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#171 2-TOM
5-METHOXY-4-METHYL-2-METHYLTHIOAMPHETAMINE
SYNTHESIS: To a
solution of 64.8 g of o-cresol and 56 g
dimethyl
sulfoxide in 300 mL
Et2O, cooled with an external ice bath with
vigorous stirring, there was added 40 mL
chlorosulfonic acid dropwise
over the course of 30 min. The cooling bath was removed, and the two
phase mixture was mechanically stirred at room tem
perature for 12 h.
The
Et2O phase was then discarded, and the deep red residue that
remained was thoroughly triturated under 300 mL IPA, producing a
suspension of pale pink solids. These were removed by filtration,
washed with an additional 150 mL IPA, and allowed to air dry. The
yield of
dimethyl (
4-hydroxy-3-methylphenyl)sulfonium chloride was
31.6 g and, upon re
crystallization from aqueous
acetone, had a mp of
155-156 °C, with
effervescence. Anal. (C9H13ClOS) C,H,S. This
analysis established the anion of this salt as the
chloride, whereas
the literature had claimed, without evidence, that it was the
bisulfate. The thermal pyrolysis of 31.0 g of
dimethyl
(
4-hydroxy-3-methylphenyl)sulfonium chloride resulted first in the
formation of a melt, followed by the vigorous evolution of
methyl
chloride. The open flame was maintained on the flask until there was
no more gas evolution. This was then cooled,
dissolved in 200 mL
CH2Cl2, and extracted with 3x100 mL of 5%
NaOH. The aqueous extracts
were pooled, acidified with concentrated HCl, and extracted with 3x75
mL
CH2Cl2. The
solvent was removed under vacuum, and the residue
distilled at 100-110 °C at 0.5 mm/
Hg yielding 22.0 g of
2-methyl-4-(methylthio)phenol as a white
crystalline solid with a mp
36-37 °C.
To a
solution of 25.5 g
2-methyl-4-(methylthio)phenol in 100 mL MeOH
there was added a
solution of 12 g 85% KOH in 60 mL hot MeOH, followed
by the addition of 12.4 mL
methyl iodide. The mixture was held at
reflux for 16 h. The
solvent was removed under vacuum, and the
residue added to 400 mL H2O. This was made basic with 25%
NaOH and
extracted with 3x100 mL
CH2Cl2. The extracts were pooled, the
solvent
removed under vacuum giving 28.3 g of a light, amber oil as residue.
This was
distilled at 72-80 °C at 0.5 mm/
Hg to provide
2-methyl-4-(methylthio)anisole as a pale yellow oil. Anal. (C9H12OS)
C,H. The same product can be made with the
sulfonyl chloride and the
thiol as intermediates. To 36.6 g
2-methylanisole there was added,
with continuous stirring, a total of 38 mL
chlorosulfonic acid at a
modest rate. The exothermic reaction went through a complete
spectrum
of colors ending up, when the evolution of HCl had finally ceased, as
deep amber. When it had returned again to room tem
perature, the
reaction mixture was poured over a liter of cracked ice which, on
mechanical stirring, produced a mass of white
crystals. These were
removed by filtration, washed with H2O, and sucked as dry as possible.
The wet weight yield was over 40 g and the mp was about 49 °C.
