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#146 3-TASB
3-THIOASYMBESCALINE; 4-ETHOXY-3-ETHYLTHIO-5-METHOXYPHENETHYLAMINE
SYNTHESIS: Without any
solvent, there was combined 21.7 g of solid
5-
bromovanillin and 11.4 mL
cyclohexylamine. There was the immediate
generation of a yellow color and the evolution of heat. The largely
solid mass was ground up under 50 mL of boiling IPA to an apparently
homogeneous yellow solid which was removed by filtration and washed
with IPA. There was thus obtained about 27 g of
3-bromo-N-
cyclohexyl-4-hydroxy-5-
methoxybenzylidenimine with a mp of
229-231 °C and which proved to be in
soluble in most
solvents (
EtOH,
CH2Cl2,
acetone). A
solution in dilute
NaOH was unstable with the
immediate
deposition of opalescent white solids of the
phenol sodium
salt. A small scale re
crystallization from boiling
cyclohexanone
yielded a fine yellow solid with a lowered mp (210-215 °C). Anal.
(
C14H18BrNO2) C,H.
A
solution of 32.5 g
3-bromo-N-
cyclohexyl-4-hydroxy-5-
methoxybenzylidenimine in 60 mL of
hot DMF was cooled to near room tem
perature, treated with 24.5 g
ethyl
iodide and followed by 14.0 g of flake KOH. This mixture was held at
reflux for 1 h, cooled, and added to 1 L H2O. Additional base was
added and the product was extracted with 3x150 mL
CH2Cl2. These
pooled extracts were washed with dilute
NaOH, then with H2O, and
finally the
solvent was removed under vacuum. The crude amber-colored
residue was
distilled. The fraction coming over at 118-135 °C at 0.4
mm/
Hg weighed 8.7 g, spontaneously
crystallized, and proved to be
3-bromo-4-ethoxy-5-
methoxybenzaldehyde, melting at 59-60 °C after
re
crystallization from MeOH. Anal. (
C10H11BrO3) C,H. The fraction
that came over at 135-155 °C at 0.2 mm/
Hg weighed 10.5 g and also
solidified in the receiver. This product was
3-bromo-N-
cyclohexyl-4-ethoxy-5-
methoxybenzylidenimine which, upon
re
crystallization from two volumes MeOH, was a white
crystalline
material with a mp of 60-61 °C. Anal. (
C16H22BrNO2) C,H. The two
materials have identical mps, but can be easily distinguished by their
infra-red
spectra. The
aldehyde has a
carbonyl stretch at 1692 cm-1,
and the Schiff base a C=N stretch at 1641 cm-1.
A
solution of 20.5 g
3-bromo-N-
cyclohexyl-4-ethoxy-5-
methoxybenzylidenimine in about 300 mL
anhydrous Et2O was placed in a He
atmosphere, well stirred, and cooled
in an external dry ice
acetone bath to -80 °C. There was then added
50 mL of 1.6 N
butyllithium in hexane. The mixture became yellow and
very viscous with the generation of solids. These loosened up with
continuing stirring. This was followed by the addition of 10.7 g
diethyldisulfide. The reaction became extremely viscous again, and
stirring was continued while the reaction was allowed to warm to room
tem
perature. After an additional 0.5 h stirring, the reaction mixture
was added to 800 mL of dilute HCl. The
Et2O phase was separated and
the
solvent removed under vacuum. The residue was returned to the
original aqueous
phase, and the entire mixture heated on the steam
bath for 2 h. The bright yellow color faded and there was the
formation of a yellowish
phase on the surface of the H2O. The aqueous
solution was cooled to room tem
perature, extracted with 3x100 mL
CH2Cl2, the extracts pooled, washed first with dilute HCl, then with
saturated brine, and the
solvent removed under vacuum. The residue
was an amber oil weighing 20.4 g, and was
distilled at 130-140 °C at
0.3 mm/
Hg to yield 12.9 g of
4-ethoxy-3-ethylthio-5-methoxybenzaldehyde as a straw colored oil that
did not
crystallize. Anal. (
C12H16O3S) C,H.
