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#170 5-TOET
4-ETHYL-2-METHOXY-5-METHYLTHIOAMPHETAMINE
SYNTHESIS: A
solution of 25 g
3-ethylphenol in 100 mL
Et2O was
equipped with a
magnetic stirrer, and cooled to 0 °C with an external
ice bath. There was added 16 mL DMSO. Then, a total of 15 mL
chlorosulfonic acid was added dropwise, over the course of 30 min.
The reaction was allowed to return to room tem
perature and stirred
overnight. The overhead
Et2O phase was removed by
decantation, and
the light-colored residue was
dissolved in 100 mL IPA. The clear
solution spontaneously generated white
crystals which were allowed to
stand for 1 h, removed by filtration, and lightly washed with IPA.
After air-drying, this crop of
dimethyl-(2-ethyl-4-hydroxyphenyl)-sulfonium chloride weighed 20.0 g
and had a mp of 168-170 °C without obvious
effervescence. A
solution
of 19.8 g of this
sulfonium salt in 200 mL H2O was diluted with 500 mL
MeOH, and there was added 30 g
NaOH. This was heated to reflux on the
steam bath. There was an initial
deposition of some white solids, but
after 36 h the
solution was almost clear. The excess MeOH was removed
under vacuum, and the non-
volatiles were poured into 1 L H2O. This
was acidified with HCl, and extracted with 3x100 mL
CH2Cl2. The
extracts were pooled, and the
solvent removed under vacuum. The
residue, 12.6 g of an amber oil, was
distilled at 95-120 °C at 0.3
mm/
Hg to give 10.0 g of
3-ethyl-4-(methylthio)phenol as an off-white
oil. This spontaneously
crystallized to a solid that had a mp of
47-49 °C. Re
crystallization of an
analytical sample from
cyclohexane
gave a mp of 47-48 °C.
To a
solution of 9.7 g
3-ethyl-4-(methylthio)phenol in 50 mL MeOH
there was added a
solution of 4.6 g 85% KOH in 50 mL hot MeOH. There
was then added 5.4 mL
methyl iodide and the mixture was held at reflux
on the steam bath for 18 h. Removal of the
solvent under vacuum gave
a residue that was poured into 1 L H2O and made strongly basic by the
addition of 5%
NaOH. This was extracted with 3x75 mL
CH2Cl2, and the
extracts were pooled and the
solvent removed under vacuum. There
remained 11.0 g of an almost white oil with a startling apple smell.
This oil was
distilled at 78-88 °C at 0.3 mm/
Hg to give 7.9 g
3-ethyl-4-(methylthio)anisole as a white oil. Anal. (C10H14OS) C,H.
A mixture of 7.8 g POCl3 and 6.9 g N-
methylformanilide was heated on
the steam bath for a few min, until there was the development of a
deep claret color. This was added to 7.7 g
3-ethyl-4-(methylthio)anisole and the mixture was heated on the steam
bath for 2 h. This was poured into 400 mL H2O and stirred overnight,
which produced an oily
phase with no signs of
crystals. The entire
reaction mixture was extracted with 3x75 mL
CH2Cl2, and the pooled
extracts washed with H2O. Removal of the
solvent under vacuum gave
9.2 g of a residue. This was suspended in 25 mL hexane, and after 1 h
standing, the overhead clear
solution was decanted from the settled
sludge. This hexane
solution was stripped of
solvent under vacuum,
giving 7.7 g of an oil that by TLC was a mixture of starting
ether and
desired
aldehyde. This was
distilled at 0.25 mm/
Hg to give three
fractions, the first boiling at 75-100 °C (2.7 g) and the second at
100-115 °C (2.6 g). These were largely starting
ether and
aldehyde,
and were chemically processed below. A third fraction, boiling at
120-140 °C, solidified in the receiver, weighed 1.6 g, and was largely
the desired
aldehyde. Cuts #1 and #2 (5.3 g of what was mostly
recovered
aldehyde) were resubmitted to the Vilsmeier reaction. A
mixture of 5.4 g POCl3 and 4.7 g N-
methylformanilide was heated on the
steam bath until it became claret-colored. The recovered
aldehyde was
added, and the mixture was heated overnight on the steam bath. This
was poured into 500 mL H2O. The heavy tar that was knocked out was
extracted with 3x75 mL
CH2Cl2, and the
solvent was removed from the
pooled extracts under vacuum. Some 5.8 g of residue was obtained, and
this was heated to 120 °C at 0.2 mm/
Hg to remove all materials lower
boiling than the desired
aldehyde. The very dark pot was extracted
with 3x50 mL boiling hexane, and removal of the
solvent from these
pooled extracts under vacuum gave 0.9 g of a yellow oil. This was
distilled at 0.2 mm/
Hg to give a fraction boiling at 130-140 °C which
spontaneously
crystallized. This pressed on a porous plate gave
almost white
crystals with a mp of 55-57 °C. Recrystallization from
0.3 mL
cyclohexane provided 0.3 g of
4-ethyl-2-methoxy-5-(methylthio)benzaldehyde with a mp of 57-58 °C.
