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#172 5-TOM
2-METHOXY-4-METHYL-5-METHYLTHIOAMPHETAMINE
SYNTHESIS: To a
solution of 6.6 g KOH pellets in 100 mL hot
EtOH there
was added a
solution of 15.4 g
methylthio-m-cresol
(
3-methyl-4-(methylthio)phenol, Crown-Zellerbach Corporation) in 25 mL
EtOH. This was followed by the addition of 17 g
methyl iodide, and
the mixture was held at reflux on the steam bath for 16 h. The
reaction mixture was poured into 400 mL H2O, acidified with HCl, and
extracted with 4x50 mL
CH2Cl2. These were pooled, washed with 3x50 mL
5%
NaOH, once with dilute HCl, and then the
solvent was removed under
vacuum. The residue was
3-methyl-4-(methylthio)anisole, a clear pale
yellow oil, weighing 12.7 g. Distillation at 150-160 °C at 1.7 mm/
Hg,
or at 80-90 °C at 0.25 mm/
Hg, did not remove the color, and gave a
product with no improvement in purity.
To a mixture of 82 g POCl3 and 72 g N-
methylformanilide that had been
heated on the steam bath for 10 min, there was added 33.6 g
3-methyl-4-(methylthio)phenol, and heating was continued for an
additional 2 h. This was poured into 1.2 L H2O, producing a brown
gummy
crystalline mass that slowly loosened on continued stirring.
This was filtered off, washed with additional H2O, and sucked as dry
as possible. This was finely ground under 60 mL of cold MeOH,
refiltered, and air dried to give 17.8 g of a nearly white
crystalline
solid with a mp of 94-96 °C. Re
crystallization from 50 mL boiling
MeOH gave a product of higher purity, but at some cost in yield. With
this step there was obtained 13.4 g of
2-methoxy-4-methyl-5-(methylthio)benzaldehyde with a mp of 98-99 °C.
An additional re
crystallization from IPA increased this mp by another
degree. From this final re
crystallization, a small amount of material
was left as an in
soluble residue. It was also insoluble in
acetone,
but
dissolved readily in
CH2Cl2. It melted broadly at about 200 °C
and was not identified. Proof of the structure of
2-methoxy-4-methyl-5-(methylthio)benzaldehyde was obtained by its
successful reduction (with
amalgamated Zn in HCl) to
2,5-dimethyl-4-(methylthio)anisole. This reference convergence
compound was prepared separately from
2,5-dimethylanisole which
reacted with
chlorosulfonic acid to give the 4-
sulfonyl chloride
derivative, which was in turn reduced to the 4-mercapto derivative
(white
crystals from MeOH, with a mp of 38 °C sharp). This, upon
methylation with
methyl iodide and KOH in MeOH, gave
2,5-dimethoxy-4-(methylthio)anisole (white
crystals from MeOH, with a
mp of 67-68 °C). The two samples (one from the
aldehyde reduction,
and the other from this independent synthesis), were identical in all
respects.
A
solution of 1.9 g
2-methoxy-4-methyl-5-(methylthio)benzaldehyde in
40 mL
nitroethane was treated with 0.5 g
anhydrous ammonium acetate
and heated under reflux, with stirring, with a heating mantle for 3.5
h, at which time TLC analysis showed no unreacted
aldehyde and only a
trace of slow moving materials. Removal of the excess
nitroethane
under vacuum gave a yellow plastic film (the wrapping of the
magnetic
stirrer had
dissolved off) which was extracted first with 35 mL
boiling MeOH, then with 2x35 mL boiling IPA. Separately, the MeOH
extract and the combined IPA extracts, on cooling,
deposited 0.6 g
each of fluffy needles. The mother liquors were combined and allowed
to
evaporate to about 15 mL final volume, providing another 0.4 g
crude product. All three samples melted at 101-102 °C. These were
combined, and re
crystallized from 50 mL boiling MeOH to provide, after
filtering and air drying, 1.4 g of
1-(2-methoxy-4-methyl-5-methyl-thiophenyl)-2-nitropropene as bright
yellow
crystals with a mp of 102-102.5 °C. Anal. (
C12H15NO3S) C,H.