A
solution of 1.0 g
4-ethoxy-3-ethylthio-5-methoxybenzaldehyde in 20 g
nitromethane was treated with about 0.2 g of
anhydrous ammonium
acetate and heated on the steam bath. TLC analysis showed that the
aldehyde was substantially gone within 20 min and that, in addition to
the expected
nitrostyrene, there were four scrudge products (see the
discussion of scrudge in the extensions and commentary section under
3-TSB). Removal of the excess
nitromethane under vacuum gave an
orange oil which was diluted with 5 mL cold MeOH but which could not
be induced to
crystallize. A seed was obtained by using a preparative
TLC plate (20x20 cm) and removing the fastest moving spot (development
was with
CH2Cl2). Placing this in the above MeOH
solution of the
crude
nitrostyrene allowed
crystallization to occur. After filtering
and washing with MeOH, 0.20 g of fine yellow
crystals were obtained
which melted at 75-77 °C. Re
crystallization from MeOH gave a bad
recovery of yellow
crystals of
4-ethoxy-3-ethylthio-5-methoxy-beta-nitrostyrene that now melted at
78.5-79 °C. Anal. (
C13H17NO4S) C,H. This route was discarded in
favor of the Wittig reaction described below.
A mixture of 27 g
methyltriphenylphosphonium bromide in 150 mL
anhydrous THF was placed under a He
atmosphere, well stirred, and
cooled to 0 °C with an external ice water bath. There was then slowly
added 50 mL of 1.6 N
butyllithium in hexane which resulted in the
initial generation of solids that largely re
dissolved by the
completion of the addition of the
butyllithium and after allowing the
mixture to return to room tem
perature. There was then added 11.7 g of
4-ethoxy-3-ethylthio-5-methoxybenzaldehyde without any
solvent. There
was the immediate formation of an unstirrable solid, which partially
broke up into a gum that still wouldn't stir. This was moved about,
as well as possible, with a glass rod, and then all was added to 400
mL H2O. The two
phases were separated and the lower, aqueous, phase
extracted with 2x75 mL of petroleum
ether. The organic fractions were
combined and the
solvents removed under vacuum to give the crude
4-ethoxy-3-ethylthio-5-methoxystyrene as a pale yellow fluid liquid.
A
solution of 10 mL of
borane-methyl sulfide complex (10 M BH3 in
methyl sulfide) in 75 mL THF was placed in a He
atmosphere, cooled to
0 °C, treated with 21 mL of
2-methylbutene, and stirred for 1 h while
returning to room tem
perature. This was added directly to the crude
4-ethoxy-3-ethylthio-5-methoxystyrene. The slightly exothermic
reaction was allowed to stir for 1 h, and then the excess
borane was
destroyed with a few mL of MeOH (in the absence of air to avoid the
formation of the
dialkylboric acid). There was then added 19 g of
elemental
iodine followed, over the course of about 10 min, by a
solution of 4 g
NaOH in 50 mL hot MeOH. The color did not fade.
Addition of another 4 mL 25%
NaOH lightened the color a bit, but it
remained pretty ugly. This was added to 500 mL H2O containing 5 g
sodium thiosulfate and extracted with 3x100 mL petroleum
ether. The
extracts were pooled, and the
solvent removed under vacuum to provide
crude
1-(4-ethoxy-3-ethylthio-5-methoxyphenyl)-2-iodoethane as a
residue.