The total yield was 1.9 g. Anal. (
C11H14O2S) C,H.
To a
solution of 1.2 g
4-ethyl-2-methoxy-5-(methylthio)benzaldehyde in
25 mL
nitroethane there was added 0.25 g
anhydrous ammonium acetate
and the mixture was heated on the steam bath. The initial color was
green, but this quickly changed to the more usual yellow which
darkened as the reaction mixture was heated. After 1.5 h heating, the
excess
solvent/reagent was removed in vacuo. The yellow residue was
dissolved in 10 mL hot MeOH and allowed to stand in the
refrigerator
overnight. There was an orange oil layer formed underneath the MeOH.
A small sample of this was scratched externally with dry ice, and seed
was obtained. The orange oil layer slowly set to
crystals which,
after a few h, were removed by filtration to give 1.3 g of a slightly
sticky orange solid with a mp of 43-45 °C. This was re
crystallized
from 8 mL boiling MeOH to give, after cooling, filtering, and air
drying to constant weight, 1.1 g of
1-(4-ethyl-2-methoxy-5-methylthiophenyl)-2-nitropropene as
electrostatic yellow
crystals melting at 59-60 °C. Anal. (
C13H17NO3S)
C,H.
A
solution of 1.0 g LAH in 25 mL
tetrahydrofuran was cooled, under He,
to 0 °C with an external ice bath. With good stirring there was added
0.6 mL 100% H2SO4 dropwise, to minimize charring. This was followed
by the addition of 1.1 g of
1-(4-ethyl-2-methoxy-5-methylthio)-2-nitropropene in a small amount of
THF. After 10 min further stirring, it was brought up to room
tem
perature and allowed to stand for several days. The excess
hydride
was destroyed by the cautious addition of IPA followed by sufficient
15%
NaOH to give a white granular character to the
aluminum oxide, and
to assure that the reaction mixture was basic. This was filtered, and
the filter cake washed first with THF and then with IPA. The filtrate
and washings were pooled and stripped of
solvent under vacuum
providing a pale amber residue. This was
dissolved in 50 mL of dilute
H2SO4 and washed with 2x50 mL
CH2Cl2. The aqueous
phase was made
basic with 5%
NaOH, and extracted wit 2x50 mL
CH2Cl2. These extracts
were pooled, stripped under vacuum, and
distilled at 0.15 mm/
Hg. The
fraction with a bp of 102-128 °C weighed 0.4 g and was a colorless
liquid. This was
dissolved in a small amount of IPA, neutralized with
concentrated HCl and diluted with
anhydrous Et2O to provide the
4-ethyl-2-methoxy-5-methylthioamphetamine hydrochloride (5-TOET) which
weighed 0.6 g and melted at 146-147 °C. Anal. (C13H22ClNOS) C,H.
DOSAGE: 12 - 25 mg.
DURATION: 8 - 24 h.
QUALITATIVE COMMENTS: (with 8 mg) After my totally freaky experience
on the very closely related compound in this series,
5-TOM, I intended
to approach this with some caution. Three milligrams was without
effects, so I tried eight milligrams. I was a little light-headed,
and saw sort of a brightness around trees against the blue sky.