Re
crystallization of an
analytical sample of
4-methoxy-3-methylbenzenesulfonyl chloride from
cyclohexane gave white
crystals with a mp of 51-52 °C. A small sample of this acid
chloride
brought into reaction with
ammonium hydroxide produced the
sulfonamide
which, after re
crystallization from
EtOAc, melted at 135-136 °C. To a
slurry of 300 mL cracked ice and 75 mL concentrated H2SO4 in a
round-bottomed flask equipped with a reflux
condenser, there was added
43 g of the slightly wet
4-methoxy-3-methylbenzenesulfonyl chloride
followed by 75 g elemental
zinc dust. The tem
perature was raised to a
reflux which was maintained for 2 h. The reaction mixture was cooled
and filtered, with the finely ground filter cake being washed
alternately with H2O and with
CH2Cl2. The combined mother liquor and
washings were diluted with 1 L H2O, the
phases separated, and the
aqueous
phase extracted with 100 mL
CH2Cl2 which was added to the
organic
phase. This was washed with 100 mL H2O, and the
solvent
removed under vacuum. The residue was a pale amber oil weighing 27.3
g and it slowly set up to a
crystalline mass that smelled of banana
oil. A portion of this, pressed on a porous plate, gave a waxy solid
with a mp of 39-43 °C which, on re
crystallization from MeOH, gave
4-methoxy-3-(methyl)thiophenol with a mp of 45-46 °C. Anal. (C8H10OS)
C,H. A
solution of 24 g of the crude thiol in 100 mL MeOH was treated
with a
solution of 17 g KOH 85% pellets in 100 mL hot MeOH, and to
this there was added 16 mL of
methyl iodide. This was held at reflux
on the steam bath for 1.5 h, then stripped of
solvent under vacuum,
added to 1 L H2O, and made strongly basic with 25%
NaOH. Extraction
with 3x100 mL
CH2Cl2, pooling of the extracts, and removal of the
solvent, gave an amber oil weighing 22.6 g. This was
distilled at
70-80 °C at 0.7 mm/
Hg to give 16.3 g of
2-methyl-4-(methylthio)anisole
as a white oil, identical in all respects to the product that came
from the
sulfonium salt pyrolysis above.
A
solution of 22.1 g
2-methyl-4-(methylthio)anisole and 17.5 g
dichloromethyl methyl
ether in 600 mL
CH2Cl2 was vigorously stirred,
and treated with 24.5 g
anhydrous aluminum chloride added portion-wise
over the course of 1 min. Stirring was continued for 20 min while the
color developed to a dark red. There was added 500 mL H2O with
caution, and stirring was continued until the initial yellow solids
re
dissolved and there were two distinct
phases formed. These were
separated, and the aqueous
phase was extracted with 3x100 mL
CH2Cl2.
The original organic
phase and the pooled extracts were combined and
washed with 5%
NaOH. The organic
solvent was removed under vacuum.
The residue was
distilled, giving two major fractions. A forerun
(85-95 °C at 0.5 mm/
Hg) proved to be largely starting
ether. The
major fraction (8.4 g, boiling at 95-120 °C) consisted of two
materials, both
benzaldehydes.
Crystallization of this fraction from
30 mL
cyclohexane provided, after filtering, washing and air drying,
2.9 g of
5-methoxy-4-methyl-2-(methylthio)benzaldehyde as a pale
yellow
crystalline solid with a mp of 69-70 °C. Anal. (
C10H12O2S)
C,H. The mother liquor from this
crystallization contained a
slower-moving component,
2-methoxy-3-methyl-5-(methylthio)benzaldehyde, which was best
separated by preparative gas
chromatography. The proof of the
structure of the major
aldehyde above was obtained by its reductive
conversion to
2,5-dimethyl-4-(methylthio)anisole with
amalgamated
zinc
and HCl. The details are given in the recipe for
5-TOM.
To 4 mL glacial acetic acid there was added 1.0 g
5-methoxy-4-methyl-2-(methylthio)benzaldehyde, 0.35 g
anhydrous
ammonium acetate, and 0.8 g
nitroethane, and the mixture was heated on
the steam bath for 4 h. Another 0.5 g of
nitroethane was added, and
the heating continued for an additional 4 h. Standing at room
tem
perature overnight allowed the
deposition of spectacular orange
crystals which were removed by filtration, washed lightly with acetic
acid, and air dried. This product melted at 82-83 °C.
Re
crystallization from 10 mL boiling MeOH gave 0.7 g of
1-(5-methoxy-4-methyl-2-methylthiophenyl)-2-nitropropene with a mp of
83-84 °C. Anal. (
C12H15NO3S) C,H. The alternate method for the
formation of
nitrostyrenes, the reaction of the
benzaldehyde in
nitroethane as both reagent and
solvent, with
ammonium acetate as a
catalyst, gave a gummy product that could be purified only with severe
losses. The overall yield with this latter method was 24% of theory.
