
behavior would be such that someone would notice me.  Everything was
OK without any question at the ninth hour.  I could walk abroad
again.

(with 80 mg) There is a body load.  The flow of people around me all
day has demanded my attention, and when I had purposefully retreated
to be by myself, there was no particular reward as to visuals or
anything with eyes closed, either.  Sleep was easy at midnight (the
twelth hour of the experiment) but the morning was sluggish, and on
recalling the day, I am not sure of the events that had taken place.
Higher might be all right, but watch the status of the body.  There
certainly wasnUt that much mental stuff.

EXTENSIONS AND COMMENTARY: No experiments have been performed that
describe the action of this drug at full level.  This compound does
not seem to have the magic that would encourage exploration at higher
levels.









#144 SB; SYMBESCALINE; 3,5-DIETHOXY-4-METHOXYPHENETHYLAMINE

SYNTHESIS: A solution of 15 g 1,3-diethoxybenzene and 15 mL of
N,N,NU,NU-tetramethylethylenediamine in 200 mL anhydrous Et2O was
placed in a He atmosphere, magnetically stirred, and cooled to 0 !C
with an ice bath.  Over the course of 10 min there was added 63 mL of
a 1.6 M solution of butyllithium in hexane, which produced a fine
white precipitate.  After an additional 15 min stirring, 20 mL of
tributyl borate was added which dissolved the precipitate.  The
stirring was continued for an additional 15 min.  The reaction was
quenched by the addition of 50 mL of a concentrated aqueous solution
of ammonium sulfate.  The resulting Rcottage cheeseS mass was
transferred to a beaker, treated with an additional 300 mL of the
ammonium sulfate solution, and allowed to stir until the solids had
dispersed to a fine texture.  The organic phase was separated and the
aqueous phase extracted with 2x100 mL Et2O.  The organic phases were
combined, evaporated under vacuum, and the off-white residue dissolved
in 100 mL MeOH.  This cloudy solution was cooled (ice bath) and, with
stirring, 20 mL of 35% hydrogen peroxide was added portionwise, .  The
reaction was allowed to continue stirring for 15 min, and then with
the addition of 600 mL H2O, crystalline solids were formed.  These
were removed, washed with H2O, and upon drying yielded 15.4 g of
2,6-diethoxyphenol with a mp of 79.5-81.5 !C.  Efforts to diethylate
pyrogallol produced mixtures of 2,6-diethoxyphenol and the isomer,
2,3-diethoxyphenol, and these proved difficult to separate.  The pure
2,3-isomer was synthesized from ortho-diethoxybenzene by the process
used above, and the product was an oil.  Both phenols yielded
crystalline 3,5-dinitrobenzoates.  This derivative of
2,6-diethoxyphenol, upon recrystallization from CH3CN had a mp of
161-162 !C.  The derivative from 2,3-diethoxyphenol, also upon
recrystallization from CH3CN, melted at 167-168 !C.  The mixed mp was
appropriately depressed (mp 137-140 !C.).

A solution of 7.6 g 2,6-diethoxyphenol in 40 mL MeOH was treated with
4.9 g of a 40% aqueous solution of dimethylamine followed by 3.6 g of
a 40% aqueous solution of formaldehyde.  The mixture was heated 1 h on
the steam bath, and all volatiles were removed under vacuum.  The
residual dark oil was dissolved in 36 mL IPA and 10.3 g of methyl
iodide was added.  There was spontaneous heating, and the deposition
of fine white solids.  After standing for 10 min, these were removed
by filtration, and the filter cake washed with more IPA.  The crude
product was freed from solvent (air dried weight, 1.7 g) and dissolved
in 7 mL hot H2O.  To this hot solution there was added 1.7 g sodium
cyanide which slowly discharged the color and again deposited
flocculant white solids.  After cooling, these were removed by
filtration, washed with H2O, and after thorough drying the isolated
3,5-diethoxy-4-hydroxyphenylacetonitrile weighed 0.5 g and had a mp of
107.5-108.5 !C.  Anal. (C12H15NO3) C,H.

To a solution of 2.1 g 3,5-diethoxy-4-hydroxyphenylacetonitrile in 20
mL anhydrous acetone, there was added 30 mg triethyldecylammonium
iodide, 4.6 g methyl iodide, and finally 2.3 g powdered anhydrous
K2CO3.  This mixture was held at reflux for 5 h.  The reaction mixture
was quenched with 200 mL acidified H2O and extracted with 3x75 mL
CH2Cl2.  The extracts were pooled, washed with 2x75 mL 5% NaOH, and
finally once with dilute HCl. The solvent was removed under vacuum,
and the residue distilled at 110-115 !C at 0.3 mm/Hg to provide
3,5-diethoxy-4-methoxyphenylacetonitrile as a solid.  This weighed 1.3
g and had a mp of 58-59 !C.  Anal. (C13H17NO3) C,H.

To 30 mL of a 1 M solution LAH in THF that had been cooled to 0 !C
with vigorous stirring, under a He atmosphere, there was added
dropwise 0.78 mL of 100% H2SO4.  When the addition was complete, there
was added dropwise a solution of 1.3 g of
3,5-diethoxy-4-methoxyphenylacetonitrile in 10 mL anhydrous THF.  The
reaction mixture was brought to room temperature and stirred an
additional 10 min, then refluxed on a steam bath for 1.5 h.  After
cooling to room temperature the excess hydride was destroyed by the
addition of about 2 mL IPA, followed by sufficient 15% NaOH to make
the reaction basic to external pH paper and to render the aluminum
oxides white and filterable.  These were removed by filtration, the
filter cake was washed with IPA, then the filtrate and washes were
combined.  The solvents were removed under vacuum and the residue
dissolved in dilute H2SO4.  This was washed with 2x75 mL CH2Cl2, the
aqueous phase made basic with 5% NaOH, and extracted with 3x75 mL
CH2Cl2.  The extracts were pooled, the solvent removed under vacuum,
and the residue distilled at 120-140 !C at 0.3 mm/Hg to yield 0.9 g of
a white oil.  This was dissolved in 4 mL of IPA and neutralized with
concentrated HCl to an end-point determined by damp external pH paper.
There was the immediate formation of solids which were removed by
filtration and washed first with IPA and then with Et2O.  This
provided 1.0 g of 3,5-diethoxy-4-methoxyphenethylamine hydrochloride
(SB) as white crystals, with a mp of 186-187 !C.  Anal. (C13H22ClNO3)
C,H.

DOSAGE: above 240 mg.

DURATION: unknown.

QUALITATIVE COMMENTS: (with 120 mg) There were no effects.  Sleep
that evening was strange, however, and I was fully awake at 4:00 AM,
alert, and mentally restless.  And there was a strange outburst of
anger in the mid-morning.  Might these be related to the material the
previous day?S

(with 240 mg) There was a slight chill that reminded me that I had
taken symbescaline a half hour earlier.  There was what might be
called a vague threshold for about three hours, then nothing more.
This material had a God-awful taste that lingers in the mouth far too
long.  If ever again, it will be in a gelatin capsule.

EXTENSIONS AND COMMENTARY: It must be concluded that SB is RprobablyS
not active.  There was no convincing evidence for much effect at
levels that would clearly be active for mescaline.  This is the kind
of result that puts some potentially ambiguous numbers in the
literature.  One cannot say that it is inactive, for there might well
be something at 400 or 800 or 1200 milligrams.  But since it has been
tried only up to 240 milligrams, I have used the phrase that the
activity is greater than 240 milligrams.  This will be interpreted by
some people as saying that it is active, but only at dosages higher
than 240 milligrams.  What is meant, is that there was no activity
observed at the highest level tried, and so if it is active, the
active dose will be greater than 240 milligrams, and so the potency
will be less than that of mescaline.  However you phrase it, someone
will misinterpret it.









#145 TA; 2,3,4,5-TETRAMETHOXYAMPHETAMINE

SYNTHESIS: To a solution of 50 g 2,3,4-trimethoxybenzaldehyde in 157
mL glacial acetic acid which was well stirred and preheated to 25 !C
there was added 55.6 g 40% peracetic acid in acetic acid.  The rate of
addition was adjusted to allow the evolved heat of the exothermic
reaction to be removed by an external ice bath at a rate that kept the
internal temperature within a degree of 25 !C.  When the addition was
complete and there was no more heat being evolved, the reaction
mixture was diluted with 3 volumes of H2O, and neutralized with solid
K2CO3.  All was extracted with 3x250 mL Et2O, and the removal of the
solvent from the pooled extracts under vacuum gave 42 g of residue
that appeared to be mainly phenol, with a little formate and aldehyde.
This was dissolved in 200 mL of 10% NaOH, allowed to stand for 2 h at
ambient temperature, washed with 2x75 mL CH2Cl2, acidified with HCl,
and extracted with 3x100 mL Et2O.  The pooled extracts were washed
with saturated NaHCO3, and the solvent removed to give 34.7 g of
2,3,4-trimethoxyphenol as an amber oil which was used without further
purification.  The infra-red spectrum showed no carbonyl group, of
either the formate or the starting aldehyde.

A solution of 11.4 g flaked KOH in 100 g EtOH was treated with 33.3 g
2,3,4-trimethoxyphenol and 21.9 g allyl bromide.  The mixture was held
at reflux for 1.5 h, then poured into 5 volumes of H2O, made basic
with the addition of 25% NaOH, and extracted with 3x200 mL CH2Cl2.
Removal of the solvent from the pooled extracts gave about 40 g of a
crude 2,3,4-trimethoxy-1-allyloxybenzene that clearly had unreacted
allyl bromide as a contaminant.

A 39 g sample of crude 2,3,4-trimethoxy-1-allyloxybenzene in a
round-bottomed flask with an immersion thermometer was heated with a
soft flame.  At 225 !C there was a light effervescence and at 240 !C
an exothermic reaction set in that raised the temperature immediately
to 265 !C.  It was held there for 5 min, and then the reaction was
allowed to cool to room temperature.  GC and IR analysis showed the
starting ether to be gone, and that the product was largely
2,3,4-trimethoxy-6-allylphenol.  It weighed 34.4 g.

To a solution of 9.4 g KOH in 100 mL MeOH, there was added 33.3 g of
2,3,4-trimethoxy-6-allylphenol and 21.2 g methyl iodide and the
mixture was held on the steam bath for 2 h.  This was poured into
aqueous base, and extracted with 3x100 mL CH2Cl2.  Removal of the
solvent from the pooled extracts gave 30 g of an amber oil residue
that was distilled at 100-125 !C at 0.5 mm/Hg to provide 23.3 g of
nearly colorless 2,3,4,5-tetramethoxyallylbenzene.

The total distillation fraction, 23.3 g
2,3,4,5-tetramethoxyallylbenzene, was dissolved in a solution of 25 g
flaked KOH in 25 mL EtOH and heated at 100 !C for 24 h.  The reaction
mixture was poured into 500 mL H2O, and extracted with 2x100 mL
CH2Cl2.  The aqueous phase was saved.  The pooled organic extracts
were stripped of solvent under vacuum to give 13.8 g of a fluid oil
that was surprising pure 2,3,4,5-tetramethoxypropenylbenzene by both
GC and NMR analysis.  The basic aqueous phase was acidified, extracted
with 2x100 mL CH2Cl2, and the solvent stripped to give 7.5 g of an oil
that was phenolic, totally propenyl (as opposed to allyl), and by
infra-red the phenolic hydroxyl group was adjacent to the olefin
chain.  This crude 2-hydroxy-3,4,5-trimethoxypropenylbenzene was
methylated with methyl iodide in alcoholic KOH to give an additional
5.6 g of the target 2,3,4,5-tetramethoxypropenylbenzene.  This was
identical to the original isolate above.  The distilled material had
an index of refraction, nD24 = 1.5409.

A well stirred solution of 17.9 g 2,3,4,5-tetramethoxypropenylbenzene
in 80 mL distilled acetone was treated with 6.9 g pyridine, and cooled
to 0 !C with an external ice bath.  There was then added 14 g
tetranitromethane over the course of a 0.5 min, and the reaction was
quenched by the addition of a solution of 4.6 g KOH in 80 mL H2O.  As
the reaction mixture stood, there was a slow deposition of yellow
crystals, but beware, this is not the product.  This solid weighed 4.0
g and was the potassium salt of trinitromethane.  This isolate was
dried and sealed in a small vial.  After a few days standing, it
detonated spontaneously.  The filtrate was extracted with 3x75 mL
CH2Cl2, and the removal of the solvent from these extracts gave a
residue of 20.8 g of crude
2-nitro-1-(2,3,4,5-tetramethoxyphenyl)propene which did not
crystallize.

A solution was made of 20.3 g of the crude
2-nitro-1-(2,3,4,5-tetramethoxyphenyl)propene in 200 mL anhydrous
Et2O, and this was filtered to remove some 2.7 g of insoluble material
which appeared to be the potassium salt of trinitromethane by
infra-red analysis.  A suspension of 14 g LAH in 1 L anhydrous Et2O
was stirred, placed under an inert atmosphere, and brought up to a
gentle reflux.  The above clarified ether solution of the propene was
added over the course of 1 h, and the mixture was held at reflux for
24 h.  After cooling, the excess hydride was destroyed by the cautious
addition of 1 L 1.5 N H2SO4 (initially a drop or two at a time) and
when the two phases were complete clear, they were separated.  The
aqueous phase was treated with 350 g potassium sodium tartrate, and
brought to a pH >9 with base.  This was extracted with 3x150 mL
CH2Cl2, and the removal of the solvent from the pooled extracts gave a
residue that was dissolved in 200 mL anhydrous Et2O, and saturated
with anhydrous HCl gas.  An Et2O-insoluble oil was deposited and,
after repeated scratching with fresh Et2O, finally gave a granular
white solid.  This product was recrystallized from acetic anhydride,
giving white crystals that were removed by filtration, Et2O washed,
and air dried.  The yield of 2,3,4,5-tetramethoxyamphetamine
hydrochloride (TA) was 1.9 g and had a mp of 135.5-136.5 !C.

DOSAGE: probably above 50 mg.

DURATION: unknown.

QUALITATIVE COMMENTS: (with 30 mg) Definite threshold.  There was eye
dilation, and some unusual humor Q a completely wild day with
chi-square calculations on the PDP-7 that were on the edge of bad
taste.  But I was definitely baseline in the afternoon during the
Motor Vehicle Department interactions.

(with 35 mg) I had some gastric upset, but nonetheless there was a
distinct intoxication.  The next morning I had a foul headache.

EXTENSIONS AND COMMENTARY: This is pretty thin stuff from which to go
out into a world that is populated by pharmacological sharks and stake
out claims as to psychedelic potency.  The structure of this molecule
has everything going for it.  It is an overlay of TMA (active) and
TMA-2 (even more active) so it is completely reasonable that it should
be doing something at a rational dosage.  But that dosage might well
be in the many tens of milligrams.

Tens of milligrams.  Now there is a truly wishy-washy phrase.  There
is an art to the assignment of an exact number or, as is sometimes
desperately needed, a fuzzy number, to a collection of things.  In my
youth (somewhere way back yonder in the early part of the century) I
had been taught rules of grammer that were unquestionably expected of
any well-educated person.  If you used a Latin stem, you used a Latin
prefix.  And if you used a Greek stem, you used a Greek prefix.
Consider a collection of things with simple geometric sides (a side is
a latus in Latin).  One would speak of a one-sided object as being
unilateral, and a bilateral object has two sides.  A trilateral, and
quadrilateral, and way up there to multilateral objects, are referred
to as having three or four or a lot of sides, respectively.  Just the
opposite occurs with geometric objects with faces.  A face is a hedra
in Greek, so one really should use the Greek structure.  If one has
just one face, one has a monohedron, a dihedron has two faces, and
there are trihedron, tetrahedron, and polyhedron for things that have
three, four, or a lot of faces.  Actually, the prefix RpolyS swings
both ways.  It was initially a Greek term, but as was the fate of many
Greek words, it wandered its way from East to West, and ended up as a
Latin term as well.

But back to the problem of how to refer to something that is more than
one or two, but not as much as a lot?  If you know exactly how many,
you should use the proper prefix.  But what if you donUt know how
many?  There are terms such as Rsome.S And there is Rseveral.S There
is a RfewS and a Rnumber ofS and RnumerousS and Ra hand full.S One
desperately looks for a term that is a collective, but which carries
the meaning of an undefined number.  There are English gems such as a
pride of lions and a host of daffodils.  But without a specific animal
or plant of reference, one must have a target collective that is
appropriate, to let the term RmanyS or RfewS imply the proper size.
There were many hundreds of persons (a few thousands of persons) at
the rally.  Several dozen hunters (a few score hunters) were gathered
at the lake.  A wonderful prefix is RoligoS which means a few, not a
lot, and it means that I am not sure just how many are meant.  Say,
for example, that you have synthesized something in a biochemical
mixture that contains three or four peptides.  Di-and tri- and
tetrapeptides are exact terms, but they do not describe what you have
done.  Polypeptide is way too big.  However, an oligopeptide means
that there are a few peptide units, IUm not sure how many.  This may
well be the most accurate description of just what you have.

I love the British modesty that is shown by hiding a person's physical
weight by referring to it with the dimension known as the stone.  This
is, as I remember, something like 14 pounds.  So, if stones were the
weight equivalent of 10 milligrams, the activity of TA would be
several stone.  And since the synthetic intermediate
1-allyl-2,3,4,5-tetramethoxybenzene is one of the ten essential oils,
the amination step from our hypothetical reaction in the human liver
would make TA one of the so-called Ten Essential Amphetamines.









#146 3-TASB; 3-THIOASYMBESCALINE;
4-ETHOXY-3-ETHYLTHIO-5-METHOXYPHENETHYLAMINE

SYNTHESIS: Without any solvent, there was combined 21.7 g of solid
5-bromovanillin and 11.4 mL cyclohexylamine.  There was the immediate
generation of a yellow color and the evolution of heat.  The largely
solid mass was ground up under 50 mL of boiling IPA to an apparently
homogeneous yellow solid which was removed by filtration and washed
with IPA.  There was thus obtained about 27 g of
3-bromo-N-cyclohexyl-4-hydroxy-5-methoxybenzylidenimine with a mp of
229-231 !C and which proved to be insoluble in most solvents (EtOH,
CH2Cl2, acetone).  A solution in dilute NaOH was unstable with the
immediate deposition of opalescent white solids of the phenol sodium
salt.  A small scale recrystallization from boiling cyclohexanone
yielded a fine yellow solid with a lowered mp (210-215 !C).  Anal.
(C14H18BrNO2) C,H.

A solution of 32.5 g
3-bromo-N-cyclohexyl-4-hydroxy-5-methoxybenzylidenimine in 60 mL of
hot DMF was cooled to near room temperature, treated with 24.5 g ethyl
iodide and followed by 14.0 g of flake KOH.  This mixture was held at
reflux for 1 h, cooled, and added to 1 L H2O.  Additional base was
added and the product was extracted with 3x150 mL CH2Cl2.  These
pooled extracts were washed with dilute NaOH, then with H2O, and
finally the solvent was removed under vacuum.  The crude amber-colored
residue was distilled.  The fraction coming over at 118-135 !C at 0.4
mm/Hg weighed 8.7 g, spontaneously crystallized, and proved to be
3-bromo-4-ethoxy-5-methoxybenzaldehyde, melting at 59-60 !C after
recrystallization from MeOH.  Anal. (C10H11BrO3) C,H.  The fraction
that came over at 135-155 !C at 0.2 mm/Hg weighed 10.5 g and also
solidified in the receiver.  This product was
3-bromo-N-cyclohexyl-4-ethoxy-5-methoxybenzylidenimine which, upon
recrystallization from two volumes MeOH, was a white crystalline
material with a mp of 60-61 !C.  Anal. (C16H22BrNO2) C,H.  The two
materials have identical mps, but can be easily distinguished by their
infra-red spectra.  The aldehyde has a carbonyl stretch at 1692 cm-1,
and the Schiff base a C=N stretch at 1641 cm-1.

A solution of 20.5 g
3-bromo-N-cyclohexyl-4-ethoxy-5-methoxybenzylidenimine in about 300 mL
anhydrous Et2O was placed in a He atmosphere, well stirred, and cooled
in an external dry ice acetone bath to -80 !C.  There was then added
50 mL of 1.6 N butyllithium in hexane.  The mixture became yellow and
very viscous with the generation of solids.  These loosened up with
continuing stirring.  This was followed by the addition of 10.7 g
diethyldisulfide.  The reaction became extremely viscous again, and
stirring was continued while the reaction was allowed to warm to room
temperature.  After an additional 0.5 h stirring, the reaction mixture
was added to 800 mL of dilute HCl.  The Et2O phase was separated and
the solvent removed under vacuum.  The residue was returned to the
original aqueous phase, and the entire mixture heated on the steam
bath for 2 h.  The bright yellow color faded and there was the
formation of a yellowish phase on the surface of the H2O.  The aqueous
solution was cooled to room temperature, extracted with 3x100 mL
CH2Cl2, the extracts pooled, washed first with dilute HCl, then with
saturated brine, and the solvent removed under vacuum.  The residue
was an amber oil weighing 20.4 g, and was distilled at 130-140 !C at
0.3 mm/Hg to yield 12.9 g of
4-ethoxy-3-ethylthio-5-methoxybenzaldehyde as a straw colored oil that
did not crystallize.  Anal. (C12H16O3S) C,H.

A solution of 1.0 g 4-ethoxy-3-ethylthio-5-methoxybenzaldehyde in 20 g
nitromethane was treated with about 0.2 g of anhydrous ammonium
acetate and heated on the steam bath.  TLC analysis showed that the
aldehyde was substantially gone within 20 min and that, in addition to
the expected nitrostyrene, there were four scrudge products (see the
discussion of scrudge in the extensions and commentary section under
3-TSB).  Removal of the excess nitromethane under vacuum gave an
orange oil which was diluted with 5 mL cold MeOH but which could not
be induced to crystallize.  A seed was obtained by using a preparative
TLC plate (20x20 cm) and removing the fastest moving spot (development
was with CH2Cl2).  Placing this in the above MeOH solution of the
crude nitrostyrene allowed crystallization to occur.  After filtering
and washing with MeOH, 0.20 g of fine yellow crystals were obtained
which melted at 75-77 !C.  Recrystallization from MeOH gave a bad
recovery of yellow crystals of
4-ethoxy-3-ethylthio-5-methoxy-'-nitrostyrene that now melted at
78.5-79 !C.  Anal. (C13H17NO4S) C,H.  This route was discarded in
favor of the Wittig reaction described below.

A mixture of 27 g methyltriphenylphosphonium bromide in 150 mL
anhydrous THF was placed under a He atmosphere, well stirred, and
cooled to 0 !C with an external ice water bath.  There was then slowly
added 50 mL of 1.6 N butyllithium in hexane which resulted in the
initial generation of solids that largely redissolved by the
completion of the addition of the butyllithium and after allowing the
mixture to return to room temperature.  There was then added 11.7 g of
4-ethoxy-3-ethylthio-5-methoxybenzaldehyde without any solvent.  There
was the immediate formation of an unstirrable solid, which partially
broke up into a gum that still wouldnUt stir.  This was moved about,
as well as possible, with a glass rod, and then all was added to 400
mL H2O.  The two phases were separated and the lower, aqueous, phase
extracted with 2x75 mL of petroleum ether.  The organic fractions were
combined and the solvents removed under vacuum to give the crude
4-ethoxy-3-ethylthio-5-methoxystyrene as a pale yellow fluid liquid.

A solution of 10 mL of borane-methyl sulfide complex (10 M BH3 in
methyl sulfide) in 75 mL THF was placed in a He atmosphere, cooled to
0 !C, treated with 21 mL of 2-methylbutene, and stirred for 1 h while
returning to room temperature.  This was added directly to the crude
4-ethoxy-3-ethylthio-5-methoxystyrene.  The slightly exothermic
reaction was allowed to stir for 1 h, and then the excess borane was
destroyed with a few mL of MeOH (in the absence of air to avoid the
formation of the dialkylboric acid).  There was then added 19 g of
elemental iodine followed, over the course of about 10 min, by a
solution of 4 g NaOH in 50 mL hot MeOH.  The color did not fade.
Addition of another 4 mL 25% NaOH lightened the color a bit, but it
remained pretty ugly.  This was added to 500 mL H2O containing 5 g
sodium thiosulfate and extracted with 3x100 mL petroleum ether.  The
extracts were pooled, and the solvent removed under vacuum to provide
crude 1-(4-ethoxy-3-ethylthio-5-methoxyphenyl)-2-iodoethane as a
residue.

To this crude 1-(4-ethoxy-3-ethylthio-5-methoxyphenyl)-2-iodoethane
there was added a solution of 20 g potassium phthalimide in 150 mL
anhydrous DMF, and all was held at reflux overnight.  After adding to
500 mL of dilute NaOH, some 1.4 g of a white solid was generated and
removed by filtration.  The aqueous filtrate was extracted with 2x75
mL Et2O.  These extracts were combined, washed with dilute HCl, and
the solvent removed under vacuum providing 23.6 g of a
terpene-smelling amber oil.  This was stripped of all volatiles by
heating to 170 !C at 0.4 mm/Hg providing 5.4 g of a sticky brown
residue.  This consisted largely of the desired phthalimide.  The
solids proved to be a purer form of
1-(4-ethoxy-3-ethylthio-5-methoxy)-2-phthalimidoethane and was
recrystallized from a very small amount of MeOH to give fine white
crystals with a mp of 107.5-108.5 !C.  Anal. (C21H23NO4S) C,H.  The
white solids and the brown impure phthalimide were separately
converted to the final product, 3-TASB.

A solution of 1.2 g of the crystalline
1-(4-ethoxy-3-ethylthio-5-methoxyphenyl)-2-phthalimidoethane in 40 mL
of warm n-butanol was treated with 3 mL of 66% hydrazine, and the
mixture was heated on the steam bath for 40 min.  The reaction mixture
was added to 800 mL dilute H2SO4.  The solids were removed by
filtration, and the filtrate was washed with 2x75 mL CH2Cl2.  The
aqueous phase was made basic with 25% NaOH, extracted with 3x75 mL
CH2Cl2, and the solvent from these pooled extracts removed under
vacuum yielding 6.2 g of a residue that was obviously rich in butanol.
This residue was distilled at 138-144 C. at 0.3 mm/Hg to give 0.6 g of
a colorless oil.  This was dissolved in 2.4 mL IPA, neutralized with
concentrated HCl, and diluted with 25 mL anhydrous Et2O.  The solution
remained clear for about 10 seconds, and then deposited white
crystals.  These were removed by filtration, washed with additional
Et2O, and air dried to give 0.4 g
4-ethoxy-3-ethylthio-5-methoxyphenethylamine hydrochloride (3-TASB)
with a mp of 140-141 !C.  Anal. (C13H22ClNO2S) C,H.  The amber-colored
impure phthalimide, following the same procedure, provided another 0.9
g of the hydrochloride salt with a mp of 138-139 !C.

DOSAGE: about 160 mg.

DURATION: 10 - 18 h.

QUALITATIVE COMMENTS: (with 120 mg) This is no more than a plus one,
and it didnUt really get there until about the third hour.  By a
couple of hours later, I feel that the mental effects are pretty much
dissipated, but there is some real physical residue.  Up with some
caution.

(with 160 mg) The taste is completely foul.  During the first couple
of hours, there was a conscious effort to avoid nausea.  Then I
noticed that people's faces looked like marvelous parodies of
themselves and that there was considerable time slowing.  There was no
desire to eat at all.  Between the eighth and twelth hour, the mental
things drifted away, but the body was still wound up. Sleep was
impossible until about 3:00 AM (the 18th hour of the experiment) and
even the next day I was extremely active, anorexic, alert, excited,
and plagued with occasional diarrhea.  This is certainly a potent
stimulant.  The next night I felt the tensions drop, and finally got
an honest and easy sleep.  There is a lot of adrenergic push to this
material.

EXTENSIONS AND COMMENTARY: No pharmacological agent has an action that
is pure this or pure that.  Some pain-killing narcotics can produce
reverie and some sedatives can produce paranoia.  And just as surely,
some psychedelics can produce stimulation.  With 3-TASB we may be
seeing the shift from sensory effects over to out-and-out stimulation.
It would be an interesting challenge to take these polyethylated
phenethylamines and assay them strictly for their amphetamine-like
action.  Sadly, the potencies are by and large so low, that the human
animal canUt be used, and any sub-human experimental animal would not
enable the psychedelic part of the equation to be acknowledged.  If an
order of magnitude of increased potency could be bought by some minor
structural change, this question could be addressed.  Maybe as the
three-carbon amphetamine homologs, or as the 2,4,5- or 2,4,6-
substitution patterns, rather than the 3,4,5-pattern used in this set.









#147 4-TASB; 4-THIOASYMBESCALINE;
3-ETHOXY-4-ETHYLTHIO-5-METHOXYPHENETHYLAMINE

SYNTHESIS: A solution of 20.5 g N,N,NU,NU-tetramethylethylenediamine
and 22.3 g of 3-ethoxyanisole was made in 100 mL hexane under a He
atmosphere with good stirring.  There was added 125 mL 1.6 M
butyllithium in hexane, which formed a white granular precipitate.
This was cooled in an ice bath, and there was added 24.4 g of
diethyldisulfide which produced an exothermic reaction and changed the
precipitate to a creamy phase.  After being held for a few min at
reflux temperature, the reaction mixture was added to 500 mL dilute
H2SO4 which produced two clear phases. The hexane phase was separated,
and the aqueous phase extracted with 2x75 mL methylcyclopentane.  The
organics were combined, and the solvents removed under vacuum.  There
was obtained a residue which was distilled under a vacuum.  At 0.3
mm/Hg the fraction boiling at 95-105 !C was a yellow liquid weighing
28.5 g which was largely 3-ethoxy-2-(ethylthio)anisole which seemed to
be reasonably pure chromatographically.  It was used as such in the
bromination step below.

To a stirred solution of 15.0 g of 3-ethoxy-2-(ethylthio)anisole in
100 mL CH2Cl2 there was added 12 g elemental bromine dissolved in 25
mL CH2Cl2.  There was the copious evolution of HBr.  After stirring at
ambient temperature for 3 h, the dark solution was added to 300 mL H2O
containing sodium dithionite.  Shaking immediately discharged the
residual bromine color, and the organic phase was separated, The
aqueous phase was extracted once with 100 mL CH2Cl2, the pooled
extracts washed with dilute base, and then the solvent was removed
under vacuum to give a light brown oil.  This wet product was
distilled at 112-122 !C at 0.3 mm/Hg to yield 4-bromo (and/or
6-bromo)-3-ethoxy-2-(ethylthio)anisole as a light orange oil.  This
was used in the following benzyne step without separation into its
components.

To a solution of 36 mL diisopropylamine in 150 mL anhydrous THF under
a He atmosphere, and which had been cooled to -10 !C with an external
ice/MeOH bath, there was added 105 mL of a 1.6 M solution of
butylithium in hexane.  There was then added 5.1 mL of dry CH3CN
followed by the dropwise addition of 15.0 g 4-bromo-(and/or
6-bromo)-3-ethoxy-2-(ethylthio)anisole diluted with a little anhydrous
THF. There was an immediate development of a dark red-brown color.
The reaction was warmed to room temperature and stirred for 0.5 h.
This was then poured into 600 mL of dilute H2SO4.  The organic phase
was separated, and the aqueous fraction extracted with 2x50 mL CH2Cl2.
These extracts were pooled and the solvent removed under vacuum.  The
residue was a dark oil and quite complex as seen by thin layer
chromatography.  This material was distilled at 0.3 mm/Hg yielding two
fractions The first boiled at 112-125 !C and weighed 3.9 g.  It was
largely starting bromo compound with a little nitrile, and was
discarded.  The second fraction distilled at 130-175 !C and also
weighed 3.9 g.  This fraction was rich in the product
3-ethoxy-4-ethylthio-5-methoxyphenylacetonitrile, but it also
contained several additional components as seen by thin layer
chromatographic analysis.  On standing for two months, a small amount
of solid was laid down which weighed 0.5 g after cleanup with hexane.
But even it consisted of three components by TLC, none of them the
desired nitrile.  The crude fraction was used for the final step
without further purification or microanalysis.

A solution of LAH in anhydrous THF under N2 (15 mL of a 1.0 M
solution) was cooled to 0 !C and vigorously stirred.  There was added,
dropwise, 0.40 mL 100% H2SO4, followed by about 3 g of the crude
3-ethoxy-4-ethylthio-5-methoxyphenylacetonitrile diluted with a little
anhydrous THF.  The reaction mixture was stirred until it came to room
temperature, and then held at reflux on the steam bath for 2 h.  After
cooling to room temperature, there was added IPA to destroy the excess
hydride (there was quite a bit of it) and then 15% NaOH to bring the
reaction to a basic pH and convert the aluminum oxide to a loose,
white, filterable consistency.  This was removed by filtration, and
washed first with THF followed by IPA.  The filtrate and washes were
stripped of solvent under vacuum, the residue added to 100 mL dilute
H2SO4.  This was washed with 2x75 mL CH2Cl2, made basic with 25% NaOH,
and extracted with 2x50 mL CH2Cl2.  After combining, the solvent was
removed under vacuum providing a residue that was distilled.  A
fraction boiling at 122-140 !C at 0.3 mm/Hg weighed 1.0 g and was a
colorless oil.  This was dissolved in 10 mL of IPA, and neutralized
with 20 drops of concentrated HCl and diluted, with stirring, with 40
mL anhydrous Et2O.  There was the slow formation of a fine white
crystalline salt, which was removed by filtration, washed with Et2O,
and air dried.  The product
3-ethoxy-4-ethylthio-5-methoxyphenethylamine hydrochloride (4-TASB),
weighed 0.5 g, and had a mp 139-140 !C.  Gas chromatographic analysis
by capillary column chromatography of the free base (in butyl acetate
solution on silica SE-54) showed a single peak at a reasonable
retention time, verifying isomeric purity of the product.  Anal.
(C13H22ClNO2S) C,H.

DOSAGE: 60 - 100 mg.

DURATION: 10 - 15 h.

QUALITATIVE COMMENTS: (with 60 mg) The compound has a
petroleum-refinery type taste.  There was a looseness of the bowels as
I got into it.  Here we have another of these 'What is it' or 'What
isnUt it' compounds.  Somehow I seemed to have to push the erotic, the
visual, the whole psychedelic shmeer, to document that this was indeed
effective.  I am not impressed.

(with 100 mg) There were some trivial physical problems during the
early stages of this experiment.  But there was fantasy stuff to
music, and some jumpy stuff to music.  Is there a neurological
hyperreflexia?  I was able to sleep at the 12 hour point but I felt
quite irritable.  I am agitated.  I am twitchy.  This has been very
intense, and I am not completely comfortable yet.  Let's wait for a
while.

(with 100 mg) Music was lovely during the experiment, but pictures
were not particularly exciting.  I had feelings that my nerve-endings
were raw and active.  There was water retention.  There was heartbeat
wrongness, and respiration wrongness.  During my attempts to sleep, my
eyes-closed fantasies became extremely negative.  I could actually
feel the continuous electrical impulses travelling between my nerve
endings.  Disturbing.  There was continuous erotic arousability, and
this seemed to be part of the same over-sensitivity of the nervous
system; orgasm didnUt soothe or smooth out the feeling of
vulnerability.  This is a very threatening material.  DO NOT REPEAT.

EXTENSIONS AND COMMENTARY: Again, another drug with more physical
problems than psychic virtue, but with no obvious structural feature
to hang it all onto.  Some day this will all make sense!









#148 5-TASB; 5-THIOASYMBESCALINE;
3,4-DIETHOXY-5-METHYLTHIOPHENETHYLAMINE

SYNTHESIS: A solution of 11.5 g
3-bromo-N-cyclohexyl-4,5-diethoxybenzylidinimine (see under ASB for
its preparation) in 150 mL anhydrous Et2O was placed in a He
atmosphere, well stirred, and cooled in an external dry ice/acetone
bath to -80 !C.  There was light formation of fine crystals.  There
was then added 25 mL of 1.6 N butyllithium in hexane and the mixture
stirred for 15 min.  This was followed by the addition of 4.3 mL
dimethyldisulfide over the course of 20 min, during which time the
solution became increasingly cloudy and then thinned out again.  The
mixture was allowed to come to room temperature over the course of an
additional h, and then added to 400 mL of dilute HCl.  There was the
generation of a lot of yellow solids, and the Et2O phase was almost
colorless.  This was separated, the solvent removed under vacuum, and
the residue combined with the original aqueous phase.  This phase was
then heated on the steam bath for 2 h.  The aqueous solution was
cooled to room temperature, extracted with 3x100 mL CH2Cl2, the
extracts pooled, washed with H2O, and the solvent removed under vacuum
to yield 9.4 g of an amber oil which spontaneously crystallized.  This
was distilled at 125-132 !C at 0.2 mm/Hg to yield 7.1 g of
3,4-diethoxy-5-(methylthio)benzaldehyde as a white oil that
spontaneously crystallized.  The crude product had a mp of 73-74 !C
that actually decreased to 72-73 !C after recrystallization from MeOH.
Anal. (C12H16O3S) C,H.

A solution of 16.2 g methyltriphenylphosphonium bromide in 200 mL
anhydrous THF was placed under a He atmosphere, well stirred, and
cooled to 0 !C with an external ice water bath.  There was then added
30 mL of 1.6 N butyllithium in hexane which resulted in the generation
of a clear yellow solution.  The reaction mixture was brought up to
room temperature, and 7.0 g 3,4-diethoxy-5-(methylthio)benzaldehyde in
50 mL THF was added dropwise, dispelling the color, and the mixture
was held at reflux on the steam bath for 1 h.  The reaction was
quenched in 800 mL H2O, the top hexane layer separated, and the
aqueous phase extracted with 2x75 mL of petroleum ether.  The organic
fractions were combined and the solvents removed under vacuum to give
12.0 g of the crude 3,4-diethoxy-5-methylthiostyrene as a pale
amber-colored oil.