Noticed movement on couch in living room, and there was some activity
in the curtains, almost
2C-B like. In the evening writing was still
difficult, and there was eye dilation but minimal nystagmus. My sleep
was fitful, but certainly there was no hint of the
5-TOM storm.
(with 18 mg) This was too much. There was an exhausting visual
hallucinatory
tinsel, continuous movement, and there was no escape.
It popped into an LSD-like thing, strong, restless, constantly
changing, with too much input. I had to take a Miltown to calm down
enough for an attempt at sleep. In the morning, a day later, I was
still 1.5 + and tired of it. It was the next day after that before I
was completely clear.
(with 20 mg) This has the makings of a superb, extraordinary
material. I didn't get to a full plus two, maybe something around a
plus one and three quarters. The eyes-closed fantasy was exceptional,
with new dimensions. The nature of the fantasy, the feeling that one
had about the fantasy figures and landscapes, was the essence of joy,
beauty, lovingness, serenity. A glimpse of what true heaven is
supposed to feel like. Or maybe a
button in the brain was pushed
which has not been pushed by previous chemicals. Insight? Don't know
yet. I was able to function without difficulty with eyes closed or
open.
Erotic absolutely exquisite. In fact, the entire experience
was exquisite. Next day, same sense of serene, quiet joy/beauty
persisted for most of the day. A true healing potential. Onwards and
upwards. This one could be extraordinary.
(with 30 mg) Tried to focus on cosmic questions, and succeeded. Very
little fantasy images for the first 2-3 hours. After that, lovely
interacting, music okay but not vital. On this compound the Brahms
Concerto #1 gave vivid 'memory' impressions of house and vegetable
garden, like a primitive painting. Tremendous nostalgia for a place
I've never seen.
EXTENSIONS AND COMMENTARY: With the extraordinary experience that had
been observed with one person with
5-TOM, this
ethyl homologue was not
only run up with special caution, but that individual ran his own
personal
titration. And he proved to be perhaps twice as sensitive to
5-TOET than any of the other subjects. An approach to what might just
be some unusual
metabolic idiosyncrasy on the part of his liver, is
discussed in the recipe for TOMSO.
The initials of TOET progressed quite logically from TOM, in an exact
parallel with the relationship between the corresponding
sulfur-free
analogues, where the
ethyl compound is DOET and the
methyl counterpart
is DOM. "T" for "thio" which is the chemical
nomenclature term for
the replacement of an oxygen atom with a
sulfur atom. And, as has
been discussed in the text of this volume, the peculiarities of
pronunciation in this series are interesting, to say the least. TOM
is no problem. But TOET could have any of several pronunciations such
as "Two-it", or "Tow-it", or "Too-wet", but somehow the one syllable
term "Twat" became regularly used, and the family was generally
referred to as the "Toms and Twats." The almost-obscene meaning of the
latter was progressively forgotten with usage, and has led to some
raised eyebrows at occasional seminars when these compounds are
discussed. And not only at seminars. Once at the between-acts
intermission at the Berkeley Repertory Theater, the topic came up and
the phrase was used. There was a stunned silence about us within the
circle of hearing, and we seemed to have been given a little extra
room immediately thereafter.
As with the other members of the TOM's and TOET's, the
phenethylamine
homologue of 5-TOET was
synthesized, but had never been started in
human evaluation. The
aldehyde from above,
4-ethyl-2-methoxy-5-(methylthio)benzaldehyde, was condensed with
nitroethane (as reagent and as
solvent) and with
ammonium acetate as
catalyst to give the
nitrostyrene as spectacular canary-yellow
electrostatic crystals with a mp of 91-92 °C. Anal. (
C12H15NO3S) C,H.
This was reduced with
aluminum hydride (from cold THF-
dissolved
lithium aluminum hydride and 100%
sulfuric acid) to the
phenethylamine
4-ethyl-2-methoxy-5-methylthiophenethylamine (2C-5-TOET) which, when
totally freed from water of
hydration by drying at 100 °C under a hard
vacuum, had a mp of 216-217 °C. Anal. (C12H20ClNOS) C,H.
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