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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