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#152 2-TIM
2-THIOISOMESCALINE; 3,4-DIMETHOXY-2-METHYLTHIOPHENETHYLAMINE
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 tem
perature. 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 tem
perature 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 tem
perature
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 cont
amination. 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
re
crystallization 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 tem
peratures,
provided dark colored
crystals. Filtration (save the mother liquors!)
and re
crystallization 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 re
crystallization, a mp of
93-95 °C. This substance acted as a single compound through a number
of re
crystallization 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
tem
perature, 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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