SYNTHESIS: A solution of 5.1 g N,N,N',N'-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--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.
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