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#6 ALEPH-6
2,5-DIMETHOXY-4-PHENYLTHIOAMPHETAMINE
SYNTHESIS: To a 300 mL three-neck round-bottom flask set up with a
magnetic stirrer and protected with a N2
atmosphere, there was added
75 mL hexane, 3.5 g
tetramethylethylenediamine, and 4.2 g
p-dimethoxybenzene. The reaction mixture was cooled to 0 °C with an
external ice bath, and there was then added 19 mL of 1.6 M
butyllithium in hexane. With stirring, the reaction was brought up to
room tem
perature, and there were produced loose, creamy solids. There
was then added, as a solid and portionwise, 6.6 g
diphenyldisulfide
which resulted in an exothermic reaction and the production of a
nearly clear
solution. After stirring an additional 10 min, the
reaction was quenched in 500 mL of dilute
NaOH. The hexane
phase was
separated, and the aqueous
phase extracted with 4x100 mL
CH2Cl2 The
organic extracts were combined, washed with dilute HCl and the
solvents were removed under vacuum to provide 6.0 g of
2,5-dimethoxyphenyl phenyl
sulfide as an impure amber oil. A small
sample was saved for microanalysis and
NMR, and the re-mainder
converted to the corresponding
benzaldehyde.
A mixture of 6.1 g POCl3 and 5.4 g N-
methylformanilide was heated for
3 min on the steam bath, and then added to the remainder of the
above-described
2,5-dimethoxyphenyl phenyl
sulfide. The reaction
became immediately a deep red and, after heating on the steam bath for
0.5 h, was dumped into a large quantity of H2O, producing a granular
brown solid. This was removed by filtration, and washed sparingly
with cold MeOH (the washes were saved). The resulting pale yellow
solids were re
crystallized from 20 mL boiling absolute
EtOH providing,
after cooling, filtration and air drying, 4.4 g of extremely pale
yellow
crystals of
2,5-dimethoxy-4-(phenylthio)benzaldehyde. This had
a mp of 119-119.5 °C. All washes and mother liquors were combined,
flooded with H2O and extracted with
CH2Cl2. This
solvent was removed
under vacuum, and the residue (a viscous oil) was
dissolved in a
little
EtOH which, on cooling in dry ice, gave 1.2 g of a second crop
of the
aldehyde, mp 117-119 °C. Re
crystallization from 5 mL 95%
EtOH
gave an additional 0.4 g product with a mp of 118-119 °C. This mp was
not improved by recry-stallization from
cyclohexane. The
NMR specrum
was excellent, with O
CH3 singlets (3H) at 3.45 and 3.80 ppm; ArH
singlets at 6.28 and 7.26 ppm, the C6H5 as a broad peak centered at
7.50, and the CHO proton at 10.37 ppm.
A
solution of 4.4 g
2,5-dimethoxy-4-(phenylthio)benzaldehyde in 32 mL
nitroethane was treated with 0.8 g
anhydrous ammonium acetate and
heated on the steam bath for 21 h. The excess
solvent/reagent was
removed under vacuum, leaving a dark red oil as residue. After much
diddling and fiddling around, this set up as a
crystalline mass.
These solids were ground under 20 mL cold MeOH and filtered, providing
5.3 g of the crude
nitrostyrene as an orange
crystalline residue
product after air-drying. This was ground up under 10 mL MeOH, the
in
solubles collected by filtration, washed with a little MeOH, and air
dried to provide 5.3 g crude
1-(2,5-dimethoxy-4-phenylthiophenyl)-2-nitropropene as yellow
crystals, with a mp of 100-102 °C (with prior sintering at about 98
°C). This was re
crystallized from 50 mL boiling 95%
EtOH. After
cooling in an ice bath, it was filtered, washed with
EtOH, and air
drying provided gold-yellow
crystals with a mp of 105-106 °C. The
proton
NMR was excellent (in CDCl3).
A suspension of 2.0 g LAH in 100 mL refluxing THF, under an inert
atmosphere and with good stirring, was treated with a
solution of 3.5
g
1-(2,5-dimethoxy-4-phenylthiophenyl)-2-nitropropene in 20 mL
anhydrous THF added dropwise at a rate that maintained the reflux.
