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#47 2C-T-15
SESQUI; 2,5-DIMETHOXY-4-CYCLOPROPYLTHIOPHENETHYLAMINE
SYNTHESIS: To a
solution of 3.3 g of KOH pellets in 150 mL hot MeOH,
there was added 10 g
2,5-dimethoxythiophenol (see recipe for
2C-T-2
for its preparation) followed by 10 g 1-bromo-3-
chloropropane. The
reaction was exothermic, and immediately
deposited white solids of
KCl. The reaction mixture was warmed for a few min on the steam bath,
and then quenched in H2O. The basic reaction mixture was extracted
with 3x75 mL
CH2Cl2. The pooled extracts were stripped of
solvent
under vacuum. The
residual oil was
distilled at 145-155 °C at 0.2
mm/
Hg to give 16.5 g of
2,5-dimethoxyphenyl 3-
chloropropyl sulfide as
a clear, colorless oil.
A
solution of the
lithium amide of
2,2,6,6-tetramethylpiperidine was
prepared by the addition of 20 mL of 2.6 M
butyllithium in hexane to a
well stirred hexane
solution of the
piperidine in 100 mL hexane, under
an
atmosphere of He. The reaction was exothermic, formed a white
solid
precipitate, and was allowed to continue stirring for a few min.
There was then added 6.5 g
2,5-dimethoxphenyl 3-
chloropropyl sulfide,
and a strongly exothermic reaction ensued. This was stirred for 30
min and then poured into dilute H2SO4 (the progress of the reaction
must be followed by TLC,
silica gel plates,
CH2Cl2:petroleum
ether
50:50 to determine when it is done; in one run over 2 h were required
for completion of the reaction). The organic
phase was separated, and
the aqueous
phase extracted with 3x75 mL
EtOAc. The combined organic
phases were washed first with dilute
NaOH, then with dilute HCl, then
the
solvents were removed under vacuum. The residue was
distilled to
provide
2,5-dimethoxyphenyl cyclopropyl sulfide as a pale yellow
liquid that boiled at 100-115 °C at 0.1 mm/
Hg. The use of other bases
to achieve this
cyclization were less successful. Incomplete
cyclization resulted from the use of
lithium diisopropyl amide and, if
the conditions were made more vigorous, there was
dehydrohalogenation
to the allyl
sulfide. An unexpected difficulty was that the allyl
sulfide (from elimination) and the 3-
chloropropyl sulfide (starting
material) behaved in an identical manner on TLC analysis. They were
easily separated, however, by GC analysis.
A completely different approach to the synthesis of this
sulfide was
explored through the reaction of
cyclopropyllithium with an aromatic
disulfide, thus avoiding the base-promoted
cyclization step. A
solution of 2.6 g
di-(2,5-dimethoxyphenyl)disulfide (from
2,5-dimethoxythiophenol and hydrogen
peroxide, bp 220-230 °C at 0.3
mm/
Hg) was made in
anhydrous Et2O, and well stirred. In a separate
flask, under an
atmosphere of He, 4 mL of 2.6 M
butyllithium was added
to a
solution of 1.2 g
cyclopropyl bromide in 20 mL
anhydrous Et2O.
This mildly exothermic combination turned a bit cloudy, was stirred
for 1 h, then trans-ferred with an air-tight
syringe to the
above-described
Et2O solution of the aromatic
disulfide. A heavy
precipitate formed, and stirring was continued for an additional 0.5
h. The reaction mixture was then poured into H2O, the layers
separated, and the aqueous
phase extracted with
CH2Cl2. The extracts
were pooled, washed with dilute aqueous KOH, and the
solvents removed
under vacuum. Distillation gave 0.7 g of
2,5-dimethoxyphenyl
cyclopropyl sulfide with identical gas
chromatographic behavior to the
sample prepared by the
cyclization of the
chloropropylthio compound.
A mixture of 7.2 g POCl3 and 6.7 g N-
methylformanilide was heated on
the steam bath until it was claret red. To this there was added 4.5 g
of
2,5-di-methoxyphenyl cyclopropyl sulfide, and the exothermic
combination heated on the steam bath for about 5 min. The deep red,
bubbling reaction mixture was added to 150 mL H2O and stirred until
all oils had been converted into loose solids. These were then
removed by filtration, washed with H2O, and sucked as dry as possible.
They were
dissolved in boiling MeOH which, after cooling in an
ice-bath,
deposited yellow
crystals of
2,5-dimethoxy-4-(cyclopropylthio)benzaldehyde that weighed 3.43 g
after air drying, and had a mp of 97-99 °C. Anal. (
C12H14O3S) C,H.
To a
solution of 3.0 g
2,5-dimethoxy-4-(cyclopropylthio)benzaldehyde
in 40 g of
nitromethane there was added 0.2 g of
anhydrous ammonium
acetate, and the mixture was heated on the steam bath for 3 h. The
excess
nitromethane was removed under vacuum yielding 3.4 g orange
crystals. These were re
crystallized from 150 mL boiling IPA
containing a little
toluene. After cooling, filtering, and air drying
there were obtained 2.75 g of
2,5-dimethoxy-4-cyclopropylthio-beta-nitro-styrene as
pumpkin-colored
crystals with a mp of 159-160 °C. Anal. (
C13H15NO4S) C,H.