A solution of 6.0 mL of borane-methyl sulfide complex (10 M BH3 in
methyl sulfide) in 45 mL THF was placed in a He atmosphere, cooled to
0 !C, treated with 12.6 g of 2-methylbutene, and stirred for 1 h while
returning to room temperature.  To this there was added a solution of
the impure 3,4-diethoxy-5-methylthiostyrene in 25 mL THF.  This was
stirred for 1 h during which time the color deepened to a dark yellow.
The excess borane was destroyed with about 2 mL MeOH (all this still
in the absence of air).  There was then added 11.4 g elemental iodine
followed by a solution of 2.4 g NaOH in 30 mL of boiling MeOH, added
over the course of 10 min.  This was followed by sufficient 25% NaOH
to discharge the residual iodine color (about 4 mL was required). The
reaction mixture was added to 500 mL water, and sodium hydrosulfite
was added to discharge the remaining iodine color (about 4 g).  This
was extracted with 3x100 mL petroleum ether, the extracts pooled, and
the solvent removed under vacuum to provide 25.9 g of crude
1-(3,4-diethoxy-5-methylthiophenyl)-2-iodoethane as a pale yellow
fluid oil.  Thin layer chromatographic analysis of this material on
silica gel plates (using a 90:10 mixture of CH2Cl2/methylcyclopentane
as solvent) showed largely the iodo-product (Rf 0.9) with no visible
starting aldehyde (Rf 0.7).

To this crude 1-(3,4-diethoxy-5-methylthiophenyl)-2-iodoethane there
was added a solution of 12 g potassium phthalimide in 90 mL anhydrous
DMF, and all was held at reflux in a heating mantle.  The reaction
progress was followed by TLC, and at 1.5 h it was substantially
complete.  After adding to 500 mL 5% NaOH, the organic phase was
separated, and the aqueous phase was extracted with 2x75 mL Et2O.  The
organic fractions were combined, and the solvent removed under vacuum
providing 19.3 g of an amber oil.  The residual volatiles were removed
by distillation up to 170 !C at 0.2 mm/Hg.  The distillate weighed 7.0
g and contained little if any phthalimide by TLC.  The pot residue was
a viscous amber oil, and also weighed 7.0 g.  About half of this was
employed in the following hydrolysis step, and the rest was rubbed
under an equal volume of MeOH providing
1-(3,4-diethoxy-5-methylthiophenyl)-2-phthalimidoethane as a white
solid.  A small sample was recrystallized from an equal volume of MeOH
to give white crystals with a mp of 79.5-81 !C.  Re-recrystallization
from MeOH produced an analytical sample with a mp of 83-84 !C.  Anal.
(C21H23NO4S) C,H.

A solution of 3.2 g of the impure
1-(3,4-diethoxy-5-methylthiophenyl)-2-phthalimidoethane in 150 mL of
n-butanol there was added 20 mL of 66% hydrazine, and the mixture was
heated on the steam bath for 2 h.  This was added to 600 mL of dilute
H2SO4, and the two layers were separated.  The butanol layer was
extracted with 2x100 mL dilute H2SO4.  These extracts were added to
the original aqueous phase, and this was washed with 3x75 mL CH2Cl2.
This was then made basic with 5% NaOH, extracted with 3x75 mL CH2Cl2,
and the solvent from these pooled extracts removed under vacuum.  The
residue (which weighed 9.7 g and contained much butanol) was distilled
at 140-145 !C at 0.3 mm/Hg to give 0.7 g of a colorless oil.  This was
dissolved in 3.0 mL IPA, neutralized with concentrated HCl, and
diluted with 12 mL anhydrous Et2O to give a solution that immediately
crystallized to provide white crystals of
3,4-diethoxy-5-methylthiophenethylamine hydrochloride (5-TASB).  These
weighed 0.7 g after washing with Et2O and drying to constant weight.
The mp was 182-183 !C, and an analytical sample was dried at 100 !C
for 24 h.  Anal. (C13H22ClNO2S) C,H.

DOSAGE: about 160 mg.

DURATION: about 8 h.

QUALITATIVE COMMENTS: (with 120 mg) Maybe there is something at about
hour 5.  My talking with innocent people had hints of strangeness.
And there was the slightest suggestion of some physical effect.  Call
it an overall (+).

(with 160 mg) I am immediately warm at the extremities. An awareness
grows upon me for a couple of hours.  I am a little light-headed, and
I feel that there is more physical than there is mental, and it is not
all entirely nice.  I am slightly hyperreflexive, and there is a touch
of diarrhea.  I am happy that I held this at 160 milligrams.  I am
mentally flat at the eighth hour, although there are some physical
residues.  The effects are real, but I donUt want to go higher.  Some
trace physical memory seems to stay with me as a constant companion.

EXTENSIONS AND COMMENTARY: There is a ponderousness about adding a
couple of ethyl groups and a sulfur that seems to say, Rno fun.
5-TASB has something going for it (but not much) and 3-TASB is quite a
bit more peppy and, actually, 4-TASB has quite a bit of life.  But
there is a sense of Rwhy bother?S There were a couple of bouts of
light-headedness, but there was no unexpected excitement discovered in
this methodical study.  No surprises.  Keep the chain lengths down.









#149 TB; 4-THIOBUSCALINE; 3,5-DIMETHOXY-4-(n)-BUTYLTHIOPHENETHYLAMINE

SYNTHESIS: A solution was made of 12.1 g
N,N,NU,NU-tetramethylethylenediamine and 13.8 g of
1,3-dimethoxybenzene in 200 mL 30-60 !C petroleum ether.  This was
stirred vigorously under a He atmosphere and cooled to 0 !C with an
external ice bath.  There was added 66 mL of 1.6 M butyl lithium in
hexane which produced a white granular precipitate.  The reaction
mixture was brought up to room temperature for a few minutes, and then
cooled again to 0 !C.  There was then added 18.7 g of di-(n)-butyl
disulfide (this reagent was quite yellow, but was used without any
purification) which changed the granular precipitate to a strange
salmon color.  Stirring was continued while the reaction mixture was
brought up to room temperature and finally up to reflux.  The reaction
mixture was then added to 600 mL of dilute H2SO4.  The two phases were
separated, and the aqueous phase extracted with 2x75 mL Et2O.  The
organic phases were combined and the solvent removed under vacuum.
The residue weighed 33.0 g and was a dark yellow oil.  Efforts to
remove this color by reductive extraction of a CH2Cl2 solution with
aqueous sodium hydrosulfite were futile.  The residue was distilled at
0.3 mm/Hg to give two fractions.  The first boiled at 95-115 !C,
weighed 4.1 g and was largely recovered dibutyl disulfide.  The
product 2-(n)-butylthio-1,3-dimethoxybenzene boiled at 115-135 !C and
weighed 19.5 g.  It was a pale amber oil that could not be induced to
crystallize.  Anal. (C12H18O2S) C,H.

To a stirred solution of 19.5 g of
2-(n)-butylthio-1,3-dimethoxybenzene in 75 mL CH2Cl2 there was added
14.5 g elemental bromine dissolved in 75 mL CH2Cl2.  The evolution of
HBr was evident, but the reaction was not exothermic.  The reaction
was allowed to stir for 1 h and then heated briefly to a reflux on the
steam bath.  It was then washed with H2O containing sodium
hydrosulfite which discharged the residual color.  After washing with
saturated brine, the solvent was removed under vacuum leaving 26.0 g
of a pale amber oil.  This was distilled at 120-140 !C at 0.4 mm/Hg
yielding 4-bromo-2-(n)-butylthio-1,3-dimethoxybenzene as a
yellow-orange oil.  It could not be crystallized.  Anal. (C12H17BrO2S)
C,H.

To a solution of 11.5 mL diisopropylamine in 50 mL hexane that was
stirred under N2 there was added 50 mL of 1.6 M butyllithium.  After
15 min stirring, the reaction mixture became very viscous, and it was
diluted with 150 mL anhydrous THF.  After cooling in an ice bath there
was added 2.0 mL CH3CN followed in 1 min with 6.0 g of
4-bromo-2-(n)-butylthio-1,3-dimethoxyanisole a bit at a time over the
course of 1 min.  There was the immediate formation of a deep red
color.  After stirring for 0.5 h, the mixture was poured into dilute
H2SO4.  The organic layer was separated, and the aqueous layer
extracted with 3x75 mL CH2Cl2.  These extracts were pooled, dried with
anhydrous K2CO3, and the solvent was removed under vacuum.  The
residue was distilled at 0.25 mm/Hg and yielded two fractions.  The
first fraction boiled at 125-145 !C, weighed 0.8 g and was discarded.
The second fraction came over at 145-175 !C as a light yellow oil and
weighed 2.2 g.  This product,
4-(n)-butylthio-3,5-dimethoxyphenylacetonitrile, was reduced as such
without further purification or analysis.

A solution of LAH under N2 (20 mL of a 1 M solution in anhydrous THF)
was cooled to 0 !C and vigorously stirred.  There was added, dropwise,
0.53 mL 100% H2SO4, followed by 2.0 g
4-(n)-butylthio-3,5-dimethoxyphenylacetonitrile in 10 mL anhydrous
THF.  The reaction mixture was stirred at 0 !C for a few min, then
brought to room temperature for 1 h, and finally to a reflux for 1 h
on the steam bath.  After cooling back to room temperature, there was
added IPA (to destroy the excess hydride) followed by 10% NaOH which
brought the reaction to a basic pH and converted the aluminum oxides
to a loose, white, filterable consistency.  These were removed by
filtration, and washed with THF and IPA.  The filtrate and washes were
stripped of solvent under vacuum, the residue was suspended in 150 mL
of dilute NaOH and extracted with 3x100 CH2Cl2.  These extracts were
pooled and extracted with 2x75 mL diluteH2SO4.  Emulsions required
that a considerable additional quantity of H2O be added.  The aqueous
phase was made basic, and extracted with 2x100 mL CH2Cl2.  After
combining these extracts, the solvent was removed under vacuum
providing a residue that was distilled.  The product distilled at
138-168 !C at 0.4 mm/Hg as a white oil weighing 0.7 g.  This was
dissolved in a small amount of IPA, neutralized with concentrated HCl
and, with continuous stirring, diluted with several volumes of
anhydrous Et2O.  After filtering, Et2O washing, and air drying,
4-(n)-butylthio-3,5-dimethoxyphenethylamine hydrochloride (TB) was
obtained, weighed 0.6 g, and had a mp of 154-155 !C.  Anal.
(C14H24ClNO2S) C,H.

DOSAGE: 60 - 120 mg.

DURATION: about 8 h.

QUALITATIVE COMMENTS: (with 35 mg) I was aware of something at about
an hour, and it developed into a benign and beautiful experience which
never quite popped into anything psychedelic.  At the fifth hour there
was a distinct drop, and I made what might be thought of as a foolish
effort to rekindle the state with an additional 20 milligrams but it
was too little and too late.  There was no regeneration of anything
additional.

(with 60 mg) A very subtle threshold, probably, and six hours into it
there seems to have been little if any effect.  My memory of it is not
that certain and now I am not sure that there had been anything at
all.

(with 80 mg) I am vaguely aware of something.  The body discomfort
may reflect the use of sardines in tomato sauce for lunch, but still
things are not quite right.  Five hours into it I am still in a
wonderful place spiritually, but there seem to be some dark edges.  I
might be neurologically sensitive to this.

(with 120 mg) The course of the action of this is extremely clear.
The development was from 5 PM to 7 PM [the experiment started at 4 PM]
and by 10 PM I was dropping and by midnight I went to bed and slept
well.  Food was not too interesting, and a glass of wine before
sleeping produced no noticeable effect.  This was an uneventful
experience that never really made it off the ground.  It was pleasant,
but certainly not psychedelic.

EXTENSIONS AND COMMENTARY: There is a term Rdose-dependentS in
pharmacology.  When there is a complex action produced by a drug, then
each of the components of this mixture of effects should be expected
to become more intense following a bigger dose of the drug.  This is
certainly true with most of the actions of psychoactive drugs.

As to the psychedelic aspects of some drugs, there can be visual
effects, eyes-open (edge-ripples or colors or retinal games) or
eyes-closed (images of the elaborately decorated doors of the mosque,
or of an orchestra floating suspended by its music) or fantasy (you
are moving beyond the confines of your body and invading someone
else's space).  The same applies to tactile enhancement, to the
anaesthetic component, to the depth of insight realized from a drug.
The more the drug, as a rule, the more the effect, up to the point
that new and disruptive effects are realized.  This latter is called
toxicity.

As to the stimulant component, the same is true.  The person gets
wired up, and there is no sleep because there is no hiding from a
cascade of images and meanings, and the body lies there unwilling to
yield guard since both the pounding heart and the interpretive psyche
are demanding attention.  These aspects also intensify with
increasingly higher doses.

But an exception to this is the euphoria-producing aspect of a drug.
One sees with increasing doses a continuing RthresholdS that makes you
aware, that fluffs the senses, but which seems not, at any level, to
take over or to command the ship.  It is truly a catalytic on or off.
You are or you are not.  In the RTomsoS effect, this action is
produced by alcohol.  There is disinhibition with alcohol which allows
a central intoxication from the drug TOMSO regardless of the amount of
drug used (see under TOMSO).  One sees again, here with TB, the case
of a perpetual series of Rthresholds.S Never the psychedelic or the
stimulant action that increases with increased dose.  Always the
simple and ephemeral catalyst of euphoria without substance and
without body.  It is a compound that can never be pinned and labeled
in the butterfly collection since it defies an accepted
classification.

This action was seen first with the compound called ARIADNE and when
it was called an anti-depressant, it proved to be commercially
interesting.  It is fully possible that TB would be of value to
certain depressed people in exactly the same way.









From: [e-mail]
Newsgroups: sci.med,sci.chem,alt.drugs
Subject: PiHKAL: The Chemical Story.  File 6 of 6

(I'm posting this for a friend.)

This is part 6 of 6 of the second half of PiHKAL: A Chemical Love
Story, by Alexander Shulgin and Ann Shulgin.  Please forgive any typos
or misprints in this file; further, because of ASCII limitations,
many of the typographical symbols in the original book could not be
properly represented in these files.

If you are seriously interested in the chemistry contained in these
files, you should order a copy of the book PiHKAL.  The book may be
purchased for $22.95 ($18.95 + $4.00 postage and handling) from
Transform Press, Box 13675, Berkeley, CA 94701.  California residents
please add $1.38 State sales tax.

At the present time, restrictive laws are in force in the United
States and it is very difficult for researchers to abide by the
regulations which govern efforts to obtain legal approval to do work
with these compounds in human beings....  No one who is lacking legal
authorization should attempt the synthesis of any of the compounds
described in these files, with the intent to give them to man.  To do
so is to risk legal action which might lead to the tragic ruination of
a life.  It should also be noted that any person anywhere who
experiments on himself, or on another human being, with any of the
drugs described herin, without being familiar with that drug's action
and aware of the physical and/or mental disturbance or harm it might
cause, is acting irresponsibly and immorally, whether or not he is
doing so within the bounds of the law.




#150 3-TE; 3-THIOESCALINE;
4-ETHOXY-5-METHOXY-3-METHYLTHIOPHENETHYLAMINE

SYNTHESIS: A solution of 10.4 g of
3-bromo-N-cyclohexyl-4-ethoxy-5-methoxybenzylidenimine (see under
3-TASB for its preparation) in 125 mL anhydrous Et2O, in a He
atmosphere, was cooled with an external dry ice acetone bath to -80 !C
with good stirring.  To this clear pale yellow solution there was
added 25 mL 1.6 M butyllithium in hexane (about a 25% excess) which
produced a fine white precipitate over the following 15 min.  There
was then added 4.2 g dimethyl disulfide.  At the half-addition point,
the generated solids became so heavy that stirring became difficult,
but towards the end of the addition the reaction thinned out again and
became quite loose.  The dry ice bath was removed and the reaction
allowed to come to room temperature, which again allowed the formation
of a heavy solid phase while warming and, again, a loose and easily
stirred mixture when finally at room temperature.  All was added to
400 mL H2O which had been strongly acidified with HCl.  The two phases
were separated, and the aqueous phase (which contained a small amount
of yellow oily matter insoluble in either phase) was heated on the
steam bath for 0.75 h.  On cooling, the oily component set to a yellow
solid, which was removed by filtration and washed with H2O.  This
crude product, 5.9 g of yellow solid, was distilled 115-125 !C at 0.3
mm/Hg to give 4.9 g of 4-ethoxy-3-methoxy-5-(methylthio)benzaldehyde
as a pale yellow solid that had a mp of 43-45 !C.  Recrystallization
from MeOH gave a mp of 47-48 !C.  Anal. (C11H14O3S) C,H.  This product
can also be prepared from the anion of 3-thiosyringaldehyde (mp
141-143 !C as crystals from MeOH) by reaction with ethyl iodide in the
presence of phase-transfer catalyst, but the yield is quite poor.

To a solution of 4.4 g 4-ethoxy-5-methoxy-3-(methylthio)benzaldehyde
in 75 mL nitromethane, there was added 0.5 g anhydrous ammonium
acetate and the mixture was heated on the steam bath for 80 min.  Care
must be taken in the length of time, and there must be frequent TLC
montoring, as there is a rapid scrudge buildup (see under 3-TSB for a
discussion of scrudge).  The reaction mixture was stripped of
nitromethane under vacuum, and the residual deep-yellow oil was
dissolved in 20 mL of boiling MeOH.  This was decanted from a small
amount of insoluble matter and, upon cooling, deposited bright yellow
crystals of 4-ethoxy-5-methoxy-3-methylthio-'-nitrostyrene.  This was
removed by filtration and, after washing with cold MeOH and air
drying, weighed 2.4 g.  The mp was ambiguous.  The above crude
material melted at 92-93 !C, which is probably too high!  Earlier
samples which melted in the low 80's appeared to have a mp, after
repeated recrystallization from MeOH, of 87-88 !C.  This latter was
the property of the analytical sample.  Anal. (C12H15NO4S) C,H.  The
mp of the TLC low-moving component is always quite high, and might
have been a factor in the assignment of this physical property.

AH was prepared in the usual manner from a suspension of 2.0 g LAH in
75 mL anhydrous THF, cooled to 0 !C, well stirred in an inert
atmosphere of He, and treated with 1.33 mL of 100% H2SO4 added
dropwise.  There was added, dropwise and over the course of 10 min, a
solution of 2.4 g 4-ethoxy-5-methoxy-3-methylthio-'-nitrostyrene in 15
mL anhydrous THF.  The reaction was exothermic, and was heated on the
steam bath at reflux for an additional 10 min.  After cooling again,
there was added enough IPA to decompose the excess hydride and
sufficient 10% NaOH to convert the aluminum oxide solids to a white,
easily filterable mass.  This was filtered, the filter cake washed
with additional IPA, the filtrate and washes combined, and the solvent
removed under vacuum.  This was dissolved in 100 mL of dilute H2SO4
which was washed with 2x50 mL CH2Cl2.  The aqueous phase was made
basic with NaOH, extracted with 2x50 mL CH2Cl2, and the extracts
pooled and the solvent removed under vacuum to yield a residue of a
colorless oil.  This distilled at 118-122 !C at 0.4 mm/Hg producing
1.9 g of a colorless oil.  This was dissolved in 10 mL IPA,
neutralized with 30 drops of concentrated HCl and, with good stirring,
diluted with 20 mL anhydrous Et2O.  The product
4-ethoxy-5-methoxy-3-methylthiophenethylamine hydrochloride (3-TE) was
removed by filtration, washed with Et2O, and air dried to provide a
white solid that weighed 1.0 g and melted at about 180 !C.  Anal.
(C12H20ClNO2S) C,H.

DOSAGE: 60 - 80 mg.

DURATION: 8 - 12 h.

QUALITATIVE COMMENTS: (with 60 mg) There may well be time slowing.  I
noticed that the voices on the radio seemed to be of a deeper pitch.
And with music there is a most easy flight of fantasy.  I tried to
keep a logical conversation going on the telephone, but I am pretty
sure there were problems.  I found myself down sooner than I would
have liked.

(with 70 mg) I found myself in a good, rich place, and thoroughly
enjoyed my introspection.  I didnUt want to talk and interact, and
that seemed just fine with everyone else.  Several of the others
seemed restless, but I lay back and let them do their thing.  My
appetite was fine towards the end, and I might have actually
overeaten.  I was able to drive home that evening, but there seemed to
be some slight residual something after waking in the morning.  I
would certainly repeat without hesitation.

(with 80 mg) Art interpretation and imagery with music are
remarkable.  This material touches on the psychedelic Q rather than
just being stoned.  The body is higher than the mind, but where the
mind is makes it all OK.  It's worth the cost.  My getting to sleep
was easy that evening, but sleep was not too restful and there was
something strange about it.

EXTENSIONS AND COMMENTARY: There is a good lesson to be learned in the
attempts to predict the potency of 3-TE before it was actually
explored.  All pharmacological prediction follows pretty much a single
mechanism.  Find things that are close in some way, and arrange them
in a manner that allows comparison.  A relates to B in this way, and A
relates to C in that way, and since D incorporates both this and that
of each, it will probably be such-and-such.  The Roman square.

Here is the square with the horizontal arrow adding a sulfur in the
3-position and the vertical arrow adding an ethyl group in place of a
methyl group at the 4-position:

  Mescaline        x 3.5         3-TM

200-400 mg                 60-100 mg

    x 6

 Escaline                 3-TE Rx20S

40-60 mg                 = 10-20 mg

and one would predict a potency of some 20x that of mescaline, or
something in the range of 15 mg.

Here is an equally likely square, based on the horizontal arrow
relocating a sulfur from the 4-position to the 3-position, and the
vertical arrow again adding an ethyl group in place of a methyl group
in the 4-position:

Thiomescaline        x 0.3         3-Thiomescaline

    20-30 mg                 60-100 mg

    x 1

Thioescaline                  3-TE Rx0.3S

   20-30 mg                 = 60-100 mg

and one would predict a potency of some one third of that of
thiomescaline, or something in the range of 80 milligrams.

This latter square gave a prediction that was very close to the
observed potency, but it would be careless, and probably wrong, to
assume that the latter relationships had any more significance than
the former ones.  As one accumulates the potencies of many compounds
it is tempting to draw complex relationships such as these, and to be
seduced into believing that they must explain things.  And,
especially, beware the multivariable power of the computer which can
explore monstrous numbers of variables at breakneck speeds, and spew
forth fantastic correlations with marvelous ease.

But nothing can ever substitute for the simple art of tasting
something new.









#151 TE; 4-TE; 4-THIOESCALINE; 3,5-DIMETHOXY-4-ETHYLTHIOPHENETHYLAMINE

SYNTHESIS: A solution was made of 45.2 g
N,N,NU,NU-tetramethylethylenediamine and 41.4 g of
1,3-dimethoxybenzene in 300 mL hexane.  This was stirred vigorously
under a He atmosphere and cooled to 0 !C with an external ice bath.
There was added 225 mL of 1.6 M butyllithium in hexane which produced
a white granular precipitate.  The reaction mixture was stirred for 15
min.  There was then added 38 mL of diethyl disulfide which changed
the granular precipitate to a creamy character.  Stirring was
continued for an additional 5 min, then the reaction mixture was
poured into 1 L of dilute H2SO4.  The two phases were separated, and
the aqueous phase extracted with 2x150 mL Et2O.  The organic phases
were combined, and the solvent removed under vacuum to provide 60 g of
2-ethylthio-1,3-dimethoxybenzene as an off-white oil that
spontaneously crystallized.  It was distilled nonetheless, boiling at
85-96 !C at 0.4 mm/Hg.  This distillate can be recrystallized from
hexane to form long needles with a mp of 45-46 !C.  Anal. (C10H14O2S)
C,H.

To a stirred solution of 60 g of 2-ethylthio-1,3-dimethoxybenzene in
300 mL CH2Cl2 there was added 49 g elemental bromine dissolved in 100
mL CH2Cl2.  The reaction was not exothermic, and it was allowed to
stir for 2 h.  The reaction mixture was washed with H2O, then with
aqueous NaOH, and finally with H2O that contained sodium hydrosulfite.
The solvent was removed under vacuum leaving 84 g of an amber oil as
residue.  This was distilled at 105-115 !C at 0.15 mm/Hg yielding 73.3
g of 4-bromo-2-ethylthio-1,3-dimethoxybenzene as a light yellow oil.
Anal. (C11H15BrO2S) C,H.

To a solution of 27 mL diisopropylamine in 150 mL anhydrous THF that
was stirred under a N2 atmosphere and cooled to -10 !C with an
external ice/MeOH bath, there was added in sequence 83 mL of 1.6 M
butyllithium in hexane, 4.4 mL of dry CH3CN over the course of 5 min,
and finally 12.1 g of 4-bromo-2-ethylthio-1,3-dimethoxybenzene which
had been dissolved in 20 mL THF (also added over the course of 5 min).
The color progressed from yellow to orange to deep red-brown.
Stirring was continued for 10 min, and then the reaction mixture was
poured into 300 mL dilute H2SO4.  The organic layer was separated, and
was washed with more dilute H2SO4.  The aqueous phases were combined,
and extracted with 2x100 mL CH2Cl2.  These extracts were pooled with
the original organic phase, and the solvents removed under vacuum.
The residue was distilled into two fractions at 0.3 mm/Hg. The first
fraction boiled at 95-115 !C and weighed 4.9 g.  It was made up of
several components, but it contained little nitrile material and was
discarded.  The second fraction came over at 145->200 !C and weighed
2.9 g.  By thin layer chromatography this fraction was largely
3,5-dimethoxy-4-ethylthiophenylacetonitrile, and was used as such in
the following reduction.

A suspension of 1.25 g LAH in 50 mL anhydrous THF under N2 was cooled
to 0 !C and vigorously stirred.  There was added, dropwise, 0.8 mL
100% H2SO4, followed by 2.7 g
3,5-dimethoxy-4-ethylthiophenylacetonitrile, neat, over the course of
5 min.  The reaction mixture was stirred at 0 !C for a few min, then
brought to a reflux for 15 min on the steam bath.  After cooling back
to room temperature, there was added 15 mL IPA to destroy the excess
hydride and 10% NaOH to bring the reaction to a basic pH and convert
the aluminum oxide to a loose, white, filterable consistency.  This
was removed by filtration, and washed with 50 mL portions of IPA.  The
filtrate and washes were stripped of solvent under vacuum, and the
residue suspended between 50 mL CH2Cl2 and 50 mL dil. H2SO4.  The
organic phase was separated, and extracted with 2x50 mL dilute H2SO4.
The original aqueous phase and these two extracts were combined, made
basic with aqueous NaOH, and extracted with 3x50 mL CH2Cl2.  These
extracts were stripped of solvent under vacuum.  The residue was
distilled at 112-135 !C at 0.2 mm/Hg to give 1.1 g of a slightly
yellow viscous liquid.  This was dissolved in 4 mL IPA, neutralized
with 14 drops of concentrated HCl and, with continuous stirring,
diluted with 10 mL anhydrous Et2O.  The product was removed by
filtration, washed with Et2O, and air dried to give 1.0 g of
3,5-dimethoxy-4-ethylthiophenethylamine hydrochloride (TE) as white
crystals with some solvent of crystallization.  The crude mp of
101-106 !C was only slightly improved by recrystallization from CH3CN
(mp 106-109 !C).  But upon fusion and resolidification, the melting
point was 167-168 !C and this sample was further dried by heating at
100 !C for 24 h before analysis.  Anal. (C12H20ClNO2S) C,H.

DOSAGE: 20 - 30 mg.

DURATION: 9 - 12 h.

QUALITATIVE COMMENTS: (with 20 mg) I feel it in my ovaries.  It is
very sensuous.  This is total energy, and I am aware of my every
membrane.  This has been a marvelous experience, very beautiful,
joyous, and sensuous.  But maybe the dose is a little too high as
there is too much body tingling.  I am jangly.

(with 20 mg) The predominant characteristic was the feeling of clean
burning, pure energy, a long-lasting clear-headedness and clarity of
thought, and an ease of talking and sharing.  I did not have a strong
feeling of Presence, but more a wonderful feeling of converting energy
into action.  I found that my initial look inwards was always a look
of fear, and I wondered if this might not be the same feeling that
others express as excitement.  They were certainly of the same nature,
they arose at the same point on the fringe of the unknown, and they
point to a basic difference in attitude.  The excitement is for the
new, and is based on trust.  The fear is a return to the past, and is
defensive, with reluctance to reexperience past pain.  The aftermath
of this experience was the most profound of any that I have had in a
long time.  For the following week, I found myself on a new level of
functioning, very energetic and very much in the flow of life and free
of mental distractions.  I have become a great deal more aware of the
traps of meditation, and how you can build walls around yourself and
around certain concepts, if you are not careful.

(with 22 mg) Totally developed at 2 hours, to a +++.  No clearing of
the sinuses, so it is not a decongestant.  There is a lot of visual
activity.  In the group there is good communication, and a lot of
laughter.

(with 25 mg) There is a disconnection, there is complex depth without
definition.  Without music, this is almost negative, as I can find no
definition.  But talking gives me some structure.  And I got into some
pretty extraordinary conversations.  About President Hoover, Omni
magazine, the colors of spices, and a couple of personal relatives.
This is extra-good for ideas and talking.  It is indeed a clean
experience, and superb for communication.

(with 30 mg) I was at a plus three for certainly three hours.  There
were some visuals, some eyes-closed fantasy, but little imagery.
Somehow I could at no time interlock with music.  It seemed always to
get in the way.  Sexual activity is an excellent way to relieve the
muscular tension and the body's heaviness.  There was little hunger
and I ate lightly, and I felt somehow depleted.  Sleep OK at the
twelth hour.  The AM was fine, but on retrospect the experience was
overall strangely cloudy, not negative, but there was not enough
mental to balance the physical.

(with 30 mg) My alert was in 40 minutes, and I was completely
developed by 2 hours.  There was a large measure of erotic fantasy,
but the body load was also quite heavy.  I had a slight cloak effect,
where I was over-energized but somehow under a blanket of quietness.
I would certainly repeat this, but at maybe 25 milligrams.

EXTENSIONS AND COMMENTARY: Although the ethyl group (of the ethylthio
on the 4-position) is just one carbon atom longer than the methyl
group (of TM) that small change already produces hints and indicators
of some physical toxicity.  The propyl compound (see TP) is still of
similar potency, but appears to be yet more difficult, physically.
The butyl homolog never made it off the ground at all as a
psychedelic, but the physical difficulties seem less as well.  All
that was left to come through was the euphoria.  If this 4-position
sulfur analogue series of mescaline is ever to be more carefully
explored, it must almost certainly be with the shortest possible chain
(TM, as a psychedelic) or with long, long chains (the four-carbon
chain of the butyl group in TB), as a feel-good compound.









#152 2-TIM; 2-THIOISOMESCALINE; 3,4-DIMETHOXY-2-
METHYLTHIOPHENETHYLAMINE

SYNTHESIS: A short foreword to the synthetic portion is needed.
First, although the required thioanisole, 2,3-dimethoxythioanisole, is
now commercially available, it is of the utmost importance that it be
free of the impurity, veratrole.  I know that the material presently
available from Aldrich Chemical Company is satisfactory, as I have had
a hand in making it.  But, if veratrole is present, there are very
difficult separations encountered during these preparations.  And
secondly, the synthesis of 2-TIM and 4-TIM requires a separation of
isomers.  The first intermediates are common to both.  They will be
presented here, under this recipe for 2-TIM.

A solution of 150 mL of 1.6 M butyllithium in hexane under N2 was
vigorously stirred and diluted with 150 mL petroleum ether (30-60 !C)
and then cooled with an external ice bath to 0 !C.  The addition of
26.7 g of veratrole produced a flocculant white precipitate.  Next,
there was added a solution of 23.2 g of
N,N,NU,NU-tetramethylethylenediamine in 100 mL anhydrous Et2O and the
stirred reaction mixture was allowed to come to room temperature.  The
subsequent addition of 20.7 g of dimethyl disulfide over the course of
several min produced an exothermic response, and this was allowed to
stir for an additional 30 min.  There was then added 10 mL EtOH
followed by 250 mL of 5% NaOH.  The organic phase was washed first
with 150 mL 5% NaOH, followed by 2x100 mL portions of 5% dilute HCl.
The removal of solvent and bulb-to-bulb distillation of the residue
provided 2,3-dimethoxythioanisole boiling at 72-80 !C at 0.4 mm/Hg as
a white oil.  This product contained some 20% unreacted veratrole as a
contaminant and the isolation of subsequent products from this impure
material was extraordinarily difficult.  The effort needed for careful
purification at this point was completely justified.  The product
could be obtained in a pure state by distillation at 0.1 mm/Hg through
a 6 cm Vigreaux column with collection of several fractions.  Those
that distilled at 84-87 !C were pure 2,3-dimethoxythioanisole.  An
analytical sample can be obtained by cooling a concentrated MeOH
solution in dry ice, filtering the generated crystals, and washing
with cold MeOH.  This product melts at 36.5-37 !C.  Anal. (C9H12O2S)
C,H,S.  The picrate can be formed by treatment with a saturated EtOH
solution of picric acid. It formed orange crystals with a mp of 73-78
!C.  Anal. (C15H15N3O9S) N.

To 18 mL of POCl3 there was added 25 mL N-methylformanilide and the
solution allowed to stand at room temperature for 0.5 h, until the
color had developed to a rich claret.  There was then added 25.0 g of
2,3-dimethoxythioanisole and the mixture heated on the steam bath for
2.5 h. This was added to 500 mL H2O and stirred at ambient temperature
for 2 h.  The product was extracted with 4x150 mL CH2Cl2, the extracts
combined, and the solvent removed under vacuum.  The residue was
distilled through a Vigreaux column under vacuum (0.1 mm/Hg) with the
fraction boiling at 125-135 !C being richest in aldehydes, as
determined by GC analysis.  If the starting 2,3-dimethoxythioanisole
contains appreciable veratrole as a contaminant, then this aldehyde
fraction contains three components.  There is present both
2,3-dimethoxy-4-(methylthio)benzaldehyde and
3,4-dimethoxy-2-(methylthio)benzaldehyde (the two desired precursors
to 4-TIM and 2-TIM, respectively), but also present is
3,4-dimethoxybenzaldehyde from the veratrole contamination.  The
weight of this fraction was 11.9 g and was a white oil free of
starting thioether.

Although efforts to separate this mixture were not effective, one of
the aldehydes could be isolated in small yield by derivative
formation.  This was too wasteful to be of preparative value, but it
did allow the generation of seed that was of great value in the later
separation of the mixed nitrostyrenes that were prepared.  If a 1 g
portion of this mixture was fused with 0.6 g p-anisidiine over an open
flame and then cooled, the melt set up as a solid.  Triturating under
MeOH gave a yellow solid (0.45 g, mp 77-80 !C) which on
recrystallization from hexane appeared to be a single one of the three
possible Schiff's bases that could theoretically be prepared.  It had
a mp of 80-81 !C.  Anal. (C17H19NO3S) C,H.  Hydrolysis with hot 3 N
HCl freed the benzaldehyde which was isolated by quenching in H2O and
extraction with CH2Cl2.  The extracts were stripped of solvent under
vacuum and the residue distilled bulb-to-bulb under vacuum to give
white crystals of 3,4-dimethoxy-2-(methylthio)benzaldehyde (the 2-TIM
aldehyde) with a mp of 23-24 !C.  A micro-scale conversion of this to
the corresponding nitrostyrene provided the seed that was effectively
used in the large scale preparation described below.

A solution of 9.0 g of a mixture of
3,4-dimethoxy-2-(methylthio)benzaldehyde and
2,3-dimethoxy-4-(methylthio)benzaldehyde in 50 mL of nitromethane was
treated with 1.5 g anhydrous ammonium acetate and held at reflux for 5
h.  The excess nitromethane was removed under vacuum to yield 10.4 g
of a dark orange oil which, upon dissolving in 40 mL hot MeOH and
being allowed to cool and slowly evaporate at ambient temperatures,
provided dark colored crystals.  Filtration (save the mother liquors!)
and recrystallization from 40 mL MeOH provided 6.3 g of a yellow
crystalline solid.  A second recrystallization from 50 mL MeOH gave
5.0 g of lemon yellow plates 3,4-dimethoxy-2-methylthio-'-nitrostyrene
with a mp of 102-103.5 !C.  An analytical sample, from IPA, had a mp
of 103-104 !C and a single spot on TLC with CHCl3, with an Rf of 0.54.
Anal. (C11H13NO4S) C,H.  When there had been veratrole left as a
contaminant in the original 2,3-dimethoxythioanisole, the nitrostyrene
that was isolated by this method had, after recrystallization, a mp of
93-95 !C.  This substance acted as a single compound through a number
of recrystallization trials, but on TLC analysis always gave two
components (silica gel, chloroform) with Rf's of 0.54 and 0.47.  It
proved to be a mixture of 3,4-dimethoxy-2-methylthio-'-nitrostyrene
and 3,4-dimethoxy-'-nitro-styrene in an exact molecular ratio of 2:1.
This latter nitrostyrene is the precursor to DMPEA, q.v.  Anal.
(C32H37N3O12S2) C,H.  The mother liquor above is the source of the
4-TIM nitrostyrene, and its isolation is described in the recipe for
4-TIM.

