SYNTHESIS: To a solution of 2.6 g of KOH pellets in 50 mL hot MeOH,
there was added a mixture of 6.8 g 2,5-dimethoxythiophenol (see under
2C-T-2 for its preparation) and 5.8 g (s)-butyl bromide. The reaction
was exothermic, with the deposition of white solids. This was heated
on the steam bath for a few h, the solvent removed under vacuum, and
the resulting solids dissolved in 250 mL H2O. Additional aqueous NaOH
was added to bring universal pH paper to a full blue color. This was
extracted with 3x40 mL CH2Cl2, the extracts pooled, and the solvent
removed under vacuum. The residue was 2,5-dimethoxyphenyl (s)-butyl
sulfide which was a pale yellow oil, weighing 10.12 g. It was
sufficiently pure for use in the next reaction without a distillation
step.
A mixture of 15.1 g POCl3 and 14.1 g N-methylformanilide was heated
for 10 min on the steam bath. To this claret-colored solution was
added 9.4 g of 2,5-dimethoxyphenyl (s)-butyl sulfide, and the mixture
heated for 35 min on the steam bath. This was then added to 200 mL of
well-stirred warm H2O (pre-heated to 55 °C) and the stirring continued
until the oily phase had completely solidified (about 15 min). These
light brown solids were removed by filtration, and washed with
additional H2O. After sucking as dry as possible, these solids (12.14
g wet) were ground under an equal weight of MeOH which produced a
yellowish crystalline solid with a mp of 76-81 °C. Recrystallization
of a 0.4 g sample from an equal weight of boiling MeOH provided 0.27 g
of 2,5-dimethoxy-4-(s-butylthio)benzaldehyde as a pale cream-colored
crystalline material with a mp of 86-87 °C.
To a solution of 8.0 g of the crude
2,5-dimethoxy-4-(s-butylthio)benzaldehyde in 40 g of nitromethane
there was added 0.38 g of anhydrous ammonium acetate, and the mixture
was heated on the steam bath for 1 h. The reddish colored solution
was decanted from some insoluble tan material and the excess
nitromethane removed under vacuum. The heavy red oil that remained
was diluted with an equal volume of boiling MeOH, and allowed to
return to room temperature. The orange-colored crystals that slowly
formed were removed by filtration and, after air drying, weighted 6.24
g. This was again recrystallized from an equal volume of MeOH,
yielding 2,5-dimethoxy-4-(s-butylthio)-beta-nitrostyrene as yellow,
somewhat beady crystals that weighed (when dry) 3.50 g and which had a
mp of 62-65 °C. A small portion of this fraction was crystallized yet
again from MeOH to provide an analytical sample that was yellow-orange
in color, and had an mp of 68-69 °C. Anal. (C13H17NO4S) C,H.
A solution of LAH (120 mL of a 1 M solution in THF) was cooled, under
He, to 0 °C with an external ice bath. With good stirring there was
added 3.3 mL 100% H2SO4 dropwise, to minimize charring. This was
followed by the addition of 8.83 g
2,5-dimethoxy-4-(s-butylthio)-beta-nitrostyrene in 80 mL anhydrous THF
dropwise over the course of 2 h. After a few min further stirring,
the temperature was brought up to a gentle reflux on the steam bath,
and then all was cooled again to 0 °C. The excess hydride was
destroyed by the cautious addition of 18 mL IPA followed first by 5 mL
of 15% NaOH and then by 15 mL of H2O. The reaction mixture was
filtered, and the filter cake washed with THF. The filtrate and
washing were combined and stripped of solvent under vacuum providing
about 8.5 g of a pale amber oil. Without any further purification,
this was distilled at 135-150 °C at 0.4 mm/Hg to give 6.12 g of a
clear white oil. This was dissolved in 30 mL IPA, and neutralized
with 2.1 mL of concentrated HCl forming crystals immediately. Another
10 mL of IPA was added to allow the solids to be finely dispersed, and
then about 100 mL of anhydrous Et2O were added. The solids were
removed by filtration, Et2O washed, and air dried to constant weight.
The product, 2,5-dimethoxy-4-(s)-butylthiophenethylamine hydrochloride
(2C-T-17) was obtained as spectacular white crystals, weighing 5.67 g.
DOSAGE: 60 - 100 mg.
DURATION: 10 - 15 h.
QUALITATIVE COMMENTS: (with 60 mg) This material took fully three
hours to get into its maximum effect. I never was at a +++, quite,
and I am not sure why it is really active, but I know it is. There
does not seem to be any interference with my concentration or mental
coordination, but I wouldn't want to drive right now. Good appetite
in the evening, for a Chicago-style pizza, and there was no Tomso
effects (the rekindling of a psychedelic effect with alcohol) with a
glass of wine. An over-all good and instructive ++, no visuals,
totally benign. There is no hesitation in doing it again some day.
