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#179 4-T-TRIS
4-THIOTRESCALINE; 4-THIOTRISESCALINE; 3,5-DIETHOXY-4-ETHYLTHIOPHENETHYLAMINE
SYNTHESIS: A
solution of 12.1 g N,N,N',N'-
tetramethylethylenediamine
and 16.6 g of
1,3-diethoxybenzene was made in 200 mL 30-60 °C
petroleum
ether. This was stirred vigorously under a He
atmosphere
and cooled to 0 °C with an external ice bath. There was added 66 mL
of 1.6 M
butyllithium in hexane. The stirred reaction mixture became
a little cloudy and then gradually formed a white granular
precipitate. This was brought to room tem
perature, stirred for 0.5 h,
and returned again to 0 °C. There was added 12.8 g of
diethyl
disulfide which seemed to produce an exothermic reaction. After being
held for a few min at reflux tem
perature, the reaction mixture was
added to 600 mL dilute H2SO4 which produced two clear
phases. The
petroleum
ether phase was separated, and the aqueous phase extracted
with 2x75 mL
Et2O. The organics were combined, and the
solvents
removed under vacuum. There was obtained as residue 24 g of a viscous
oil. This was
distilled at 93-110 °C at 0.3 mm/
Hg yielding 21.5 g
1,3-diethoxy-2-ethylthiobenzene which spontaneously
crystallized.
Grinding under a small amount of hexane, filtering, and hexane washing
provided 18.5 g of white
crystals with a mp of 26-27 °C. Anal.
(C12H18O2S) C,H.
To a stirred
solution of 17.3 g of
1,3-diethoxy-2-ethylthiobenzene in
175 mL
CH2Cl2 there was added 11.8 g elemental
bromine dissolved in
100 mL
CH2Cl2. There was an immediate loss of color, and the obvious
evolution of HBr gas. After stirring at ambient tem
perature for 1 h,
the dark
solution was added to 150 mL H2O containing 1 g of
sodium
dithionite. Shaking immediately discharged the
residual bromine
color, and the organic
phase was separated, The aqueous phase was
extracted once with 75 mL
CH2Cl2, the pooled extracts washed first
with H2O, and then with saturated brine. Removal of the
solvent under
vacuum provided 34.2 g of a pale yellow oil with several globs of H2O
that were mechanically removed. This wet product was
distilled at
105-125 °C at 0.35 mm/
Hg to yield
4-bromo-1,3-diethoxy-2-ethylthiobenzene as an off-white oil weighing
21.6 g. It could not be
crystallized. Anal. (C12H17BrO2S) C,H.
To a
solution of 20.2 g
diisopropylamine in 200 mL
anhydrous THF that
had been cooled to -10 °C under a He
atmosphere with an external
ice/MeOH bath, there was added 125 mL of a 1.6 M
solution of
butyllithium in hexane. There was then added, in sequence, 5.1 mL of
dry
CH3CN followed by the dropwise addition of 15.3 g
4-bromo-1,3-diethoxy-2-ethylthiobenzene diluted with a little
anhydrous THF. There was only a modest color development. Analysis by
thin-layer
chromatography showed that the reaction components were
largely starting
bromide and only a little product
nitrile. An
additional 2.5 mL dry
CH3CN was added, followed immediately by a
solution of
lithium diisopropylamide prepared separately from 14 mL
isopropylamine in 50 mL hexane treated with 60 mL
butyllithium
solution. There was an immediate darkening of color. After 15 min
stirring, the bromo starting material was gone, by TLC analysis. The
reaction mixture was then poured into 1 L dilute H2SO4. The organic
phase was separated and the aqueous fraction extracted with 2x100 mL
CH2Cl2. These extracts were pooled, washed with H2O, dried with
anhydrous K2CO3, and the
solvent was removed under vacuum. The
residue was
distilled at 0.3 mm/
Hg yielding two fractions. The first
fraction boiled at 124-145 °C and gave an amber liquid weighing 2.4 g.
It was largely starting bromo compound with a little
nitrile, and was
not processed further. The second fraction
distilled at 140-190 °C
and weighed 6.2 g. Although this was largely product
nitrile, it was
quite complex by
chromatographic analysis. It was redistil-led at 0.3
mm/
Hg and several fractions taken. The material collected at 145-165
°C weighed 3.2 g and was approximately 80%
3,5-diethoxy-4-ethylthiophenylacetonitrile by TLC assay. This was
used in the subsequent reduction. The earlier fraction in this second
distillation (130-145 °C) weighed 2.1 g but contained only 50% product
nitrile by TLC analysis, and was discarded.
A
solution of LAH in
anhydrous THF under N2 (20 mL of a 1.0 M
solution) was cooled to 0 °C and vigorously stirred. There was added,
dropwise, 0.53 mL 100% H2SO4, followed by 3.0 g
3,5-diethoxy-4-ethylthiophenylacetonitrile diluted with a little
anhydrous THF. The reaction mixture was stirred at room tem
perature
for 1 h, and then at reflux on the steam bath for an additional 0.5 h.
After cooling back to room tem
perature, there was added IPA to destroy
the excess
hydride and 10%
NaOH to bring the reaction to a basic
pH
and convert the
aluminum oxide to a loose, white, filterable
consistency. This was removed by filtration, and washed first with
THF followed by IPA. The combined filtrate and washes were stripped
of
solvent under vacuum, the residue added to 1 L dilute H2SO4. This
was washed with 2x75 mL
CH2Cl2, made basic with 25%
NaOH, and
extracted with 3x100 mL
CH2Cl2. After combining, the
solvent was
removed under vacuum providing a residue that was
distilled. A
fraction boiling at 135-150 °C at 0.3 mm/
Hg weighed 1.2 g and was a
light yellow oil. This was
dissolved in 20 mL of IPA, and neutralized
with 17 drops of concentrated HCl which produces white
crystals
spontaneously. These were
dissolved by bringing the IPA suspension to
a boil on the steam bath and, with stirring, there was added 40 mL of
hot
anhydrous Et2O. There was the immediate formation of
crystals
which were removed by filtration, washed with an IPA/
Et2O mixture,
followed by
Et2O. After air drying there was obtained 1.0 g of
3,5-diethoxy-4-ethylthiophenethylamine hydrochloride (4-T-TRIS) as
sparkling white
crystals. The mp was 177-178 °C. Anal.
(C14H24ClNO2S) C,H.
DOSAGE: greater than 200 mg.
DURATION: unknown.
QUALITATIVE COMMENTS: (with 120 mg) Maybe there is some physical
effect? There is a slight tingling or numbing of my hands and
fingers, and a certain amount of gas. It is certainly negative on the
mental side, but go up slowly due to the physical.
(with 200 mg) There was a passing awareness at the third hour.
Otherwise, no effects, either mental or physical.
EXTENSIONS AND COMMENTARY: As with the
sulfur-free counterpart, the
phenethylamine with three ethyl groups hanging out from it is not
active in man. It doesn't matter where the
sulfur is, since the
3-T-TRIS
isomer is also without action. The labor of making the
amphetamine analogues of these
triethylated things seems hardly worth
the effort.
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