A solution of 4.2 g LAH in 70 mL anhydrous THF was cooled to 0 !C
under He and with stirring.  There was added, dropwise, 2.8 mL of 100%
H2SO4, followed by 4.4 g of
3,4-dimethoxy-2-(methylthio)-'-nitrostyrene dissolved in 25 mL THF.
Stirring was continued for a few min as the reaction returned to room
temperature, and then it was heated to a reflux for 10 min on the
steam bath.  The reaction was cooled again, and 25% NaOH was added
dropwise until a white granular precipitate was obtained.  This was
removed by filtration, and the filter cake was washed with 2x50 mL
Et2O.  The filtrate was extracted into 100 mL dilute H2SO4 which was,
in turn, made basic again and extracted with 2x100 mL CH2Cl2.  The
extracts were pooled, and the solvent removed under vacuum to give a
residue of crude product.  This was distilled from 100-115 !C at 0.3
mm/Hg yielding 3.2 g of a clear white oil.  This was dissolved in 25
mL IPA, neutralized with 23 drops of concentrated HCl, and diluted
with 75 mL anhydrous Et2O.  There was a deposition of beautiful white
platelets of 3,4-dimethoxy-2-methylthiophenethylamine hydrochloride
(2-TIM) which were removed by filtration, washed with ether, and air
dried.  This hydrochloride salt contained a quarter mole of H2O of
crystallization.  The mp was 183-184 !C.  Anal. (C11H18ClNO2Sa1/4 H2O)
C,H,N.

DOSAGE: greater than 240 mg.

DURATION: unknown.

QUALITATIVE COMMENTS: (with 160 mg) There was perhaps some awareness
in an hour or so, but in another hour there was absolutely nothing.  A
small amount of wine in the evening was quite intoxicating.

(with 240 mg) No effects of any kind.

EXTENSIONS AND COMMENTARY: The problems that might be associated with
the making of the three amphetamines that correspond to 2-TIM, 3-TIM
and 4-TIM might very well prove quite exciting.  These would be the
three thio analogues of TMA-3; vis,
3,4-dimethoxy-2-methylthioamphetamine,
2,4-dimethoxy-3-methylthioamphetamine, and
2,3-dimethoxy-4-thioamphetamine.  The first challenge would be to name
them.  Using the 2C-3C convention, they would be the 3C analogs of
trivially named 2-carbon compounds, namely 3C-2-TIM, 3C-3-TIM and
3C-4-TIM.  Using the thio convention (the number before the T is the
position of the sulfur atom), they would be 2-T-TMA-3, 3-T-TMA-3 and
4-T-TMA-3.  The second challenge would be their actual synthesis.  The
information gained from the separation of the 2-carbon nitrostyrenes
and that most remarkable mixed-nitrostyrene thing that acted as a
single pure material, would not be usable.  But it is intriguing to
speculate if there might be some parallel problems in the 3-carbon
world.  It seems almost certain that none of the compounds would be
pharmacologically active, so the incentive would be the challenge of
the chemistry.  Some day, maybe.









#153 3-TIM; 3-THIOMESCALINE; 2,4-DIMETHOXY-3-METHYLTHIOPHENETHYLAMINE

SYNTHESIS: A mixture of 3.1 g POCl3 2.8 g N-methylformanilide was
heated on a steam bath until it was a deep claret color (about 5 min).
To this there was then added 3.0 g of 2,6-dimethoxythioanisole (see
under 4-TM for its preparation), and heating was continued for 30 min.
The reaction mixture was then added to 75 mL H2O and stirred
overnight.  The dark oily mixture was extracted with 3x75 mL CH2Cl2,
the extracts pooled, and the solvent removed under vacuum.  The
residue was extracted with 3x20 mL boiling hexane, each extract being
poured off from the insoluble residue.  Pooling and cooling these
extracts yielded 1.5 g of 2,4-dimethoxy-3-(methylthio)benzaldehyde as
an off-white crystalline solid with a mp of 67-69 !C.
Recrystallization from either MeOH or cyclohexane tightened the mp,
but lowered it to 67-68 !C and 66-67 !C, resp.  Anal. (C10H12O3S) C,H.

To a solution of 1.3 g 2,4-dimethoxy-3-(methylthio)benzaldehyde in 60
mL nitromethane there was added 0.3 g anhydrous ammonium acetate and
the mixture was heated at reflux for 3 h.  The hot solution was
decanted from a little insoluble material, and the excess nitromethane
was removed under vacuum.  The residue dissolved in 10 mL hot MeOH.
On cooling, yellow crystals of
2,4-dimethoxy-3-methylthio-'-nitrostyrene were obtained which were
removed by filtration and air-dried, and weighed 0.9 g.  The mp was
130-133 !C and could be improved to 136-137 !C following
recrystallization from MeOH (10 g/g).  Anal. (C11H13NO4S) C,H.

A well-stirred solution of 0.6 g LAH in 10 mL anhydrous THF was cooled
to 0 !C under He.  There was added, dropwise, 0.4 mL of 100% H2SO4,
followed by 0.6 g of 2,4-dimethoxy-3-methylthio-'-nitrostyrene
dissolved in a little THF.  Stirring was continued for a few min as
the reaction returned to room temperature, and then it was heated to a
reflux for 5 min on the steam bath.  The reaction was cooled again,
and 25% NaOH was added dropwise until a white granular precipitate was
obtained.  This was removed by filtration, and the filter cake was
washed with 2x25 mL Et2O.  The filtrate was extracted into 25 mL
dilute H2SO4 which was, in turn, made basic again and extracted with
2x25 mL CH2Cl2.  The extracts were pooled, and the solvent removed
under vacuum to give a residue of crude product.  This was distilled
from 120-140 !C at 0.3 mm/Hg yielding 0.25 g of a clear white oil.
This was dissolved in 5 mL IPA, neutralized with about 3 drops of
concentrated HCl, and diluted with 15 mL anhydrous Et2O.  Scratching
with a glass rod instigated crystallization of bright white solids
which were filtered, washed with Et2O, and air dried.  The weight of
2,4-dimethoxy-3-methylthiophenethylamine hydrochloride (3-TIM) was 0.2
g and the mp was 204-206 !C with decomposition.  This hydrochloride
appeared to be a hemihydrate.  Anal. (C11H18ClNO2Sa1/2 H2O) C,H,N.

DOSAGE: greater than 240 mg.

DURATION: unknown.

QUALITATIVE COMMENTS: (with 240 mg) Briefly I thought that there
might have been an alert at the 2 to 3 hour point, but I now think it
was nothing.  During the following day I had a mild stomach upset off
and on, but I canUt believe that it was connected with 3-TIM.

EXTENSIONS AND COMMENTARY: Isomescaline itself is not active, but
there is no way of knowing just how Rnon-activeS it really is.  If it
were to be active just beyond the levels assayed, then the
introduction of a sulfur into the molecule in place of an oxygen could
have increased the potency to where it might have some effect. The
absence of any activity from this TIM, and the other two TIMs, might
well suggest that isomescaline is really very Rnon-active,S if that
makes sense!









#154 4-TIM; 4-THIOISOMESCALINE;
2,3-DIMETHOXY-4-METHYLTHIOPHENETHYLAMINE

SYNTHESIS: The mother liquors from the initial crystallization of the
2-TIM nitrostyrene (see under 2-TIM) was the source and raw material
for all 4-TIM chemistry.  Once the bulk of the 2-TIM nitrostyrene has
been removed, these mother liquors could be processed to give the
4-TIM nitrostyrene.  The easier procedure was to evaporate these
mother liquors to a residue under vacuum, and hope for a spontaneous
crystallization.  If this failed, flash chromatography could be used.
For reference purposes, the three nitrostyrenes involved in the
2-TIM/4-TIM problem movedon silica gel TLC with CHCl3 solvent in the
following manner: 2,3-dimethoxy-4-methylthio-'-nitrostyrene (leading
to 4-TIM), Rf = 0.61; 3,4-dimethoxy-2-methylthio-'-nitrostyrene
(leading to 2-TIM), Rf = 0.54; and 3,4-dimethoxy-'-nitrostyrene
(leading to DMPEA), Rf = 0.47.  For flash chromatography, a small
portion of the residue from the mother liquor was dissolved in CHCl3,
and placed on a silica gel column.  CHCl3 was used as the eluding
solvent.  The first material breaking through from the column was the
4-TIM nitrostyrene and on evaporation of this fraction, seed was
obtained as gold-colored crystals that had a mp of 71-73 !C.  This,
when added to the residues from the described 2-TIM synthesis
nitrostyrenes, started the crystallization process.  The gummy solid
that was produced was triturated under MeOH, and the crystals so
revealed were removed by filtration.  Recrystallization from 10 mL
MeOH gave 1.9 g of solids.  A second recrystallization from 5 mL MeOH
provided 0.7 g of pumpkin-colored crystals of
2,3-dimethoxy-4-methylthio-'-nitrostyrene with a mp of 70-71 !C.

A solution of 1.2 g LAH in 20 mL anhydrous THF was cooled to 0 !C
under He and stirred.  There was added, dropwise, 0.8 mL of 100%
H2SO4, followed by 0.9 g of 2,3-dimethoxy-4-methylthio-'-nitrostyrene
dissolved in 20 mL THF.  Stirring was continued for a few min as the
reaction returned to room temperature, and then it was heated to a
reflux for 5 min on the steam bath.  The reaction was cooled again,
EtOAc was added to destroy the excess hydride, followed by 25% NaOH
added dropwise until a white granular precipitate was obtained.  This
was removed by filtration, and the filter cake was washed with 2x35 mL
Et2O.  The filtrate was extracted into 50 mL dilute H2SO4 which was
washed with Et2O and, in turn, made basic again and extracted with
2x50 mL CH2Cl2.  The extracts were pooled, and the solvent removed
under vacuum to give a residue of crude product.  This distilled
cleanly from 100-115 !C at 0.3 mm/Hg yielding 0.45 g of a clear white
oil.  This was dissolved in 6 mL IPA, neutralized with 5 drops of
concentrated HCl, and diluted with 25 mL anhydrous Et2O.  There was a
deposition of white solids which were removed by filtration, washed
with Et2O, and air dried.  The
2,3-dimethoxy-4-methylthiophenethylamine hydrochloride so obtained
(4-TIM) weighed 0.3 g and contained a molecule of H2O of
crystallization.  The mp was 212-213 !C.  Anal. (C11H18ClNO2SaH2O)
C,H,N.

DOSAGE: greater than 160 mg.

DURATION: unknown.

QUALITATIVE COMMENTS: (with 160 mg) Everything seemed normal.  Pulse
was under 80, there was nothing with eyes-closed, my appetite was
normal.  The compound was completely inactive.

EXTENSIONS AND COMMENTARY: There has been much noise made about the
effectiveness of an unusual substitution group at the 4-position of
the phenethylamine molecule.  Here is a methylthio group at this
position, and it is an inactive compound.  I was just a little bit
surprised.









#155 3-TM; 3-THIOMESCALINE; 3,4-DIMETHOXY-5-METHYLTHIOPHENETHYLAMINE

SYNTHESIS: To an ice cold and well stirred solution of 15 g vanillin
and 20 g sodium thiocyanate in 150 mL acetic acid there was added,
dropwise over the course of 15 min, a solution of 16 g elemental
bromine in 40 mL acetic acid.  This was followed by the addition of 30
mL of 5% HCl and 300 mL EtOH, and stirring was continued for an
additional 30 min.  The mixture was heated to its boiling point, and
filtered while hot.  The mother liquor was diluted with an equal
volume of H2O, which initiated the crystallization of crude
5-formyl-7-methoxy-2-oxo-1,3-benzoxathiole as a flocculant yellow
solid.  On filtration and air-drying, this weighed 12.5 g.  After
recrystallization from EtOH, the product was white and had a mp of 164
!C sharp.

A suspension of 12.5 g of crude
5-formyl-7-methoxy-2-oxo-1,3-benzoxathiole in 100 mL MeOH containing
28.4 g methyl iodide was treated with a solution of 12 g NaOH in 100
mL warm MeOH.  The mixture was held at reflux for 1 h and then the
solvents were removed under vacuum.  A solution of 14.2 g methyl
iodide in 100 mL DMSO was added and the mixture stirred for 1 h.  An
additional 2.4 g of NaOH and 16 g methyl iodide were added, and the
stirring was continued for another 2 h.  The reaction mixture was
poured into 800 mL H2O, acidified with HCl, and extracted with 3x75 mL
CH2Cl2.  The pooled extracts were washed with 5% NaOH, then water, and
the solvent removed under vacuum.  Distillation at 110-130 !C at 0.4
mm/Hg gave 0.9 g 3,4-dimethoxy-5-(methylthio)benzaldehyde which had a
mp of 57-58 !C after crystallization from EtOH.  Anal. (C10H12O3S)
C,H.

A solution of 0.9 g 3,4-dimethoxy-5-(methylthio)benzaldehyde in 100 mL
nitromethane containing 0.5 g anhydrous ammonium acetate was held at
reflux for 4 h.  The excess nitromethane was removed under vacuum, and
the deep brown residue was dissolved in 4 mL hot MeOH.  On cooling,
the yellow crystals were removed by filtration, washed with cold MeOH
and air dried yielding 0.4 g yellow crystals of
3,4-dimethoxy-5-methoxy-'-nitrostyrene, with a mp of 119.5-120.5 !C
after recrystallization from EtOH.  Anal. (C11H13NO4S) C,H.

To a solution of 1.0 g LAH in 25 mL anhydrous THF under He, cooled to
0 !C and vigorously stirred, there was added, dropwise, 0.7 mL of 100%
H2SO4, followed by a solution of 0.7 g
3,4-dimethoxy-5-methylthio-'-nitrostyrene in 10 mL anhydrous THF.  The
mixture was brought briefly to a reflux, cooled again, and the excess
hydride destroyed with H2O in THF, followed by the dropwise addition
of 15% NaOH until the solids became white and granular.  The solids
were removed by filtration, the filter cake washed with THF, the
mother liquor and filtrates combined, diluted with an equal volume of
Et2O, and extracted with 2x40 mL dilute H2SO4.  The aqueous extracts
were combined, washed with Et2O, made basic with aqueous NaOH, and
extracted with 2x50 mL CH2Cl2.  The solvent was removed from these
extracts and the residue distilled to provide 0.4 g of a white oil
boiling at 124-130 !C at 0.2 mm/Hg.  This oil was dissolved in 8 mL
IPA, neutralized with concentrated HCl, and diluted with 30 mL
anhydrous Et2O.  The white crystalline product was the monohydrate of
3,4-dimethoxy-5-methylthiophenethylamine hydrochloride (3-TM) which
melted at 167-168 !C and weighed 0.29 g.  Anal. (C11H18ClNO2SaH2O)
C,H,N.

DOSAGE: 60 - 100 mg.

DURATION: 8 - 12 h.

QUALITATIVE COMMENTS: (with 80 mg) I went into the experience with
the question of whether it (3-TM) might be a writing aid.  I found a
considerable color enhancement (this was at the one hour point) and
there seems to be no problem in writing physical words.  But there is
no urge to, as there are no new things.  This is progressing into
something more complex and there is an interesting shielding effect.
I still have the desire to write and I sense that many things are
going on underneath, but my conscious control suppresses their
availability.  It is now the third hour.  Music.  I would like to try
this material at 100 milligrams.  Now awareness seems much more
pointed.  I have need to build a writing table.  This material is
physically relaxing, insisting repose, but with conflicting energy.
Seated in a chair, but I seem unable to find a comfortable position in
order to write.

RPine trees seem a good place

To start.  Notwithstanding this table

Of pine, unfinished, unruled,

The pulp upon which we reveal

The unnerved thoughts.

How casual we are at discarding

Our feelings, a rubble we

Leave behind for the living.

Who among us can absorb

The spiritual load we see as

What others carry.

RThis material is not poetic, I should say, does not enhance poetry,
prose is much more comfortable.  I think I should let the experience
develop further.  It is now the fifth hour.  There is something of a
violence (emotional) suppressed in all of us, a socially repressed
vision of oneself in a direct conflict with oneself. The music has a
lot to do with this material.  And it changes with time.  In the first
part there is sublimity, peacefulness, mild intoxication.  And a lot
more tension in the part that followed the four hour point.  There the
territories seem much better defined, with the benign shielding of the
first half largely dissipated.  I have developed a slightly irritated
view of myself, probably wanting once again to regain the serenity.

(with 80 mg) Delightful day.  Not insight depth but persistent
feeling of pleasant good humor.  It is good-natured and very verbal.
Everyone talked and the instinct was to express and comment on
everything.  There were no visuals during the first three to four
hours Q with the eyes open one could barely detect the intoxication.
Eyes closed Q quiet lovely window, no images.  About +2.  And then
someone brought in a radio with music on, into the room.  There was a
tremendous eruption of closed-eyes visual images and fantasy.  Bright
colors, funny, rich and elaborate.  Marvelous.  I was suddenly at +3.
Next day, no hangover.  Pleasant feeling persisted.

(with 100 mg) I found the day had two halves.  The first few hours
were characterized by occasional defensiveness (paranoia) and
irritability.  In interpersonal interactions there was a guardedness,
due to a feeling of vulnerability.  I went off by myself, and with
eyes closed, there was rich imagery and color synthesis to musical
imput.  And then things smoothed out, and I could express an easy flow
of ideas and concepts without always watching my step.  And then all
too soon, the intensity of the experience began fading away.

EXTENSIONS AND COMMENTARY: The amphetamine which would correspond with
this base would be 3,4-dimethoxy-5-methylthioamphetamine (3-T-TMA) and
should be an active compound.  Its synthesis should be straightforward
from the benzaldehyde described above, employing nitroethane rather
than nitromethane.  It is apparently an unknown compound.









#156 TM; 4-TM; 4-THIOMESCALINE;
3,5-DIMETHOXY-4-METHYLTHIOPHENETHYLAMINE

SYNTHESIS: A solution of 24.2 g N,N,NU,NU-tetramethylethylenediamine
and 27.6 g of 1,3-dimethoxybenzene was dissolved in 400 mL anhydrous
hexane.  This was stirred vigorously under a N2 atmosphere and cooled
to 0 !C with an external ice bath.  There was added 125 mL of 2.0 M
butyllithium in hexane.  The stirred reaction mixture became yellow
and sludgy, and was briefly warmed back to room temperature to allow
easy stirring.  After cooling again to 0 !C, there was added 18.8 g of
dimethyl disulfide which converted the viscous yellow phase to a loose
white solid.  Stirring was continued while the reaction mixture was
brought up to room temperature, and then all was added to 2 L of
dilute H2SO4.  There was the immediate formation of a white cystalline
solid which was removed by filtration, sucked relatively free of
water, and recrystallized from 50 mL of boiling MeOH.  There was thus
obtained 18.9 g of 2,6-dimethoxythioanisole as white crystals with a
mp of 81-82 !C.  Extraction of the aqueous filtrate with 2x50 mL
CH2Cl2 and removal of the solvent under vacuum gave a residue which,
when combined with the mother liquors from the MeOH crystallization,
afforded an additional 3.3 g product with a mp 77-79 !C.

To a stirred solution of 18.9 g of 2,6-dimethoxythioanisole in 200 mL
CH2Cl2 there was added 16 g elemental bromine dissolved in 75 mL
CH2Cl2.  The initial dark red color gradually faded to a pale yellow
color and there was a copious evolution of HBr.  The solvent was
removed under vacuum leaving 27.5 g of a pale yellow residual oil.
This was distilled at 118-121 !C at 0.25 mm/Hg to yield
3-bromo-2,6-dimethoxythioanisole as a white oil weighing 25.3 g.
Crystallization from hexane provided white crystals with a mp of
30-30.5 !C.  Anal. (C9H11BrO2S) C,H.

To a solution of 19.3 g diisopropylamine in 150 mL anhydrous THF that
was stirred under a N2 atmosphere and cooled to -10 !C with an
external ice/MeOH bath, there was added in sequence 83 mL of 1.6 M
butyllithium in hexane, 4.4 mL of dry CH3CN, and 11.6 g of
3-bromo-2,6-dimethoxythioanisole (which had been dissolved in a little
anhydrous THF).  The turbid reaction mixture gradually developed
color, initially yellow and progressively becoming orange and finally
a deep red brown.  Stirring was maintained for a total of 20 min, and
then the reaction mixture was poured into 1 L H2O that containing 10
mL concentrated H2SO4.  This was extracted with 3x75 mL CH2Cl2, these
extracts pooled, washed with dilute H2SO4 followed by saturated brine,
and the solvent was removed under vacuum yielding 8.7 g of a viscous
oil as a residue.  This was distilled at 0.11 mm/Hg yielded two
fractions.  The first boiled at 115-125 !C and weighed 3.8 g.  This
material set to an oily crystalline mass which was filtered, washed
with cold MeOH and then recrystallized from MeOH.  The white solids
had a mp of 60-63 !C and were not the desired product.  This material
has not yet been identified.  The second fraction came over at 150-180
!C, weighed 1.8 g and spontaneously crystallized.  It was triturated
under cold MeOH and filtered yielding, after air drying, 1.1 g
3,5-dimethoxy-4- methylthiophenylacetonitrile, which had a mp of
95-96.5 !C.  Anal. (C11H13NO2S) C,H.

A suspension of 1.0 g LAH in 40 mL anhydrous THF under N2 was cooled
to 0 !C and vigorously stirred.  There was added, dropwise, 0.7 mL
100% H2SO4, followed by 1.2 g
3,5-dimethoxy-4-methylthiophenylacetonitrile in 10 mL anhydrous THF.
The reaction mixture was stirred at 0 !C for a few min, then brought
to room temperature for 1 h, and finally to a reflux for 30 min on the
steam bath.  After cooling to room temperature, there was added 1 mL
H2O in 5 mL THF to destroy the excess hydride, followed by 3 mL of 15%
NaOH to bring the reaction to a basic pH, and finally 2 mL H2O which
converted the aluminum oxide to a loose, white, filterable
consistency.  This was removed by filtration, and washed with THF.
The filtrate and washes were stripped of solvent under vacuum, the
residue was dissolved in 200 mL CH2Cl2, and this was extracted with
3x100 mL diute H2SO4. These extracts were pooled, washed with CH2Cl2,
made basic with 25% NaOH, and extracted with 3x100 mL CH2Cl2.  After
combining, the solvent was removed under vacuum providing 1.2 g of a
colorless oil as a residue.  This was distilled at 122-132 !C at 0.05
mm/Hg to give a colorless oil.  This was dissolved in 8 mL of IPA,
neutralized with concentrated HCl and, with continuous stirring,
diluted with 100 mL anhydrous Et2O.  The product was removed by
filtration, washed with Et2O, and air dried to give 0.95 g.
3,5-dimethoxy-4-methylthiophenethylamine hydrochloride (4-TM) as
spectacular white crystals with a mp of 193-194 !C.  Anal.
(C11H18ClNO2S) C,H.

DOSAGE: 20 - 40 mg.

DURATION: 10 - 15 h.

QUANTITATIVE COMMENTS: (with 25 mg) I was first aware of any effects
as I was sitting in back of the house on a big fluffy pillow.  The sun
was warm and the grass tall and green, but I felt strange inside.
There was distinct uterine cramping, and I could not find a
comfortable position for sitting.  The others had gone out to the
garden leaving me here.  It seemed that walking might relieve the
physical discomfort, so I went to find them.  Walking was easy, but I
was a little light-headed and I had to watch my steps with care.  They
were not there (we had passed on opposite sides of the house) and I
returned in some haste to my warm nest behind the house to find my
pillow gone.  A strange detail, but it perhaps gave me the flavor for
my day.  The pillow was for me.  It was gone.  My place was gone.
Therefore I am gone.  I am dead and yet I can see and think.  The
small touch of panic at finding myself dead dispelled any internal
concerns and I ran inside to find the others; they had brought my
pillow in.  I was alive again, but the entire day balanced between the
alive unreality and the illusion that I was something removed and
merely watching the surrounding alive unreality.  Everything that
happened was completely unlikely.

RLike the soup scene.  We decided that some hot soup would be welcome,
and so R. brought out three cans of Campbell soup for the three of us.
But one was cream mushroom, one asparagus, and one tomato.  The
discussion as to how to use two cans only, which two, without mixing,
and even how to decide to decide was totally beyond any of us.  The
situation was hopelessly unresolvable, hilariously funny, and
distinctly schizophrenic.

ROr like the kite scene.  We were returning from a short walk to the
back of the property, and I spotted a red thing in the parking area.
It had not been there before.  None of us could identify it from this
distance, and we speculated wildly as to what it was, as we came
closer.  And at the last approach, we found that there was loose
string everywhere about the driveway, all part of a downed kite.  The
red object had apparently fallen from the sky, right here in front of
the garage.  There had been no sounds of voices of kite-flyers, and
there was no one to be seen in any direction.  And then one of us
spotted a sheet of paper, torn to the center where there was a small
hole, and it was flattened up against the kite.  There was a message.
Apparently whoever had been flying it had put a message on the string,
and let the wind take it up to the kite itself.  I reached for the
sheet of paper, and removed it.  Nothing on either side.  The message
was that there was no message.  Exactly out of Marshall McLuhan.
Completely appropriate for this particular day.

RThat evening we were to be picked up by my friends for dinner.
Choosing what to wear, how to dress myself, how to adjust my persona
to fit other people, all this was chaotic.  Somehow the dinner
succeeded, but I was able to flip in and out of the immediate company
easily, but not completely voluntarily.  Sleep was com-fortable that
night, and I feel that the entire day had been very intense, not too
much fun, but somehow quite rewarding.

(with 30 mg) At the one and a half hour point, I was reminded more
than anything of LSD, with a distinct feeling of standing just a few
feet to the right of ordinary reality.  There has been a mild tremor
ever since the first effects were evident, but it doesnUt bother me
except to make my handwriting uncertain.  I would not want to double
this level.  Suddenly the concept of my 5:30's swept over me.  I had a
penetrating view of myself as a person who had become invested in a
pattern of behavior that I had succumbed to, to come home and complete
my day with a transition from the work-world to the home-world, by
changing the inside clock at 5:30.  My wife had been my 5:30 for
nearly 30 years and this had been my tacit agreement with her.  Never
questioned, never challenged, and certainly never violated.  And with
her death, I have found myself imposing this same 5:30-ness on myself,
as some form of an emasculating pattern that is comfortable and
stable.  No, it is not comfortable, it is simply the course of the
least thought and the least disruption.  If I were to meet someone
else, would I have such a negative image of myself that I would expect
her to become my 5:30 so as not to have to disrupt these tired and
comfortable patterns?  That would be completely unfair to this other
person.  And I can see where it is completely destructive to me.  No
new person should ever have to play my wife's old role.  I need never
again play my old role.  And I wonUt.

(with 30 mg) At 2:20 PM I ingested 30 mg of TM.  It had a mildly
alkaloid taste.  Since the afternoon was warm, I took a two mile walk
with the dog, and with my two companions K.T. and T.T., both also with
30 mg.  We talked without any difficulty even after the onset of the
first signs of effect.  The major emotional and physical effects came
on very gradually and quite pleasantly as we sat in the patio.  But
soon we all grew chilled, and put on more clothing.  Nothing really
helped the inward chill, and we were to discover that it stayed with
us throughout the ex-perience.  At 3:30 we went inside where the room
temperature was set at 70 degrees, and we all lay down.  I launched
into an engrossing, somewhat chaotic and erotic reverie, that followed
no linear progression, but which lasted perhaps an hour.  The ease of
talking surprised me; the content was cogent and I felt myself to be
articulate.  It dawned on me after about two hours had gone by, that
the height of the experiment had already passed without any real
exhilaration on my part.  But my companions suggested that my
expectations from the past had been misleading me and, as time went
on, they proved to be correct.  The clarity and the continued ability
to talk, especially with K.T. on a personally difficult topic, were
for me the particular genius of this material.  When I went inward,
which I could do without effort, the sensations were neutral in affect
but restful in some way.  But coming out was entirely lucid and
pleasant.  I soon found that I preferred this.  I enjoyed a light
supper at 8:30 and found the dropoff gentle, and the conversation most
amiable until we separated at 1:00 AM.  Sleep did not come until 3:00
AM and then only after 10 mg Librium to quell the active mental
processes.  The next day I awoke around 8:30 AM feeling languid but
cheerful.

(with 40 mg) For quite a while there was some physical concern.  Not
actual nausea but a generalized uneasiness, with a distinct body
tremor.  There was little urine produced (500 mL in 18 hours), and I
felt the need to search out fluids.  There was mild intestinal
cramping.  I found that my thoughts were able to go in several
directions at once, but since they stayed nowhere long enough to
structure anything, this was more annoying than constructive.  I saw
this as a reality shell about me like a Mbius strip, continuous, yet
with no consistent side being presented.  I was reminded of a similar
place with DOB, some few years ago.  While lying down with eyes
closed, I found the imagery to be very impressive, but my thought
processes were quite convoluted and disjointed.  Some were most
interesting, and some were ugly.  I cannot see this as a party drug.

EXTENSIONS AND COMMENTARY: The dosage range has been broadened to
include the 20 milligram level, in that several subjects found that
even with that small amount there was difficulty in walking and in
keeping one's equilibrium.  Walking was described as a floating
procedure, and one could tilt to one side or the other if care was not
taken.  Anorexia was occasionally noted, and most people commented on
some degree of anesthesia to touch.

All in all, this drug evoked a mixed bag of responses.  The most
startling and unexpected property was the dramatic increase in potency
over the parent prototype, mescaline.  The substitution of a sulfur
atom for an oxygen atom increased the power of the drug some ten-fold,
without any apparent decrease in complexity of action.  As there were
many materials that were outgrowths of mescaline with the studies of
ethyl this and diethyl that, each and all of these would be
interesting candidates for synthesis with this or that oxygen atom
replaced with sulfur.  Most of these have been made, and many of them
have proven to be interesting.

What is meaning of the phrase, Rsulfur-for-oxygen replacement?S Let me
try to explain it for non-chemists.

One of the most exciting bits of architecture in science is the
Periodic Table.  The principles of electrons and orbitals and
different counts of protons in a nucleus gets to be a complex story to
try to explain the grid-like structure of the arrangements of atoms.
It is easier to simply give the music.  And this melody goes: As you
look across a row, elements are simple in their binding arrangements
on the left, become more complex towards the center where they kind of
change polarity, and then get progressively simple again but with the
opposite charge as you approach the right-hand side.

And when you look at a column from top to bottom, the bonding
complexity stays pretty much the same but the atom gets more and more
massive as you go down the column.

The combinations of atoms from the Periodic Table, by and large, is
the province of the inorganic chemist.  Take one of this, and two of
that, and the combination is called a salt, or a complex, or an
adduct, and probably has interesting colors, and may even be found in
nature as part of a rock somewhere, or coming out of the vent of a
volcano.

But if one were to look at just four elements, three in the middle
right of the first row, namely carbon, nitrogen and oxygen, and the
one up there at the top and the lightest of all, hydrogen, you would
find quite a different story.  These can be combined in an infinity of
ways since there can be dozens of atoms hooked to one-another; this is
the territory of the organic chemist, and this is the chemistry of
life.  With a few exceptions, every molecule within the body, and the
food that maintains the body, and the drugs that affect the body, are
made up of a bunch of carbons, and an occasional oxygen or two,
usually a nitrogen somewhere, and all the remaining loose ends
satisfied with hydrogen atoms.

Almost every drug that is to be found in this book is nothing more
than a different arrangement of atoms of these four elements.

This compound, thiomescaline, is a byway that takes advantage of one
of those vertical columns.  Directly below the element oxygen, there
is found sulfur, which has much the same binding complexity, but is
twice as massive.  The prototype of all the phenethylamine drugs being
discussed in this book is mescaline, a very simple compound containing
these basic four elements of life and pharmacology; it contains eleven
carbon atoms, three oxygen atoms, one nitrogen atom, and there are a
total of seventeen hydrogen atoms required to balance the books.  One
of the oxygen atoms holds a central position, and the other two are
reflections of one another and cannot be distinguished chemically.
The structure of thiomescaline is generated by plucking out that
central oxygen atom of mescaline, and putting a sulfur atom back in
its place.  The definition of the term RthioS is quite simple Q it
means a sulfur-in-place-of-an-oxygen, with everything else left alone.
It is a little awe-inspiring to think that every oxy anything can have
a thio something as a spatially similar analogue.  And there are a lot
of oxy things in the body and in the medicine cabinet.  A number of
them are discussed in this book.









#157 TMA; 3,4,5-TRIMETHOXYAMPHETAMINE

SYNTHESIS: To a solution of 39.2 g 3,4,5-trimethoxybenzaldehyde in 30
mL warm EtOH there was added 15.7 g nitroethane followed by 1.5 mL
n-butylamine.  The reaction mixture was allowed to stand at 40 !C for
7 days.  With cooling and scratching, fine yellow needles were
obtained which, after removal by filtration and air drying, weighed 48
g.  Recrystallization from EtOH gave
2-nitro-1-(3,4,5-trimethoxyphenyl)propene as yellow crystals with a mp
of 94-95 !C.  Anal. (C12H15NO5) C,H,N.  Alternatively, a solution of
20 g of the aldehyde in 75 mL nitroethane was treated with 4 g
anhydrous ammonium acetate and heated on the steam bath until a deep
red color had been generated.  Removal of the excess solvent/reagent
under vacuum gave a red oil which was dissolved in an equal volume of
boiling MeOH.  On cooling, yellow crystals of the nitropropene
separated.  Recrystallization from MeOH gave, after air drying to
constant weight, 13.0 g with the same mp.

Under an inert atmosphere, 38 g LAH was wetted with 100 mL anhydrous
Et2O, and then suspended in 1 L dry THF.  This was brought up to a
gentle reflux, and there was added, slowly, a solution of 43.7 g
2-nitro-1-(3,4,5-trimethoxyphenyl)propene in 160 mL THF.  Refluxing
was continued for 36 h, and then the reaction mixture was cooled with
an external ice bath.  The excess hydride was destroyed by the
cautious addition of 38 mL H2O, and this was followed by 38 mL 15%
NaOH, and finally another 114 mL H2O.  The inorganic salts which
should have ended up as a loose, granular, easily filterable mass,
looked rather like library paste, but they were filtered nonetheless.
Washing with THF was attempted, but it was not efficient.  The
combined filtrate and washes were stripped of solvent under vacuum
giving 31.5 g of the crude base as an amber oil.  This was dissolved
in 140 mL IPA, neutralized with concentrated HCl (15 mL was required),
and diluted with 650 mL anhydrous Et2O.  There was an initial oily
phase which on continued stirring changed to pale pink solids.  These
were finely ground under CH3CN to give 15.2 g of
3,4,5-trimethoxyamphetamine hydrochloride (TMA) as white crystals that
melted at 195-211 !C.  All aluminum salts from everywhere were
dissolved in dilute HCl, and 1 Kg of potassium sodium tartrate was
added.  There as added 25% NaOH allowed the pH to bring the pH to >9
without the precipitation of basic alumina.  Extraction of this phase
with CH2Cl2 was followed by removal of the solvent and salt formation
as described above, allowed the isolation of an additional 6.4 g TMA.
The product prepared in this manner contains some 10-15%
3,5-dimethoxy-4-hydroxyamphetamine as an impurity.  A solution of 20 g
of the TMA made in this manner in 200 mL 5% NaOH was extracted with
2x200 mL CH2Cl2.  The pooled extracts were washed with 4x100 mL 5%
NaOH, and the aqueous washes were pooled with the original base phase.
The organic phase was stripped of its CH2Cl2 under vacuum to give an
oil that was dissolved in 40 mL IPA, neutralized with concentrated
HCl, and diluted with 400 mL anhydrous Et2O.  There was the immediate
formation of spectacular white crystals of pure
3,4,5-trimethoxyamphetamine hydrochloride, weighing 15.4 g and having
a mp of 220-221 !C.  The aqueous phase was brought to neutrality,
treated with 10 g potassium di-hydrogen phosphate, brought to pH 9.0
with the careful addition of NaOH, and extracted with 5x100 mL CH2Cl2.
Evaporation of the solvent under vacuum gave an oil that spontaneously
crystallized.  This product, 3,5-dimethoxy-4-hydroxyamphetamine could
be further purified by sublimation at 130 !C at 0.2 mm/Hg.  It was a
white crystalline solid that slowly discolored in the air.  The
literature describes a picrate salt with a mp of 225 !C from EtOH.

DOSAGE: 100 - 250 mg.

DURATION: 6 - 8 h.

QUALITATIVE COMMENTS: (with 135 mg) I had no nausea, although I
always vomit with mescaline.  Somehow my personality was divided and
exposed, and this allowed me to understand my psychic structure more
clearly.  But maybe others could look in there, too.  The psychiatric
use of this drug would be interesting to pursue.  It is not completely
pleasant, maybe because of this personal intimacy.

(with 140 mg) There were not the color changes of mescaline there,
but certainly a good humor and an over-appreciation of jokes.  The
images behind the eyes were remarkable and tied in with the music, and
I became annoyed at other people's conversations that got in the way.
I was out of it in eight hours.  I would equate this to 300 or 350
milligrams of mescaline and I rather think that I would prefer the
latter.

