SYNTHESIS: A short foreword to the synthetic portion is needed.
First, although the required thioanisole, 2,3-dimethoxythioanisole, is
now commercially available, it is of the utmost importance that it be
free of the impurity, veratrole. I know that the material presently
available from Aldrich Chemical Company is satisfactory, as I have had
a hand in making it. But, if veratrole is present, there are very
difficult separations encountered during these preparations. And
secondly, the synthesis of 2-TIM and 4-TIM requires a separation of
isomers. The first intermediates are common to both. They will be
presented here, under this recipe for 2-TIM.
A solution of 150 mL of 1.6 M butyllithium in hexane under N2 was
vigorously stirred and diluted with 150 mL petroleum ether (30-60 °C)
and then cooled with an external ice bath to 0 °C. The addition of
26.7 g of veratrole produced a flocculant white precipitate. Next,
there was added a solution of 23.2 g of
N,N,N',N'-tetramethylethylenediamine in 100 mL anhydrous Et2O and the
stirred reaction mixture was allowed to come to room temperature. The
subsequent addition of 20.7 g of dimethyl disulfide over the course of
several min produced an exothermic response, and this was allowed to
stir for an additional 30 min. There was then added 10 mL EtOH
followed by 250 mL of 5% NaOH. The organic phase was washed first
with 150 mL 5% NaOH, followed by 2x100 mL portions of 5% dilute HCl.
The removal of solvent and bulb-to-bulb distillation of the residue
provided 2,3-dimethoxythioanisole boiling at 72-80 °C at 0.4 mm/Hg as
a white oil. This product contained some 20% unreacted veratrole as a
contaminant and the isolation of subsequent products from this impure
material was extraordinarily difficult. The effort needed for careful
purification at this point was completely justified. The product
could be obtained in a pure state by distillation at 0.1 mm/Hg through
a 6 cm Vigreaux column with collection of several fractions. Those
that distilled at 84-87 °C were pure 2,3-dimethoxythioanisole. An
analytical sample can be obtained by cooling a concentrated MeOH
solution in dry ice, filtering the generated crystals, and washing
with cold MeOH. This product melts at 36.5-37 °C. Anal. (C9H12O2S)
C,H,S. The picrate can be formed by treatment with a saturated EtOH
solution of picric acid. It formed orange crystals with a mp of 73-78
°C. Anal. (C15H15N3O9S) N.
To 18 mL of POCl3 there was added 25 mL N-methylformanilide and the
solution allowed to stand at room temperature for 0.5 h, until the
color had developed to a rich claret. There was then added 25.0 g of
2,3-dimethoxythioanisole and the mixture heated on the steam bath for
2.5 h. This was added to 500 mL H2O and stirred at ambient temperature
for 2 h. The product was extracted with 4x150 mL CH2Cl2, the extracts
combined, and the solvent removed under vacuum. The residue was
distilled through a Vigreaux column under vacuum (0.1 mm/Hg) with the
fraction boiling at 125-135 °C being richest in aldehydes, as
determined by GC analysis. If the starting 2,3-dimethoxythioanisole
contains appreciable veratrole as a contaminant, then this aldehyde
fraction contains three components. There is present both
2,3-dimethoxy-4-(methylthio)benzaldehyde and
3,4-dimethoxy-2-(methylthio)benzaldehyde (the two desired precursors
to 4-TIM and 2-TIM, respectively), but also present is
3,4-dimethoxybenzaldehyde from the veratrole contamination. The
weight of this fraction was 11.9 g and was a white oil free of
starting thioether.
Although efforts to separate this mixture were not effective, one of
the aldehydes could be isolated in small yield by derivative
formation. This was too wasteful to be of preparative value, but it
did allow the generation of seed that was of great value in the later
separation of the mixed nitrostyrenes that were prepared. If a 1 g
portion of this mixture was fused with 0.6 g p-anisidiine over an open
flame and then cooled, the melt set up as a solid. Triturating under
MeOH gave a yellow solid (0.45 g, mp 77-80 °C) which on
recrystallization from hexane appeared to be a single one of the three
possible Schiff's bases that could theoretically be prepared. It had
a mp of 80-81 °C. Anal. (C17H19NO3S) C,H. Hydrolysis with hot 3 N
HCl freed the benzaldehyde which was isolated by quenching in H2O and
extraction with CH2Cl2. The extracts were stripped of solvent under
vacuum and the residue distilled bulb-to-bulb under vacuum to give
white crystals of 3,4-dimethoxy-2-(methylthio)benzaldehyde (the 2-TIM
aldehyde) with a mp of 23-24 °C. A micro-scale conversion of this to
the corresponding nitrostyrene provided the seed that was effectively
used in the large scale preparation described below.
