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 N2 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 temperature, stirred for 0.5 h,
and returned again to 0 °C. There was added 9.45 g of dimethyl
disulfide which converted the loose precipitate to a creamy texture.
The reaction was exothermic. After being held 0.5 h at reflux
temperature, the reaction mixture was added to 600 mL dilute H2SO4.
There was the immediate formation of white solids which were insoluble
in either phase. The petroleum ether phase was separated, and the
aqueous phase extracted with 3x100 mL Et2O. The organics were
combined, and the solvents removed under vacuum. There was obtained
as residue 24.8 g of a slightly oily crystalline solid that, after
trituration under 30 mL cold hexane, filtering, and air drying,
weighed 16.9 g. This product, 2,6-diethoxythioanisole, had a mp of
71-72 °C which was not im-proved by recrystallization from
methylcyclopentane. Anal. (C11H16O2S) C,H.
To a stirred solution of 16.7 g of 2,6-diethoxythioanisole in 175 mL
CH2Cl2 there was added 13 g elemental bromine dissolved in 100 mL
CH2Cl2. After stirring at ambient temperature 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 100 mL
CH2Cl2, the pooled extracts washed first with H2O, and then with
saturated brine. Removal of the solvent under vacuum provided 28.6 g
of a pale yellow oil with several globs of H2O present. This wet
product was distilled at 118-125 °C at 0.25 mm/Hg to yield
3-bromo-2,6-diethoxythioanisole as a white oil weighing 21.5 g. It
could not be crystallized. Anal. (C11H15BrO2S) C,H.
To a solution of 19.3 g diisopropylamine in 75 mL hexane under a He
atmosphere there was added 100 mL of 1.6 M butyllithium. The viscous
mixture was loosened by the addition of 200 mL anhydrous THF, and this
stirred mixture was cooled with an external ice bath. There was then
added 4.0 mL of dry CH3CN, and 11.6 g of
3-bromo-2,6-diethoxythioanisole (which had been diluted with a little
anhydrous THF). The deep red brown reaction mixture was stirred for
0.5 h, and then poured into 1 L dilute H2SO4. This was extracted with
3x75 mL CH2Cl2, the extracts 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 120-140 °C and weighed 1.2 g. This fraction
partially crystallized, but was not investigated further. The second
fraction was 3,5-diethoxy-4-methylthiophenylacetonitrile, which came
over at 135-160 °C, was a yellow liquid, weighed 3.2 g, but did not
crystallize.
A solution of LAH in anhydrous THF (30 mL of a 1.0 M solution) under
N2 was cooled to 0 °C and vigorously stirred. There was added,
dropwise, 0.78 mL 100% H2SO4, followed by 3.0 g
3,5-diethoxy-4-methylthiophenylacetonitrile diluted with a little
anhydrous THF. The reaction mixture was stirred at 0 °C for a few
min, then brought to reflux on the steam bath for 1.5 h. 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 with
the conversion of aluminum oxide to a loose, white, filterable
consistency. This was removed by filtration, and washed first with
THF followed by 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 25% NaOH, and extracted with
3x100 mL CH2Cl2. After combining, the solvent was removed under
vacuum providing an orange oil. This was distilled at 135-160 °C at
0.4 mm/Hg to give a light yellow oil. This was dissolved in 20 mL of
IPA, and neutralized with 32 drops of concentrated HCl producing white
crystals spontaneously. These were dissolved by bringing the IPA
suspension to a boil on the steam bath and, with stirring, diluted
with 80 mL of warm anhydrous Et2O. There was the immediate formation
of crystals which were removed by filtration, washed with an IPA/Et2O
mixture, and then with Et2O. After air drying there was obtained 1.5
g of 3,5-diethoxy-4-methylthiophenethylamine hydrochloride (4-TSB) as
white crystals. The mp was 194.5-196 °C. Anal. (C13H22ClNO2S) C,H.
DOSAGE: greater than 240 mg.
DURATION: unknown.
QUALITATIVE COMMENTS: (with 80 mg) There was a real effect about
three hours into this experiment--a little bit spacey while I was
talking to Mr. X. But the talk went well, and we were all really
friendly. There was no hint that he suspected anything. A couple of
hours later, nothing.
(with 160 mg) Twinges at a couple of hours, but the rest of the day
disappointing as to any effect from the drug.
(with 240 mg) No effects at all.
EXTENSIONS AND COMMENTARY: Here is an excellent presentation of a
report that shows false positives or maybe false negatives. Something
at low levels. Nothing at higher levels. Always tend to trust the
absence of an effect in preference to the presence of an effect, if
one of the two observations is presumed to be in error.
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