(with 225 mg) There was quite a bit of nausea in the first hour.
Then I found myself becoming emotionally quite volatile, sometimes
gentle and peaceful, sometimes irritable and pugnacious.  It was a day
to be connected in one way or another with music. I was reading
Bernstein's 'Joy of Music' and every phrase was audible to me.  On the
radio, Rachmaninoff's 2nd piano concerto on the radio put me in an
eyes-closed foetal position and I was totally involved with the
structure of the music.  I was suspended, inverted, held by fine
filigreed strands of the music which had been woven from the arpeggios
and knotted with the chords.  The commercials that followed were
irritating, and the next piece, Slaughter on Fifth Avenue, made me
quite violent.  I was told that I had a, 'DonUt cross me if you know
what is good for you,' look to me.  I easily crushed a rose, although
it had been a thing of beauty.

EXTENSIONS AND COMMENTARY: TMA was the very first totally synthetic
psychedelic phenethylamine that was found to be active in man, for
which there had been any attempt to describe such drug effects in any
detail.  This was the report of research done in Canada, and it
appeared in 1955, six years before my own report on the material.
There was an earlier report on TMPEA which is mentioned in the
appropriate recipe, but there were few details given.  Also there had
been interest in reports that adrenalin that had become old and
discolored seemed to elicit central effects in man.  The oxidation
products were identified as the deeply colored indolic compound
adrenochrome and the colorless analogue adrenolutin.  The controversy
that these reports created just sort of died away, and the
adrenochrome family has never been accepted as being psychedelic.  No
one in the scientific community today is looking in and about the
area, and at present this is considered as an interesting historical
footnote.  But, in any case, they are not phenethylamines and so not
part of this book.

The Canadian studies with TMA involved the use of a stroboscope as a
tool for the induction of visual phenomena.  These experiments used
levels in the 50-150 milligram range, and generally employed
pre-treatment with Dramamine for the successful prevention of nausea.
There was reported giddiness and light-headedness, and some remarkable
flash-induced visualizations.  With higher levels, the visual
syntheses are present without external stimulation.  But there is a
thread of negativity that seems to pervade the experience at these
higher levels, and the appearance of a publication that emphasized the
possible antisocial nature to TMA seemed to discourage further medical
exploration.  Military interest was maintained however, apparently, as
TMA became a part of the chemical warfare studies where it was
referred to with the code name EA-1319.  It had been used in human
trials with psychiatric patients, but no details of these experiments
have been published.

The presence of a potentially active impurity in TMA deserves some
comment.  In the Canadian work, the material used was described as
melting at 219-220 !C, which is the property given for the
impurity-free material above.  If this was the actual material used in
those studies, this impurity (3,5-dimethoxy-4-hydroxyamphetamine) was
probably not present.  The Army studies use a material of unreported
melting point.  In my own studies, the lower melting product was used.
There is an intriguing and unanswered question: what contribution did
this phenolic component make to the nature of the observed effects of
TMA?  Assays on the isolated contaminant could answer that, but they
have not yet been made.

There is an old saying that has gotten many people into trouble: RIf
one is good, then two is better.S And if a statement of the measure of
worth of a compound can be made from its potency, then TMA is a step
in the right direction.  And this was a chemically simple direction to
follow further.  Looking at mescaline as a compound with no carbons on
its side-chain, and TMA as a mescaline molecule with one carbon on its
side chain, then what about a compound with two carbons there, or
three, or nine carbons?

Using this pattern of naming, TMA can be seen as
alpha-methylmescaline, or AMM.  And the two carbon homologue would be
alpha-ethyl mescaline, or AEM.  Its proper name is
2-amino-1-(3,4,5-trimethoxyphenyl)butane.  It and its several higher
homologues are discussed in a separate recipe entry called AEM (#1).

A final comment.  But maybe a long one!  Elsewhere, I have made
comparisons between myristicin and MMDA, and between safrole and MDA.
And here there is a similar parallel between elemicin and TMA.  What
are these relationships between the essential oils and the
amphetamines?  In a word, there are some ten essential oils that have
a three carbon chain, and each lacks only a molecule of ammonia to
become an amphetamine.  So, maybe these essential oils, or RalmostS
amphetamines, can serve as an index for the corresponding real
amphetamine counterparts.  I had originally called this family the
RnaturalS amphetamines, but my son suggested calling them the
RessentialS amphetamines, and I like that.  At the time that I had
synthesized TMA, back there in the U50s, I had the impulse to explore
this body of Essential Amphetamines.  As the old folk-wisdom says:
RNature is trying to tell us something.

One of the banes of the archivist is having to choose one pattern of
organization over another.  The book store owned by a language scholar
will have the German poets and playwrights and novelists here, and the
French ones over there.  Next door, the book store is run by a letters
scholar, and the poetry of the world is here, and the plays of the
world are there, regardless of the language of origin.  The same
obtains with spices, and essential oils, and amphetamines.  The spice
cabinet is a rich source of chemical treasures, each source plant
containing a host of com-pounds, some of which are true essential
oils.  And the next spice from the next plant has some of the same
components and some new ones.  Does one organize by plant (spice or
herb) or by essential oil (amphetamine)?  Let's do it by the ring
substitution pattern of the amphetamine, and gather the spices and
oils as a secondary collection.

(1) The 4-methoxy pattern.  The pivotal essential oil is
4-allylanisole, or methyl chavicol, or estragole (called esdragol in
the old literature).  This allyl compound is found in turpentine,
anise, fennel, bay, tarragon, and basil.  Its smell is light, and
reminiscent of fennel. The propenyl analogue is called anethole, or
anise camphor, and it is found in both anise and camphor.  It is a
waxy solid, and has a very intense smell of anise or fennel.  At low
concentrations, it is sweet, as in magnolia blossoms, where it is also
found.  The drinks that turn cloudy with water dilution (Pernod-like
liqueurs, and ouzo and roki), are heavy with it, since it was the
natural flavoring in the original absinthe.  That drink was very
popular in the last century, as an intoxicant which produced an
altered state of consciousness beyond that which could be ascribed to
alcohol alone.  It contained wormwood, which proved to be
neurologically damaging.  The flavorings, such as anethole, are still
big things in synthetic liqueurs such as vermouth.  Old anethole, when
exposed to air and light, gets thick and sticky and yellowish, and
becomes quite disagreeable to taste.  Maybe it is polymerizing, or
maybe oxidizing to stuff that dimerizes.  Whatever.  These changes are
why old spices in the cabinet are best discarded.  And adding ammonia
to any of these natural product oils produces, in principle,
4-methoxyamphetamine, 4-MA.

(2) The 3,4-dimethoxy pattern.  The main actor here is methyleugenol,
or 4-allyl-1,2-dimethoxybenzene.  This is located in almost every item
in the spice cabinet.  It is in citronella, bay (which is laurel,
which is myrtle), pimiento, allspice, pepper, tree-tea oil, and on and
on.  It has a faint smell of cloves, and when dilute is immediately
mistaken for carnations.  The propenyl analogue is, not unreasonably,
methylisoeugenol, a bit more scarce, and seems to always be that
little minor peak in any essential oil analysis.  The compounds
missing that methyl group on the 4-oxygen are famous.  The allyl
material is eugenol, 4-allylguaiacol, and it is in cinnamon, nutmeg,
cloves, sassafras and myrrh.  You taste it and it burns.  You smell it
and think immediately of cloves.  And its property as an anesthetic,
in the form of a clove, is well known in the folk-treatment of
toothaches.  Actually, flowers of clove (the gillyflower, like the
carnation) are the small, pointy things that decorate baked hams and,
when stuck into apples, make pomander balls.  This anesthetic property
has recently led to a drug abuse fad, called clove cigarettes.  Very
strong, very flavorful, and very corrosive things from Southeast Asia.
The eugenol that is present numbs the throat, and allows many strong
cigarettes to be smoked without pain.  The propenyl analogue is
isoeugenol, with a smell that is subtle but very long lasting, used
more in soaps and perfumes than in foods.  The amine addition to the
methyleugenol world produces 3,4-dimethoxyamphetamine, or 3,4-DMA.
The isomer with the other methyl group missing is chavibetol
(3-hydroxy-4-methoxyallylbenzene) and is found in the pepper leaf that
is used with betel nut.  A couple of positional rearrangement isomers
of methyleugenol are known in the plant world.  The 2,4-isomer is
called osmorrhizole, and the conjugated form is isoosmorrhizole or
nothosmyrnol; both are found in carrot-like vegetables.  They, with
ammonia, would give 2,4-DMA.  And the 3,5-dimethoxyallylbenzene isomer
from artemisia (a pungent herb commonly called mugwort) and from sage,
would give rise to 3,5-DMA.  This is an unexplored isomer which would
be both an antidote for opium as well as a stimulant, if the classical
reputation of mugwort is transferred to the amphetamine.

(3) The 3,4-methylenedioxy pattern.  One of the most famous essential
oils is safrole, or 4-allyl-1,2-methylenedioxybenzene.  This is the
mainstay of sassafras oil, and it and its conjugated isomer isosafrole
have a smell that is immediately familiar: root beer!  These are among
the most widely distributed essential oils, being present in most of
the spices, including the heavies such as cinnamon and nutmeg.  I am
not aware of the 2,3-isomer ever having been found in nature.  Adding
ammonia to either would give MDA.

(4) The 3-methoxy-4,5-methylenedioxy pattern.  The parent compound is
myristicin, 5-allyl-1-methoxy-2,3-methylenedioxybenzene, and the
source of this is nutmeg (or the botanically parallel material, mace).
The nutmeg is the seed of the tree Myristica fragrans and mace is the
fibrous covering of the seed.  The two spices are virtually identical
as to their chemical composition.  Myristicin and the conjugated
isomer isomyristicin are also found in parsley oil, and in dill.  This
was the oil that was actually shown to be converted to MMDA by the
addition of ammonia by passage through an in vitro liver preparation.
So here is the major justification for the equation between the
essential oils and the Essential Amphetamines.  Care must be taken to
make an exact distinction between myristicin (this essential oil) and
myristin (the fat) which is really trimyristin or glyceryl
trimyristate from nutmeg and coconut.  This is the fat from myristic
acid, the C-14 fatty acid, and these two similar names are often
interchanged even in the scientific literature.

(5) The 2-methoxy-3,4-methylenedioxy pattern.  This is the second of
the three natural methoxy methylenedioxy orientations.  Croweacin is
2-methoxy-3,4-methylenedioxyallylbenzene, and it takes its name from
the binomial for the plant Eriostemon crowei from the worlds of rue
and the citrus plants.  It corresponds to the essential amphetamine
MMDA-3a.  This oil is found in plants of the Family Rutaceae.  My
memories of this area of botany are of Ruta graveolens, the common
rue, whose small leaves smelled to me, for all the world, like cat
urine.  This plant has always fascinated me because of a most
remarkable recipe that I was given by a very, very conservative
fellow-club member, one evening, after rehearsal.  He told me of a
formula that had provided him with the most complete relief from
arthritic pain he had ever known.  It was a native decoction he had
learned of many years eariler, when he was traveling in Mexico.  One
took equal quantities of three plants, Ruta graveolens (or our common
rue), Rosmarinus officinalis (better known as rosemary), and Cannabis
sativa (which is recognized in many households simply as marijuana).
Three plants all known in folklore, rue as a symbol for repentance,
rosemary as a symbol of remembrance, and pot, well, I guess it is a
symbol of a lot of things to a lot of people.  Anyway, equal
quantities of these three plants are allowed to soak in a large
quantity of rubbing alcohol for a few weeks.  Then the alcoholic
extracts are clarified, and allowed to evaporate in the open air to a
thick sludge.  This then was rubbed on the skin, where the arthritis
was troublesome, and always rubbed in the direction of the extremity.
It was not into, but onto the body that it was applied.  All this from
a very conservative Republican friend!

The methoxy-methylenedioxy pattern is also found in nature with the
2,4,5-orientation pattern.  The allyl-2,4,5-isomer is called asaricin.
It, and its propenyl-isomer, carpacin, are from the Carpano tree which
grows in the Solomon Islands.  All these plants are used in folk
medicine.  These two systems, the 2,3,4- and the 2,4,5-orientations,
potentially give rise, with ammonia, to MMDA-3a and MMDA-2.

(6) The 3,4,5-trimethoxy pattern.  Elemicin is the well studied
essential oil, 5-allyl-1,2,3-trimethoxybenzene, primarily from the oil
of elemi.  It is, like myristicin, a component of the Oil of Nutmeg,
but it is also found in several of the Oils of Camphor, and in the
resin of the Pili in the Philippines.  This tree is the source of the
Oil of Elemi.  I had found a trace component in nutmeg many years ago
that proved to be 5-methoxyeugenol, or elemicin without the 4-methyl
group; it is also present in the magnolia plant.  The aldehyde that
corresponds to this is syringaldehyde, and its prefix has been spun
into many natural products.  Any natural product with a syring
somewhere in it has a hydroxy between two methoxys.  The amphetamine
base from elemicin or isoelemicin would be TMA, the topic of this very
recipe.

(7) The 2,4,5-trimethoxy pattern.  There is an essential oil called
asarone that is 2,4,5-trimethoxy-1-propenylbenzene.  It is the trans-
or alpha-isomer, and the cis-isomer is known as beta-asarone.  It is
the isomerization analogue of the much more rare
1-allyl-2,4,5-trimethoxybenzene, gamma-asarone, or euasarone, or
sekishone.  Asarone is the major component of Oil of Calamus obtained
from the rhizomes of Acorus calamus, the common Sweet Flag that grows
wild on the edges of swamps throughout North America, Europe, and
Asia.  It has been used as a flavoring of liqueurs and, as almost
every other plant known to man, has been used as a medicine.  In fact,
in Manitoba this plant was called Rat-root by the Cree Indians in the
Lake Winnipeg area known as New Iceland, and Indian-root by the
Icelandic pioneers.  It was used externally for the treatment of
wounds, and internally for most illnesses.  There apparently is no
report of central effects.  The corresponding propanone, acoramone (or
2,4,5-trimethoxyphenylacetone), is also present in Oil of Calamus.
The styrene that corresponds to asarone is found in a number of
plants, and is surprisingly toxic to brine shrimp.  The older
literature describes an allyl-trimethoxy benzene called calamol, but
it has never been pinned down as to structure.  The isolation of
gamma-asarone or euasarone from Oil of Xixin (from wild ginger) has
given rise to a potential problem of nomenclature.  One of the Genus
names associated with wild ginger is Asiasarum which looks very much
like the name asarone, which comes from the Genus Acorus.  And a
second Genus of medical plants also called wild ginger is simply
called Asarum.  There is an Asarum forbesi from central China, and it
is known to give a pleasant smell to the body.  And there is Asarum
seiboldi which is largely from Korea and Manchuria.  It has many
medical uses, including the treatment of deafness, epilepsy, and
rheumatism.  The amphetamine that would arise from this natural
treasure chest is TMA-2.

(8) The 2,5-dimethoxy-3,4-methylenedioxy pattern.  The parent allyl
benzene is apiole (with a final ReS) or parsley camphor, and it is the
major component of parsley seed oil.  Its conjugated isomer is called
isoapiole, and they are valuable as the chemical precurors to the
amination product, DMMDA.  Whereas both of these essential oils are
white solids, there is a green oily liquid that had been broadly used
years ago in medicine, called green, or liquid apiol (without the
final ReS).  It comes from the seeds of parsley by ether extraction,
and when the chlorophyll has been removed, it is known as yellow
apiol.  With the fats removed by saponification and distillation, the
old term for the medicine was apiolin.  I would assume that any of
these would give rise to white, crystalline apiole on careful
distillation, but I have never tried to do it.  The commercial Oil of
Parsley is so readily available.

(9) The 2,3-dimethoxy-4,5-methylenedioxy pattern.  The second of the
three tetraoxygenated essential oils is
1-allyl-2,3-dimethoxy-4,5-methylenedioxybenzene, commonly called
dillapiole and it comes, not surprisingly, from the oils of any of the
several dill plants around the world.  It is a thick, almost colorless
liquid, but its isomerization product, isodillapiole, is a white
crystalline product which melts sharply.  This, by the theoretical
addition of ammonia, gives DMMDA-2.

(10) The tetramethoxy pattern.  The third and last of the
tetra-oxygenated essential oils, is
1-allyl-2,3,4,5-tetramethoxybenzene.  This is present as a minor
component in the oil of parsley, but it is much more easily obtained
by synthesis.  It, and its iso-compound, and the amination product,
are discussed under the last of theTen Essential Amphetamines, TA.

One must remember that the term RessentialS has nothing to do with the
meaning of needed, or required.  The word's origin is essence,
something with an odor or smell.  Thus, the essential oils are those
oils that have a fragrance, and the Essential Amphetamines are those
compounds that can, in principle, be made from them by the addition of
ammonia in the body.

There were a few interesting experimental trials that were based on
these natural oils.  Methoxyeugenol was assayed up to a 10 milligram
level, and asarone at up to a 70 milligram level, and neither had any
effects at all.  And, in an attempt to challenge the
Roil-to-amphetamineS concept, I made up a mixture of 1 part MDA, 2
parts TMA and 5 parts MMDA.  A total of 100 milligrams of this
combination (which I had named the RPseunut CocktailS for
pseudo-nutmeg) should be equivalent to the safrole, elemicin and
myristicin that would be in 5 grams of nutmeg.  And 100 milligrams
indeed produced quite a sparkle and considerable eye-dilation.  But
then, I have never taken 5 grams of nutmeg, so I cannot make any
comparisons.









#158 TMA-2; 2,4,5-TRIMETHOXYAMPHETAMINE

SYNTHESIS: To a solution of 50 g 2,4,5-trimethoxybenzaldehyde in 175
mL nitroethane there was added 10 g anhydrous ammonium acetate and the
mixture was heated on the steam bath for 2 h.  The excess nitroethane
was removed under vacuum, and the deep orange oily residue was drained
out into a beaker, and the flask washed with 3x60 mL boiling MeOH.  On
stirring the combined decantation and washings, there was a
spontaneous formation of crystals.  After cooling, these were removed
by filtration, washed sparing with MeOH, and air dried to constant
weight to yield 35.1 g of 2-nitro-1-(2,4,5-trimethoxyphenyl)propene as
yellow crystals with a mp of 98-99 !C.  Recrystallization from MeOH
increased the mp to 101-102 !C.

A suspension of 31.6 g powdered LAH in 1 L anhydrous THF containing a
little anhydrous Et2O was brought to a gentle reflux, and then there
was added a solution of 40.0 g of
2-nitro-1-(2,4,5-trimethoxyphenyl)propene in 200 mL anhydrous THF over
the course of 4 h.  The mixture was held at reflux temperature for 24
h, cooled to 0 !C with external ice, and the excess hydride destroyed
by the addition, in sequence, of 32 mL H2O (which had been diluted
with a little THF), 32 mL 15% NaOH, and finally with 96 mL H2O.  The
white inorganic solids were removed by filtration, and the filter cake
was washed with THF.  The combined filtrate and washings were stripped
of solvent under vacuum to give 48 g of an impure amber oil.  This was
dissolved in 180 mL IPA, neutralized with 30 mL concentrated HCl, and
the mixture diluted with 1500 mL anhydrous Et2O.  After a short
induction period, an oily precipitate separated, which on stirring
changed into a loose crystalline phase.  This was removed by
filtration, washed with Et2O, and air dried to yield 29.0 g of
2,4,5-trimethoxyamphetamine hydrochloride (TMA-2) as fine white
crystals with a mp of 188.5-189.5 !C.  Anal. (C12H20ClNO3) C,H,N.  A
4.0 g sample of the free base was dissolved in 15 mL pyridine, treated
with 2.5 mL acetic anhydride, heated on the steam bath for 20 min,
added to 400 mL H2O, acidified with HCl, and extracted with 3x75 mL
CH2Cl2.  After washing with H2O the pooled extracts were stripped of
solvent under vacuum to give 4.5 g of flakey, off-white solids which,
on recrystallization from MeOH, were white, weighed 2.3 g, and had a
mp of 132-133 !C.  Recrystallization from this acetamide from MEK did
not improve its quality.  Anal. (C14H21NO4) C,H,N.

DOSAGE: 20 - 40 mg.

DURATION: 8 - 12 h.

QUALITATIVE COMMENTS: (with 20 mg) I took it in two 10 milligram
doses, spaced by two hours.  There was a slight movement of surface
textures, my hearing was deepened and spatially defined.  The body was
relaxed and stretching seemed necessary.  The further I got into it
the more I realized that I was totally lazy.  Very lethargic, to the
point of laughter.  At the sixth hour, I was seeing more life in the
woodwork, and the wooden angel hanging on the ceiling was flesh and
feathers when I stared at it.  Great vision.  But by no means
overwhelming.  Sleep was fine.

(with 20 mg) The first two hours seemed like an eternity, with time
passing slowly.  Then it settled into a very calm and enjoyable event
(not that it wasnUt already).  The material seemed somewhat hypnotic.
I suspect that I would believe suggestions, or at least not challenge
them too much.  I had a little confusion but it was not troublesome.
On reflection, the material was quite good.  It was benign in the
sense that there appeared to be no dark spots.  I would try it again,
perhaps at 30 milligrams.  Almost base-line after 12 hours, but not
quite.

(with 24 mg) I took the dosage in two halves, an hour apart.
Initially, I was a little nauseous, with light tremors and modest eye
dilation.  But after another hour, there was the entire package of
mescaline, missing only the intense color enhancement.  The world is
filled with distorted. moving things.  Then my little fingers on both
hands got periodically numb.  And there was an occasional
light-headedness that hinted at fainting.  The two phenomena
alternated, and never got in each other's ways.  Both passed, once I
realized that I would recover from this experience.  Then the humor
and joy of the world returned.  The drop-off was quite rapid from the
fifth to eighth hour, and no effects remained at all by the twelfth
hour.

(with 40 mg) Very slow coming on.  DidnUt feel it for an hour, but
then at a full +++ in another hour.  Beautiful experience.  Erotic
excellent.  Eyes-closed imagery and fantasy to music.  No dark
corners.  Benign and peaceful and lovely.  There were brief intestinal
cramps early, and a little diarrhea, but no other problems.  I was
able to sleep after eight hours, but had guarded dreams.

(with 40 mg) Beautiful plus 3.  Some visuals, but not intrusive.
Moderate, good-mannered kaleidoscopic imagery against dark.  Music
superb.  Clear thinking.  Calmly cosmic.  This is a seminal, or
archetypal psychoactive material.  A very good experience and good for
repeats.  About 10-12 hrs.  Sleep difficult but OK.

EXTENSIONS AND COMMENTARY: There was absolutely no reason to suspect
that the simple rearrangement of the methoxy groups of TMA from the
classic 3,4,5-positions to this new, 2,4,5-orientation, would
dramatically increase potency like this.  Mescaline,
3,4,5-trimethoxyphenethylamine, is an extraordinary compound, but it
is not particularly potent, requiring hundreds of milligrams for a
trip.  And going from its 3,4,5-pattern to the 2,4,5-pattern of TMPEA
makes the compound even less potent.  There was essentially nothing
reported in the scientific literature about central activity of
2,4,5-substituted stuff, so there could not have been any logical
preparation for the activity of TMA-2.  My very first trials were with
a rather liberal 400 micrograms, and the levels being explored leaped
up in fairly large steps, mostly on separate days.  On November 26,
1962, at 6:00 AM, when 12 milligrams proved to be inactive, another 12
milligrams went in and down an hour later.  This was the 24 milligram
discovery experiment, a fragment of which is given above.  The anxiety
of being thrust into the unknown certainly played a role in what can
now be seen as obvious psychosomatic difficulties.

The unexpected ten-fold increase of effectiveness uncovered by the
simple relocation of a single methoxy group of TMA gave the further
juggling of methoxy groups a very high priority.  There are a total of
six arrangements possible for the three groups, namely, 3,4,5- (the
original TMA), 2,4,5- (the present TMA-2), and then and in systematic
sequence, 2,3,4-, 2,3,5-, 2,3,6-, and 2,4,6.  These compounds were
totally unknown at that time, and they could and would be assigned the
sequential names TMA-3, TMA-4, TMA-5 and TMA-6, respectively.  I made
them all, and they are all included in this book.

Having found the treasure of 2,4,5-ness, it is instructive to look
back at nature, to see what its plant equivalents might be.  There are
indeed a few essential oils that have their methoxy groups in this
arrangement.  TMA-2 is thus one of the Essential Amphetamines, and
most of the botanical connections are discussed under TMA.  The
natural skeleton is found in asarone, with alpha-asarone being
trans-propenyl, beta-asarone the cis-propenyl and gamma-asarone (also
called euasarone) being the allyl-isomer.  I had mentioned, in the
spice cabinet discussion under TMA, the tasting of asarone at up to 70
milligrams without any effects.

A couple of additional experiments involving TMA-2 had been set up and
started, but somehow never had enough fire to get completed.  Studies
on the optical isomers had gotten up to assays of 6 milligrams on each
of the separate isomers, but had never been taken higher.  The RRS
isomer is much the more potent in rabbit assays, but the human
comparisons remain unknown at present.  Also, a study of the 14C
labeled racemate (5 microcuries in 40 milligrams) was conducted with a
view to metabolite analysis, but again, the project was abandoned
before any results were obtained.  In the rat, the 4-methoxyl carbon
appeared as expired carbon dioxide to the extent of about 20%.  And
this is some four times the amount seen from either of the other two
methoxyl carbon atoms.

One final memory in the TMA-2 area.  About twenty years ago I
co-authored a rather thorough review article in the British journal
Nature, that described the structure-activity relationships between
the simpler one-ringed psychotomimetics.  It also quietly served as a
vehicle for mentioning a number of newly-discovered compounds and
their human activities.  But as a magnificent attestment to youth and
brashness, we proposed a complex compound that embraced each and every
clue and hint that might tie it to the neurological process.  This
hybrid monster was 2,'-dihydroxy-4,5-dimethoxyphenethylamine.  It had
everything.  The 6-hydroxydopamine hydroxy group and the rest of the
dopamine molecule intact as represented by the two methoxyl groups.
And the beta-hydroxy group gave it the final RnorepinephrineS touch.
And, with due modesty, we proposed that it might be Ran endogenous
psychotogen.S Why not Rthe endogenous psychotogen?S And then, to
compound the picture, what should arrive in the mail a month or two
later, and from a most respected scientist, but a sample of just this
stuff, synthesized for our investigations.  I must have bought a
little of my own promotion, as I noted that even after my first four
graded dosages with the compound, I was still only up to a 250
microgram dose.  And then, as the sample became increasingly brown and
was clearly decomposing, the project was finally abandoned.

A sad note on how things have changed since that time.  I recently
queried the editors of Nature, about their thoughts concerning a
twenty year retrospective of this area, written by the three authors
of the original review.  We had each followed quite divergent paths,
but each of us was still keenly the researcher.  It would have been a
marvelous paper to put together, and it would have delighted the
reading audience of Nature, had it been the audience of twenty years
ago.  But not today.  The journal is now dedicated to neutron stars
and x-ray sources.  The respected old English journal of
interdisciplinary interests is not the grand and curious lady she used
to be.  The Editor's reply was polite, but negative.  RSuch an article
would be unsuitable for publication in Nature at present,S they said.
And, I am sad to say, theyUre right.

And I am afraid that the American counterpart journal, Science, has
suffered a similar deterioration.  It, too, has abandoned
multidisciplinary interest, but in a different direction.  They are
now dedicated to chromosomes, and nucleotide identification, and are
totally captivated by the attention paid to, and the apparent
importance of, the human genome project.  There is where you
automatically go to publish, now, if you have unraveled some DNA
sequence from the Latvian cockroach.









#159 TMA-3; 2,3,4-TRIMETHOXYAMPHETAMINE

SYNTHESIS: To a solution of 12.4 g 2,3,4-trimethoxybenzaldehyde in 45
mL glacial acetic acid, there was added 7 mL nitroethane and 4.1 g
anhydrous ammonium acetate, and all was held at reflux temperature for
1.5 h.  To the cooled and well stirred reaction mixture, H2O was added
slowly, dropping out an oily crystalline solid mass.  This was
separated by filtration, and ground under a quantity of 50% aqueous
acetic acid, and re-filtered.  The 6.5 g of crude product was
recrystallized from boiling MeOH to give, after air drying to constant
weight, 5.0 g of 2-nitro-1-(2,3,4-trimethoxyphenyl)propene, with a mp
of 56-57 !C.  Anal. (C12H15NO5) C,H.

To a gently refluxing suspension of 3.0 g LAH in 300 mL anhydrous Et2O
under a He atmosphere, there was added 3.65 g
2-nitro-1-(2,3,4-trimethoxyphenyl)propene by allowing the condensing
Et2O drip into a shunted Soxhlet thimble containing the nitrostyrene
and effectively adding a warm saturated solu-tion of it dropwise.
Refluxing was maintained for 5 h following the completion of the
addition of the nitrostyrene.  The milky reaction mixture was cooled
and the excess hydride destroyed by the addition of 200 mL 10% H2SO4.
When the aqueous and Et2O layers were finally clear, they were
separated, and 75 g of potassium sodium tartrate was dissolved in the
aqueous fraction.  NaOH (25%) was then added until the pH was >9, and
this was then extracted with 3x75 mL CH2Cl2.  Evaporation of the
solvent under vacuum produced 2.5 g of a nearly colorless clear oil
that was dissolved in 300 mL anhydrous Et2O which was saturated with
anhydrous HCl gas.  The product, 2,3,4-trimethoxyamphetamine
hydrochloride (TMA-3) separated as a fine white solid.  This was
removed by filtration, Et2O washed, and air dried to constant weight.
The yield was 1.65 g of a product which, after recrystallization from
IPA, had a mp of 148-149 !C.  Anal. (C12H20ClNO3) C,H.

DOSAGE: greater than 100 mg.

DURATION: unknown.

QUALITATIVE COMMENTS: (with 100 mg) There were no effects at all.  No
eye dilation, no believable diversion from complete normalcy.
Appetite was normal, as well.

EXTENSIONS AND COMMENTARY: There is a small lesson to be learned from
this completely inactive compound.  There is no way of saying that it
is or is not in-active.  All that can be said is that trials were made
(in this case using three separate individuals) at an oral level of
100 milligrams.  And, at this level, nothing happened.  And since a
bottom threshold for mescaline would be perhaps 200 milligrams, it can
be honestly said that the activity of this compound, if expressed
relative to mescaline (using mescaline units) is less than 2 M.U.  Had
200 milligrams been inactive, it would have been less than 1.0 M.U.
If 2 grams had been inactive, it would have been less than 0.1 M.U.
But the actual printed form, activity < 2.0 M.U. was accepted by many
readers as indicating that TMA-3 was active, but at dosages greater
than 100 milligrams.  All that can be said is, if there is activity,
then it will be at oral levels greater than 100 milligrams At the
moment, as far as I know, this compound is not active in man, but then
I know of no trials in excess of 100 milligrams.

This admonition applies to all the published M.U. values that are
preceded by the Rless thanS sign, the R<.









#160 TMA-4; 2,3,5-TRIMETHOXYAMPHETAMINE

SYNTHESIS: To a solution of 68 g 2,4-dimethoxybenzaldehyde in 250 mL
glacial acetic acid that had been warmed to 25 !C and well stirred,
there was added, dropwise, 86 g of a 40% peracetic acid solution (in
acetic acid).  The reaction was exothermic, and the rate of addition
was dictated by the need to maintain the internal temperature within a
few degrees of 28 !C.  External cooling was used as needed.  The
addition took 1 h, and when the reaction had clearly been completed
(no further temperature rise) the entire reaction mixture was added to
3 volumes of H2O.  The excess acid was neutralized with solid K2CO3
(283 g were required).  This was extracted with 3x100 mL Et2O, the
extracts pooled, and stripped of solvent under vacuum to give 66 g of
crude 2,4-dimethoxyphenyl formate.  This was suspended in 125 mL 10%
NaOH, and the mixture heated on the steam bath for 1.5 h.  On cooling,
the reaction mixture set to a heavy black solid.  This was removed by
filtration, washed with H2O, and dissolved in 250 mL CH2Cl2.  The
organic phase was washed with dilute HCl, and then with aqueous
NaHCO3, which removed much of the color.  Removal of the solvent under
vacuum gave a deep red goo that was dissolved in 200 mL anhydrous Et2O
and filtered through paper.  The resulting clear solution was stripped
of solvent, yielding 34.4 g of 2,4-dimethoxyphenol as a red oil that
crystallized on cooling.  A 1.0 g sample in 4 mL pyridine was treated
with 0.9 g benzoyl chloride and heated on the steam bath for a few
min.  The addition of H2O gave a pasty solid that was isolated by
pressing on a porous plate.  The yield of crude 2,4-dimethoxyphenyl
benzoate was 1.1 g.  Recrystallization from cyclohexane gave a white
product with a mp of 86-87 !C.  A second recrystallization from
cyclohexane raised this to 89-90 !C, which is in agreement with the
literature value.

To a solution of 31.0 g crude 2,4-dimethoxyphenol in 60 mL absolute
EtOH there was added a solution of 11.25 g KOH in 90 mL boiling EtOH.
To this, there was then added 28 g allyl bromide which produced an
immediate white precipitate of KBr.  The mixture was held at reflux
for 2 h and then quenched in 3 volumes of H2O.  Sufficient 10% NaOH
was added to make the reaction strongly basic, and this was extracted
with 3x100 mL Et2O.  Removal of the solvent under vacuum gave 33.2 g
of 1-allyloxy-2,4-dimethoxybenzene, shown to be free of phenol
starting material by GC analysis.  Analyses must be carried out at low
column temperatures (below 180 !C) on an ethylene glycol succinate
substrate.  If a silicone column is used, even at these low
temperatures, there is considerable Claisen rearrangement taking place
on the column.  Low temperature distillation can be used for further
purification (107-110 !C at 1.0 mm/Hg).

A 31.0 g sample of 1-allyloxy-2,4-dimethoxybenzene was gently heated
with a soft flame until the internal temperature reached 215 !C.  An
exothermic reaction took place, with the temperature rising to 270 !C.
The residue left in the flask was largely 2-allyl-4,6-dimethoxyphenol,
that contained perhaps 10% of 2,4-dimethoxyphenol which resulted from
the pyrolytic loss of the allyl group.  This mixture was methylated
without further purification.

To a solution of 30 g impure 2-allyl-4,6-dimethoxyphenol in a little
absolute EtOH there was added a boiling solution of 8.7 g KOH in 75 mL
absolute EtOH followed, immediately, by 22.4 g methyl iodide in a
little EtOH.  The mixture was held at reflux for 3 h, then added to 4
volumes of H2O.  Sufficient 10% NaOH was added to make the mixture
strongly basic, and this was extracted with 4x100 mL Et2O.  Removal of
the solvent gave 28 g of 1-allyl-2,3,5-trimethoxybenzene.  GC analysis
showed some 10% of the expected impurity, 1,2,4-trimethoxybenzene.

To a solution of 26 g crude 1-allyl-2,3,5-trimethoxybenzene in an
equal weight of absolute EtOH there was added 52 g of flaked KOH.  The
mixture was heated on the steam bath overnight, and then quenched with
much H2O.  This was extracted with 3x100 mL Et2O which, on removal
under vacuum gave 24.6 g of product.  This contained, by GC analysis,
largely cis- and trans-1-propenyl-2,3,5-trimethoxybenzene and the
expected 1,2,4-trimethoxybenzene.  This mixture was dissolved in an
equal volume of pentane, and cooled in dry ice.  Quick filtration gave
9.2 g of an amber solid which had a melting point of 39-41.5 !C.
Recrystallization from hexane provided pure
trans-1-propenyl-2,3,5-trimethoxybenzene with a mp of 44-45 !C.
Evaporation of the original pentane mother liquor provided an impure
sample of mixed cis- and trans- isomers.

A solution of 7.2 g trans-1-propenyl-2,3,5-trimethoxybenzene in 41 g
dry acetone was treated with 3.3 g dry pyridine and, with good
stirring, cooled to 0 !C.  There was then added 6.9 g of
tetranitromethane over the course of 1 min, and the reaction mixture
was allowed to stir for an additional 2 min.  The reaction mixture was
then quenched with a solution of 2.2 g KOH in 40 mL H2O.  After the
addition of more H2O, the product was extracted with 3x50 mL CH2Cl2.
Removal of the solvent under vacuum yielded 7.0 g of an impure product
which would not crystallize.  This was distilled under vacuum to give
four fractions, all of which crys-tallized spontaneously.  Cuts #1 and
#2 (bp 100-120 !C and 120-130 !C at 2 mm/Hg) were combined, weighed
0.8 g, and after crystallization from hexane yielded white crystals
with a mp of 62-63 !C.  The NMR spectrum (in CDCl3) was in agreement
with 2,3,5-trimethoxybenzaldehyde, and the literature mp has been
reported as being 62-63 !C.  Cuts #3 and #4 (bp 130-170 !C and 170-175
!C at 2 mm/Hg with the bulk coming over in the latter fraction) were
combined to give 3.0 g of yellow crystals.  These were triturated
under a little cold MeOH, and then recrystallized from MeOH to give
1.15 g of yellow crystals of
2-nitro-1-(2,3,5-trimethoxyphenyl)propene, with a mp of 87-88 !C.  The
forerun of the distillation contained considerable unreacted
trans-1-propenyl-2,3,5-trimethoxybenzene and some
1,2,4-trimethoxybenzene, by GC analysis.

