SYNTHESIS: To 26.4 g veratrol that was being magnetically stirred
without any solvent, there was added 50 g chlorosulfonic acid a bit at
a time over the course of 20 min. The reaction was exothermic, and
evolved considerable HCl. The deeply colored mixture that resulted
was poured over 400 mL crushed ice and when all had thawed, it was
extracted with 2x150 mL CH2Cl2. Removal of the solvent under vacuum
gave a residue that set up as a crystalline mass. The weight of the
crude 3,4-dimethoxybenzenesulfonyl chloride was 37.1 g and it had a mp
of 63-66 °C. Recrystallization raised this to 72-73 °C. Reaction
with ammonium hydroxide gave the sulfonamide as colorless needles from
EtOH, with a mp of 132-133 °C.
The finely pulverized 3,4-dimethoxybenzenesulfonyl chloride (33 g) was
added to 900 mL of crushed ice in a 2 L round-bottomed flask equipped
with a heating mantle and reflux condenser. There was then added 55
mL concentrated H2SO4 and, with vigorous mechanical stirring, there
was added 50 g of zinc dust in small portions. This mixture was
heated until a vigorous reaction ensued and refluxing was continued
for 1.5 h. After cooling to room temperature and decantation from
unreacted metallic zinc, the aqueous phase was extracted with 3x150 mL
Et2O. The pooled extracts were washed once with saturated brine and
the solvent was removed under vacuum. The residue was distilled to
give 20.8 g of 3,4-dimethoxythiophenol boiling at 86-88 °C at 0.4
mm/Hg.
A solution of 10 g 3,4-dimethoxythiophenol in 50 mL absolute EtOH was
protected from the air by an atmosphere of N2. There was added a
solution of 5 g 85% KOH in 80 mL EtOH. This was followed by the
addition of 6 mL methyl iodide, and the mixture was held at reflux for
30 min. This was poured into 200 mL H2O and extracted with 3x50 mL
Et2O. The pooled extracts were washed once with aqueous sodium
hydrosulfite, then the organic solvent was removed under vacuum. The
residue was distilled to give 10.3 g of 3,4-dimethoxythioanisole with
a bp of 94-95 °C at 0.4 mm/Hg. The product was a colorless oil that
crystallized on standing. Its mp was 31-32 °C.
To a mixture of 15 g POCl3 and 14 g N-methylformanilide that had been
warmed briefly on the steam bath there was added 8.2 g of
3,4-dimethoxythioanisole, the exothermic reaction was heated on the
steam bath for an additional 20 min, and then poured into 200 mL H2O.
Stirring was continued until the insolubles had become completely
loose and granular. These were removed by filtration, washed with
H2O, sucked as dry as possible, and then recrystallized from 100 mL
boiling EtOH. The product, 4,5-dimethoxy-2-(methylthio)benzaldehyde,
was an off-white solid, weighing 8.05 g and having a mp of 112-113 °C.
Anal. (C10H12O3S) C,H.
A solution of 2.0 g 4,5-dimethoxy-2-(methylthio)benzaldehyde in 8 mL
nitroethane was treated with 0.45 g anhydrous ammonium acetate and
heated on the steam bath for 4.5 h. Removal of the excess solvent
under vacuum gave a red residue which was dissolved in 5 mL boiling
MeOH. There was the spontaneous formation of a crystalline product
which was recrystallized from 25 mL boiling MeOH to give, after
cooling, filtering and air drying, 1.85 g of
1-(4,5-dimethoxy-2-methylthiophenyl)-2-nitropropene as bright orange
crystals with a mp of 104-105 °C. Anal. (C12H15NO4S) C,H,N.
A suspension of 1.3 g LAH in 50 mL anhydrous THF was placed under an
inert atmosphere and stirred magnetically. When this had been brought
to reflux conditions, there was added, dropwise, 1.65 g of
1-(4,5-dimethoxy-2-methylthiophenyl)-2-nitropropene in 20 mL THF. The
reaction mixture was maintained at reflux for 18 h. After being
brought back to room temperature, the excess hydride was destroyed by
the addition of 1.3 mL H2O in 10 mL THF. There was then added 1.3 mL
of 3N NaOH followed by an additional 3.9 mL H2O. The loose, inorganic
salts were removed by filtration, and the filter cake washed with
additional 20 mL THF. The combined filtrate and washes were stripped
of solvent under vacuum yielding a light yellow oil as a residue.
This was dissolved in 20 mL IPA, neutralized with 0.9 mL concentrated
HCl, and diluted with 200 mL anhydrous Et2O. There was thus formed
1.20 g of 4,5-dimethoxy-2-methylthioamphetamine hydrochloride
(ORTHO-DOT) as a pale yellow crystalline product. This melted at
218-219.5 °C, and recrystallization from EtOH yielded a white product
and increased the mp to 222-223 °C with decomposition Anal.
(C12H20ClNO2S) C,H,N.
DOSAGE: greater than 25 mg.
DURATION: unknown.
QUALITATIVE COMMENTS: (with 25 mg) Vague awareness, with the feeling
of an impending something. Light food sat uncomfortably. By the late
afternoon there was absolutely nothing. Threshold at best.
EXTENSIONS AND COMMENTARY: This material, ORTHO-DOT, can be looked at
as the sulfur homologue of TMA-2 with the sulfur atom located in place
of the oxygen at the 2-position of the molecule. At what level this
compound might show activity is completely unknown, but wherever that
might be, it is at a dosage greater than that for the PARA-DOT isomer,
ALEPH-1 (or ALEPH), which was fully active at 10 milligrams (ALEPH can
be looked at as TMA-2 with the sulfur atom located in place of the
oxygen at the 4-position of the molecule). A lot of variations are
easily makable based on this structure, but why bother? ALEPH is the
much more appealing candidate for structural manipulation.
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