A
solution of 2.0 g LAH in 100 mL
anhydrous THF was cooled, under He,
to 0 °C with an external ice bath. With good stirring there was added
1.28 mL 100% H2SO4 dropwise, to minimize charring. This was followed
by the addition of 1.35 g
1-(2-methoxy-4-methyl-5-methylthiophenyl)-2-nitropropene in 50 mL
anhydrous THF over the course of 5 min. 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 5 mL IPA followed by
sufficient 5%
NaOH to give a white granular character to the
oxides,
and to assure that the reaction mixture was basic (about 5 mL was
used). The reaction mixture was filtered, and the filter cake washed
first with THF and then with IPA. The combined filtrate and washings
were stripped of
solvent under vacuum and the residue
dissolved in 150
mL dilute H2SO4. This was washed with 3x50 mL
CH2Cl2 (the color
stayed in the organic layer), made basic with aqueous
NaOH, and
extracted with 2x50 mL
CH2Cl2. After the
solvent was removed under
vacuum, the residue was
distilled at 110-125 °C at 0.4 mm/
Hg to give
0.9 g of a colorless oil. This was
dissolved in 4 mL IPA, neutralized
with about 11 drops of concentrated HCl, and then diluted with 20 mL
anhydrous Et2O. After about a ten second delay, white
crystals
formed. These were removed by filtration and air dried, to give 0.6 g
of
2-methoxy-4-methyl-5-methylthioamphetamine hydrochloride (5-TOM) as
white
crystals with a mp of 156-157 °C. A second crop obtained from
the mother liquors on standing weighed 0.3 g and melted at 150-156 °C.
Anal. (C12H20ClNOS) C,H.
DOSAGE: 30 - 50 mg.
DURATION: 6 - 10 h.
QUALITATIVE COMMENTS: (with 35 mg) There was an awful lot of visual
activity, and in general I found the day quite good, once I got past
the early discomfort.
(with 40 mg) I knew that I was sinking into a deep reverie after an
hour into it. I was not totally unconscious since I seemed to respond
to external stimuli (at least most of the time). But I certainly
wasn't all that much there. The exper-ience dominated completely. At
one point (perhaps the peak?) I remember seeing a very quiet sea with
a horizontal shoreline and a clear sky. This image seemed to come
back rather frequently. At other times I would see a set of
disjointed horizontal lines on this beach. These lines reminded me of
spectral lines. For a short period of time I thought they were some
kind of expression of my energy levels that I didn't understand. In
retrospect, I suspect the horizontal lines were only expressions of
how my mind was reacting to the material. I don't remember talking to
anyone until I had started to come down from the experience. I
eventually could see real images, but they were greatly distorted. It
was as if I was looking at
Cubism paintings by
Picasso, having intense
and strange colorations. As I came back into the real world, I
realized that I had had an extraordinary trip. I had not been afraid
at any time. The experience seemed unique, but quite benign. The
experience for my fellow travelers was probably much more anxious. I
wasn't particularly interested in food when I came down. I slept
well. I was quite lethargic the next day. It really took me another
day to integrate back into normal life. Would I repeat it? Possibly,
but at a way smaller dose.
(with 50 mg) The body was complete whacked, and the mental simply
didn't keep up with it. There was some early nausea going into it,
and my sinuses never cleared, and I somehow became irritable and
angry. In fact, the impatience and grimness lasted for a couple of
days. There were some visual events that might have been interesting
to explore, but too much other stuff got in the way.
(with 50 mg) There was much eyes-closed fantasy, and quite a bit of
it with erotic undertones. In efforts to direct my actions, I found
it difficult to find the point of initiation of a task. Reading and
writing both impossible. I am somehow de-focused. But art work
became quite rewarding. The experience was heavy going in, but rich
coming out. Good dosage.
EXTENSIONS AND COMMENTARY: The bottom line is that 5-TOM is a pretty
heavy-duty experience, with more negative reports than positive ones.
I have received no mentions of a completely ecstatic time, and not
even very many neutral experiences. The consensus is that it wasn't
worth the struggle. Some cramping, some nausea, and a generalized
discomfort. And that one case of a
catatonic response. An approach
to possible individual variation in the
metabolic handling of the
sulfur atom is the rationale for the preparation of the compound
TOMSO, and it is discussed there.
The two-
carbon homologue of 5-TOM has been prepared. It uses, of
course, the same
aldehyde, but the
condensation was with
nitromethane
which yielded the
nitrostyrene as an orange powder with a melting
point of 118-119 °C from
methanol. This was reduced with LAH in
ether
containing
anhydrous AlCl3, giving
2-methoxy-4-methyl-5-methylthiophenethylamine hydrochloride as white
crystals with a melting point of 257-258 °C. It has been named
2C-5-TOM, but it has not yet been entered into the screening program
so it is
pharmacologically still a mystery.
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