To a refluxing and stirred suspension of 1.1 g LAH in 150 mL anhydrous
Et2O and under an inert atmosphere, there was added a solution of 1.1
g 2-nitro-1-(2,3,5-trimethoxyphenyl)propene in 50 mL anhydrous Et2O.
The creamy mixture was held at reflux for 4 h, cooled, and then the
excess hydride cautiously destroyed by the addition of 1.5 N H2SO4.
There was then added 20 g potassium sodium tartrate followed by
sufficient aqueous NaOH to raise the pH to >9.  The Et2O phase was
separated, and the remaining aqueous phase extracted with 3x75 mL
CH2Cl2.  The organic phase and extracts were combined, and the solvent
removed under vacuum yielding 0.9 g of a colorless oil.  This was
dissolved in 200 mL anhydrous Et2O which was saturated with anhydrous
HCl gas.  There was generated a thick oil that did not crystallize.
The Et2O was decanted from this, and allowed to stand for several days
in a sealed container at room temperature.  There was the deposition
of fine white needles of 2,3,5-trimethoxyamphetamine hydrochloride
(TMA-4) weighing, after Et2O washing and air drying, 0.31 g.  The mp
was 118-119 !C.  Anal. (C12H20ClNO3) C,H.  The residual oil was
dissolved in H2O, made basic with NaOH, and extracted with CH2Cl2.
Evaporation of the solvent gave 0.40 of a white oil which was
dissolved in a little MeOH containing 0.22 g oxalic acid.  There was
the immediate deposition of crystals of the oxalate salt of
2,3,5-trimethoxyamphetamine, with a mp of about 110 !C.

DOSAGE: greater than 80 mg.

DURATION: perhaps 6 h.

QUALITATIVE COMMENTS: (with 80 mg) I was concerned about life issues,
with much introspection, for about 6 hours.  There were no subjective
physical symptoms.  It was comparable to about 50 micrograms of LSD,
or to 120 milligrams TMA, for me.

EXTENSIONS AND COMMENTARY: That is the sum total of the knowledge of
subjective effects that exist.  There was such a precious small amount
of the final hydrochloride salt that, by the time the needed build-up
of dosage had been completed, there was just enough left for this
single trial, which was conducted in South America.  Based upon the
volunteered comparisons to LSD and TMA, a potency for this compound
has been published that states that it is 4x the potency of mescaline,
or 4 M.U.  The material must be re-synthesized, and re-evaluated with
the now-accepted protocol.

In the future re-synthesis, there will be a considerable improvement
made with the several steps that are described above.  The products
from the preparations of the phenol, the allyl ether, the Claisen
rearrangement, the methylation of the new phenol, and the
isomerization to the mixture of cis- and trans-propenylbenzenes were
all conducted without the benefit of a Kugel-Rohr apparatus.  The
products became progressively thick and blacker, and it was only by
the grace of getting a solid at the trans-propenyl stage that some
degree of purity could finally be obtained.  All of the intermediates
are certainly white oils, and when this preparation is repeated, they
will be distilled at each and every stage.

This 2,3,5-orientation of the methoxy groups on the aromatic ring is
far and away the most difficult tri-substitution pattern known to
chemists.  There just isnUt any simple way to put it together.  The
2-carbon phenethylamine (2,3,5-trimethoxyphenethylamine) had been
synthesized quite a while ago.  Its role as a substrate for liver
amine oxidase in in vitro studies has been explored, but it has never
been tried in man.  Even more bizarre is the amphetamine with this
oxygenation pattern, in which a methylenedioxy ring has replaced the
two adjacent methoxyl groups.  This is the material
2,3-methylenedioxy-5-methoxyamphetamine, or MMDA-4.  Despite its
theoretical appeal (being one of the six possible MMDA derivatives)
and it's synthetic challenge (as with the 2,3,5-trimethoxy things
above, everything is simply in the wrong position) the compound is of
unknown pharmacology.  This follows, quite logically, from the fact
that it has never been synthesized.  No one has yet put together a
workable procedure that would make it.  In the course of making all
possible positional isomers of MMDA explicitly Schedule I drugs, the
DEA has named this compound, and since it was specifically named, it
was entered into the Chemical Abstracts.  So it is listed in the
literature, at least it is in the Chem. Abstracts.  But it is in
reality completely unknown.  Some day, some one somewhere will have a
light bulb go on over his head, and find a synthetic process that will
make it.  Of course, the moment it is made, an illegal act will have
occurred, at least in the United States as long as the present laws
remain unchanged, as it is currently a Schedule I drug.

Needless to say, the 2-carbon analog of MMDA-4,
2,3-methylenedioxy-5-methoxyphenethylamine (would 2C-MMDA-4 be a
reasonable name?) is also unknown.









#161 TMA-5; 2,3,6-TRIMETHOXYAMPHETAMINE

SYNTHESIS: A solution of 100 g 1,2,4-trimethoxybenzene in 1 L hexane
was cooled to 15 !C and treated with 400 mL of a 15% solution of
n-butyllithium in hexane.  A white precipitate formed immediately, and
stirring was continued for an additional 2 h while the reaction
returned to room temperature.  There was then added a solution of 40 g
freshly distilled propionaldehyde in 100 mL hexane.  The reaction was
exothermic and, as the stirring was continued, the precipitate
gradually dissolved.  Stirring was continued overnight at room
temperature.  There was then added 1 L H2O, and the reaction was
acidified with HCl.  The hexane phase was separated, and the remaining
aqueous phase was extracted with hexane, then with Et2O.  The pooled
organic extracts were stripped of solvent under vacuum, and the
residue distilled to give 60 g ethyl 2,3,6-trimethoxyphenyl carbinol,
with an index of refraction nD20 = 1.5192.  Anal. (C12H18O4) C,H.
From the Et2O extracts above, additional carbinol was obtained,
containing a small amount of the starting 1,2,4-trimethoxybenzene.
The two materials were readily separated by vacuum distillation,
providing an additional 21 g of carbinol.

The above alcohol, 60 g of ethyl 2,3,6-trimethoxyphenyl carbinol, was
stirred without solvent and cooled to 0 !C with an external ice bath.
There was then added 80 g PBr3 at a rate that maintained the
temperature below 60 !C.  At the end of the addition, there were added
quantities of chipped ice, followed by H2O.  The reaction mixture was
extracted with 3x100 mL Et2O, and removal of the solvent provided 60 g
of 1-bromo-1-(2,3,6-trimethoxyphenyl)propane which was used in the
following dehydrobromination step without further purification.

A solution of the above 60 g of
1-bromo-1-(2,3,6-trimethoxyphenyl)propane in an equal weight of EtOH
was treated with 120 g of flaked KOH.  The exothermic reaction was
allowed to run its course with stirring continued overnight.  The
mixture was then quenched in H2O and extracted with 3x200 mL CH2Cl2.
Removal of the solvent from the pooled extracts gave a crude product
which contained no starting bromo material, but which was contaminated
with an appreciable quantity of the ethoxy analogue,
1-ethoxy-1-(2,3,6-trimethoxyphenyl)propane.  This impure product was
heated briefly to 80 !C with 50% H2SO4.  Cooling, dilution with water,
and re-extraction with 3x100 mL CH2Cl2 gave, after removal of the
volatiles under vacuum, 1-(2,3,6-trimethoxyphenyl)propene.  This was
distilled to provide 7.0 g of a clear oil that was a 12:1 ratio of the
trans- and cis-isomers.

A well-stirred solution of 6.8 g of the mixed isomers of
1-(2,3,6-trimethoxyphenyl)propene in 40 g of dry acetone was treated
with 3.2 g pyridine and cooled to 0 !C with an external ice bath.
There was then added 6.5 g tetranitromethane over the course of 1 min,
the stirring was continued for an additional 2 min, and then the
reaction mixture was quenched by the addition of 2.2 g KOH in 40 mL
H2O.  There was additional H2O added, and the organics were extracted
with 3x75 mL CH2Cl2.  The solvent from the pooled extracts was removed
under vacuum, and the 5.3 g residue distilled at 0.2 mm/Hg.  A
fraction boiling at 150-170 !C proved to be largely
2,3,6-trimethoxybenzaldehyde.  A second fraction (170-200 !C at 0.2
mm/Hg) also spontaneously crystallized to a yellow solid.  This was
recrystallized from MeOH to provide, after drying to constant weight,
2.8 g of 2-nitro-1-(2,3,6-trimethoxyphenyl)propene with a mp of 73-74
!C.  Anal. (C12H15NO5) C,H.

To a refluxing and stirred suspension of 2.4 g LAH in 300 mL anhydrous
Et2O and under an inert atmosphere, there was added a solution of 2.4
g 2-nitro-1-(2,3,6-trimethoxyphenyl)propene in 100 mL anhydrous Et2O.
The mixture was held at reflux for 4 h, cooled, and then the excess
hydride cautiously destroyed by the addition of 1.5 N H2SO4.  There
was then added 40 g potassium sodium tartrate followed by sufficient
aqueous NaOH to raise the pH to >9.  The Et2O phase was separated, and
the remaining aqueous phase extracted with 3x100 mL CH2Cl2.  The
organic phase and extracts were combined, and the solvent removed
under vacuum yielding 1.8 g of a colorless oil.  This was dissolved in
200 mL anhydrous Et2O which was saturated with anhydrous HCl gas.
There was generated a thick oil that slowly crystallized.  The
resulting white crystalline solid was removed by filtration, providing
2.2 g 2,3,6-trimethoxyamphetamine hydrochloride (TMA-5).  The mp was
124-125 !C.  Anal. (C12H20ClNO3) C,H.

DOSAGE: 30 mg or more.

DURATION: 8 - 10 h.

QUALITATIVE COMMENTS: (with 20 mg) There appeared to be a slight
stimulation.  Modest eye dilation, but normal pulse.  If this is the
marginal edge of intoxication, then it is not a psychotomimetic, but a
stimulant.  Go up with care.

(with 30 mg) Intense introspection.  Comparable to about 75
micrograms of LSD, or more.

EXTENSIONS AND COMMENTARY: TMA-5, as was the case with TMA-4, has only
been superficially explored.  The above two quotations are from two
different people, and together no more than hint at the possibility
that it might be active in the several tens of milligrams.

Pharmacologists have developed quite an art in the design and
evaluation of animal behavior models for the study of psychedelic
drugs.  They have always faced two formidable tasks, however.  There
is the qualitative question: is the drug a psychedelic?  And there is
the quantitative question: how potent is it?

The first question is addressed by taking a number of known
psychedelic drugs, and searching for some animal responses that are
common to all.  Since there is little logic in the argument that
animals can experience, let alone reveal, altered states of
consciousness or fantasy fugues or colored imagery, the investigator
must look for objective signs such as conditioned responses to
stimuli, or unusual behavior.  If one explores ten drugs that are
known psychedelics, and all ten produce, say, bizarre nest-building
behavior in mice, and an eleventh drug of unknown pharmacology does
exactly the same thing, then the eleventh drug can be suspected of
being a psychedelic drug.

And the second question, how potent, is answered by seeing how much of
the drug is required to evoke this standardized behavior.  This is
called the dose-response curve, in which the more drug you give, the
more response you get.  This curve gives confidence that the drug is
indeed responsible for the activity that is seen, as well as giving a
quantitative measure of that activity.

But this entire discipline depends on the acceptance of the fact that
the first ten drugs are indeed psychedelic materials.  And these
inputs can only come from human trials.  What is the validity of these
assumptions with TMA-5?  Not very good.  The statement that it is
psychedelic has actually been published in reviews solely on the basis
of the above two studies; the potency has been put at some ten times
that of mescaline.  Mescaline is certainly an effective psychedelic
drug in the 300-500 milligram range, and this factor of ten implies
that TMA-5 is also a psychedelic drug and is active in the 30-50
milligram range.  And indeed, both statements may be true, but
confidence in these conclusions must await more extensive trials.

The two-carbon analogue of TMA-5 is 2,3,6-trimethoxyphenethylamine (or
2C-TMA-5 or 2,3,6-TMPEA).  This is a known material, although there
has been some controversy as to its physical properties.  It has been
studied in monoamine oxidase systems, and appears to be either a
competitive substrate or an inhibitor of that enzyme.  But as far as I
know, no one has nibbled it, so its human activity is unknown.









#162 TMA-6; 2,4,6-TRIMETHOXYAMPHETAMINE

SYNTHESIS: To a solution of 100 g phloroglucinol dihydrate in 320 mL
MeOH there was added 55 mL of concentrated H2SO4, and the clear
solution held under reflux conditions overnight.  After cooling, there
was added 500 mL H2O, and the bulk of the MeOH was removed under
vacuum.  The residual oil was extracted with Et2O, and the removal of
this left 60 g of a red oil as residue.  This was dissolved in 300 g
methyl sulfate (caution, this is extremely toxic through skin contact,
and any exposure must be flushed thoroughly with dilute ammonium
hydroxide).  With good stirring, this was cautiously treated with 500
g of 40% aqueous KOH, and the exothermic reaction allowed to run its
course.  Extraction with 3x100 mL Et2O gave, after evaporation of the
solvent from the pooled extracts, an oil that became largely
crystalline.  This was suspended in 100 mL hexane, and filtered
through a coarse fritted funnel.  With evaporation there was obtained
57 g of 1,3,5-trimethoxybenzene as a pale amber solid that melted at
44-50 !C.  A sample purified by recrystallization from EtOH had the
proper mp of 54-55 !C.

A mixture of 62.9 g N-methylformanilide and 71.3 g of POCl3 was
allowed to stand for 0.5 h producing a light claret color.  There was
then added 30.9 g of 1,3,5- trimethoxybenzene and the mixture heated
on the steam bath for 2 h.  The reaction mixture then was poured into
chipped ice, and allowed to stir for several h.  The dark gummy mess
was extracted with 2x100 mL Et2O (this was discarded) and then with
4x200 mL CH2Cl2.  The latter extracts were pooled, and stripped of
solvent under vacuum yielding 14 g of an amber solid.  This was
recrystallized from 80 mL boiling MeOH (with decolorizing charcoal
employed and filtration of the boiling solution through paper) to give
10.0 g of 2,4,6-trimethoxybenzaldehyde as a white crystalline solid
with a mp of 115-116 !C.  The literature values are generally
one-degree ranges, and they are reported as high as 121 !C.  The
malononitrile adduct was prepared from a solution of 0.5 g aldehyde
and 0.5 g malononitrile in 10 mL warm MeOH treated with a drop of
triethylamine.  There was an immediate formation of a yellow
crystalline mass which was removed by filtration, washed with EtOH,
and air dried.  The yield of 2,4,6-trimethoxybenzalmalononitrile was
0.5 g and the mp was 174-175 !C.  Anal. (C13H12N2O3) N.

A solution of 5 g 2,4,6-trimethoxybenzaldehyde in 20 g nitroethane was
treated with 1.0 g of anhydrous ammonium acetate and held on the steam
bath for 24 h.  The excess solvent/reagent was stripped from the
deep-red colored solution under vacuum yielding a residue that
spontaneously set to a crystalline mass.  This was well triturated
under 5 mL MeOH, filtered, and washed with 3 mL additional MeOH to
give 5.4 g of 2-nitro-1-(2,4,6-trimethoxyphenyl)propene as yellow
crystals.  The mp of the crude material was 135-142 !C which could be
raised to 147-148 !C by recrystallization from EtOH.  The use of an
alternate procedure for the synthesis of this nitrostyrene, using
acetic acid as solvent and a stoichiometric amount of nitroethane (and
ammonium acetate as catalyst), gave very poor yields.  The use of
butylamine as catalyst gave considerably better results.

A suspension of 50 g LAH in 1 L anhydrous THF was placed under an
inert atmosphere, stirred magnetically, and brought to a gentle
reflux.  There was added a total of 56.9 g
2-nitro-1-(2,4,6-trimethoxyphenyl)propene as a saturated solution in
THF.  This was achieved by letting the condensed THF drip through a
Soxhlet thimble containing the nitrostyrene with direct addition to
the reaction mixture.  The solubility was extremely low.  The stirred
mixture was maintained at reflux for 36 h, generating a smooth creamy
gray color.  After being brought to room temperature, the excess
hydride was destroyed by the patient addition of 50 mL H2O, followed
with 50 mL 15% NaOH (still some heat evolved) and then 150 mL
additional H2O.  Stirring was continued until the insoluble salts were
white and loose.  These solids were removed by filtration, and the
filter cake washed with additional THF.  The combined filtrate and
washes were stripped of solvent under vacuum, and the 73 g of pale
amber residue dissolved in 200 mL IPA, neutralized with approximately
50 mL concentrated HCL, and diluted with 2 L anhydrous Et2O.  A lower,
oily phase separated slowly set up as a crystalline mass.  This was
removed by filtration, Et2O washed, and allowed to air dry to constant
weight.  The weight of 2,4,6-trimethoxyamphetamine hydrochloride was
41.3 g and the color was an off-white.  There was a tendency to
discolor upon air exposure.  The mp was 204-205 !C which was increased
to 207-208 !C upon recrystallization from IPA.  The literature gives a
mp of 214-215 !C for this salt after isolation and purification as the
picrate salt (with a mp 212-213 !C from EtOH).

DOSAGE: 25 - 50 mg.

DURATION: 12 - 16 h.

QUALITATIVE COMMENTS: (with 25 mg) I was outside at the
California-Washington State football game, which was completely nutty.
As was I.  With the crowd activity, it was impossible to separate the
drug's action from the environment.  Later I simply sat in the car,
and tried to define what the effects really were.  Things were
completely benign, there was ease with concepts, and writing was good
and smooth.  At twelve hours, comfortably down.  Maybe a plus two.

(with 35 mg) My body was tingling all over, and there were times when
walking was unsteady.  Thinking was a little difficult, as I was quite
intoxicated most of the day (all of the day, now that I think that
over).  To accomplish anything, such as toasting the toast in the
toaster, was difficult.  And things were so funny most of the time.
Setting the table for supper, six hours later, proved to be hilarious.
I like to think of the day as a mixture of the mad hatter's tea party,
and a trip to the moon.  We were all still intoxicated at bedtime,
whatever time that was.  Had difficult time sleeping.  If I were to
repeat, would go lighter in dosage, I feel.

(with 40 mg) This experiment was begun at noon of a cool rainy day.
Almost all of the day had to be spent indoors, without benefit of
sunshine, This is worth mentioning because there was, for the first
eight hours of the experiment, a decided feeling of inner chill which
might not have occurred so strongly had it been a warm day.  Most, if
not all, of the other eight subjects also reported the same chill.
There was some visual sparkle which persisted throughout.  At the two
hour point a minor but persistent stomach queasiness came on, preceded
by a diarrhea-like bowel movement.  There was no impairment of speech,
but there was some halting quality to all thought processes.  It was
easy to talk about personal matters, but there did not seem to be a
significant insight increase.  Appetite for food was lessened.  Sleep
was decidedly difficult after the effects of the material seemed
otherwise gone.

(with 40 mg) As the experience grows in intensity for the first four
hours, I feel a strange mixture of plateaus, exuberance, and strong
negative feelings, all replacing each other.  I found myself inside a
stout, hemispherical shell, curled up in the solid part, thoroughly
walled off but absolute master within the shell, calling all shots,
making all decisions, in complete control.  Moving beyond the
half-shell meant becoming vulnerable, which I refused to do.
Consequently my difficulty in hearing what other people say, becoming
involved in their perceptions and lives.  I keep relationships
shallow, pull away inside my shell rather than become involved.  I
like to be by myself.  This was a great revelation; I had never seen
it before.  This material had an enormous drive.  I feel extremely
grateful for exposing a very deep personal problem.

(with 50 mg) My previous try at this level produced a record that
said, 'alteration of consciousness, but no visual, no anything,' and
oh my, surprise!  It was very, very active, visual, colorful, etc.,
etc.  Good talking, clear and steady control of body, despite intense
energy flow.  Extremely funny Q great humor, wonderful laughter.

EXTENSIONS AND COMMENTARY: Here is a simple and easily made compound
that might well bid fair to be one of the most rewarding and
pleasurable of the methoxylated amphetamines.  It is fully as potent
as its counterpart, TMA-2.  This latter compound, with its
2,4,5-trisubstitution pattern, has served as a template from which an
immense family of very active and fascinating drugs have arisen.  The
2,5-dimethoxy aspect has been kept intact, and modifications in the
4-position have given rise to treasures such as DOM, DOB, DOET, DOI,
and the Aleph compounds.  And, of course, the entire world of the
2C-X's has exploited this same orientation.

Here, there is the blatant, parallel call from TMA-6.  It can serve,
as the 2,4,6-counterpart, as a similar template compound.  And the
first indicators are that, in keeping the 2,6-dimethoxy aspect intact,
a completely analogous series could be made, again with modifications
of the 4-position.  These have been named the psu-series, or
psi-series, as an abbreviation for the prefix, pseudo, and can be
differentiated from the 2,4,5-things with the use of the Greek letter
RYS.  Thus there is the Y-DOM (called Z-7 in this book, and certainly
an active compound), and Y-DOB, Y-DOET, Y-DOI, and the Y-ALEPH
compounds.  And, of course, the Y-2C-X counterparts.  I would expect
all of them to be active and, certainly, some of them interesting.
They will be considerably more difficult to synthesize.  However, some
of them, specifically things such as Y-2C-T-4, have already been
prepared, and are being evaluated.

One of the guiding premises of this Book II was to make all recipes
employ commercially available materials as starting materials.  And in
the case of TMA-6, the required benzaldehyde
(2,4,6-trimethoxybenzaldehyde) is an easily obtained trade item from
any of several supply houses.  Why not start the recipe there?  Why
tell how to make it from 1,3,5-trimethoxybenzene (also presently
available from commercial sources) and how to make the ether in turn,
from phloroglucinol?  This simply reflects a valid paranoia of our
times.  Today the aldehyde is available (at $2/g) and can be easily
purchased.  But tomorrow?  What about in the year 2003?  Who can tell
what will, or will not, be easily available then?  There might be a
world-wide acknowledgment that the Rwar on drugsS is more destructive
than any drug itself could ever be, and every law that had been
written in the attempt to dictate human behavior will have been
transformed into a force that truly educates and allows choice.  This
might really happen.  But maybe, on the other hand, no fine chemicals
may be permitted to be held in any hands, at any price, except for
those of licensed chemists and in authorized laboratories.  The black
market price for the aldehyde might be $1000/g with another $1000 for
protection.

But, it will be impossible to remove phloroglucinol from availability.
It is available as a natural component in the free form, in sources as
diverse as the cones of the Sequoia sempervirens (the coast redwood
tree) and species of Camillia (that provides the leaves of our morning
tea).  And combined with a molecule of glucose in the form of its
glucoside, it is called phlorin, and it is present in the discarded
rinds of almost all citrus fruits as well as the resins from many of
the Eucalyptus species.  And one step yet further back into nature,
there is a dihydrochalcone glucoside called phloridzin which
practically drips out of all parts of the apple and pear trees except
for the apple or pear itself.  It, on base hydrolysis, gives phlorin,
which on acid hydrolysis gives phloroglucinol, which when dissolved in
methanol and sulfuric acid gives Q.  Nature is indeed most bountiful.

The phenethylamine homologue of TMA-6 is well known, but is virtually
unexplored pharmacologically.  The above benzaldehyde with
nitromethane in glacial acetic acid containing ammonium acetate gave
the appropriate beta-nitrostyrene as yellow crystals with a mp
177-177.5 !C.  This, with LAH in ether, gave
2,4,6-trimethoxyphenethylamine (2,4,6-TMPEA, or 2C-TMA-6) as the
picrate salt (mp 204-205 !C) or the hydrochloride salt (mp 234-235
!C).  It has been shown not to be a substrate to the soluble amine
oxidase from rabbit liver, a property it shares with mescaline, but
whether it is or is not active in man is at present unknown.









#163 3-TME; 3-THIOMETAESCALINE;
4,5-DIMETHOXY-3-ETHYLTHIOPHENETHYLAMINE)

SYNTHESIS: A solution of 13.0 g of
3-bromo-N-cyclohexyl-4,5-dimethoxybenzylidenimine (see under MP for
its preparation) in 125 mL anhydrous Et2O in a He atmosphere was
cooled with an external dry ice acetone bath to -80 !C with good
stirring.  To this clear pale yellow solution there was added 32 mL
1.55 M butyllithium in hexane (about a 25% excess) which was stirred
for 10 min producing a fine white precipitate.  There was then added
7.0 g diethyl disulfide.  The dry ice bath was removed and the
reaction stirred as it came to room temperature.  This was then added
to 300 mL dilute HCl and the aqueous phase separated and heated on the
steam bath for 45 min.  A yellow oil was formed with a nearly
colorless aqueous overhead.  This was removed by decantation, and the
remaining oil was diluted with a little MeOH and additional
concentrated HCl.  After further heating on the steam bath, this was
added to the separated phase, all was cooled and extracted with 2x50
mL CH2Cl2.  Removal of the solvent from these pooled extracts gave
11.8 g of a residue that was distilled.  The product,
3-ethylthio-4,5-dimethoxybenzaldehyde boiling at 106-125 !C at 0.4
mm/Hg and was an almost colorless oil weighing 8.3 g.  Anal.
(C11H14O3S) C,H.

To a solution of 8.2 g 3-ethylthio-4,5-dimethoxybenzaldehyde in 125 mL
nitromethane, there was added 1.0 g of anhydrous ammonium acetate and
the mixture was heated on the steam bath for 1.5 h.  The reaction
mixture was stripped of nitromethane under vacuum, and the residual
red oil was dissolved in 20 mL of boiling MeOH.  This was decanted
from a small amount of insolubles, and allowed to cool to room
temperature.  After considerable manipulation of a small sample with
dry ice cooling, a seed of crystal was obtained, which successfully
promoted crystallization of the entire MeOH solution.  After standing
for 1 h, the product 3-ethylthio-4,5-dimethoxy-'-nitrostyrene was
removed by filtration and, after air drying, weighed 3.2 g with a mp
of 96-98 !C.  Upon recrystallization from MeOH, the mp was tightened
to 98-99 !C.  Anal. (C12H15NO4S) C,H.

AH was prepared in the usual manner from a suspension of 2.0 g LAH in
75 mL anhydrous THF, cooled to 0 !C and well stirred in an inert
atmosphere of He, and treated with 1.33 mL of 100% H2SO4 added
dropwise.  There was added, dropwise and over the course of 10 min, a
solution of 3.1 g 3-ethylthio-4,5-dimethoxy-'-nitrostyrene in 15 mL
anhydrous THF.  At the end of the addition, the reaction mixture was
returned to room temperature, and finally heated on the steam bath for
10 min.  After cooling again, there was added enough IPA to decompose
the excess hydride and sufficient 10% NaOH to convert the aluminum
oxide to a white, easily filterable mass.  This was removed by
filtration, the filter cake washed with additional IPA, and the
filtrate and washes combined and the solvent removed under vacuum.
This was dissolved in 100 mL of dilute H2SO4, which was washed with
2x50 mL CH2Cl2.  The aqueous phase was made basic with NaOH, extracted
with 2x50 mL CH2Cl2, and the extracts pooled and the solvent removed
under vacuum to yield a residue of a colorless oil.  This was
distilled at 160-170 !C at 1.0 mm/Hg yielding 2.6 g of a colorless
liquid.  This was dissolved in 12 mL IPA, neutralized with 24 drops of
concentrated HCl and diluted with 25 mL anhydrous Et2O.  The clear
solution was decanted from a little solid material, and the decantings
diluted with a further 50 mL anhydrous ether.  The still clear
solution became cloudy after a few min, and then there was the slow
formation of 3-ethylthio-4,5-dimethoxyphenethylamine hydrochloride
(3-TME) as a fine white crystalline product.  Removal by filtration,
washing with Et2O, and air drying yielded 2.8 g of white gran-ular
solids that melted at 171-172 !C.  Anal. (C12H20ClNO2S) C,H.

DOSAGE: 60 - 100 mg.

DURATION: 10 - 15 h.

QUALITATIVE COMMENTS: (with 60 mg) As important as the experience
was, itself, I feel that it was in the two or three days that followed
that it had the most profound impact on me.  It was at the time of the
death of my wife's mother, and I found that I could look directly
towards death and its ramifications.  Including my own death.  I felt
very close to the Higher Powers that seemed to make their presence
felt all around.  And there was still the deep internal strength that
was the direct product of the 3-TME experience.  I feel it very
strongly, still, but I have no desire to repeat the experience right
away.  It is almost as if the effects are still in evidence, and one
should take one's time in letting it manifest all its ramifications.
But it is certainly an experience one should have once a year, if not
oftener.

(with 100 mg) I was aware of the development quite early, and by the
end of an hour and a half, I was in quite a remarkable state.  I was
extremely disinhibited, with easy verbal play and easily
self-revealing, but not at too deep a level.  There was great fun with
a set of water colors but, when a used Kleenex became my canvas, the
others failed to share my humor.  I drove home at midnight with
considerable care and was unable to sleep for another two hours.  I
would be very willing to repeat this experiment, at this level, to see
if the good humor of it all was a consistent property.

(with 100 mg) I had a sudden revelation Q what I called the wet-paint
theory of Christ.  How does one find and identify the Messiah?  It is
most simple.  All of life is nothing more than a freshly painted fence
separating us from the rest of the world.  And the fence has many,
many signs on it that say: Beware.  DonUt Touch.  Wet Paint.  And if
you touch too soon, indeed you get a dirty finger because the paint
really is still wet.  But the very first man to touch it and find it
dry?  There is your natural leader, your Son of God, and all those who
touch later than He are the followers of the leader who first touched
and found the paint dry.

EXTENSIONS AND COMMENTARY: A short unraveling of the codes used here
for the various materials is very much needed.  There are 3's and 4Us
and M's and IUs and incipient confusion.  Mescaline is mescaline.
That much is simple.  All homologs are the first letter of the
homolog.  Escaline is E, Proscaline is P, etc.  If the group is at the
three-position, then the term RmetaS is used and an M preceeds the
name of the homolog, i.e., ME is Metaescaline.  The number (3- or 4-
or 5-) gives the position of the sulfur, which is represented by the
prefix RThioS so this compound, 3-TME, has the sulfur at the
3-position, and by chance, the ethyl group there as well.

Here is a brief presentation of the needed Rosetta Stone:

 Number of            all three
are                One oxygen is re-

ethyl groups            oxygen atoms            placed
with sulfur


none                    M                        3-TM

                                                    4-TM


one                    E                        3-TE

                                                    4-TE

                            ME                        3-TME

                                                    4-TME

                                                    5-TME


two                    SB                        3-TSB

                                                    4-TSB

                            ASB                    3-TASB

                                                    4-TASB

                                                    5-TASB


three                    TRIS                    3-T-TRIS

                                                    4-T-TRIS









#164 4-TME; 4-THIOMETAESCALINE;
3-ETHOXY-5-METHOXY-4-METHYLTHIOPHENETHYLAMINE

SYNTHESIS: A solution of 5.1 g N,N,NU,NU-tetramethylethylenediamine
and 6.8 g of 3-ethoxyanisole was dissolved in 80 mL hexane.  This was
stirred vigorously under a He atmosphere and cooled to 0 !C with an
external ice bath.  There was added 27.5 mL of 1.6 M solution of
butyllithium in hexane.  The stirred reaction mixture deposited a fine
white precipitate.  It was warmed to room temperature and stirred for
15 min.  After cooling again to 0 !C, there was added 4.6 mL of
dimethyl disulfide which converted the precipitate to a creamy white
material.  Stirring was continued while the reaction mixture was
brought up to room temperature, and continued for an additional h.
All was then added to 200 mL dilute H2SO4.  The solids dissolved and
there was the formation of two phases.  These were separated, the
aqueous phase extracted with with 2x75 mL Et2O, the organic phases
combined and evaporated under vacuum.  The residue weighed 11.1 g and
set up to a waxy solid.  This was ground under 1 mL of hexane,
filtered, washed sparingly with hexane, and air dried yielding 7.6 g
of 3-ethoxy-2-(methylthio)anisole as white crystals.  The mp was 35-36
!C which was not improved following recrystallization from hexane.
Anal. (C10H14O2S) C,H.

To a stirred solution of 7.6 g of 3-ethoxy-2-(methylthio)anisole in
100 mL CH2Cl2 there was added 6.2 g elemental bromine dissolved in 50
mL CH2Cl2.  The initial dark red color gradually faded to a pale
yellow and there was a steady evolution of HBr.  An added crystal of
iodine did not appear to increase the rate of reaction.  After 4 min
the color was a pale orange.  The reaction mixture was extracted with
H2O containing sufficient dithionite to remove most of the residual
color.  The solvent was removed under vacuum leaving 12.2 g of a pale
yellow fluid oil.  This was distilled at 100-110 !C at 0.3 mm/Hg to
yield a mixture of 4-bromo-3-ethoxy-2-(methylthio)anisole and
6-bromo-3-ethoxy-2-(methylthio)anisole as a pale yellow, highly
refractory oil that was used as such in the following reaction.  Anal.
(C10H13BrO2S) C,H.

To a solution of 12 mL diisopropylamine in 75 mL anhydrous THF that
was stirred under an N2 atmosphere and cooled to -10 !C with an
external ice/MeOH bath, there was added in sequence 35 mL of 1.6 M
butyllithium in hexane, 1.8 mL of dry acetonitrile, and 5.0 g of
4-bromo- (and 6-bromo)-3-ethoxy-2-(methylthio)anisole.  The reaction
mixture changed color from yellow to red to reddish brown.  Stirring
was maintained for an additional 0.5 h, and then the reaction mixture
was poured into 80 mL of dilute H2SO4.  The phases were separated, and
the aqueous phase was extracted with 100 mL CH2Cl2.  The organic
phases were combined, and the solvent was removed under vacuum.  The
oily residue was distilled at 0.2 mm/Hg yielded two fractions.  The
first fraction boiled at 90-115 !C and weighed 1.7 g.  This material
proved to be largely the unreacted bromo starting materials.  The
second fraction came over at 140- 170 !C, weighed 1.7 g, and it
crystallized when seeded with a small crystal obtained externally with
dry ice. This fraction was recrystallized from 10 mL MeOH, filtered,
and washed sparingly with cold MeOH.  After air drying, there was
obtained 0.5 g 3-ethoxy-5-methoxy-4-methylthiophenylacetonitrile which
had a mp of 65-66 !C.  Anal. (C12H15NO2S) C,H.

A suspension of 0.5 g LAH in 50 mL anhydrous THF under N2 was cooled
to 0 !C and vigorously stirred.  There was added, dropwise, 0.35 mL
100% H2SO4, followed by 0.45 g
3-ethoxy-5-methoxy-4-methylthiophenylacetonitrile in 10 mL anhydrous
THF.  The reaction mixture was stirred at 0 !C for a few min, then
brought to a reflux for a few min on the steam bath.  After allowing
the mixture to return to room temperature, there was added IPA
sufficient to destroy the excess hydride followed by 10% NaOH to bring
the reaction to a basic pH and to convert the aluminum oxide to a
loose, white, filterable consistency.  This was removed by filtration,
and washed with 50 mL IPA.  The filtrate and washes were stripped of
solvent in vacuo, and the residue suspended in dilute H2SO4.  This was
washed with 2x75 mL CH2Cl2, made basic with aqueous NaOH, and the
product extracted with 2x75 mL CH2Cl2.  After combining these
extracts, the solvent was removed under vacuum providing 1.2 g of a
residue which was distilled at 132-140 !C at 0.4 mm/Hg to give 0.35 g
of a colorless oil.  This was dissolved in 7 mL of IPA, neutralized
with 7 drops of concentrated HCl and diluted with 3 volumes of
anhydrous Et2O.  The product was removed by filtration, washed with
Et2O, and air dried to give 0.30 g
3-ethoxy-5-methoxy-4-methylthiophenethylamine hydrochloride (4-TME) as
white crystals with a mp of 164-165 !C.  Anal. (C12H20ClNO2S) C,H.

DOSAGE: 60 - 100 mg.

DURATION: 10 - 15 h.

QUALITATIVE COMMENTS: (with 60 mg) There was a strange off-baseness
for several hours in the middle of the day, which was replaced by a
mild gastric upset in the evening.  The mild mental disturbance is
neither visual nor particularly interesting.

(with 100 mg) A benign and gentle altered state became progressively
sad and morbid.  Nothing went together well Q I could not empathize
with anyone, and trying to write at the typewriter was useless.  So
were efforts to sleep at midnight, but this was totally relieved with
200 milligrams of Miltown.  In the morning I seemed still to be off
baseline, and I was extremely sleepy, with much lethargy.  Even
several days later there were problems trying to integrate my emotions
and feelings.  I am not yet completely at peace.

EXTENSIONS AND COMMENTARY: Sometimes things work well in their
mysterious ways.  The reports with 4-TME were more to the toxic than
to the joyous side, and this by chance with a compound that could only
be obtained in an atrociously small yield.









#165 5-TME; 5-THIOMETAESCALINE;
3-ETHOXY-4-METHOXY-5-METHYLTHIOPHENETHYLAMINE

SYNTHESIS: A solution of 10.4 g of
3-bromo-N-cyclohexyl-4-methoxy-5-ethoxybenzylidenimine (see under ME
for its preparation) in 150 mL anhydrous Et2O in a He atmosphere was
cooled with an external dry ice acetone bath to -80 !C with good
stirring.  The addition of 52 mL 1.6 M butyllithium in hexane produced
a thick precipitate which was stirred for 5 min.  There was then added
8.5 mL of dimethyl disulfide and the reaction mixture gradually became
thinner and lighter.  The dry ice bath was removed and the reaction
allowed to come to room temperature over the course of 15 min.  This
was then added to 400 mL of dilute HCl.  The two phases were
separated, and the aqueous phase was heated on the steam bath for 1 h
which generated a separate yellow oily phase.  On cooling, this set to
a yellow solid, which was removed by filtration, washed with H2O, and
sucked relatively free of H2O.  These yellow solids weighed 14.4 g and
were ground under 20 mL of cold cyclohexane which removed almost all
the color and, after filtering and air drying, there remained 12.9 g
of an off-white crystalline solid that melted at 83-84 !C.
Recrystallization from cyclohexane produced
3-ethoxy-4-methoxy-5-(methylthio)benzaldehyde as a white fluffy
crystalline material with a melting point of 84-85 !C.  Anal.
(C11H14O3S) C,H.