Heating and stirring were maintained for an additional 36 h, and then
the reaction mixture was stirred at room tem
perature for an additional
24 h. There was added 2.0 mL H2O (
dissolved in a little THF),
followed by 2.0 mL 15%
NaOH, and finally another 6.0 mL H2O. Stirring
was continued until all formed solids had turned white. The reaction
mixture was filtered, and the filter cake washed with THF. The
filtrate and the washings were combined and the
solvent removed under
vacuum. The residue was 2.8 g of an oil that quite obviously
contained some H2O. This was
dissolved in 400 mL
CH2Cl2, washed first
with dilute
NaOH and then with 4x150 mL 1N HCl. The organic
phase was
stripped of
solvent under vacuum, yielding a pale amber oil that
crystallized. This was ground first under
Et2O, giving 3.4 g of a
yellow solid. This was then ground under 10 mL of
acetone, yielding
2.4 g of a white
crystalline solid that darkened at 170 °C, sintered
at 187 °C and had a mp of 191-193 °C. This was
dissolved in 20 mL hot
95%
EtOH, and diluted with 40 mL
Et2O to provide a clear
solution
which, after a minute's scratching with a glass rod,
deposited
2,5-dimethoxy-4-phenylthioamphetamine hydrochloride (ALEPH-6) as white
solids. After filtration and air drying, the weight was 1.8 g, with a
mp of 194-195 °C. The dilute HCl washes, after being made basic with
aqueous
NaOH and extraction with
CH2Cl2 gave a trivial quantity of
additional product.
DOSAGE: greater than 40 mg.
DURATION: probably long.
QUALITATIVE COMMENTS: (with 30 mg) I had an alert at the one hour
point, and in another hour there was a clear 1+. There was a not well
defined, gentle un-worldliness. And it was still there quite
unchanged twelve hours later. In a group I find that all voices about
me are of equal intensity and equal importance. But this is not at
all distracting. This will be a long lived thing for sure.
(with 40 mg) I am into a subtle but real effect, no more than one
plus, but real. I feel primed, but nothing more. It is not
interfering with work, maybe even helping with it. After another hour
of static one-plusness I decided to use it as a primer to LSD, using
the usual 60 microgram quantity that is standard for primer studies.
The combination showed definite
synergism, with a rapid show of the
LSD effects (within fifteen minutes) and an almost three plus effect.
This is most unusual for the usual 60 microgram challenge amount. An
absolutely delightful intoxication that had sufficiently descended
towards baseline that I accepted a ride to a party that evening in
Marin County to attend a poetry reading. There I felt myself at
baseline and accepted (unusual for me) a little marijuana. And with
the utmost quiet and delicacy, a rather incredible change of state
took place. The most memorable event was the awareness of a clarinet
playing somewhere, and the sneaky sounds from it actually coming along
the carpet out of the dining room and into the hallway and through the
door and into the room where I was, and all of them gathering at my
feet like docile kittens waiting for me to acknowledge them. I did,
non-verbally, and I was amazed at the many additional follow-up sounds
that came from the same clarinet along the same twisty path along the
floor and through the door and into my space, over what seemed to be
the next million hours. I ended up with a marvelous collection of
notes and
phrases at my feet, and I felt somehow honored. My speech
sounded OK to me, but I knew that it would be odd to the ears of
others, so I kept quiet. A final measure of the weirdness of the
ALEPH-6/LSD/Pot combination was the viewing of the Larkspur ferry at
its dock, abandoned for the evening and with no one aboard it, and
with all that clean, dry sleeping space going to waste with so many
people sleeping on the streets these days. Once home, I slept soundly
and for a long while. Incredible experience.
EXTENSIONS AND COMMENTARY: In a sense, this compound was a
disappointment. The beauty of putting a whole new ring into an active
structure is that it provides a marvelous vehicle for introducing new
substituents in new arrangements. Had Aleph-6 been a cleanly active
and potent compound, then the new
phenyl group could have been made
electronegative to varying degrees (with methoxy
substitution for
example) or
electropositive to varying degrees (with
trifluoromethyls
or nitros) and this fine-tuning could have been extremely rewarding.
But this material had the earmarks of one of those forever threshold
things. The 40 milligram experiment was hopelessly compromised, and
nothing higher was ever scheduled or tried. The two-
carbon homologue,
2,5-dimethoxy-4-phenylthiophenethylamine, or 2C-T-6, has never even
been
synthesized, let alone assayed.
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