A
solution of 1.5 g LAH in 75 mL THF was cooled, under He, to 0 °C
with an external ice bath. With good stirring there was added 1.0 mL
100% H2SO4 drop-wise, to minimize charring. This was followed by the
addition of 3.0 g
1-(5-methoxy-4-methyl-2-methylthiophenyl)-2-nitropropene in 20 mL
anhydrous THF. After a few min further stirring, the tem
perature was
brought up to a gentle reflux on the steam bath, and then all was
cooled again to 0 °C. The excess
hydride was destroyed by the
cautious addition of IPA followed by sufficient 5%
NaOH to give a
white granular character to the
oxides, and to assure that the
reaction mixture was basic. The reaction mixture was filtered, and
the filter cake washed first with THF and then with IPA. The filtrate
was stripped of
solvent under vacuum providing a light yellow oil.
This was
dissolved in 100 mL dilute H2SO4 and then washed with 2x50 mL
CH2Cl2. The aqueous
phase was made basic with 5%
NaOH and extracted
with 2x50 mL
CH2Cl2. These were pooled, the
solvent removed under
vacuum, and the residue
distilled at 105-130 °C at 0.25 mm/
Hg to give
1.6 g of a white oil. This was
dissolved in 8 mL IPA, neutralized
with 24 drops of concentrated HCl which formed
crystals spontaneously.
Another 20 mL of hot IPA was added to effect complete
solution, and
then this was diluted with
anhydrous Et2O. On cooling fine white
crystals of
5-methoxy-4-methyl-2-methylthioamphetamine hydrochloride
(2-TOM) separated. These weighed 1.55 g and had a mp of 195-196 °C.
Anal. (C12H20ClNOS) C,H.
DOSAGE: 60 - 100 mg.
DURATION: 8 - 10 h.
QUALITATIVE COMMENTS: (with 60 mg) There is a superb body feeling,
and food tasted excellent but then it just might have been excellent
food. By the tenth hour, there were absolutely no residues, and I had
the feeling that there was no price to pay. Venture up a bit with
confidence.
(with 80 mg) For me this was excellent, in a down-to-earth, humorous,
matter-of-fact universe-perspective sense. Very pleasant feeling,
although there was a strong body awareness below the waist (not the
erotic thing, but rather a slight heaviness, and the next day I came
down with a G.I. cold). Very good feeling, and I sense that the depth
of the experience is way out there where the big questions lie. I
found it easy to go out of body (in the good sense) into a warm,
loving darkness. Sliding down by 6, 7th hour, and had no trouble
sleeping. Fully scripted dreams, vivid. Very, very good. Want to
try 100 mg.
(with 80 mg) Completely foul taste. The effects were quite subtle,
and I found this to be a strange but friendly ++. There was much
eyes-closed fantasizing to music, even to Bruchner, whom I found
unexpectedly pleasant. There was a feeling of tenseness at the
twilight of the experience.
EXTENSIONS AND COMMENTARY: There is a most extraordinary loss of
potency with the simple
substitution of a
sulfur atom for an oxygen
atom. DOM is fully active at the 5 or so milligram area, whereas
2-TOM is active at maybe the 80 milligram area, a loss of potency by a
factor of x15 or so. And the duration is quite a bit shorter. It
might take a fair amount of learning to become completely at peace
with it, but it might be worth the effort. And there are none of the
disturbing hints of
neurological and physical roughness of
5-TOM.
Again, as with the other TOM's and TOET's, the two-
carbon homologue of
this has been
synthesized but not yet evaluated. The common
intermediate
benzaldehyde,
5-methoxy-4-methyl-2-(methylthio)benzaldehyde was condensed with
nitromethane and
ammonium acetate to give the
nitrostyrene which, upon
re-
crystallization from
ethanol, had a melting point of 118-118.5 °C.
Anal. (C11H13NO3S) C,H. Reduction with
aluminum hydride in THF gave
the
crystalline free base which, as the
hydrochloride salt, melted at
233-234 °C. Anal. (C11H18ClNOS) C,H. Quite logically, it has been
called 2C-2-TOM.
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