A
solution of LAH (40 mL of a 1 M. solution in THF) was cooled, under
He, to 0 °C with an external ice bath. With good stirring there was
added 1.05 mL 100% H2SO4 dropwise, to minimize charring. This was
followed by the addition of 2.5 g
2,5-dimethoxy-4-cyclopropylthio-beta-nitrostyrene in 40 mL
anhydrous THF
over the course of 15 min. There was an immediate loss of color.
After a few min further stirring, the tem
perature was brought up to a
gentle reflux on the steam bath and held there for 2 h. After
recooling, there was added IPA (to destroy the excess
hydride)
followed by sufficent 15%
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 with THF.
The filtrate and washes were stripped of
solvent under vacuum
providing a yellow oil that was treated with dilute H2SO4. This
produced a
flocculant white solid, apparently the
sulfate salt of the
product. This was washed with 4x75 mL
CH2Cl2 which removed most of
the yellow color. The aqueous
phase was made basic with aqueous
NaOH
and extracted with 3x75 mL
CH2Cl2. Removal of the
solvent under
vacuum gave a light yellow colored oil that was
distilled at 0.3
mm/
Hg. The fraction boiling at 140-150 °C was a colorless, viscous
oil that weighed 1.97 g. This was
dissolved in a few mL IPA, and
neut-ralized with concentrated HCl forming immediate cottage
cheese-like
crystals of the
hydrochloride salt. This was diluted by
suspension in
anhydrous Et2O, removed by filtration, and air dried to
give 1.94 g of
2,5-dimethoxy-4-cyclopropylthiophenethylamine
hydrochloride (2C- T-15) that had a mp of 203-5-204.5 °C. Anal.
(
C13H20ClNO2S) C,H.
DOSAGE: greater than 30 mg.
DURATION: several hours.
QUALITATIVE COMMENTS: (at 30 mg) I was somewhere between a threshold
and a plus one for several hours, and appeared to be quite talkative
in the evening.
EXTENSIONS AND COMMENTARY: The commonly used name for 2C-T-15, during
its synthesis, was SESQUI. The general name for a 15-
carbon terpene
is
sesquiterpene, from the Latin prefix for one and a half. The
active level of 2C-T-15 is not known. The highest level yet tried was
30 milligrams orally, and there had been threshold reports pretty
regularly all the way up from 6 milligrams. But no definite activity
yet. This compound is
isosteric with the
isopropyl group as seen in
the
analogous compound
2C-T-4 (the three
carbons are in exactly the
same positions, only the
electrons are located differently) and it is
a little surprising that the potency appears to be considerably less.
Just over 20 milligrams of the latter compound was overwhelmingly
psychedelic.
The entire mini-project of hanging
cyclic things onto the
sulfur atom
was an interesting problem. This is the three
carbon ring. The six
carbon ring (the
cyclohexyl homologue) was discussed as 2C-T-5 in the
recipe for of ALEPH-2. The
cyclobutyl and
cyclopentyl homologs were
assigned the names of 2C-T-18 and 2C-T-23, respectively, and their
preparations taken as far as the
nitrostyrene and the
aldehyde stages,
respectively, before the project ran out of steam.
Towards the
cyclobutyl homologue, a
solution of
2,5-dimethoxythiophenol and
cyclobutyl bromide in DMSO containing
anhydrous potassium carbonate was stirred for several hours at room
tem
perature and yielded
2,5-dimethoxyphenyl cyclobutyl sulfide as a
white oil that boiled at 135-140 °C at 0.3 mm/
Hg. Anal. (C12H16O2S)
C,H. This was brought to react with a mixture of
phosphorus
oxy-
chloride and N-
methylformanilide producing
2,5-dimethoxy-4-(cyclobutylthio)benzaldehyde that had a melting point
of 108-109.5 °C from MeOH. Anal. (C13H16O3S) C,H. Coupling with
nitromethane in the presence of
ammonium acetate produced
2,5-dimethoxy-4-cyclobutylthio-beta-nitrostyrene as lustrous orange
crystals from boiling
acetonitrile, melting point 160-161 °C. Anal,
(
C14H17NO4S) C,H. This will some day be reduced to
2,5-dimethoxy-4-cyclobutylthiophenethylamine hydrochloride, 2C-T-18.
Towards the
cyclopentyl homologue, a
solution of
2,5-dimethoxythiophenol and
cyclopentyl bromide in DMSO containing
anhydrous potassium carbonate was stirred for several hours at room
tem
perature and yielded
2,5-dimethoxyphenyl cyclopentyl sulfide as a
white oil that boiled at 135-145 °C at 0.3 mm/
Hg. This was brought to
react with a mixture of
phosphorus oxychloride and N-
methylformanilide
producing
2,5-dimethoxy-4-(cyclopentylthio)benzaldehyde as yellow
crystals from MeOH. This will some day be converted to the
nitrostyrene and then reduced to
2,5-dimethoxy-4-cyclopentylthiophenethylamine hydrochloride, 2C-T-23.
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