To this crude
1-(4-ethoxy-3-ethylthio-5-methoxyphenyl)-2-iodoethane
there was added a
solution of 20 g
potassium phthalimide in 150 mL
anhydrous DMF, and all was held at reflux overnight. After adding to
500 mL of dilute
NaOH, some 1.4 g of a white solid was generated and
removed by filtration. The aqueous filtrate was extracted with 2x75
mL
Et2O. These extracts were combined, washed with dilute HCl, and
the
solvent removed under vacuum providing 23.6 g of a
terpene-smelling amber oil. This was stripped of all
volatiles by
heating to 170 °C at 0.4 mm/
Hg providing 5.4 g of a sticky brown
residue. This consisted largely of the desired
phthalimide. The
solids proved to be a purer form of
1-(4-ethoxy-3-ethylthio-5-methoxy)-2-phthalimidoethane and was
re
crystallized from a very small amount of MeOH to give fine white
crystals with a mp of 107.5-108.5 °C. Anal. (C21H23NO4S) C,H. The
white solids and the brown impure
phthalimide were separately
converted to the final product, 3-TASB.
A
solution of 1.2 g of the
crystalline
1-(4-ethoxy-3-ethylthio-5-methoxyphenyl)-2-phthalimidoethane in 40 mL
of warm n-
butanol was treated with 3 mL of 66%
hydrazine, and the
mixture was heated on the steam bath for 40 min. The reaction mixture
was added to 800 mL dilute H2SO4. The solids were removed by
filtration, and the filtrate was washed with 2x75 mL
CH2Cl2. The
aqueous
phase was made basic with 25%
NaOH, extracted with 3x75 mL
CH2Cl2, and the
solvent from these pooled extracts removed under
vacuum yielding 6.2 g of a residue that was obviously rich in
butanol.
This residue was
distilled at 138-144 C. at 0.3 mm/
Hg to give 0.6 g of
a colorless oil. This was
dissolved in 2.4 mL IPA, neutralized with
concentrated HCl, and diluted with 25 mL
anhydrous Et2O. The
solution
remained clear for about 10 seconds, and then
deposited white
crystals. These were removed by filtration, washed with additional
Et2O, and air dried to give 0.4 g
4-ethoxy-3-ethylthio-5-methoxyphenethylamine hydrochloride (3-TASB)
with a mp of 140-141 °C. Anal. (
C13H22ClNO2S) C,H. The amber-colored
impure
phthalimide, following the same procedure, provided another 0.9
g of the
hydrochloride salt with a mp of 138-139 °C.
DOSAGE: about 160 mg.
DURATION: 10 - 18 h.
QUALITATIVE COMMENTS: (with 120 mg) This is no more than a plus one,
and it didn't really get there until about the third hour. By a
couple of hours later, I feel that the mental effects are pretty much
dissipated, but there is some real physical residue. Up with some
caution.
(with 160 mg) The taste is completely foul. During the first couple
of hours, there was a conscious effort to avoid nausea. Then I
noticed that people's faces looked like marvelous parodies of
themselves and that there was considerable time slowing. There was no
desire to eat at all. Between the eighth and twelth hour, the mental
things drifted away, but the body was still wound up. Sleep was
impossible until about 3:00 AM (the 18th hour of the experiment) and
even the next day I was extremely active,
anorexic, alert, excited,
and plagued with occasional
diarrhea. This is certainly a potent
stimulant. The next night I felt the tensions drop, and finally got
an honest and easy sleep. There is a lot of
adrenergic push to this
material.
EXTENSIONS AND COMMENTARY: No
pharmacological agent has an action that
is pure this or pure that. Some pain-killing narcotics can produce
reverie and some
sedatives can produce paranoia. And just as surely,
some
psychedelics can produce stimulation. With 3-TASB we may be
seeing the shift from sensory effects over to out-and-out stimulation.
It would be an interesting challenge to take these
polyethylated
phenethylamines and assay them strictly for their
amphetamine-like
action. Sadly, the potencies are by and large so low, that the human
animal can't be used, and any sub-human experimental animal would not
enable the
psychedelic part of the equation to be acknowledged. If an
order of magnitude of increased potency could be bought by some minor
structural change, this question could be addressed. Maybe as the
three-
carbon amphetamine homologs, or as the 2,4,5- or 2,4,6-
substitution patterns, rather than the
3,4,5-pattern used in this set.
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