To a solution of 8.0 g 3-ethoxy-4-methoxy-5-(methylthio)benzaldehyde
in 100 mL nitromethane, there was added 0.5 g anhydrous ammonium
acetate and the mixture was heated on the steam bath for 1.5 h, at
which time most of the aldehyde had disappeared and there was a
sizeable quantity of nitrostyrene as well as a cascade of wrong things
down to the origin, as seen by TLC on silica gel, with CH2Cl2.  The
excess nitromethane was removed under vacuum, and the residual red oil
was dissolved in 25 mL of hot MeOH and decanted from a small amount of
insoluble material.  With cooling in an ice bath for 20 min, bright
yellow crystals were formed which were removed by filtration, washed
with MeOH and air dried, producing 4.1 g
3-ethoxy-4-methoxy-5-methylthio-'-nitrostyrene which melted at 80-82
!C.  This sample, on resolidification and remelting, melted at 109-110
!C.  This higher-melting polymorphic form was also produced by
recrystallization of the product from cyclohexane.  The two polymorphs
were chromatographically and analytically identical.  Anal.
(C12H15NO4S) C,H.

AH was prepared in the usual manner from a suspension of 3.0 g LAH in
100 mL anhydrous THF, cooled to 0 !C, well stirred in an inert
atmosphere of He, and treated with 2.0 mL of 100% H2SO4 added
dropwise.  There was then added a solution of 2.4 g
3-ethoxy-4-methoxy-5-methylthio-'-nitrostyrene in 20 mL anhydrous THF.
The reaction was exothermic, and had come nearly to a boil at the
half-addition point.  The reaction was cooled again to 0 !C and the
remaining nitro-styrene then added.  This was brought to a reflux
briefly on the steam bath, then cooled again and stirred for an
additional 1 h.  IPA was carefully added to decompose the excess
hydride followed by sufficient 10% NaOH to convert the aluminum oxide
to a white, easily filterable mass.  This was filtered, the filter
cake washed with additional IPA, and the filtrate and washes combined
and the solvent removed under vacuum.  This was dissolved in 100 mL of
dilute H2SO4, which was washed with 2x50 mL CH2Cl2. The aqueous phase
was made basic with sodium hydroxide, extracted with 2x50 mL CH2Cl2,
and the extracts pooled, dried over anhydrous K2CO3, and stripped of
solvent under vacuum to yield a nearly colorless residue.  This was
distilled at 125-135 !C at 0.3 mm/Hg producing 2.0 g of a water-white
oil.  This was dissolved in 8 mL IPA, neutralized with 23 drops of
con-centrated HCl and, with good stirring, diluted with 20 mL
anhydrous Et2O.  The product
3-ethoxy-4-methoxy-5-methylthiophenethylamine hydrochloride (5-TME)
was removed by filtration, washed with Et2O, and air dried to provide
a white solid that weighed 2.0 g and melted at 168-169 !C.  Anal.
(C12H20ClNO2S) C,H.

DOSAGE: greater than 200 mg.

DURATION: unknown.

QUALITATIVE COMMENTS: (with 200 mg) There was a noticeable tinnitus,
but then that comes and goes at odd times without any reason needed.
There was perhaps a brush of light-headedness at the third hour point,
but other than that, nothing.  No effect that can be ascribed to
today's drug trial.

EXTENSIONS AND COMMENTARY: Nothing comes to mind.  This, along with
most of the di- and triethylated thiomescaline analogues, represents a
lot of synthetic effort without useful qualitative data.  If there is
any activity, it would only be seen with monster dosages, and why put
the body through such potential impact?









#166 2T-MMDA-3a; 3,4-METHYLENEDIOXY-2-METHYLTHIOAMPHETAMINE

SYNTHESIS: A solution of 30 g piperonal in 25 mL cyclohexylamine was
brought to a boil on a hot plate, until there was no more water
apparently being evolved.  The resulting melt was distilled giving 45
g of N-cyclohexyl-3,4-methylenedioxybenzylideneimine boiling at
114-135 !C at 0.2 mm/Hg as a light yellow oil.

In 400 mL anhydrous Et2O there was dissolved 40.3 g
N-cyclohexyl-3,4-methylenedioxybenzylidenimine and 30 mL
N,N,NU,NU-tetramethylethylenediamine (TMEDA).  This solution was put
under an inert atmosphere, and with good stirring brought to -78 !C
with an external dry ice/acetone bath, which produced a light white
crystalline precipitate.  There was then added 120 mL of 1.55 M
butyllithium, which produced an immediate darkening and a dissolving
of the fine precipitate.  After 10 min stirring, there was added 20 mL
of dimethyl disulfide.  The color immediately vanished and there was
the formation of a white precipitate.  The temperature was allowed to
return to ice bath temperature, and then all volatiles were removed
under vacuum.  The residue was poured into 500 mL H2O and acidified
with HCl.  After heating for 1 h on the steam bath, the reaction
mixture was cooled, producing a gummy solid that was shown to be a
complex mixture by TLC.  But there was a single fluorescent spot that
was the product aldehyde and it was pursued.  Extraction with 3x75 mL
CH2Cl2 gave, after pooling and stripping of the solvent, a residue
which was extracted with four separate passes, each with 75 mL boiling
hexane.  The deposited crystals from each were separated, and all
recrystallized from boiling MeOH to give 3.3 g of
3,4-methylenedioxy-2-(methylthio)benzaldehyde, with a mp of 77-80 !C.

To a solution of 3.0 g 3,4-methylenedioxy-2-(methylthio)benzaldehyde
in 25 mL IPA there was added 2 mL nitroethane, 0.11 mL ethylenediamine
and 0.1 mL acetic acid.  This was held at reflux temperature for 18 h,
and the solvents removed under vacuum.  The residue showed a total of
eight spots on TLC analysis, extending from the origin to the spot of
the product nitrostyrene itself.  Trituration of this residue under 25
mL MeOH gave a crude nitrostyrene which was, after separation,
recrystallized from 20 mL of boiling MeOH.  The final isolation of
1-(3,4-methylenedioxy-2-methylthiophenyl)-2-nitropropene gave 0.5 g of
a product that had a mp of 94-95 !C.  The mixed mp with the
nitrostyrene from piperonal (mp 97-98 !C) was soundly depressed (mp
67-79 !C).

A solution of AH was prepared by the treatment of a solution of 0.5 g
LAH in 10 mL THF, at 0 !C and under He, with 0.32 mL 100% H2SO4.  A
solution of 0.45 g
1-(3,4-methylenedioxy-2-methylthiophenyl)-2-nitropropene in 10 mL THF
was added dropwise, and the stirring was continued for 1 h.  After a
brief period at reflux, the reaction mixture was returned to room
temperature, and the excess hydride destroyed by the addition of IPA.
The salts were converted to a filterable mass by the addition of 5%
NaOH, and after filtering and washing with IPA, the combined filtrate
and washings were stripped of solvent under vacuum.  The residue was
dissolved in dilute H2SO4 which was washed with 3x75 mL CH2Cl2.  After
alkalinification with 25% aqueous NaOH, the product was extracted with
2x75 mL CH2Cl2.  The extracts were pooled, and the solvent removed
under vacuum.  Distillation of the residue gave a fraction that boiled
at 137-150 !C at 0.3 mm/Hg and weighed 0.3 g.  This was dissolved in
1.6 mL IPA, neutralized with 6 drops of concentrated HCl, warmed to
effect complete solution, and diluted with 4 mL of anhydrous Et2O.
The formed crystals were collected by filtration, and after Et2O
washing and air drying to constant weight, gave 0.3 g
3,4-methylenedioxy-2-methylthioamphetamine hydrochloride (2T-MMDA-3a).

DOSAGE: greater than 12 mg.

DURATION: unknown.

EXTENSIONS AND COMMENTARY: And visions of sugar-plums danced through
their heads.  There are many trisubstituted amphetamine analogues that
have been documented with varying degrees of activity.  There are six
TMA's and if one were to systematically make every possible
thio-analogue of each of these, there would be a total of sixteen
thio-analogues of the TMA.  Let's go for it, said I to myself.  LetUs
get the 16 thio analogues in hand.  That is where the action's at.
But hold on a minute.  Each and every MMDA isomer has, by definition,
three possible thio analogues, so there are eighteen more possible
thio compounds just with them.  Sure, let's make them all!  It will be
an unprecedented coup for students of structure-activity
relationships.  Let's whip out some 34 compounds, and test them all,
and maybe we will begin to understand just why those which are active
are, indeed, active.  And maybe not.

Anyway, this was the most manic of all manic programs ever, involving
thio-analogues.  And it was totally compelling.  Another synthetic
clue stemmed from the fact that vanillin also formed the cyclic
carbonate with sodium thiocyanate and it could, in principle, be
brought around in time to 3-methoxy-5,4-methylenethiooxyamphetamine,
or 5T-MMDA.  That made two of the magic analogues, and only some 32 to
go.  What a marvelous task for a graduate student.  (What a horribly
dull task for a graduate student.)  But in any case there was no
graduate student, and this appeared to be the end of the line.  Some
day, let's make all these possibilities.  A magnificent tour-de-force,
but at the present time, not worth the effort.  Other directions are
more exciting and more appealing.

A last note of simple humor.  One of the compounds used in this
preparation was N,N,NU,NU-tetramethylethylenediamine, which has been
abbreviated TMEDA.  There is a pattern, within any active inner clique
of research chemists intently pursuing a goal, to begin condensing
complex comcepts into deceptively simple terms.  We RMOM-ed the
hydroxy group of the T-BOC-ed amine.S I have recently heard the above
tetramethyl monster referred to in the chemist's jargon as a
pronounced, rather than a spelled out, word.  It sounds very much like
RtomatoS spoken by a native of the Bronx.









#167 4T-MMDA-2; 6-(2-AMINOPROPYL)-5-METHOXY-1,3-BENZOXATHIOL;
2-METHOXY-4,5-METHYLENETHIOOXYAMPHETAMINE

SYNTHESIS: To a well-stirred solution of 120 g thiourea in 800 mL 2N
HCL, there was added a solution of 100 g benzoquinone in 500 mL acetic
acid over the course of 15 min.  Stirring was continued for an
additional 0.5 h at room temperature, and then the reaction mixture
was heated on the steam bath for 1 h.  With cooling in ice water, a
heavy crop of crystals separated.  These were removed by filtration
and air dried to provide 90.1 g of 5-hydroxy-1,3-benzoxathiol-2-one
(2-mercaptohydroquinone cyclic carbonate ester) with a melting point
of 170.5-172.5 !C.

To a suspension of 100 g finely powdered anhydrous K2CO3 in 400 mL
acetone containing 50 g methyl iodide there was added 41 g
5-hydroxy-1,3-benzoxathiol-2-one, and the mixture stirred overnight at
room temperature.  The solids were removed by filtration, and the
solvent removed under vacuum.  The residue was distilled to give a
fraction subliming over as a solid at an oven temperature of 110 !C at
0.1 mm/Hg.  This was a yellowish solid, weighing 27.4 g and having a
mp of 66-72 !C.  Recrystallization from MeOH gave
5-methoxy-1,3-benzoxathiol-2-one as a white solid with a mp of
75.5-76.5 !C.

To a solution of 30 g 85% KOH in 75 mL warm H2O, there was added an
equal volume of warm MeOH followed by 16 g
5-methoxy-1,3-benzoxathiol-2-one, and the mixture was held under
reflux conditions for 2 h.  After cooling to room temperature, the mix
was acidified with HCl and extracted with 2x100 mL CH2Cl2.  Removal of
the solvent from the pooled extracts gave a yellow oil that
crystallized on standing.  The product, 2-mercapto-4-methoxyphenol,
weighed 14 g and had a mp of 56-57 !C.

A solution of 10 g 2-mercapto-4-methoxyphenol in 100 mL MEK was added
over the course of 1 h to a vigorously stirred suspension of 25 g
finely powdered anhydrous K2CO3 in 200 mL MEK that contained 14 g
methylene bromide.  The reflux was maintained for 48 h.  After
cooling, the mixture was freed of solids by filtration and the filter
cake washed with 50 mL additional MEK.  The combined washes and
filtrate were stripped of solvent under vacuum, and the product
distilled to give 3.3 g of 5-methoxy-1,3-benzoxathiol as a yellowing
oil that had a bp of 110-120 !C at 1.7 mm/Hg.  There was considerable
residue in the pot, which was discarded.  The NMR spectrum was
excellent, with the methylene protons a two-hydrogen singlet at 5.6
ppm.

To a mixture of 3.2 g POCl3 and 2.8 g N-methylformanilide that had
been heated briefly on the steam bath (to the formation of a deep
claret color) there was added 2.3 g 5-methoxy-1,3-benzoxathiol, and
steam bath heating was continued for an additional 5 min.  The
reaction mixture was poured into 100 mL H2O, and after a few minutes
stirring, the insolubles changed to a loose solid.  This was collected
by filtration, H2O washed and, after sucking as dry as possible,
recrystallized from 30 mL boiling MeOH.  This provided 1.9 g of
6-formyl-5-methoxy-1,3-benzoxathiol as brownish needles that melted at
119-120 !C.

A solution of 1.5 g 6-formyl-5-methoxy-1,3-benzoxathiol in 50 mL
nitroethane was treated with 0.3 g anhydrous ammonium acetate and
heated on the steam bath for 5 h.  Removal of the solvent under vacuum
gave a residue that crystallized.  This was recrystallized from 110 mL
boiling EtOH providing, after fil-tering and air drying, 1.3 g
5-methoxy-6-(2-nitro-1-propenyl)-1,3-benzoxathiol as San Francisco
Giants-orange-colored crystals.

A solution of AH was prepared by the treatment of a solution of 1.3 g
LAH in 10 mL THF, at 0 !C and under He, with 0.8 mL 100% H2SO4.  A
solution of 1.1 g of 5-methoxy-6-(2-nitro-1-propenyl)-1,3-benzoxathiol
in 25 mL THF was added dropwise, and the stirring was continued for 1
h.  After a brief period at reflux, the reaction mixture was returned
to room temperature, and the excess hydride destroyed by the addition
of IPA.  The salts were converted to a filterable mass by the addition
of 5% NaOH and, after filtering and washing with IPA, the combined
filtrate and washings were stripped of solvent under vacuum.  The
residue was dissolved in dilute H2SO4 which was washed with 3x75 mL
CH2Cl2 and then, after being made basic with 25% NaOH, the product was
extracted with 2x75 mL CH2Cl2.  The extracts were pooled, and the
solvent removed under vacuum.  Distillation of the residue gave a
fraction that boiled at 140-155 !C at 0.3 mm/Hg which weighed 0.7 g.
This was dissolved in 4 mL IPA, neutralized with 14 drops of
concentrated HCl, heated to effect complete solution, then diluted
with 10 mL of anhydrous Et2O.  The white crystals that formed were
removed, Et2O washed, and air dried to give 0.6 g
6-(2-aminopropyl)-5-methoxy-1,3-benzoxathiol hydrochloride
(4T-MMDA-2).

DOSAGE: greater than 25 mg.

DURATION: unknown.

QUALITATIVE COMMENTS: (with 25 mg) At three hours after having taken
the material, I felt that there might have been a little exhilaration.
And maybe a hint of tremor and of teeth clench.  Perhaps this is a
threshold dose.

EXTENSIONS AND COMMENTARY: There is no logical way to try to guess
where the active level of this might be.  In a comparison of 4-oxy
with 4-thio- and with 4-alkyl (as, for example, TMA-2, PARA-DOT and
DOM) the analogue with the sulfur atom lies intermediate in potency
between the oxygen atom and the carbon atom.  Then, perhaps, 4T-MMDA-2
should be somewhat more potent than MMDA-2.  Which is where the trials
have gone to, and the absence of effects therefore declares that line
of reasoning invalid.  What else could be used for clues?  The whole
benzofuran project, which had the same cyclic nature, was without
activity.  They had a carbon where the sulfur was of 4T-MMDA- 2, so,
by that reckoning, this compound should be even less active.  Maybe
that is the formula to follow.  The bottom line is inescapable.  None
of these extrapolations can hold a candle to the only experiment that
can give believable findings, the actual trial of a new compound in
man.

The positional isomer of the heterocyclic carbonate used here is also
known.  Instead of using benzoquinone as a starting material with
thiourea as the sulfur source (giving the 1,4- oxygen orientation),
one can start with resorcinol in reaction with ammonium thiocyanate as
the sulfur source (in the presence of copper sulfate) and get the
positional isomer with a 1,3- oxygen orientation.  This material (also
known as thioxolone, or tioxolone, or
6-hydroxy-1,3-benzoxathiol-2-one, and which is commercially available)
should follow the same chemistry shown here for the 5-hydroxy
analogue, and give 5T-MMDA-2
(5-(2-aminopropyl)-6-methoxy-1,3-benzoxathiole or
2-methoxy-5,4-methylenethiooxyamphetamine) as a final product.  I
would guess, based on the findings that compare 5-TOM with DOM, that
this would be a relatively low-potency compound.  At least it should
be an easy one to make!









#168 TMPEA; 2,4,5-TRIMETHOXYPHENETHYLAMINE

SYNTHESIS: To a solution of 39.2 g 2,4,5-trimethoxybenzaldehyde in 160
mL nitromethane there was added 7.0 g anhydrous ammonium acetate, and
the mixture was heated on the steam bath for 2 h.  The
excesssolvent/reagent was removed under vacuum, leaving a deeply
colored residue that spontaneously crystallized.  This was
mechanically removed and triturated under 60 mL cold MeOH.
Filtration, washing with cold MeOH and air drying, gave 49.3 g of
bright orange crystals.  Trial recrystallizations from EtOAc gave a mp
of 132-133 !C; from CH3CN, 130.5-131.5 !C.  The entire product was
recrystallized from 1.1 L boiling IPA to provide, after filtration,
IPA washing, and air drying, 34.5 g of '-nitro-2,4,5-trimethoxystyrene
as yum-yum orange crystals with a mp of 132-133 !C.  Literature values
are usual one-degree ranges, anywhere in the area of 127-130 !C.

To a suspension of 30 g powdered LAH in 800 mL of well stirred and
refluxing anhydrous THF there was added a solution of 34.9 g
'-nitro-2,4,5-trimethoxystyrene in 200 mL anhydrous THF.  The mixture
was maintained at reflux for an additional 36 h, cooled, and the
excess hydride activity destroyed by the addition of 30 mL H2O
followed by 30 mL 15% NaOH, and finally with another 90 mL H2O.  The
solids were removed by filtration, washed with THF, and the pooled
mother liquor and washings stripped of solvent under vacuum.  The
residue was dissolved in CH2Cl2, washed with both 5% NaOH and then
H2O, removing much of the color.  It was then extracted with 3x75 mL N
HCl.  The pooled red-colored acid extracts were washed with CH2Cl2,
made basic with 25% NaOH, and extracted with 3x75 mL CH2Cl2.  Removal
of the solvent gave some 25 g of residue which was dissolved in 100 mL
IPA and neutralized with concentrated HCl.  The crystalline mass that
formed was diluted with an equal volume of Et2O, and the solids
removed by filtration.  Washing with cold IPA, followed by Et2O and
air drying, gave 17.7 g of 2,4,5-trimethoxyphenethylamine
hydrochloride (TMPEA) as a white product.  The reported melting point
was 187-188 !C.

DOSAGE: greater than 300 mg.

DURATION: unknown.

QUALITATIVE COMMENTS: (with less than 300 mg) Since it was not easy,
however, to judge the extent of a 'Rausch'-action from experiments on
animals, some injections of beta-2,4,5-trimethoxyphenethylamine were
administered to the author, and finally a control test was carried out
with an equal quantity of mescaline.  The action of both these
substances in these experiments agreed only to a limited extent with
the effects described for mescaline by, for example, Beringer.  It
must be remembered, however, in this connection, that the quantities
used by Beringer were larger than the doses administered in these
experiments.  Nevertheless, it may be concluded that the
pharmacological action of beta-2,4,5-trimethoxyphenethylamine agrees
to a large extent with that of mescaline.  However, the new compound
had more unpleasant secondary effects (nausea) and did not bring about
the euphoristic state caused by mescaline.

(with 300 mg) Under double blind conditions, I was unable to
distinguish this from a placebo.  Both were without any of the changes
described after the ingestion of psychotomimetic drugs.

(with 200 mg, followed after 45 minutes, with 100 mg mescaline) RThe
normally modest effects known to be due to mescaline alone at this
level, were strongly potentiated with the earlier taking of
2,4,5-TMPEA.  The effects were stronger as well as longer lived.

EXTENSIONS AND COMMENTARY: The code letters used for this drug are not
as ambiguous as they might seem at first glance.  A large number of
the 2-carbon homologues are given names based on the code for the
3-carbon compound.  On that basis, this should be 2C-TMA-2, since it
is the 2-carbon counterpart of TMA-2.  But since the first of the
trimethoxyphenethylamines already had a trivial name, mescaline, the
code TMPEA was unassigned.  So, here is the logical place to use it.

There have been just two reports published of self-experimentation
with TMPEA, and these comments are taken from them.

The first is presented here, word for word, as it was originally
published (this was in 1931).  It leaves much to be desired.  The
administration was by injection (intramuscular injection?).  The dose
was not given, but it was less than those reported by Beringer in his
studies with mescaline, and this latter experimenter's published
levels were all between 300 and 500 milligrams.  What can one conclude
from all this?  Only that TMPEA apparently did not measure up to
mescaline in his comparisons.

The second, reported some 40 years later, is not really contradictory.
Here the TMPEA was administered orally, and the subject surrounded
himself with a battery of psychological tests.  This might allow
statistics to provide an aura of validity to the observations.  But
the comments are pretty self-explanatory.  The drug was not active in
its own right, but when employed preliminary to mescaline, greatly
enhanced the effects of the latter.

This is an area of research that deserves more attention.  The simple
compound that results from the stripping of all three of the O-methyl
groups from TMPEA is the extremely potent neurotoxin,
6-hydroxydopamine.  When it is ad-ministered to an otherwise intact
experimental animal, it produces sympathectomy, effectively destroying
the sympathetic nervous system.  And some of the methyl groups of
TMPEA are known to be stripped off through the normal metabolic
processes that occur in the liver.  There are many fascinating
psychedelics that have a signature of methoxyl groups para to
one-another.  It is known that they, too, can lose a methyl group or
two.  It would be intriguing to see if there was some biochemical
overlap between the metabolism of some of these centrally active drugs
and the metabolic fate of 6-hydroxydopamine.  But in a test animal, of
course, rather than in man.









#169 2-TOET; 4-ETHYL-5-METHOXY-2-METHYLTHIOAMPHETAMINE

SYNTHESIS: A mixture of 24.4 g ortho-ethylphenol and 18.9 mL methyl
iodide was added to a solution of 15.6 g 85% KOH in 100 mL hot MeOH.
The mixture was kept at reflux temperature overnight, stripped as much
as possible of the MeOH, and poured into 1 L H2O.  An excess of 5%
NaOH was added and this was extracted with 3x75 mL CH2Cl2.  The pooled
extracts were washed with 1% NaOH, and the solvent removed under
vacuum to give 32.8 g of a pale amber oil.  This was distilled at
55-65 !C at 0.4 mm/Hg to yield 22.0 g of 2-ethylanisole as a colorless
oil.

To a 21.7 g sample of 2-ethylanisole, well stirred but without
solvent, there was added, 1 mL at a time, 21 mL of chlorosulfonic
acid.  The color progressed from white to yellow, and finally to deep
purple, with the evolution of much HCl.  The exothermic reaction
mixture was allowed to stir until it had returned to room temperature
(about 0.5 h).  It was then poured over 400 mL cracked ice with good
mechanical stirring, which produced a mass of pale pink solids.  These
were removed by filtration, washed well with H2O, and air dried to
give about 27 g of 3-ethyl-4-methoxybenzenesulfonyl chloride as an
off-white solid that retained some H2O.  A sample recrystallized from
cyclohexane had a mp of 44-46 !C.  A sample treated with ammonium
hydroxide provided white crystals of
3-ethyl-4-methoxybenzenesulfonamide which could be recrystallized from
H2O to give tufts of crystals with a mp of 97-98 !C.  Anal.
(C9H13NO3S) C,H.

In a 2 L round bottomed flask equipped with a mechanical stirrer there
was added 200 mL cracked ice, 45 mL of concentrated H2SO4, 26.7 g of
still moist 3-ethyl-4-methoxybenzenesulfonyl chloride, and 45 g
elemental zinc dust.  With external heating, an exothermic reaction
set in and the temperature was maintained at reflux conditions for 4
h.  After cooling to room temperature, the reaction mixture was
filtered and the insolubles washed alternately with H2O and with
CH2Cl2.  The mother liquors and washings were diluted with sufficient
H2O to allow CH2Cl2 to become the lower phase.  These phases were
separated, and the aqueous phase extracted with 3x100 mL CH2Cl2.  The
original organic phase and the extracts were pooled, washed with H2O,
and the solvent removed to give 15.7 g of a smelly amber oil.  This
was distilled at 72-84 !C at 0.3 mm/Hg to give 12.1 g of
3-ethyl-4-methoxythiophenol as a water-white oil.  The infra-red was
perfect (with the SH stretch at 2562, OCH3 at 2837 and 1061, and with
fingerprint peaks at 806, 880, 1052, (1061), 1142 and 1179 cm-1).
Anal. (C9H12OS) C,H.

To a solution of 11.7 g of 3-ethyl-4-methoxythiophenol and 6.5 mL
methyl iodide in 100 mL MeOH there was added, with good stirring and a
bit at a time, a solution of 5.5 g 85% KOH in 25 mL hot MeOH.  The
mixture was held at reflux on the steam bath for 1.5 h, and then
stripped of volatiles under vacuum.  The residues were added to 400 mL
H2O, made strongly basic with 5% NaOH, and extracted with 3x75 mL
CH2Cl2.  The pooled extracts were back-washed with 1% NaOH, and the
solvent removed under vacuum.  The 13.2 g residue was distilled giving
2-ethyl-4-(methylthio)anisole as a fraction boiling at 78-85 !C at 0.2
mm/Hg.  The weight was 11.6 g for an isolated yield of over 90% of
theory.  The mp was at about 0 !C.  The infra-red showed no SH or
other functionality, but an OCH3 at 2832 and 1031, and a fingerprint
spectrum with peaks at 808, 970, (1031), 1051, 1144 and 1179 cm-1.
Anal. (C10H14OS) C,H.

A solution of 11.2 g 2-ethyl-4-(methylthio)anisole and 9 g
dichloro-methyl methyl ether in 200 mL dry CH2Cl2 was treated with 13
g anhydrous aluminum chloride, added a bit at a time.  The color
progressed from pink to claret to deep claret, with a modest evolution
of HCl.  Stirring was continued for 1 h, then the reaction was
quenched by the cautious addition of 250 mL H2O.  The two phase
mixture was stirred an additional hour and then separated.  The
aqueous phase was extracted with 2x100 mL CH2Cl2.  The organics were
pooled, washed with 5% NaOH, then with saturated brine, and the
solvent removed under vacuum.  The residue was an amber oil weighing
13.7 g.  This was distilled at 0.2 mm/Hg.  A first fraction was a
yellow oil boiling at 90-100 !C, and weighing 2.9 g.  It was a mixture
of starting anisole and the desired benzaldehyde.  A second fraction,
boiling at 100-130 !C was a viscous yellow oil weighing 4.8 g.  By TLC
it was free of starting anisole, and contained a sizeable quantity of
a second benzaldehyde.  From this fraction, seed crystal was obtained,
and when the oil was dissolved in an equal volume of MeOH, the seed
took, producing a yellow solid.  This was filtered and air dried, to
give 2.2 g of 4-ethyl-5-methoxy-2-(methylthio)benzaldehyde with a mp
of 62-63 !C.  A small sample from MeOH was almost white, and melted at
61-62 !C.  The mixed mp with
4-ethyl-2-methoxy-5-(methylthio)benzaldehyde (57-58 !C) was severely
depressed (37-44 !C).  A cooled solution of the first fraction of the
distillation, in MeOH, provided an additional 1.6 g product, with a mp
59-61 !C.  The combined mother liquors gave additional product for an
overall weight of 5.3 g.  Anal. (C11H14O2S) C,H.

A solution of 1.9 g 4-ethyl-5-methoxy-2-(methylthio)benzaldehyde in 75
mL nitroethane was treated with 0.3 g anhydrous ammonium acetate, and
held on the steam bath for 2.5 h.  The excess solvent/reagent was
removed under vacuum, and the deep orange oil residue was dissolved in
10 mL boiling MeOH.  As this cooled, there was the spontaneous
generation of crystals.  After cooling in an ice bath for a few h,
these were removed by filtration, washed with MeOH, and air dried to
constant weight.  A total of 1.4 g of
1-(4-ethyl-5-methoxy-2-methylthiophenyl)-2-nitropropene was obtained
as canary-yellow crystals melting at 83-84 !C which was not improved
by recrystallization from MeOH.  Anal. (C13H17NO3S) C,H.

To a solution of 1.5 g LAH in 30 mL anhydrous THF that was cooled to 0
!C and stirred under a He atmosphere, there was added, slowly, 1.05 mL
freshly prepared 100% H2SO4 (prepared by adding 0.9 g 20% fuming H2SO4
to 1.0 g 96% concentrated H2SO4).  This was followed by the addition
of a solution of 1.4 g
1-(4-ethyl-5-methoxy-2-methylthiophenyl)-2-nitropropene in 20 mL THF,
over the course of 10 min.  The color of the nitrostyrene solution was
discharged immediately upon addition.  With continued stirring, this
was allowed to come to room temperature, and then to a gentle reflux
for 2 h.  After cooling again to room temperature, the excess hydride
was destroyed by the addition of IPA.  Sufficient 5% NaOH was added to
generate the inorganic salts as a loose filterable mass, and these
were removed by filtration.  The filter cake was well washed with
additional IPA, and the combined mother liquors and washes were
stripped of solvent under vacuum.  The residue was dissolved in 100 mL
dilute H2SO4, washed with CH2Cl2, made basic with 5% NaOH, and
extracted with 2x75 mL CH2Cl2.  Removal of the solvent gave a residue
that was distilled at 102-117 !C at 0.15 mm/Hg.  The colorless liquid
that distilled (0.7 g) was dissolved in 6 mL IPA and neutralized with
11 drops of concentrated HCl.  The solids that formed were dissolved
by heating the mixture briefly to a boil, and this clear solution was
diluted with 20 mL anhydrous Et2O.  The white crystals of
4-ethyl-5-methoxy-2-methylthioamphetamine hydrochloride (2-TOET)
weighed 0.6 g and had a mp of 164-167 !C.  Anal. (C13H22ClNOS) C,H.

DOSAGE: greater than 65 mg.

DURATION: unknown.

QUALITATIVE COMMENTS: (with 50 mg) After about an hour and a half, I
found myself a little light-headed.  And maybe a feeling of being
physically a bit fragile.  I ate something, but there was not much joy
in eating.  And the next day there was some residual fragility,
whatever that means.  Ahead with caution.

(with 65 mg) During the day this was barely noticeable, but
pleasant.

EXTENSIONS AND COMMENTARY: It seems as if the sulfur in the 2-position
makes things less interesting, and less potent, than when it is in the
5-position.  2-TOM required twice the dosage of 5-TOM, and here it
appears that it could well take a dosage of twice that required for
5-TOET, to get 2-TOET off the ground.  There is an understandable
reluctance to push on upwards in dosage with a new and unknown
compound, when there are feelings of physical discomfort that outweigh
the mental effects.  There is nothing tangible here.  In the complete
report of the 50 milligram trial, there is a mention of an inability
to effect erection, and this with the light-headedness and disinterest
in food, all suggest some involvement with the sympathetic nervous
system.  And with these subtle effects persisting into the next day,
why push higher?  Instinct said to leave it alone.  So I left it
alone.

The 2-carbon analogue, 2C-2-TOET, was made from the same aldehyde
intermediate.  The appropriate nitrostyrene came smoothly from the
aldehyde and nitromethane, and gave glistening pumpkin-orange crystals
from methanol, that melted at 93-94 !C.  Anal. (C12H15NO3S) C,H.  The
final phenethylamine hydrochloride salt was prepared from its
reduction with aluminum hydride in THF, and was isolated in the usual
manner.  It was a white crystalline mass that melted at 226-227 !C.
It, as with the other 2-carbon analogues of the TOMs and TOETs,
remains untasted as of the moment.









#170 5-TOET; 4-ETHYL-2-METHOXY-5-METHYLTHIOAMPHETAMINE

SYNTHESIS: A solution of 25 g 3-ethylphenol in 100 mL Et2O was
equipped with a magnetic stirrer, and cooled to 0 !C with an external
ice bath.  There was added 16 mL DMSO.  Then, a total of 15 mL
chlorosulfonic acid was added dropwise, over the course of 30 min.
The reaction was allowed to return to room temperature and stirred
overnight.  The overhead Et2O phase was removed by decantation, and
the light-colored residue was dissolved in 100 mL IPA.  The clear
solution spontaneously generated white crystals which were allowed to
stand for 1 h, removed by filtration, and lightly washed with IPA.
After air-drying, this crop of
dimethyl-(2-ethyl-4-hydroxyphenyl)-sulfonium chloride weighed 20.0 g
and had a mp of 168-170 !C without obvious effervescence.  A solution
of 19.8 g of this sulfonium salt in 200 mL H2O was diluted with 500 mL
MeOH, and there was added 30 g NaOH.  This was heated to reflux on the
steam bath.  There was an initial deposition of some white solids, but
after 36 h the solution was almost clear.  The excess MeOH was removed
under vacuum, and the non-volatiles were poured into 1 L H2O.  This
was acidified with HCl, and extracted with 3x100 mL CH2Cl2.  The
extracts were pooled, and the solvent removed under vacuum.  The
residue, 12.6 g of an amber oil, was distilled at 95-120 !C at 0.3
mm/Hg to give 10.0 g of 3-ethyl-4-(methylthio)phenol as an off-white
oil.  This spontaneously crystallized to a solid that had a mp of
47-49 !C.  Recrystallization of an analytical sample from cyclohexane
gave a mp of 47-48 !C.

To a solution of 9.7 g 3-ethyl-4-(methylthio)phenol in 50 mL MeOH
there was added a solution of 4.6 g 85% KOH in 50 mL hot MeOH.  There
was then added 5.4 mL methyl iodide and the mixture was held at reflux
on the steam bath for 18 h.  Removal of the solvent under vacuum gave
a residue that was poured into 1 L H2O and made strongly basic by the
addition of 5% NaOH.  This was extracted with 3x75 mL CH2Cl2, and the
extracts were pooled and the solvent removed under vacuum.  There
remained 11.0 g of an almost white oil with a startling apple smell.
This oil was distilled at 78-88 !C at 0.3 mm/Hg to give 7.9 g
3-ethyl-4-(methylthio)anisole as a white oil.  Anal. (C10H14OS) C,H.

A mixture of 7.8 g POCl3 and 6.9 g N-methylformanilide was heated on
the steam bath for a few min, until there was the development of a
deep claret color.  This was added to 7.7 g
3-ethyl-4-(methylthio)anisole and the mixture was heated on the steam
bath for 2 h.  This was poured into 400 mL H2O and stirred overnight,
which produced an oily phase with no signs of crystals.  The entire
reaction mixture was extracted with 3x75 mL CH2Cl2, and the pooled
extracts washed with H2O.  Removal of the solvent under vacuum gave
9.2 g of a residue.  This was suspended in 25 mL hexane, and after 1 h
standing, the overhead clear solution was decanted from the settled
sludge.  This hexane solution was stripped of solvent under vacuum,
giving 7.7 g of an oil that by TLC was a mixture of starting ether and
desired aldehyde.  This was distilled at 0.25 mm/Hg to give three
fractions, the first boiling at 75-100 !C (2.7 g) and the second at
100-115 !C (2.6 g).  These were largely starting ether and aldehyde,
and were chemically processed below.  A third fraction, boiling at
120-140 !C, solidified in the receiver, weighed 1.6 g, and was largely
the desired aldehyde.  Cuts #1 and #2 (5.3 g of what was mostly
recovered aldehyde) were resubmitted to the Vilsmeier reaction.  A
mixture of 5.4 g POCl3 and 4.7 g N-methylformanilide was heated on the
steam bath until it became claret-colored.  The recovered aldehyde was
added, and the mixture was heated overnight on the steam bath.  This
was poured into 500 mL H2O.  The heavy tar that was knocked out was
extracted with 3x75 mL CH2Cl2, and the solvent was removed from the
pooled extracts under vacuum.  Some 5.8 g of residue was obtained, and
this was heated to 120 !C at 0.2 mm/Hg to remove all materials lower
boiling than the desired aldehyde.  The very dark pot was extracted
with 3x50 mL boiling hexane, and removal of the solvent from these
pooled extracts under vacuum gave 0.9 g of a yellow oil.  This was
distilled at 0.2 mm/Hg to give a fraction boiling at 130-140 !C which
spontaneously crystallized.  This pressed on a porous plate gave
almost white crystals with a mp of 55-57 !C.  Recrystallization from
0.3 mL cyclohexane provided 0.3 g of
4-ethyl-2-methoxy-5-(methylthio)benzaldehyde with a mp of 57-58 !C.
The total yield was 1.9 g.  Anal. (C11H14O2S) C,H.