(with 100 mg) A small fragment hadn't dissolved when I drank the
solution, and it must have stuck to the back of my mouth, because it
made a searing spot that burned for 5 minutes. The first central
effects were noted at an hour. The plateau stretched from the 3rd to
the 7th hour, then tapered off quite quickly. My sleep was fitful,
with some hints of nervous sensitivity. I felt that there were some
residuals even into the next morning. A truly heavy psychedelic, but
with very few explicit sensual changes or unusual perceptions to
justify that comment. Why is it heavy? It just is. This dosage is
high enough.
EXTENSIONS AND COMMENTARY: An interesting, and quite logical, habit
that seems to always pop up when a lot of talk and energy become
directed at a specific compound, is the habit of using a nickname for
it. The Tweetios are an example, and in the 2C-T-X family I had
mentioned the term SESQUI. Here, this compound was called NIMITZ, for
the obvious reason that the major freeway from Oakland to San Jose,
the Nimitz freeway, was also called State Highway 17. Its name has
been changed to Interstate 880, and I guess it could now only be used
as a reference point if efforts were being made for a 2C-T-880.
The reason that 2C-T-17 is of special theoretic interest is that it is
one of the very first of the active psychedelic compounds (along with
2C-G-5) to have a potential optically active center on the side of the
ring away from the nitrogen atom. One of the oldest and best studied
variants of the phenethylamine chain are the alpha-methyl homologues,
the substituted amphetamines. Here there is an asymmetric carbon atom
right next to the amine group, allowing the molecule to be prepared in
either a right-hand way or a left-hand way. The "R" or the "S"
isomer. And in the several studies that have looked at such isomers
separately, it has always been the "R" isomer that has carried the
psychedelic effects. This probably says something about the nitrogen
end, the metabolic end, the "north" end of the receptor site that
recognizes these compounds, and suggests that there is some intrinsic
asymmetry in the area that binds near to the basic nitrogen atom.
But very little is known of the receptor's "south" end, so to speak,
the geometry of the area where the opposite end of the molecule has to
fit. Here, with 2-C-17, there is a secondary butyl group, and this
contains an asymmetric carbon atom. But now this center of asymmetry
is clear across the benzene ring from the nitrogen, and should
certainly be in some entirely new part of the receptor site. Why not
make this compound with the "R" and the "S" forms in this new and
unusual location? Why not, indeed! Why not call them the right-lane
and the left lane of the Nimitz? Fortunately, both "R" and "S"
secondary butyl alcohols were easily obtained, and the synthesis given
above for the racemic compound was paralleled for each of these
isomers, separately. Is there any chemistry that is different with
the specific optical isomers from that which has been reported with
the racemic? There certainly is for the first step, since the butyl
alcohols rather than the butyl bromides must be used, and this first
step must go by inversion, and it cannot be allowed any racemization
(loss of the optical purity of the chiral center).
The synthesis of 2C-T-17 "R" required starting with the "S" isomer of
secondary butanol. The "S" 2-butanol in petroleum ether gave the
lithium salt with butyllithium which was treated with tosyl chloride
(freshly crystallized from naphtha, hexane washed, used in toluene
solution) and the solvent was removed. The addition of
2,5-dimethoxythiophenol, anhydrous potassium carbonate, and DMF
produced "S"-2,5-dimethoxyphenyl s-butyl sulfide. The conversion to
"R"-2,5-dimethoxy-4-(s-butyl-thio)benzaldehyde (which melted at 78-79
°C compared to 86-87 °C for the racemic counterpart) and its
conversion in turn to the nitrostyrene,
"S"-2,5-dimethoxy-4-(s)-butylthio-beta-nitrostyrene which melted at 70-71
°C compared to 68-69 °C for the racemic counterpart, followed the
specific recipes above. The preparation of the intermediates to
2C-T-17 "S" follows the above precisely, but starting with "R"
2-butanol instead. And it is at these nitrostyrene stages that this
project stands at the moment.
It would be fascinating if one of the two optically active 2C-T-17's
carried all of the central activity, and the other, none of it. What
is more likely is that the spectrum of effects will be teased apart,
with one isomer responsible for some of them and the other isomer
responsible for the others. Then, again, maybe the south end of the
receptor site in the brain is totally symmetric, and the two optical
antipodes will be indistinguishable.
An incidental bit of trivia--yet another bit of evidence that we are
all totally asymmetric in our personal body chemistry. "R" and "S"
secondary butanols smell different. The "R" has a subtle smell, which
is rather fragrant . The "S" is stronger, hits the nasal passages
harder, and reminds one of isopropanol more than does the "S" isomer.
Back]
]