A solution of 9.0 g of a mixture of
3,4-dimethoxy-2-(methylthio)benzaldehyde and
2,3-dimethoxy-4-(methylthio)benzaldehyde in 50 mL of nitromethane was
treated with 1.5 g anhydrous ammonium acetate and held at reflux for 5
h. The excess nitromethane was removed under vacuum to yield 10.4 g
of a dark orange oil which, upon dissolving in 40 mL hot MeOH and
being allowed to cool and slowly evaporate at ambient temperatures,
provided dark colored crystals. Filtration (save the mother liquors!)
and recrystallization from 40 mL MeOH provided 6.3 g of a yellow
crystalline solid. A second recrystallization from 50 mL MeOH gave
5.0 g of lemon yellow plates 3,4-dimethoxy-2-methylthio-beta-nitrostyrene
with a mp of 102-103.5 °C. An analytical sample, from IPA, had a mp
of 103-104 °C and a single spot on TLC with CHCl3, with an Rf of 0.54.
Anal. (C11H13NO4S) C,H. When there had been veratrole left as a
contaminant in the original 2,3-dimethoxythioanisole, the nitrostyrene
that was isolated by this method had, after recrystallization, a mp of
93-95 °C. This substance acted as a single compound through a number
of recrystallization trials, but on TLC analysis always gave two
components (silica gel, chloroform) with Rf's of 0.54 and 0.47. It
proved to be a mixture of 3,4-dimethoxy-2-methylthio-beta-nitrostyrene
and 3,4-dimethoxy-beta-nitro-styrene in an exact molecular ratio of 2:1.
This latter nitrostyrene is the precursor to DMPEA, q.v. Anal.
(C32H37N3O12S2) C,H. The mother liquor above is the source of the
4-TIM nitrostyrene, and its isolation is described in the recipe for
4-TIM.
A solution of 4.2 g LAH in 70 mL anhydrous THF was cooled to 0 °C
under He and with stirring. There was added, dropwise, 2.8 mL of 100%
H2SO4, followed by 4.4 g of
3,4-dimethoxy-2-(methylthio)-beta-nitrostyrene dissolved in 25 mL THF.
Stirring was continued for a few min as the reaction returned to room
temperature, and then it was heated to a reflux for 10 min on the
steam bath. The reaction was cooled again, and 25% NaOH was added
dropwise until a white granular precipitate was obtained. This was
removed by filtration, and the filter cake was washed with 2x50 mL
Et2O. The filtrate was extracted into 100 mL dilute H2SO4 which was,
in turn, made basic again and extracted with 2x100 mL CH2Cl2. The
extracts were pooled, and the solvent removed under vacuum to give a
residue of crude product. This was distilled from 100-115 °C at 0.3
mm/Hg yielding 3.2 g of a clear white oil. This was dissolved in 25
mL IPA, neutralized with 23 drops of concentrated HCl, and diluted
with 75 mL anhydrous Et2O. There was a deposition of beautiful white
platelets of 3,4-dimethoxy-2-methylthiophenethylamine hydrochloride
(2-TIM) which were removed by filtration, washed with ether, and air
dried. This hydrochloride salt contained a quarter mole of H2O of
crystallization. The mp was 183-184 °C. Anal. (C11H18ClNO2Sa1/4 H2O)
C,H,N.
DOSAGE: greater than 240 mg.
DURATION: unknown.
QUALITATIVE COMMENTS: (with 160 mg) There was perhaps some awareness
in an hour or so, but in another hour there was absolutely nothing. A
small amount of wine in the evening was quite intoxicating.
(with 240 mg) No effects of any kind.
EXTENSIONS AND COMMENTARY: The problems that might be associated with
the making of the three amphetamines that correspond to 2-TIM, 3-TIM
and 4-TIM might very well prove quite exciting. These would be the
three thio analogues of TMA-3; vis,
3,4-dimethoxy-2-methylthioamphetamine,
2,4-dimethoxy-3-methylthioamphetamine, and
2,3-dimethoxy-4-thioamphetamine. The first challenge would be to name
them. Using the 2C-3C convention, they would be the 3C analogs of
trivially named 2-carbon compounds, namely 3C-2-TIM, 3C-3-TIM and
3C-4-TIM. Using the thio convention (the number before the T is the
position of the sulfur atom), they would be 2-T-TMA-3, 3-T-TMA-3 and
4-T-TMA-3. The second challenge would be their actual synthesis. The
information gained from the separation of the 2-carbon nitrostyrenes
and that most remarkable mixed-nitrostyrene thing that acted as a
single pure material, would not be usable. But it is intriguing to
speculate if there might be some parallel problems in the 3-carbon
world. It seems almost certain that none of the compounds would be
pharmacologically active, so the incentive would be the challenge of
the chemistry. Some day, maybe.
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