To a solution of 1.2 g 4-ethyl-2-methoxy-5-(methylthio)benzaldehyde in
25 mL nitroethane there was added 0.25 g anhydrous ammonium acetate
and the mixture was heated on the steam bath.  The initial color was
green, but this quickly changed to the more usual yellow which
darkened as the reaction mixture was heated.  After 1.5 h heating, the
excess solvent/reagent was removed in vacuo.  The yellow residue was
dissolved in 10 mL hot MeOH and allowed to stand in the refrigerator
overnight.  There was an orange oil layer formed underneath the MeOH.
A small sample of this was scratched externally with dry ice, and seed
was obtained.  The orange oil layer slowly set to crystals which,
after a few h, were removed by filtration to give 1.3 g of a slightly
sticky orange solid with a mp of 43-45 !C.  This was recrystallized
from 8 mL boiling MeOH to give, after cooling, filtering, and air
drying to constant weight, 1.1 g of
1-(4-ethyl-2-methoxy-5-methylthiophenyl)-2-nitropropene as
electrostatic yellow crystals melting at 59-60 !C.  Anal. (C13H17NO3S)
C,H.

A solution of 1.0 g LAH in 25 mL tetrahydrofuran was cooled, under He,
to 0 !C with an external ice bath.  With good stirring there was added
0.6 mL 100% H2SO4 dropwise, to minimize charring.  This was followed
by the addition of 1.1 g of
1-(4-ethyl-2-methoxy-5-methylthio)-2-nitropropene in a small amount of
THF.  After 10 min further stirring, it was brought up to room
temperature and allowed to stand for several days.  The excess hydride
was destroyed by the cautious addition of IPA followed by sufficient
15% NaOH to give a white granular character to the aluminum oxide, and
to assure that the reaction mixture was basic.  This was filtered, and
the filter cake washed first with THF and then with IPA.  The filtrate
and washings were pooled and stripped of solvent under vacuum
providing a pale amber residue.  This was dissolved in 50 mL of dilute
H2SO4 and washed with 2x50 mL CH2Cl2.  The aqueous phase was made
basic with 5% NaOH, and extracted wit 2x50 mL CH2Cl2.  These extracts
were pooled, stripped under vacuum, and distilled at 0.15 mm/Hg.  The
fraction with a bp of 102-128 !C weighed 0.4 g and was a colorless
liquid.  This was dissolved in a small amount of IPA, neutralized with
concentrated HCl and diluted with anhydrous Et2O to provide the
4-ethyl-2-methoxy-5-methylthioamphetamine hydrochloride (5-TOET) which
weighed 0.6 g and melted at 146-147 !C.  Anal. (C13H22ClNOS) C,H.

DOSAGE: 12 - 25 mg.

DURATION: 8 - 24 h.

QUALITATIVE COMMENTS: (with 8 mg) After my totally freaky experience
on the very closely related compound in this series, 5-TOM, I intended
to approach this with some caution.  Three milligrams was without
effects, so I tried eight milligrams.  I was a little light-headed,
and saw sort of a brightness around trees against the blue sky.
Noticed movement on couch in living room, and there was some activity
in the curtains, almost 2C-B like.  In the evening writing was still
difficult, and there was eye dilation but minimal nystagmus.  My sleep
was fitful, but certainly there was no hint of the 5-TOM storm.

(with 18 mg) This was too much.  There was an exhausting visual
hallucinatory tinsel, continuous movement, and there was no escape.
It popped into an LSD-like thing, strong, restless, constantly
changing, with too much input.  I had to take a Miltown to calm down
enough for an attempt at sleep.  In the morning, a day later, I was
still 1.5 + and tired of it.  It was the next day after that before I
was completely clear.

(with 20 mg) This has the makings of a superb, extraordinary
material.  I didnUt get to a full plus two, maybe something around a
plus one and three quarters.  The eyes-closed fantasy was exceptional,
with new dimensions.  The nature of the fantasy, the feeling that one
had about the fantasy figures and landscapes, was the essence of joy,
beauty, lovingness, serenity.  A glimpse of what true heaven is
supposed to feel like.  Or maybe a button in the brain was pushed
which has not been pushed by previous chemicals.  Insight?  DonUt know
yet.  I was able to function without difficulty with eyes closed or
open.  Erotic absolutely exquisite.  In fact, the entire experience
was exquisite.  Next day, same sense of serene, quiet joy/beauty
persisted for most of the day.  A true healing potential.  Onwards and
upwards.  This one could be extraordinary.

(with 30 mg) Tried to focus on cosmic questions, and succeeded.  Very
little fantasy images for the first 2-3 hours. After that, lovely
interacting, music okay but not vital.  On this compound the Brahms
Concerto #1 gave vivid 'memory' impressions of house and vegetable
garden, like a primitive painting.  Tremendous nostalgia for a place
IUve never seen.

EXTENSIONS AND COMMENTARY: With the extraordinary experience that had
been observed with one person with 5-TOM, this ethyl homologue was not
only run up with special caution, but that individual ran his own
personal titration.  And he proved to be perhaps twice as sensitive to
5-TOET than any of the other subjects.  An approach to what might just
be some unusual metabolic idiosyncrasy on the part of his liver, is
discussed in the recipe for TOMSO.

The initials of TOET progressed quite logically from TOM, in an exact
parallel with the relationship between the corresponding sulfur-free
analogues, where the ethyl compound is DOET and the methyl counterpart
is DOM.  RTS for RthioS which is the chemical nomenclature term for
the replacement of an oxygen atom with a sulfur atom.  And, as has
been discussed in the text of this volume, the peculiarities of
pronunciation in this series are interesting, to say the least.  TOM
is no problem.  But TOET could have any of several pronunciations such
as RTwo-itS, or RTow-itS, or RToo-wetS, but somehow the one syllable
term RTwatS became regularly used, and the family was generally
referred to as the RToms and Twats.S The almost-obscene meaning of the
latter was progressively forgotten with usage, and has led to some
raised eyebrows at occasional seminars when these compounds are
discussed.  And not only at seminars.  Once at the between-acts
intermission at the Berkeley Repertory Theater, the topic came up and
the phrase was used.  There was a stunned silence about us within the
circle of hearing, and we seemed to have been given a little extra
room immediately thereafter.

As with the other members of the TOM's and TOETUs, the phenethylamine
homologue of 5-TOET was synthesized, but had never been started in
human evaluation.  The aldehyde from above,
4-ethyl-2-methoxy-5-(methylthio)benzaldehyde, was condensed with
nitroethane (as reagent and as solvent) and with ammonium acetate as
catalyst to give the nitrostyrene as spectacular canary-yellow
electrostatic crystals with a mp of 91-92 !C.  Anal. (C12H15NO3S) C,H.
This was reduced with aluminum hydride (from cold THF-dissolved
lithium aluminum hydride and 100% sulfuric acid) to the phenethylamine
4-ethyl-2-methoxy-5-methylthiophenethylamine (2C-5-TOET) which, when
totally freed from water of hydration by drying at 100 !C under a hard
vacuum, had a mp of 216-217 !C.  Anal. (C12H20ClNOS) C,H.









#171 2-TOM; 5-METHOXY-4-METHYL-2-METHYLTHIOAMPHETAMINE

SYNTHESIS: To a solution of 64.8 g of o-cresol and 56 g dimethyl
sulfoxide in 300 mL Et2O, cooled with an external ice bath with
vigorous stirring, there was added 40 mL chlorosulfonic acid dropwise
over the course of 30 min. The cooling bath was removed, and the two
phase mixture was mechanically stirred at room temperature for 12 h.
The Et2O phase was then discarded, and the deep red residue that
remained was thoroughly triturated under 300 mL IPA, producing a
suspension of pale pink solids.  These were removed by filtration,
washed with an additional 150 mL IPA, and allowed to air dry.  The
yield of dimethyl (4-hydroxy-3-methylphenyl)sulfonium chloride was
31.6 g and, upon recrystallization from aqueous acetone, had a mp of
155-156 !C, with effervescence.  Anal. (C9H13ClOS) C,H,S.  This
analysis established the anion of this salt as the chloride, whereas
the literature had claimed, without evidence, that it was the
bisulfate.  The thermal pyrolysis of 31.0 g of dimethyl
(4-hydroxy-3-methylphenyl)sulfonium chloride resulted first in the
formation of a melt, followed by the vigorous evolution of methyl
chloride.  The open flame was maintained on the flask until there was
no more gas evolution.  This was then cooled, dissolved in 200 mL
CH2Cl2, and extracted with 3x100 mL of 5% NaOH.  The aqueous extracts
were pooled, acidified with concentrated HCl, and extracted with 3x75
mL CH2Cl2.  The solvent was removed under vacuum, and the residue
distilled at 100-110 !C at 0.5 mm/Hg yielding 22.0 g of
2-methyl-4-(methylthio)phenol as a white crystalline solid with a mp
36-37 !C.

To a solution of 25.5 g 2-methyl-4-(methylthio)phenol in 100 mL MeOH
there was added a solution of 12 g 85% KOH in 60 mL hot MeOH, followed
by the addition of 12.4 mL methyl iodide.  The mixture was held at
reflux for 16 h.  The solvent was removed under vacuum, and the
residue added to 400 mL H2O.  This was made basic with 25% NaOH and
extracted with 3x100 mL CH2Cl2.  The extracts were pooled, the solvent
removed under vacuum giving 28.3 g of a light, amber oil as residue.
This was distilled at 72-80 !C at 0.5 mm/Hg to provide
2-methyl-4-(methylthio)anisole as a pale yellow oil.  Anal. (C9H12OS)
C,H.  The same product can be made with the sulfonyl chloride and the
thiol as intermediates.  To 36.6 g 2-methylanisole there was added,
with continuous stirring, a total of 38 mL chlorosulfonic acid at a
modest rate.  The exothermic reaction went through a complete spectrum
of colors ending up, when the evolution of HCl had finally ceased, as
deep amber.  When it had returned again to room temperature, the
reaction mixture was poured over a liter of cracked ice which, on
mechanical stirring, produced a mass of white crystals.  These were
removed by filtration, washed with H2O, and sucked as dry as possible.
The wet weight yield was over 40 g and the mp was about 49 !C.
Recrystallization of an analytical sample of
4-methoxy-3-methylbenzenesulfonyl chloride from cyclohexane gave white
crystals with a mp of 51-52 !C.  A small sample of this acid chloride
brought into reaction with ammonium hydroxide produced the sulfonamide
which, after recrystallization from EtOAc, melted at 135-136 !C.  To a
slurry of 300 mL cracked ice and 75 mL concentrated H2SO4 in a
round-bottomed flask equipped with a reflux condenser, there was added
43 g of the slightly wet 4-methoxy-3-methylbenzenesulfonyl chloride
followed by 75 g elemental zinc dust.  The temperature was raised to a
reflux which was maintained for 2 h.  The reaction mixture was cooled
and filtered, with the finely ground filter cake being washed
alternately with H2O and with CH2Cl2.  The combined mother liquor and
washings were diluted with 1 L H2O, the phases separated, and the
aqueous phase extracted with 100 mL CH2Cl2 which was added to the
organic phase.  This was washed with 100 mL H2O, and the solvent
removed under vacuum.  The residue was a pale amber oil weighing 27.3
g and it slowly set up to a crystalline mass that smelled of banana
oil.  A portion of this, pressed on a porous plate, gave a waxy solid
with a mp of 39-43 !C which, on recrystallization from MeOH, gave
4-methoxy-3-(methyl)thiophenol with a mp of 45-46 !C.  Anal. (C8H10OS)
C,H.  A solution of 24 g of the crude thiol in 100 mL MeOH was treated
with a solution of 17 g KOH 85% pellets in 100 mL hot MeOH, and to
this there was added 16 mL of methyl iodide.  This was held at reflux
on the steam bath for 1.5 h, then stripped of solvent under vacuum,
added to 1 L H2O, and made strongly basic with 25% NaOH.  Extraction
with 3x100 mL CH2Cl2, pooling of the extracts, and removal of the
solvent, gave an amber oil weighing 22.6 g.  This was distilled at
70-80 !C at 0.7 mm/Hg to give 16.3 g of 2-methyl-4-(methylthio)anisole
as a white oil, identical in all respects to the product that came
from the sulfonium salt pyrolysis above.

A solution of 22.1 g 2-methyl-4-(methylthio)anisole and 17.5 g
dichloromethyl methyl ether in 600 mL CH2Cl2 was vigorously stirred,
and treated with 24.5 g anhydrous aluminum chloride added portion-wise
over the course of 1 min.  Stirring was continued for 20 min while the
color developed to a dark red.  There was added 500 mL H2O with
caution, and stirring was continued until the initial yellow solids
redissolved and there were two distinct phases formed.  These were
separated, and the aqueous phase was extracted with 3x100 mL CH2Cl2.
The original organic phase and the pooled extracts were combined and
washed with 5% NaOH.  The organic solvent was removed under vacuum.
The residue was distilled, giving two major fractions.  A forerun
(85-95 !C at 0.5 mm/Hg) proved to be largely starting ether.  The
major fraction (8.4 g, boiling at 95-120 !C) consisted of two
materials, both benzaldehydes.  Crystallization of this fraction from
30 mL cyclohexane provided, after filtering, washing and air drying,
2.9 g of 5-methoxy-4-methyl-2-(methylthio)benzaldehyde as a pale
yellow crystalline solid with a mp of 69-70 !C.  Anal. (C10H12O2S)
C,H.  The mother liquor from this crystallization contained a
slower-moving component,
2-methoxy-3-methyl-5-(methylthio)benzaldehyde, which was best
separated by preparative gas chromatography.  The proof of the
structure of the major aldehyde above was obtained by its reductive
conversion to 2,5-dimethyl-4-(methylthio)anisole with amalgamated zinc
and HCl.  The details are given in the recipe for 5-TOM.

To 4 mL glacial acetic acid there was added 1.0 g
5-methoxy-4-methyl-2-(methylthio)benzaldehyde, 0.35 g anhydrous
ammonium acetate, and 0.8 g nitroethane, and the mixture was heated on
the steam bath for 4 h.  Another 0.5 g of nitroethane was added, and
the heating continued for an additional 4 h.  Standing at room
temperature overnight allowed the deposition of spectacular orange
crystals which were removed by filtration, washed lightly with acetic
acid, and air dried.  This product melted at 82-83 !C.
Recrystallization from 10 mL boiling MeOH gave 0.7 g of
1-(5-methoxy-4-methyl-2-methylthiophenyl)-2-nitropropene with a mp of
83-84 !C.  Anal. (C12H15NO3S) C,H.  The alternate method for the
formation of nitrostyrenes, the reaction of the benzaldehyde in
nitroethane as both reagent and solvent, with ammonium acetate as a
catalyst, gave a gummy product that could be purified only with severe
losses.  The overall yield with this latter method was 24% of theory.

A solution of 1.5 g LAH in 75 mL THF was cooled, under He, to 0 !C
with an external ice bath.  With good stirring there was added 1.0 mL
100% H2SO4 drop-wise, to minimize charring.  This was followed by the
addition of 3.0 g
1-(5-methoxy-4-methyl-2-methylthiophenyl)-2-nitropropene in 20 mL
anhydrous THF.  After a few min further stirring, the temperature was
brought up to a gentle reflux on the steam bath, and then all was
cooled again to 0 !C.  The excess hydride was destroyed by the
cautious addition of IPA followed by sufficient 5% NaOH to give a
white granular character to the oxides, and to assure that the
reaction mixture was basic.  The reaction mixture was filtered, and
the filter cake washed first with THF and then with IPA.  The filtrate
was stripped of solvent under vacuum providing a light yellow oil.
This was dissolved in 100 mL dilute H2SO4 and then washed with 2x50 mL
CH2Cl2.  The aqueous phase was made basic with 5% NaOH and extracted
with 2x50 mL CH2Cl2.  These were pooled, the solvent removed under
vacuum, and the residue distilled at 105-130 !C at 0.25 mm/Hg to give
1.6 g of a white oil.  This was dissolved in 8 mL IPA, neutralized
with 24 drops of concentrated HCl which formed crystals spontaneously.
Another 20 mL of hot IPA was added to effect complete solution, and
then this was diluted with anhydrous Et2O.  On cooling fine white
crystals of 5-methoxy-4-methyl-2-methylthioamphetamine hydrochloride
(2-TOM) separated.  These weighed 1.55 g and had a mp of 195-196 !C.
Anal. (C12H20ClNOS) C,H.

DOSAGE: 60 - 100 mg.

DURATION: 8 - 10 h.

QUALITATIVE COMMENTS: (with 60 mg) There is a superb body feeling,
and food tasted excellent but then it just might have been excellent
food.  By the tenth hour, there were absolutely no residues, and I had
the feeling that there was no price to pay.  Venture up a bit with
confidence.

(with 80 mg) For me this was excellent, in a down-to-earth, humorous,
matter-of-fact universe-perspective sense.  Very pleasant feeling,
although there was a strong body awareness below the waist (not the
erotic thing, but rather a slight heaviness, and the next day I came
down with a G.I. cold).  Very good feeling, and I sense that the depth
of the experience is way out there where the big questions lie.  I
found it easy to go out of body (in the good sense) into a warm,
loving darkness.  Sliding down by 6, 7th hour, and had no trouble
sleeping.  Fully scripted dreams, vivid.  Very, very good.  Want to
try 100 mg.

(with 80 mg) Completely foul taste.  The effects were quite subtle,
and I found this to be a strange but friendly ++.  There was much
eyes-closed fantasizing to music, even to Bruchner, whom I found
unexpectedly pleasant.  There was a feeling of tenseness at the
twilight of the experience.

EXTENSIONS AND COMMENTARY: There is a most extraordinary loss of
potency with the simple substitution of a sulfur atom for an oxygen
atom.  DOM is fully active at the 5 or so milligram area, whereas
2-TOM is active at maybe the 80 milligram area, a loss of potency by a
factor of x15 or so.  And the duration is quite a bit shorter.  It
might take a fair amount of learning to become completely at peace
with it, but it might be worth the effort.  And there are none of the
disturbing hints of neurological and physical roughness of 5-TOM.

Again, as with the other TOM's and TOETUs, the two-carbon homologue of
this has been synthesized but not yet evaluated.  The common
intermediate benzaldehyde,
5-methoxy-4-methyl-2-(methylthio)benzaldehyde was condensed with
nitromethane and ammonium acetate to give the nitrostyrene which, upon
re-crystallization from ethanol, had a melting point of 118-118.5 !C.
Anal. (C11H13NO3S) C,H.  Reduction with aluminum hydride in THF gave
the crystalline free base which, as the hydrochloride salt, melted at
233-234 !C.  Anal. (C11H18ClNOS) C,H.  Quite logically, it has been
called 2C-2-TOM.









#172 5-TOM; 2-METHOXY-4-METHYL-5-METHYLTHIOAMPHETAMINE

SYNTHESIS: To a solution of 6.6 g KOH pellets in 100 mL hot EtOH there
was added a solution of 15.4 g methylthio-m-cresol
(3-methyl-4-(methylthio)phenol, Crown-Zellerbach Corporation) in 25 mL
EtOH.  This was followed by the addition of 17 g methyl iodide, and
the mixture was held at reflux on the steam bath for 16 h.  The
reaction mixture was poured into 400 mL H2O, acidified with HCl, and
extracted with 4x50 mL CH2Cl2.  These were pooled, washed with 3x50 mL
5% NaOH, once with dilute HCl, and then the solvent was removed under
vacuum.  The residue was 3-methyl-4-(methylthio)anisole, a clear pale
yellow oil, weighing 12.7 g.  Distillation at 150-160 !C at 1.7 mm/Hg,
or at 80-90 !C at 0.25 mm/Hg, did not remove the color, and gave a
product with no improvement in purity.

To a mixture of 82 g POCl3 and 72 g N-methylformanilide that had been
heated on the steam bath for 10 min, there was added 33.6 g
3-methyl-4-(methylthio)phenol, and heating was continued for an
additional 2 h.  This was poured into 1.2 L H2O, producing a brown
gummy crystalline mass that slowly loosened on continued stirring.
This was filtered off, washed with additional H2O, and sucked as dry
as possible.  This was finely ground under 60 mL of cold MeOH,
refiltered, and air dried to give 17.8 g of a nearly white crystalline
solid with a mp of 94-96 !C.  Recrystallization from 50 mL boiling
MeOH gave a product of higher purity, but at some cost in yield.  With
this step there was obtained 13.4 g of
2-methoxy-4-methyl-5-(methylthio)benzaldehyde with a mp of 98-99 !C.
An additional recrystallization from IPA increased this mp by another
degree.  From this final recrystallization, a small amount of material
was left as an insoluble residue.  It was also insoluble in acetone,
but dissolved readily in CH2Cl2.  It melted broadly at about 200 !C
and was not identified.  Proof of the structure of
2-methoxy-4-methyl-5-(methylthio)benzaldehyde was obtained by its
successful reduction (with amalgamated Zn in HCl) to
2,5-dimethyl-4-(methylthio)anisole.  This reference convergence
compound was prepared separately from 2,5-dimethylanisole which
reacted with chlorosulfonic acid to give the 4-sulfonyl chloride
derivative, which was in turn reduced to the 4-mercapto derivative
(white crystals from MeOH, with a mp of 38 !C sharp).  This, upon
methylation with methyl iodide and KOH in MeOH, gave
2,5-dimethoxy-4-(methylthio)anisole (white crystals from MeOH, with a
mp of 67-68 !C).  The two samples (one from the aldehyde reduction,
and the other from this independent synthesis), were identical in all
respects.

A solution of 1.9 g 2-methoxy-4-methyl-5-(methylthio)benzaldehyde in
40 mL nitroethane was treated with 0.5 g anhydrous ammonium acetate
and heated under reflux, with stirring, with a heating mantle for 3.5
h, at which time TLC analysis showed no unreacted aldehyde and only a
trace of slow moving materials.  Removal of the excess nitroethane
under vacuum gave a yellow plastic film (the wrapping of the magnetic
stirrer had dissolved off) which was extracted first with 35 mL
boiling MeOH, then with 2x35 mL boiling IPA.  Separately, the MeOH
extract and the combined IPA extracts, on cooling, deposited 0.6 g
each of fluffy needles.  The mother liquors were combined and allowed
to evaporate to about 15 mL final volume, providing another 0.4 g
crude product.  All three samples melted at 101-102 !C.  These were
combined, and recrystallized from 50 mL boiling MeOH to provide, after
filtering and air drying, 1.4 g of
1-(2-methoxy-4-methyl-5-methyl-thiophenyl)-2-nitropropene as bright
yellow crystals with a mp of 102-102.5 !C.  Anal. (C12H15NO3S) C,H.

A solution of 2.0 g LAH in 100 mL anhydrous THF was cooled, under He,
to 0 !C with an external ice bath.  With good stirring there was added
1.28 mL 100% H2SO4 dropwise, to minimize charring.  This was followed
by the addition of 1.35 g
1-(2-methoxy-4-methyl-5-methylthiophenyl)-2-nitropropene in 50 mL
anhydrous THF over the course of 5 min.  After a few min further
stirring, the temperature was brought up to a gentle reflux on the
steam bath, and then all was cooled again to 0 !C.  The excess hydride
was destroyed by the cautious addition of 5 mL IPA followed by
sufficient 5% NaOH to give a white granular character to the oxides,
and to assure that the reaction mixture was basic (about 5 mL was
used).  The reaction mixture was filtered, and the filter cake washed
first with THF and then with IPA.  The combined filtrate and washings
were stripped of solvent under vacuum and the residue dissolved in 150
mL dilute H2SO4.  This was washed with 3x50 mL CH2Cl2 (the color
stayed in the organic layer), made basic with aqueous NaOH, and
extracted with 2x50 mL CH2Cl2.  After the solvent was removed under
vacuum, the residue was distilled at 110-125 !C at 0.4 mm/Hg to give
0.9 g of a colorless oil.  This was dissolved in 4 mL IPA, neutralized
with about 11 drops of concentrated HCl, and then diluted with 20 mL
anhydrous Et2O.  After about a ten second delay, white crystals
formed.  These were removed by filtration and air dried, to give 0.6 g
of 2-methoxy-4-methyl-5-methylthioamphetamine hydrochloride (5-TOM) as
white crystals with a mp of 156-157 !C.  A second crop obtained from
the mother liquors on standing weighed 0.3 g and melted at 150-156 !C.
Anal. (C12H20ClNOS) C,H.

DOSAGE: 30 - 50 mg.

DURATION: 6 - 10 h.

QUALITATIVE COMMENTS: (with 35 mg) There was an awful lot of visual
activity, and in general I found the day quite good, once I got past
the early discomfort.

(with 40 mg) I knew that I was sinking into a deep reverie after an
hour into it.  I was not totally unconscious since I seemed to respond
to external stimuli (at least most of the time).  But I certainly
wasnUt all that much there.  The exper-ience dominated completely.  At
one point (perhaps the peak?) I remember seeing a very quiet sea with
a horizontal shoreline and a clear sky.  This image seemed to come
back rather frequently.  At other times I would see a set of
disjointed horizontal lines on this beach.  These lines reminded me of
spectral lines.  For a short period of time I thought they were some
kind of expression of my energy levels that I didnUt understand.  In
retrospect, I suspect the horizontal lines were only expressions of
how my mind was reacting to the material.  I donUt remember talking to
anyone until I had started to come down from the experience.  I
eventually could see real images, but they were greatly distorted.  It
was as if I was looking at Cubism paintings by Picasso, having intense
and strange colorations.  As I came back into the real world, I
realized that I had had an extraordinary trip.  I had not been afraid
at any time.  The experience seemed unique, but quite benign.  The
experience for my fellow travelers was probably much more anxious.  I
wasnUt particularly interested in food when I came down.  I slept
well.  I was quite lethargic the next day.  It really took me another
day to integrate back into normal life.  Would I repeat it?  Possibly,
but at a way smaller dose.

(with 50 mg) The body was complete whacked, and the mental simply
didnUt keep up with it.  There was some early nausea going into it,
and my sinuses never cleared, and I somehow became irritable and
angry.  In fact, the impatience and grimness lasted for a couple of
days.  There were some visual events that might have been interesting
to explore, but too much other stuff got in the way.

(with 50 mg) There was much eyes-closed fantasy, and quite a bit of
it with erotic undertones.  In efforts to direct my actions, I found
it difficult to find the point of initiation of a task.  Reading and
writing both impossible.  I am somehow de-focused.  But art work
became quite rewarding.  The experience was heavy going in, but rich
coming out.  Good dosage.

EXTENSIONS AND COMMENTARY: The bottom line is that 5-TOM is a pretty
heavy-duty experience, with more negative reports than positive ones.
I have received no mentions of a completely ecstatic time, and not
even very many neutral experiences.  The consensus is that it wasnUt
worth the struggle.  Some cramping, some nausea, and a generalized
discomfort.  And that one case of a catatonic response.  An approach
to possible individual variation in the metabolic handling of the
sulfur atom is the rationale for the preparation of the compound
TOMSO, and it is discussed there.

The two-carbon homologue of 5-TOM has been prepared.  It uses, of
course, the same aldehyde, but the condensation was with nitromethane
which yielded the nitrostyrene as an orange powder with a melting
point of 118-119 !C from methanol.  This was reduced with LAH in ether
containing anhydrous AlCl3, giving
2-methoxy-4-methyl-5-methylthiophenethylamine hydrochloride as white
crystals with a melting point of 257-258 !C.  It has been named
2C-5-TOM, but it has not yet been entered into the screening program
so it is pharmacologically still a mystery.









#173 TOMSO; 2-METHOXY-4-METHYL-5-METHYLSULFINYLAMPHETAMINE

SYNTHESIS: A suspension of 12.7 g
1-(2-methoxy-4-methyl-5-methylthiophenyl)-2-nitropropene (see under
5-TOM for its preparation) in 50 mL warm acetic acid was added to a
suspension of 22.5 g electrolytic grade elemental iron in 100 mL warm
acetic acid.  The temperature was raised cautiously until an
exothermic reaction set in, and the mixture was maintained under
reflux conditions as the color progressed from yellow to deep brown to
eventually colorless.  After coming back to room temperature, the
somewhat gummy mixture was poured into 1 L H2O, and all insolubles
were removed by filtration.  These were washed with CH2Cl2, and the
aqueous filtrate was extracted with 3x100 mL CH2Cl2.  The washes and
extracts were combined, washed with 5% NaOH until the bulk of the
color was removed and the washes remained basic, and the solvent was
then removed under vacuum.  The residue, 11.6 g of a pale amber oil
that crystallized, was distilled at 110-120 !C at 0.4 mm/Hg to give
9.9 g 2-methoxy-4-methyl-5-methylthiophenylacetone with a mp of 41-42
!C.  This was not im-proved by recrystallization from hexane.  Anal.
(C12H16O2S) C,H.

To a solution of 7.3 g 2-methoxy-4-methyl-5-methylthiophenylacetone in
35 mL methanol there was added 7.3 mL 35% hydrogen peroxide, and the
mixture held under reflux conditions for 40 min.  All volatiles were
removed under vacuum, and the residue suspended in 250 mL H2O.  This
was extracted with 3x50 mL CH2Cl2, the extracts pooled, and the
solvent removed under vacuum.  The residue, 8.6 g of an oily solid,
was recrystallized from 10 mL boiling toluene to provide, after
filtering and air drying, 5.4 g of
2-methoxy-4-methyl-5-methylsulfinylphenylacetone as a white solid with
a mp of 89-89.5 !C.  Anal. (C12H16O3S) C,H.

To a vigorously stirred solution of 5.2 g of
2-methoxy-4-methyl-5-methylsulfinylphenylacetone in 70 mL MeOH there
was added 17 g anhydrous ammonium acetate followed by 1.0 g sodium
cyanoborohydride.  HCl was added as needed to maintain the pH at about
6 as determined with damp universal pH paper.  No further base was
generated after 3 days, and the reaction mixture was poured into 500
mL H2O.  After acidification with HCl (caution, highly poisonous HCN
is evolved), this was washed with 2x100 mL CH2Cl2, made strongly basic
with NaOH, and then extracted with 3x100 mL CH2Cl2.  The pooled
extracts were stripped of solvent under vacuum, and the residue
weighed 7.1 g and was a pale amber oil.  This was distilled at 150-160
!C at 0.3 mm/Hg to give a colorless oil weighing 4.4 g.  A solution of
this in 13 mL IPA was neutralized with 30 drops of concentrated HCl
and the resulting solution warmed and diluted with 20 mL of warm
anhydrous Et2O.  White crystals separated immediately and, after
filtering, ether washing and air drying, provided 4.4 g of
2-methoxy-4-methyl-5-methylsulfinylamphetamine hydrochloride (TOMSO)
that melted at 227-229 !C after vacuum drying for 24 hrs.  Anal.
(C12H20ClNO2S) C,H.  The presence of two chiral centers (the
alpha-carbon of the amphetamine side chain and the sulfoxide group at
the 5-position of the ring) dictates that this product was a mixture
of diastereoisomeric racemic compounds.  No effort was made to
separate them.

DOSAGE: greater than 150 mg (alone) or 100 - 150 mg (with alcohol).

DURATION: 10 - 16 h.

QUALITATIVE COMMENTS: (with 100 mg) There were no effects at all, and
it was at the so-called surprise pot-luck birthday lunch for the
department chairman that I ate a little and had two glasses of
Zinfandel.  I shot up to an immediate ++ and this lasted all
afternoon.  I went to San Francisco by BART, and walked up Market
Street and saw all the completely bizarre faces.  I was absolutely
unable to estimate the age of anybody who was female, at least by
looking at her face.  All aspects, both child-like and old, seemed to
be amalgamated into each face, all at the same time.  There was
remarkable time-slowing; overall the experience was favorable.  That
certainly was not the effect of the alcohol in the wine.  Food
poisoning?  No.  It must have been the TOMSO that had been kindled and
promoted to something.

(with 150 mg) At best there is a threshold and it is going nowhere.
At the third hour I drank, over the course of an hour, a tall drink
containing 3 oz. of vodka.  Soon I was clearly somewhere, and three
hours later I was a rolling plus three.  This lasted until well after
midnight, and was not an alcohol response.

EXTENSIONS AND COMMENTARY: This entire venture into the study of TOMSO
was an outgrowth of the extraordinary response that had been shown by
one person to 5-TOM.  There were two obvious approaches that might
throw some light on the reason for this dramatic sensitivity.  One
would be to see if he was unusually capable of metabolizing
sulfur-containing molecules, and the second would be to assume he was,
and to try to guess just what product he had manu-factured with his
liver.

The individual sensitivity question was addressed in a tidy and direct
manner.  Why not study a simple sulfur-containing model compound that
would probably be metabolized only at the sulfur and that would itself
probably be pharmacologically inactive in its own rights?  Sounded OK
to me, so I made up a goodly supply of 4-tert-butyl thioanisole, which
proved to be a gorgeous white crystalline solid.  It seemed quite
logical that this would be metabolized at the sulfur atom to produce
either or both the sulfoxide and the sulfone.  So I treated a methanol
solution of this with a little hydrogen peroxide and distilled the
neutral extracts at 100-115 !C at 0.2 mm/Hg to give the sulfoxide as a
solid that melted at 76-77 !C from hexane: Anal. (C11H16OS) C,H.  On
the other hand, if a solution of the thioanisole in acetic acid
containing hydrogen peroxide was heated on the steam bath for a few
hours and then worked up, a new solid was isolated that proved to be
the sulfone (a negative Fries-Vogt test).  This was obtained as white
crystals with a mp of 94-95 !C from aqueous methanol.  Anal.
(C11H16SO2) C,H.  And I found that these three compounds separated
well from one another by GC, and that they could be extracted from
urine.  Everything was falling into place.  My thought was to
determine a safe (inactive) level of the parent thioanisole, and
determine the distri-bution of metabolites in my urine, and then in
the urine of several other people, and then finally in the urine of
the person who was the intense reactor to 5-TOM.  I found that there
were no effects, either physical or psychological, at an oral dose of
60 milligrams of 4-tert-butyl-thioanisole.  But then everything fell
apart.  There was not a detectable trace of anything, neither parent
compound nor either of the potential metabolites, to be found in my
urine.  The material was obviously being completely converted to one
or more metabolites, but the sulfoxide and sulfone were not among
them.  It would be fun, someday, to methodically trace the fate of
this compound.

So, on to the second approach.  What might the active metabolite of
5-TOM actually be?  The sulfoxide seemed completely reasonable, and
that encouraged the synthesis of TOMSO.  This name was given, as it is
the sulfoxide analogue (SO) of 5-TOM.  And since only one of these
analogues has been made, the R5S distinction is not needed.  But it is
apparent that this approach to the finding of an explanation for the
idiosyncratic sensitivity to 5-TOM also failed, in that TOMSO itself
appeared to be without activity.

But the fallout of this study was the uncovering of an unusual
property that alcohol can occasionally have when it follows the
ingestion of certain inactive drugs.  Or if it is used at the tail end
of an experience with an active drug.  Usually some alcohol has been
employed as a softener of the residual effects of the dayUs
experiment, or as a social habit to accompany the post-mortem
discussions of a day's experiences, and perhaps as a help to sleeping.
But if there is a rekindling of the effect, rather than the sedation
expected, then the verb Rto tomsoS can be used in the notes.  It
represents the promotion of an inactive situation into an active one,
with the catalysis of alcohol.  But the effect is not that of alcohol.
Might the extreme sensitivity of some alcoholics to even a small
amount of alcohol be due to some endogenous RinactiveS factor that is
promoted in this way into some centrally florid toxicity?  I remember
seeing proposals of some tetrahydroisoquinolines as potential
mis-metabolites in efforts to explain the toxicity of alcohol.  Maybe
they are nothing more than psychedelics that are thought to be
inactive, but which might be ignited with a glass of wine.  And the
person is tomsoing with his small amount of alcohol.









#174 TP; THIOPROSCALINE; 3,5-DIMETHOXY-4-(n)-PROPYLTHIOPHENETHYLAMINE

SYNTHESIS: A solution was made of 12.1 g
N,N,NU,NU-tetramethylethylenediamine and 13.8 g of
1,3-dimethoxybenzene in 200 mL 30-60 !C petroleum ether.  This was
stirred vigorously under a He atmosphere and cooled to 0 !C with an
external ice bath.  There was added 66 mL of 1.6 M butyllithium in
hexane which produced a white granular precipitate.  The reaction
mixture was brought up to room temperature for a few minutes, and then
cooled again to 0 !C.  There was then added 15.8 g of di-(n)-propyl
disulfide which changed the granular precipitate to a creamy
appearance.  Stirring was continued while the reaction mixture was
brought up to room temperature and finally up to reflux.  The reaction
mixture was then added to 600 mL of dilute H2SO4.  The two phases were
separated, and the aqueous phase extracted with 2x75 mL Et2O.  The
organic phases were combined, and the solvent removed under vacuum.
The residue was 24.2 g of a pale amber liquid which was distilled at
0.35 mm/Hg to give two fractions.  The first boiled at 85-90 !C,
weighed 0.5 g and appeared to be recovered dipropyl disulfide.  The
product 2-(n)-propylthio-1,3-dimethoxybenzene boiled at at 105-125 !C,
and weighed 20.8 g.  A small sample recrystallized from hexane had a
mp of 27-28 !C.  Anal. (C11H16O2S) C,H.

To a stirred solution of 19.8 g of
2-(n)-propylthio-1,3-dimethoxybenzene in 200 mL CH2Cl2 there was added
15.4 g elemental bromine dissolved in 100 mL CH2Cl2.  The reaction was
not exothermic, and it was allowed to stir for 1 h.  The reaction
mixture was washed with H2O containing sodium hydrosulfite (which
rendered it nearly colorless) and finally washed with saturated brine.
The solvent was removed under vacuum leaving 33.5 g of a pale yellow
liquid.  This was distilled at 112-120 !C at 0.3 mm/Hg to yield
4-bromo-2-(n)-propylthio-1,3-dimethoxybenzene as a pale yellow oil.
Anal. (C11H15BrO2S) C,H.

