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noding PiHKAL for Everything2.
#147 4-TASB
4-THIOASYMBESCALINE; 3-ETHOXY-4-ETHYLTHIO-5-METHOXYPHENETHYLAMINE
SYNTHESIS: A
solution of 20.5 g N,N,N',N'-
tetramethylethylenediamine
and 22.3 g of 3-
ethoxyanisole was made in 100 mL hexane under a He
atmosphere with good stirring. There was added 125 mL 1.6 M
butyllithium in hexane, which formed a white granular
precipitate.
This was cooled in an ice bath, and there was added 24.4 g of
diethyldisulfide which produced an exothermic reaction and changed the
precipitate to a creamy
phase. After being held for a few min at
reflux tem
perature, the reaction mixture was added to 500 mL dilute
H2SO4 which produced two clear
phases. The hexane phase was separated,
and the aqueous
phase extracted with 2x75 mL
methylcyclopentane. The
organics were combined, and the
solvents removed under vacuum. There
was obtained a residue which was
distilled under a vacuum. At 0.3
mm/
Hg the fraction boiling at 95-105 °C was a yellow liquid weighing
28.5 g which was largely
3-ethoxy-2-(ethylthio)anisole which seemed to
be reasonably pure
chromatographically. It was used as such in the
bromination step below.
To a stirred
solution of 15.0 g of
3-ethoxy-2-(ethylthio)anisole in
100 mL
CH2Cl2 there was added 12 g elemental
bromine dissolved in 25
mL
CH2Cl2. There was the copious evolution of HBr. After stirring at
ambient tem
perature for 3 h, the dark
solution was added to 300 mL H2O
containing
sodium dithionite. Shaking immediately discharged the
residual bromine color, and the organic
phase was separated, The
aqueous
phase was extracted once with 100 mL
CH2Cl2, the pooled
extracts washed with dilute base, and then the
solvent was removed
under vacuum to give a light brown oil. This wet product was
distilled at 112-122 °C at 0.3 mm/
Hg to yield 4-bromo (and/or
6-bromo)-3-ethoxy-2-(ethylthio)anisole as a light orange oil. This
was used in the following
benzyne step without separation into its
components.
To a
solution of 36 mL
diisopropylamine in 150 mL
anhydrous THF under
a He
atmosphere, and which had been cooled to -10 °C with an external
ice/MeOH bath, there was added 105 mL of a 1.6 M
solution of
butylithium in hexane. There was then added 5.1 mL of dry
CH3CN
followed by the dropwise addition of 15.0 g 4-bromo-(and/or
6-bromo)-3-ethoxy-2-(ethylthio)anisole diluted with a little
anhydrous
THF. There was an immediate development of a dark red-brown color.
The reaction was warmed to room tem
perature and stirred for 0.5 h.
This was then poured into 600 mL of dilute H2SO4. The organic
phase
was separated, and the aqueous fraction extracted with 2x50 mL
CH2Cl2.
These extracts were pooled and the
solvent removed under vacuum. The
residue was a dark oil and quite complex as seen by thin layer
chromatography. This material was
distilled at 0.3 mm/
Hg yielding two
fractions The first boiled at 112-125 °C and weighed 3.9 g. It was
largely starting bromo compound with a little
nitrile, and was
discarded. The second fraction
distilled at 130-175 °C and also
weighed 3.9 g. This fraction was rich in the product
3-ethoxy-4-ethylthio-5-methoxyphenylacetonitrile, but it also
contained several additional components as seen by thin layer
chromatographic analysis. On standing for two months, a small amount
of solid was laid down which weighed 0.5 g after cleanup with hexane.
But even it consisted of three components by TLC, none of them the
desired
nitrile. The crude fraction was used for the final step
without further purification or microanalysis.
A
solution of LAH in
anhydrous THF under N2 (15 mL of a 1.0 M
solution) was cooled to 0 °C and vigorously stirred. There was added,
dropwise, 0.40 mL 100% H2SO4, followed by about 3 g of the crude
3-ethoxy-4-ethylthio-5-methoxyphenylacetonitrile diluted with a little
anhydrous THF. The reaction mixture was stirred until it came to room
tem
perature, and then held at reflux on the steam bath for 2 h. After
cooling to room tem
perature, there was added IPA to destroy the excess
hydride (there was quite a bit of it) and then 15%
NaOH to bring the
reaction to a basic
pH and convert the
aluminum oxide to a loose,
white, filterable consistency. This was removed by filtration, and
washed first with THF followed by IPA. The filtrate and washes were
stripped of
solvent under vacuum, the residue added to 100 mL dilute
H2SO4. This was washed with 2x75 mL
CH2Cl2, made basic with 25%
NaOH,
and extracted with 2x50 mL
CH2Cl2. After combining, the
solvent was
removed under vacuum providing a residue that was
distilled. A
fraction boiling at 122-140 °C at 0.3 mm/
Hg weighed 1.0 g and was a
colorless oil. This was
dissolved in 10 mL of IPA, and neutralized
with 20 drops of concentrated HCl and diluted, with stirring, with 40
mL
anhydrous Et2O. There was the slow formation of a fine white
crystalline salt, which was removed by filtration, washed with
Et2O,
and air dried. The product
3-ethoxy-4-ethylthio-5-methoxyphenethylamine hydrochloride (4-TASB),
weighed 0.5 g, and had a mp 139-140 °C. Gas
chromatographic analysis
by capillary column
chromatography of the free base (in butyl
acetate
solution on
silica SE-54) showed a single peak at a reasonable
retention time, verifying
isomeric purity of the product. Anal.
(
C13H22ClNO2S) C,H.
DOSAGE: 60 - 100 mg.
DURATION: 10 - 15 h.
QUALITATIVE COMMENTS: (with 60 mg) The compound has a
petroleum-refinery type taste. There was a looseness of the bowels as
I got into it. Here we have another of these 'What is it' or 'What
isn't it' compounds. Somehow I seemed to have to push the erotic, the
visual, the whole
psychedelic shmeer, to document that this was indeed
effective. I am not impressed.
(with 100 mg) There were some trivial physical problems during the
early stages of this experiment. But there was fantasy stuff to
music, and some jumpy stuff to music. Is there a
neurological
hyperreflexia? I was able to sleep at the 12 hour point but I felt
quite irritable. I am agitated. I am twitchy. This has been very
intense, and I am not completely comfortable yet. Let's wait for a
while.
(with 100 mg) Music was lovely during the experiment, but pictures
were not particularly exciting. I had feelings that my nerve-endings
were raw and active. There was water retention. There was heartbeat
wrongness, and respiration wrongness. During my attempts to sleep, my
eyes-closed fantasies became extremely negative. I could actually
feel the continuous electrical impulses travelling between my nerve
endings. Disturbing. There was continuous erotic arousability, and
this seemed to be part of the same over-sensitivity of the nervous
system;
orgasm didn't soothe or smooth out the feeling of
vulnerability. This is a very threatening material. DO NOT REPEAT.
EXTENSIONS AND COMMENTARY: Again, another drug with more physical
problems than
psychic virtue, but with no obvious structural feature
to hang it all onto. Some day this will all make sense!
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