To a solution of 16.8 g diisopropylamine in 100 mL anhydrous THF that
was stirred under a N2 atmosphere and cooled to -10 !C with an
external ice/MeOH bath, there was added in sequence 75 mL of 1.6 M
butyllithium in hexane, 3.0 mL of dry CH3CN, and 8.7 g of
4-bromo-2-(n)-propylthio-1,3-dimethoxybenzene which had been dissolved
in 20 mL THF.  The bromo compound was added dropwise over the course
of 5 min.  The color became deep red-brown.  Stirring was maintained
for a total of 30 min while the reaction came to room temperature.  It
was then poured into 750 mL dilute H2SO4, the organic layer separated,
and the aqueous phase extracted with 2x100 mL CH2Cl2.  These extracts
were pooled, washed with dilute H2SO4, and the solvent was removed
under vacuum yielding a residue that was distilled.  Two distillation
cuts were taken at 0.3 mm/Hg.  The first fraction boiled at 110-138 !C
and weighed 0.7 g and was discarded.  The second fraction came over at
148-178 !C and weighed 3.0 g.  By thin layer chromatography this
fraction was about 80% pure, and was used as such in the following
reduction.  A small sample was ground under methyl cyclopentane
yielding white crystals of
3,5-dimethoxy-4-(n)-propylthiophenylacetonitrile with a mp of
35.5-37.5 !C.

A solution of LAH in THF (15 mL of a 1 M solution) under N2 was cooled
to 0 !C and vigorously stirred.  There was added, dropwise, 0.4 mL
100% H2SO4, followed by 2.7 g
3,5-dimethoxy-4-(n)-propylthiophenylacetonitrile dissolved in 10 mL
anhydrous THF.  The reaction mixture was stirred at 0 !C for a few
min, then brought to a reflux for 30 min on the steam bath.  After
cooling back to room temperature, there was added IPA to destroy the
excess hydride and 10% NaOH to bring the reaction to a basic pH and
converted the aluminum oxide to a loose, white, filterable
consistency.  This was removed by filtration and washed with both THF
and IPA.  The filtrate and washes were stripped of solvent under
vacuum, the residue added to 1 L dilute H2SO4.  This was washed with
2x75 mL CH2Cl2, made basic with aqueous NaOH, extracted with 3x75 mL
CH2Cl2, the extracts pooled, and the solvent removed under vacuum.
The residue was distilled at 137-157 !C at 0.3 mm/Hg to give 1.3 g of
a colorless oil.  This was dissolved in 10 mL of IPA, neutralized with
20 drops of concentrated HCl and, with continuous stirring, diluted
with 50 mL anhydrous Et2O.  The product was removed by filtration,
washed with Et2O, and air dried to give 1.4 g of
3,5-dimethoxy-4-(n)-propylthiophenethylamine hydrochloride (TP) as
bright white crystals with a mp of 164-165 !C.  Anal. (C13H22ClNO2S)
C,H.

DOSAGE: 20 - 25 mg.

DURATION: 10 - 15 h.

QUALITATIVE COMMENTS: (with 18 mg) There was very little effect until
more than two hours, when I came inside out of the cold and jumped to
an immediate +1.  It is hard to define, and I am quite willing to have
it develop more, and if not, quite willing to go higher next time.  I
got into several quite technical conversations, but through it all I
was aware of a continuous alteration.  There was a drop at the seventh
hour, and nothing at all was left at twelve hours.

(with 27 mg) My body feels heavy.  This is not a negative thing, but
it is there.  I feel a heavy pressure at the back of the neck, which
is probably unresolved energy.  The nervous system seems to be somehow
vunerable.  Towards the end of the experience I considered a Miltown,
but settled on an aspirin, and I still couldnUt sleep for about 24
hours.  The imagery is extremely rich and there is quite a bit of
eyes-open visual, but mostly eyes closed.  I think the rewards are not
worth the body price.  Sometime again, maybe lower?S

EXTENSIONS AND COMMENTARY: There is a high potency here, but clearly
there are signs of increased toxicity as well even over the ethyl
homologue, TE.  The butyl compound (see TB) was the last of this
series of phenethylamines and as is noted there, the physical problems
lessen, but so do the psychedelic properties.  The three-carbon
amphetamine homologues are completely unexplored.  The most reasonable
starting material for these would be 4-thiosyringaldehyde, with
S-alkylation and then the conventional nitroethane coupling followed
with LAH reduction.  The most appealing target as a potential
psychedelic would be the methylthio homologue
(3,5-dimethoxy-4-methylthioamphetamine, 3C-TM) or, as a potential
euphoriant, the butylthio homologue
(3,5-dimethoxy-4-(n)-butylthioamphetamine, 3C-TB).  I am not sure that
these alkylthio analogues would justify the labor needed to make them.









#175 TRIS; TRESCALINE; TRISESCALINE; 3,4,5-TRIETHOXYPHENETHYLAMINE

SYNTHESIS: A solution of 16.9 g of ethyl 3,4,5-triethoxybenzoate in 25
mL THF was added to a well stirred suspension of 8 g LAH in 150 mL
THF.  The mixture was heated at reflux for 24 h and and, after
cooling, treated with IPA to destroy the excess hydride.  There was
then added sufficient 25% NaOH to produce a granular, white form of
the aluminum oxide.  This was removed by filtration, the filter cake
washed with IPA, and the filtrate and washes were combined and
stripped of solvent under vacuum.  The residue weighed 12.2 g and was
distilled at 120-140 !C at 0.4 mm/Hg to yield 8.6 g of
3,4,5-triethoxybenzyl alcohol that spontaneously crystallized.  It had
a mp of 29-30 !C and was free of the parent ester carbonyl absorp-tion
at 1709 cm-1 in the infra-red.

This product 3,4,5-triethoxybenzyl alcohol was suspended in 30 mL
con-centrated HCl, heated briefly on the steam bath, cooled to room
temperature, and suspended in a mixture of 75 mL CH2Cl2 and 75 mL H2O.
The phases were separated, and the aqueous phase extracted with
another 75 mL CH2Cl2.  The organic fractions were combined, washed
first with H2O and then with saturated brine.  Removal of the solvent
under vacuum yielded an off-white oil that was distilled at 112-125 !C
at 0.4 mm/Hg to provide 7.5 g of 3,4,5-triethoxybenzyl chloride that
spontaneously crystallized.  The crude product had a mp of 34-37 !C
which was increased to 37.5-38.5 !C upon recrystallization from
hexane.  Anal. (C13H19ClO3) C,H.

A solution of 4.5 g 3,4,5-triethoxybenzyl chloride in 10 mL DMF was
treated with 5.0 g sodium cyanide and heated for 1 h on the steam
bath.  The mixture was then poured into 100 mL H2O and the oily phase
that resulted immediately crystallized.  This was filtered off, washed
well with H2O, air dried, and distilled at 128-140 !C at 0.25 mm/Hg to
yield 3.7 g of 3,4,5-triethoxyphenylacetonitrile which melted at
54-56.5 !C.  There was a sharp nitrile band at 2249 cm-1.  Anal.
(C14H19NO3) C,H.

To 18.8 mL of a 1 M solution of LAH in THF under N2 , vigorously
stirred and cooled to 0 !C, there was added, dropwise, 0.50 mL 100%
H2SO4.  This was followed by 3.6 g 3,4,5-triethoxyphenylacetonitrile
in 10 mL anhydrous THF over the course of 5 min.  The reaction mixture
was brought to room temperature and stirred for a few min, and finally
held at reflux on the steam bath for 1 h.  After cooling back to room
temperature, there was added about 2 mL IPA (to destroy the excess
hydride) followed by sufficient 15% NaOH to make the aluminum oxide
granular and white, and the organic solution basic.  The solids were
removed by filtration, and washed with IPA. The filtrate and washes
were stripped of solvent under vacuum, the residue added to 400 mL
dilute H2SO4.  This was washed with 2x75 mL CH2Cl2, the aqueous phase
made basic with aqueous. NaOH, and the product extracted with 2x75 mL
CH2Cl2.  These extracts were pooled, the solvent removed under vacuum,
and the residue distilled at 115-135 !C at 0.4 mm/Hg to give a white
oil.  This was dissolved in a few mL of IPA, neutralized with
concentrated HCl, and diluted with anhydrous Et2O to the point of
turbidity.  When the crystal formation was complete, the product was
removed by filtration, washed with Et2O, and air dried to give 2.8 g
3,4,5-triethoxyphenethylamine hydrochloride (TRIS) as white crystals
with a mp of 177-178 !C.

DOSAGE: greater than 240 mg.

DURATION: unknown.

QUALITATIVE COMMENTS: (with 240 mg) No effects were noted at any time
following 240 milligrams of trisescaline.  This would have been a
thoroughly active level of the trimethoxy counterpart, mescaline.

EXTENSIONS AND COMMENTARY: With the progressive diminution of human
potency with increased ethylation of the mescaline molecule, there is
no suprise in finding that this base is devoid of activity.  Studies
done years ago in the cat at a dosage of 25 mg/Kg (i.m.) gave none of
the expected, and looked for, signs of behavioral changes (pilomotor
activity, pupillary dilation, growling, hissing, aggressive behavior,
withdrawal, or salivation) that are often seen with the less bulky
substituents.  It was without action.

More lengthy substituents in the 3,4,5-positions (with combinations of
ethyls and propyls, for example) are presently unknown compounds, and
there is small incentive to make them.









#176 3-TSB; 3-THIOSYMBESCALINE;
3-ETHOXY-5-ETHYLTHIO-4-METHOXYPHENETHYLAMINE

SYNTHESIS: A solution of 13.4 g
3-bromo-N-cyclohexyl-4-methoxy-5-ethoxybenzylidenimine (see under ME
for its preparation) in 150 mL anhydrous Et2O was placed in a He
atmosphere, well stirred, and cooled in an external dry ice/acetone
bath to -80 !C.  There was the formation of a granular precipitate.
There was then added 28 mL of 1.6 N butyllithium in hexane over the
course of 5 min, and the mixture (which had turned quite creamy) was
stirred for 15 min.  This was followed by the addition of 5.5 g
diethyl disulfide over the course of 1 min.  The mixture was allowed
to come to room temperature over the course of 1 h, and then added to
100 mL of dilute HCl.  The Et2O phase was separated and the solvent
removed under vacuum.  The residue was dissolved in 50 mL MeOH,
combined with the original aqueous phase, and the entire mixture
heated on the steam bath for 0.5 h.  The aqueous solution was cooled
to room temperature, extracted with 3x100 mL CH2Cl2, the extracts
pooled, and the solvent removed under vacuum.  The residue was
distilled at 132-140 !C at 0.3 mm/Hg to yield 9.1 g of
3-ethoxy-5-ethylthio-4-methoxybenzaldehyde as a white oil that, on
standing for several months, spontaneously crystallized.  A small bit
of the crystalline solid was wastefully recrystallized from MeOH to
provide white crystals with a mp of 31.5-32.5 !C.  Anal. (C12H16O3S)
C,H.  The crude distillate was used in the following reactions.

Several attempts were made to prepare the nitrostyrene from this
aldehyde and nitromethane.  The most successful, but still inadequate,
procedure is described here.  A solution of 1.0 g
3-ethoxy-5-ethylthio-4-methoxybenzaldehyde in 10 mL nitromethane was
treated with about 150 mg of anhydrous ammonium acetate and heated on
the steam bath.  The course of the reaction was followed by TLC.  The
bulk of the aldehyde had disappeared in 45 min, and there were several
UV-absorbing spots visible.  Removal of the excess nitromethane under
vacuum gave an orange oil which, when rubbed under cold MeOH, gave 200
mg of yellow solids.  This was (by TLC) a mixture of nitrostyrene,
starting aldehyde, and several slow-moving scrudge impurities.
Recrystallization from MeOH gave a poor recovery of a yellow solid
with a mp of 102.5-104 !C but this was still contaminated with the
same impurities.  Several repetitions of this synthetic procedure gave
little if any of the desired
3-ethoxy-5-ethylthio-4-methoxy-'-nitrostyrene.

A suspension of 5.4 g methyltriphenylphosphonium bromide in 30 mL
anhydrous THF was placed under a He atmosphere, well stirred, and
cooled with an external water bath.  There was then added 10 mL of 1.6
N butyllithium in hexane which resulted in the generation of a bright
pumpkin color.  The initial heavy solids changed into a granular
precipitate.  There was then added 2.4 g of
3-ethoxy-5-ethylthio-4-methoxybenzaldehyde in a little THF.  An
initial gummy phase became granular with patient swirling and
stirring.  After 30 min, the reaction was quenched in 500 mL H2O, the
top hexane layer separated, and the aqueous phase extracted with 2x75
mL of petroleum ether.  The organic fractions were combined, washed
with H2O, dried over anhydrous K2CO3, and the solvents removed under
vacuum to give the crude 3-ethoxy-5-ethylthio-4-methoxystyrene as a
yellow mobile liquid.

A solution of 2 mL of borane-methyl sulfide complex (10 M BH3 in
methyl sulfide) in 20 mL THF was placed in a He atmosphere, cooled to
0 !C, treated with 4.2 mL of 2-methylbutene, and stirred for 1 h while
returning to room temperature.  To this there was added a solution of
the impure 3-ethoxy-5-ethylthio-4-methoxystyrene in a little anhydrous
THF.  This was stirred for 1 h.  The excess borane was destroyed with
1 mL MeOH, followed by the addition of 3.8 g elemental iodine,
followed in turn by a solution of 0.8 g NaOH in hot MeOH added over
the course of 5 min.  The color gradually faded, and became a pale
lime green.  This was added to 300 mL dilute aqueous sodium
thiosulfate which was extracted with 2x100 mL petroleum ether.  The
extracts were pooled, and the solvent evaporated under vacuum to
provide crude 1-(3-ethoxy-5-ethylthio-4-methoxyphenyl)-2-iodoethane as
a residue.

To this crude 1-(3-ethoxy-5-ethylthio-4-methoxyphenyl)-2-iodoethane
there was added a solution of 3.7 g potassium phthalimide in 50 mL
anhydrous DMF, and all was heated on the steam bath.  The reaction
seemed to be complete after 15 min (as seen by TLC) and the addition
of a second batch of potassium phthalimide in DMF produced no further
change.  After adding to 500 mL of dilute NaOH, the aqueous phase was
extracted with 2x75 mL Et2O.  These extracts were combined, washed
first with dilute NaOH and then with dilute H2SO4, dried over
anhydrous K2CO3, and the solvent removed under vacuum which provided
an amber oil as residue.  This was triturated under cold MeOH giving
white solids which were recrystallized from 20 mL MeOH.  Thus there
was obtained 0.9 g of
1-(3-ethoxy-5-ethylthio-4-methoxyphenyl)-2-phthalimidoethane as white
crystals that melted at 79-80.5 !C.  A small sample was recrystallized
from EtOH to give large flat needles with a mp of 81-82 !C.  Anal.
(C21H23NO4S) C,H.

A suspension of 0.8 g of the crystallized
1-(3-ethoxy-5-ethylthio-4-methoxyphenyl)-2-phthalimidoethane in 25 mL
of n-butanol was treated with 2 mL of 66% hydrazine, and the mixture
was heated on the steam bath for 0.5 h.  Initially all went into
solution, and then there was the separation of solids that resembled
cottage cheese.  The reaction mixture was added to 150 mL dilute
H2SO4.  The solids were removed by filtration, and the filtrate was
washed with 3x50 mL CH2Cl2.  These washes were discarded.  The H2O
phase was then made basic with aqueous NaOH, extracted with 2x75 mL
CH2Cl2, and the solvent from these pooled extracts removed under
vacuum.  The residue was distilled at 135-155 !C at 0.3 mm/Hg to give
0.45 g of a colorless oil.  This was dissolved in 2.5 mL IPA,
neutralized with 5 drops of concentrated HCl, and diluted with 10 mL
anhydrous Et2O.  The solution became cloudy, and then deposited
lustrous white plates.  These were removed by filtration, washed with
additional Et2O, and air dried to give 0.4 g of
3-ethoxy-5-ethylthio-4-methoxyphenethylamine hydrochloride (3-TSB)
with a mp of 153.5-154.5 !C.  Anal. (C13H22ClNO2S) C,H.

DOSAGE: greater than 200 mg.

DURATION: unknown.

QUALITATIVE COMMENTS: (with 200 mg) No effects whatsoever, neither
mental nor physical.

EXTENSIONS AND COMMENTARY: The elephant labored and brought forth a
mouse.  A lot of work for a material without activity.

I have used the term RscrudgeS in this and other recipes, without
defining it.  With this aldehyde, as with most aldehydes in this
nitrostyrene synthesis reaction where there is no ortho-substituent on
the benzaldehyde, the reaction progress should be carefully followed
by thin-layer chromatography.  As the aldehyde disappears from the
reaction mixture, the nitrostyrene appears, but there is usually the
development of one or more slower moving components as seen by TLC.
Such a wrong-product is called scrudge.  The reaction should be
continuously titrated, and stopped when there is a favorable balance
between the aldehyde being mostly gone, the nitrostyrene being mostly
made, and the slower-moving scrudge components being not yet too
plentiful.  Methylene chloride is an excellent solvent to try first,
with silica gel plates and UV detection.  The nitrostyrene is always
the fastest moving component of the reaction mixture and often
fluoresces a dull purple.  The starting aldehyde is the second spot
and usually fluoresces white or pale yellow.  The scrudge spots then
occur in a cascade from the aldehyde to the origin.  A maddening
property is that they are yellow or brown colored, and in the probe
mass spectrograph they can crack to give rise to what appears to be
the right nitrostyrene.  Usually, they are high melting.

In this preparation, there was not one but several scrudges, and
little if any nitrostyrene.  The same was true for the other of the
diethyl compounds such as 3-TASB, 5-TASB and 3-T-TRIS.  Thus, it is
preferable to circumvent this usual synthetic step by using the Wittig
reaction instead, as described here.









#177 4-TSB; 4-THIOSYMBESCALINE;
3,5-DIETHOXY-4-METHYLTHIOPHENETHYLAMINE

SYNTHESIS: A solution of 12.1 g N,N,NU,NU-tetramethylethylenediamine
and 16.6 g of 1,3-diethoxybenzene was made in 200 mL 30-60 !C
petroleum ether.  This was stirred vigorously under a N2 atmosphere
and cooled to 0 !C with an external ice bath.  There was added 66 mL
of 1.6 M butyllithium in hexane.  The stirred reaction mixture became
a little cloudy and then gradually formed a white granular
precipitate.  This was brought to room temperature, stirred for 0.5 h,
and returned again to 0 !C.  There was added 9.45 g of dimethyl
disulfide which converted the loose precipitate to a creamy texture.
The reaction was exothermic.  After being held 0.5 h at reflux
temperature, the reaction mixture was added to 600 mL dilute H2SO4.
There was the immediate formation of white solids which were insoluble
in either phase.  The petroleum ether phase was separated, and the
aqueous phase extracted with 3x100 mL Et2O.  The organics were
combined, and the solvents removed under vacuum.  There was obtained
as residue 24.8 g of a slightly oily crystalline solid that, after
trituration under 30 mL cold hexane, filtering, and air drying,
weighed 16.9 g.  This product, 2,6-diethoxythioanisole, had a mp of
71-72 !C which was not im-proved by recrystallization from
methylcyclopentane.  Anal. (C11H16O2S) C,H.

To a stirred solution of 16.7 g of 2,6-diethoxythioanisole in 175 mL
CH2Cl2 there was added 13 g elemental bromine dissolved in 100 mL
CH2Cl2.  After stirring at ambient temperature 1 h, the dark solution
was added to 150 mL H2O containing 1 g of sodium dithionite.  Shaking
immediately discharged the residual bromine color, and the organic
phase was separated.  The aqueous phase was extracted once with 100 mL
CH2Cl2, the pooled extracts washed first with H2O, and then with
saturated brine.  Removal of the solvent under vacuum provided 28.6 g
of a pale yellow oil with several globs of H2O present.  This wet
product was distilled at 118-125 !C at 0.25 mm/Hg to yield
3-bromo-2,6-diethoxythioanisole as a white oil weighing 21.5 g.  It
could not be crystallized.  Anal. (C11H15BrO2S) C,H.

To a solution of 19.3 g diisopropylamine in 75 mL hexane under a He
atmosphere there was added 100 mL of 1.6 M butyllithium.  The viscous
mixture was loosened by the addition of 200 mL anhydrous THF, and this
stirred mixture was cooled with an external ice bath.  There was then
added 4.0 mL of dry CH3CN, and 11.6 g of
3-bromo-2,6-diethoxythioanisole (which had been diluted with a little
anhydrous THF).  The deep red brown reaction mixture was stirred for
0.5 h, and then poured into 1 L dilute H2SO4. This was extracted with
3x75 mL CH2Cl2, the extracts pooled, washed with H2O, dried with
anhydrous K2CO3, and the solvent was removed under vacuum.  The
residue was distilled at 0.3 mm/Hg yielding two fractions.  The first
fraction boiled at 120-140 !C and weighed 1.2 g.  This fraction
partially crystallized, but was not investigated further.  The second
fraction was 3,5-diethoxy-4-methylthiophenylacetonitrile, which came
over at 135-160 !C, was a yellow liquid, weighed 3.2 g, but did not
crystallize.

A solution of LAH in anhydrous THF (30 mL of a 1.0 M solution) under
N2 was cooled to 0 !C and vigorously stirred.  There was added,
dropwise, 0.78 mL 100% H2SO4, followed by 3.0 g
3,5-diethoxy-4-methylthiophenylacetonitrile diluted with a little
anhydrous THF.  The reaction mixture was stirred at 0 !C for a few
min, then brought to reflux on the steam bath for 1.5 h.  After
cooling back to room temperature, there was added IPA to destroy the
excess hydride and 10% NaOH to bring the reaction to a basic pH with
the conversion of aluminum oxide to a loose, white, filterable
consistency.  This was removed by filtration, and washed first with
THF followed by IPA.  The filtrate and washes were stripped of solvent
under vacuum, the residue added to 1 L dilute H2SO4.  This was washed
with 2x75 mL CH2Cl2, made basic with 25% NaOH, and extracted with
3x100 mL CH2Cl2.  After combining, the solvent was removed under
vacuum providing an orange oil.  This was distilled at 135-160 !C at
0.4 mm/Hg to give a light yellow oil.  This was dissolved in 20 mL of
IPA, and neutralized with 32 drops of concentrated HCl producing white
crystals spontaneously.  These were dissolved by bringing the IPA
suspension to a boil on the steam bath and, with stirring, diluted
with 80 mL of warm anhydrous Et2O.  There was the immediate formation
of crystals which were removed by filtration, washed with an IPA/Et2O
mixture, and then with Et2O.  After air drying there was obtained 1.5
g of 3,5-diethoxy-4-methylthiophenethylamine hydrochloride (4-TSB) as
white crystals.  The mp was 194.5-196 !C.  Anal. (C13H22ClNO2S) C,H.

DOSAGE: greater than 240 mg.

DURATION: unknown.

QUALITATIVE COMMENTS: (with 80 mg) There was a real effect about
three hours into this experiment Q a little bit spacey while I was
talking to Mr. X.  But the talk went well, and we were all really
friendly.  There was no hint that he suspected anything.  A couple of
hours later, nothing.

(with 160 mg) Twinges at a couple of hours, but the rest of the day
disappointing as to any effect from the drug.

(with 240 mg) No effects at all.

EXTENSIONS AND COMMENTARY: Here is an excellent presentation of a
report that shows false positives or maybe false negatives.  Something
at low levels.  Nothing at higher levels.  Always tend to trust the
absence of an effect in preference to the presence of an effect, if
one of the two observations is presumed to be in error.









#178 3-T-TRIS; 3-THIOTRESCALINE; 3-THIOTRISESCALINE;
3,4-DIETHOXY-5-ETHYLTHIOPHENETHYLAMINE

SYNTHESIS: A solution of 11.5 g
3-bromo-N-cyclohexyl-4,5-diethoxybenzylidenimine (see under ASB for
its preparation) in 150 mL anhydrous Et2O was placed in a He
atmosphere, well stirred, and cooled in an external dry ice acetone
bath to -80 !C.  There was light formation of fine crystals.  There
was then added 25 mL of 1.6 N butyllithium in hexane and the mixture
stirred for 15 min.  This was followed by the addition of 5.8 g
diethyl disulfide over the course of 20 min during which time the
solution became increasingly cloudy with the eventual deposition of an
insoluble gummy phase.  The mixture was allowed to come to room
temperature over the course of 1 h, and then added to 400 mL of dilute
HCl.  The organic phase was separated and stripped of solvent under
vacuum.  This residue was combined with the original aqueous phase,
and the mixture was heated on the steam bath for 2 h.  The aqueous
mixture was cooled to room temperature, extracted with 3x100 mL
CH2Cl2, the extracts pooled, washed with H2O, and the solvent removed
under vacuum to yield 11.0 g of an amber oil.  This was distilled at
130-150 !C at 0.2 mm/Hg to yield 7.2 g of
3,4-diethoxy-5-(ethylthio)benzaldehyde as a white oil that
spontaneously crystallized.  The crude product had a mp of 52-57 !C
that increased to 57-58 !C upon recrystallization from EtOH.  Anal.
(C13H18O3S) C,H.

A solution of 14.9 g methyltriphenylphosphonium bromide in 200 mL
anhydrous THF was placed under a He atmosphere, well stirred, and
cooled to 0 !C with an external ice water bath.  There was then added
27.6 mL of 1.6 N butyllithium in hexane which resulted in the
generation of a yellow color which was at first transient, and then
stable.  The reaction mixture was brought up to room temperature, and
6.8 g 3,4-diethoxy-5-(ethylthio)benzaldehyde in 50 mL THF was added
dropwise dispelling the color, and the mixture was held at reflux on
the steam bath for 1 h.  The reaction was quenched in 800 mL H2O, the
top layer separated, and the aqueous phase extracted with 2x75 mL of
petroleum ether.  The organic fractions were combined and the solvents
removed under vacuum to give 12.0 g of the crude
3,4-diethoxy-5-ethylthiostyrene as a deep yellow oil.

A solution of 5.6 g of borane-methyl sulfide complex (10 M BH3 in
methyl sulfide) in 45 mL THF was placed in a He atmosphere, cooled to
0 !C, treated with 11.6 g of 2-methylbutene, and stirred for 1 h while
returning to room temperature.  To this there was added the crude
3,4-diethoxy-5-ethylthiostyrene in 25 mL THF and the stirring was
continued for 1 h.  The excess borane was destroyed with about 2 mL
MeOH.  There was then added 11.4 g elemental iodine followed by a
solution of 2.2 g NaOH in 40 mL hot MeOH.  This was followed by
sufficient 25% NaOH to minimize the residual iodine color (about 4 mL
was required).  The reaction mixture was added to 500 mL H2O
containing 4 g sodium hydrosulfite.  This was extracted with 3x75 mL
petroleum ether, and the pooled extracts stripped of solvent under
vacuum to yield 24.5 g of crude
1-(3,4-diethoxy-5-ethylthiophenyl)-2-iodoethane as a viscous yellow
oil.

This crude 1-(3,4-diethoxy-5-ethylthiophenyl)-2-iodoethane was added
to a solution of 11.1 g potassium phthalimide in 80 mL DMF, and all
was heated on the steam bath for 1.5 h.  It was then flooded with 600
mL H2O, made basic with NaOH, and extracted with 3x100 mL Et2O.
Removal of the solvent under vacuum provided 18.5 g of a residue that
was dried to a constant weight by heating under vacuum (0.2 mm/Hg).
The solid residue was ground under MeOH, and then recrystallized from
MeOH providing 1-(3,4-diethoxy-5-ethylthiophenyl)-2-phthalimidoethane
as white granular crystals, with a mp of 86.5-87.5 !C.  Anal.
(C22H25NO4S) C,H.

The recrystallized
1-(3,4-diethoxy-5-ethylthiophenyl)-2-phthalimidoethane was dissolved
in n-butanol, treated with 66% hydrazine, and the mixture heated on
the steam bath for 1.5 h.  This was then added to dilute H2SO4, the
butanol separated, the aqueous phase washed with 2x75 mL Et2O.  After
being made basic with aqueous NaOH, the aqueous phase was extracted
with 3x75 mL CH2Cl2 and the solvent removed under vacuum to provide a
pale amber oil.  This was distilled at 140-155 !C at 0.25 mm/Hg to
give about 1 g of a white oil.  The distillate was dissolved in 5 mL
IPA, neutralized with concentrated HCl, and treated with 10 mL
anhydrous Et2O to give a solution from which a white crystalline
product slowly separated.  These crystals,
3,4-diethoxy-5-ethylthiophenethylamine hydrochloride (3-T-TRIS)
weighed 1.1 g and had a mp of 161-162 !C.  Anal. (C14H24ClNO2S) C,H.

DOSAGE: greater than 160 mg.

DURATION: unknown.

QUALITATIVE COMMENTS: (with 160 mg) There were no effects.  At the
9th or 10th hour after having taken the material I was aware of some
neurological irritability.  I will not try this at any higher dosage,
and let me stretch things a bit by a few percent in good conscience
and say that this is less active than mescaline.  This would allow it
to be reported as < 1 M.U.

EXTENSIONS AND COMMENTARY: The term RM.U.S pops up here and there in a
lot of the earlier literature on these phenethylamines.  It stands for
Rmescaline unitsS and was used to give a quantitative measure for the
relative potency of a compound.  Since it became obvious quite early
in these studies that mescaline, although the prototypic compound, was
probably going to remain the least potent, it seemed reasonable to use
it as a bench mark of unity.  By dividing the dose needed of mescaline
(to produce central effects) by the dose needed of another drug, one
would generate a number that represented just how many times more
potent this new drug was than mescaline.  I used this term in a very
early review of the one-ring psychotomimetics, and it served
satisfactorily for quite a while.

Its intrinsic worth proved, however, to be its very limitation.  It
was quickly apparent that the principal value, to behavioral
researchers, of the reports of new hallucinogenic drugs, was not in
the nature of their action but in the amount of stuff needed to
produce that action.  This was an essential axis against which the
animal pharmacologist could plot his findings.  A number was wanted,
and the mescaline unit was just that number.  Sadly, the major
question that is asked by most academic researchers in their
evaluation of the psychedelic materials is, RHow much does it take,S
rather than RWhat does it do.S The marvelous nuances of action, the
subtle variations of effect, are dismissed as being hopelessly
subjective and thus without scientific worth.  But they are, I
believe, of great worth.  That is exactly what this book is all about.









#179 4-T-TRIS; 4-THIOTRESCALINE; 4-THIOTRISESCALINE;
3,5-DIETHOXY-4-ETHYLTHIOPHENETHYLAMINE

SYNTHESIS: A solution of 12.1 g N,N,NU,NU-tetramethylethylenediamine
and 16.6 g of 1,3-diethoxybenzene was made in 200 mL 30-60 !C
petroleum ether.  This was stirred vigorously under a He atmosphere
and cooled to 0 !C with an external ice bath.  There was added 66 mL
of 1.6 M butyllithium in hexane.  The stirred reaction mixture became
a little cloudy and then gradually formed a white granular
precipitate.  This was brought to room temperature, stirred for 0.5 h,
and returned again to 0 !C.  There was added 12.8 g of diethyl
disulfide which seemed to produce an exothermic reaction.  After being
held for a few min at reflux temperature, the reaction mixture was
added to 600 mL dilute H2SO4 which produced two clear phases. The
petroleum ether phase was separated, and the aqueous phase extracted
with 2x75 mL Et2O.  The organics were combined, and the solvents
removed under vacuum.  There was obtained as residue 24 g of a viscous
oil.  This was distilled at 93-110 !C at 0.3 mm/Hg yielding 21.5 g
1,3-diethoxy-2-ethylthiobenzene which spontaneously crystallized.
Grinding under a small amount of hexane, filtering, and hexane washing
provided 18.5 g of white crystals with a mp of 26-27 !C.  Anal.
(C12H18O2S) C,H.

To a stirred solution of 17.3 g of 1,3-diethoxy-2-ethylthiobenzene in
175 mL CH2Cl2 there was added 11.8 g elemental bromine dissolved in
100 mL CH2Cl2.  There was an immediate loss of color, and the obvious
evolution of HBr gas.  After stirring at ambient temperature for 1 h,
the dark solution was added to 150 mL H2O containing 1 g of sodium
dithionite.  Shaking immediately discharged the residual bromine
color, and the organic phase was separated, The aqueous phase was
extracted once with 75 mL CH2Cl2, the pooled extracts washed first
with H2O, and then with saturated brine.  Removal of the solvent under
vacuum provided 34.2 g of a pale yellow oil with several globs of H2O
that were mechanically removed.  This wet product was distilled at
105-125 !C at 0.35 mm/Hg to yield
4-bromo-1,3-diethoxy-2-ethylthiobenzene as an off-white oil weighing
21.6 g.  It could not be crystallized.  Anal. (C12H17BrO2S) C,H.

To a solution of 20.2 g diisopropylamine in 200 mL anhydrous THF that
had been cooled to -10 !C under a He atmosphere with an external
ice/MeOH bath, there was added 125 mL of a 1.6 M solution of
butyllithium in hexane. There was then added, in sequence, 5.1 mL of
dry CH3CN followed by the dropwise addition of 15.3 g
4-bromo-1,3-diethoxy-2-ethylthiobenzene diluted with a little
anhydrous THF. There was only a modest color development. Analysis by
thin-layer chromatography showed that the reaction components were
largely starting bromide and only a little product nitrile.  An
additional 2.5 mL dry CH3CN was added, followed immediately by a
solution of lithium diisopropylamide prepared separately from 14 mL
isopropylamine in 50 mL hexane treated with 60 mL butyllithium
solution.  There was an immediate darkening of color.  After 15 min
stirring, the bromo starting material was gone, by TLC analysis.  The
reaction mixture was then poured into 1 L dilute H2SO4. The organic
phase was separated and the aqueous fraction extracted with 2x100 mL
CH2Cl2.  These extracts were pooled, washed with H2O, dried with
anhydrous K2CO3, and the solvent was removed under vacuum.  The
residue was distilled at 0.3 mm/Hg yielding two fractions.  The first
fraction boiled at 124-145 !C and gave an amber liquid weighing 2.4 g.
It was largely starting bromo compound with a little nitrile, and was
not processed further.  The second fraction distilled at 140-190 !C
and weighed 6.2 g.  Although this was largely product nitrile, it was
quite complex by chromatographic analysis.  It was redistil-led at 0.3
mm/Hg and several fractions taken.  The material collected at 145-165
!C weighed 3.2 g and was approximately 80%
3,5-diethoxy-4-ethylthiophenylacetonitrile by TLC assay.  This was
used in the subsequent reduction.  The earlier fraction in this second
distillation (130-145 !C) weighed 2.1 g but contained only 50% product
nitrile by TLC analysis, and was discarded.

A solution of LAH in anhydrous THF under N2 (20 mL of a 1.0 M
solution) was cooled to 0 !C and vigorously stirred.  There was added,
dropwise, 0.53 mL 100% H2SO4, followed by 3.0 g
3,5-diethoxy-4-ethylthiophenylacetonitrile diluted with a little
anhydrous THF.  The reaction mixture was stirred at room temperature
for 1 h, and then at reflux on the steam bath for an additional 0.5 h.
After cooling back to room temperature, there was added IPA to destroy
the excess hydride and 10% NaOH to bring the reaction to a basic pH
and convert the aluminum oxide to a loose, white, filterable
consistency.  This was removed by filtration, and washed first with
THF followed by IPA.  The combined filtrate and washes were stripped
of solvent under vacuum, the residue added to 1 L dilute H2SO4.  This
was washed with 2x75 mL CH2Cl2, made basic with 25% NaOH, and
extracted with 3x100 mL CH2Cl2.  After combining, the solvent was
removed under vacuum providing a residue that was distilled.  A
fraction boiling at 135-150 !C at 0.3 mm/Hg weighed 1.2 g and was a
light yellow oil.  This was dissolved in 20 mL of IPA, and neutralized
with 17 drops of concentrated HCl which produces white crystals
spontaneously. These were dissolved by bringing the IPA suspension to
a boil on the steam bath and, with stirring, there was added 40 mL of
hot anhydrous Et2O.  There was the immediate formation of crystals
which were removed by filtration, washed with an IPA/Et2O mixture,
followed by Et2O.  After air drying there was obtained 1.0 g of
3,5-diethoxy-4-ethylthiophenethylamine hydrochloride (4-T-TRIS) as
sparkling white crystals.  The mp was 177-178 !C.  Anal.
(C14H24ClNO2S) C,H.

DOSAGE: greater than 200 mg.

DURATION: unknown.

QUALITATIVE COMMENTS: (with 120 mg) Maybe there is some physical
effect?  There is a slight tingling or numbing of my hands and
fingers, and a certain amount of gas.  It is certainly negative on the
mental side, but go up slowly due to the physical.

(with 200 mg) There was a passing awareness at the third hour.
Otherwise, no effects, either mental or physical.

EXTENSIONS AND COMMENTARY: As with the sulfur-free counterpart, the
phenethylamine with three ethyl groups hanging out from it is not
active in man.  It doesnUt matter where the sulfur is, since the
3-T-TRIS isomer is also without action.  The labor of making the
amphetamine analogues of these triethylated things seems hardly worth
the effort.







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