SYNTHESIS: To a solution of 6.9 g of KOH pellets in 100 mL hot MeOH,
there was added 13.0 g 2,5-dimethoxythiophenol (see under 2C-T-2 for
its preparation) followed by 9.6 g 2-fluoroethyl bromide. The
reaction was exothermic, with the immediate deposition of white
solids. This was allowed to stand for 2 h, added to 1 L H2O, and
extracted with 3x75 mL CH2Cl2. The extracts were pooled and the
solvent removed under vacuum. The residue was 2,5-dimethoxyphenyl
2-fluoroethyl sulfide which was a colorless oil and weighed 17.2 g.
It was sufficiently pure for use in the next reaction without a
distillation step.
A mixture of 26.8 g POCl3 and 24.8 g N-methylformanilide was heated
for 10 min on the steam bath. To this claret-colored solution was
added 17.0 g of 2,5- dimethoxyphenyl 2-fluoroethyl sulfide, and the
mixture heated an additional 25 min on the steam bath. This was then
added to 1.5 L of well-stirred warm H2O (pre-heated to 55 °C) and the
oily phase that formed solidified almost immediately. This brown
sugar-like product was removed by filtration, and washed with
additional H2O. After sucking as dry as possible, the residual solids
(weighing 19.0 g wet) were dissolved in an equal weight of boiling
MeOH which, after cooling in an ice-bath, deposited pale ivory colored
crystals of 2,5-dimethoxy-4-(2-fluoroethylthio)benzaldehyde. This was
air dried to constant weight, which was 15.1 g.
To a solution of 15.0 g 2,5-dimethoxy-(2-fluoroethylthio)benzaldehyde
in 75 mL nitromethane there was added 1.35 g of anhydrous ammonium
acetate, and the mixture was heated on the steam bath for 70 min (the
progress of the reaction must be followed by continuous TLC
monitoring). The clear deeply-colored solution was decanted from some
insoluble material and the excess nitromethane removed under vacuum.
There resulted 17.78 g of almost dry brick-red crystals which were
dissolved in 110 mL boiling EtOAc. After cooling overnight in the
refrigerator, the crystalline product was removed, washed with EtOAc,
and air dried. There was obtained 14.33 g of
2,5-dimethoxy-4-(2-fluoroethylthio)-beta-nitro-styrene as bright orange
crystals.
A solution of LAH (140 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 3.7 mL 100% H2SO4 dropwise, to minimize charring. This was
followed by the addition of 8.9 g
2,5-dimethoxy-4-(2-fluoroethylthio)-beta-nitrostyrene in 40 mL of hot
anhydrous THF (a heat lamp was needed to keep the nitrostyrene in
solution). As the nitrostyrene entered the hydride solution, there
was an immediate loss of color. After 1 h stirring at room
temperature, the temperature was brought up to a gentle reflux on the
steam bath, then all was cooled again to 0 °C. The excess hydride was
destroyed by the cautious addition of 15 mL IPA and the inorganic
solids were made white and filterable by the addition of 15 ml 15%
NaOH. The loose cottage-cheesy solids were removed by filtration, and
washed with additional THF. The filtrate and washes were pooled and
stripped of solvent under vacuum providing 7.39 g of a pale amber oil.
This was dissolved in 600 mL dilute H2SO4, and washed with 3x50 mL
CH2Cl2 (which removed the light yellow color). The aqueous phase was
made strongly basic with 25% NaOH, extracted with 3x75 mL CH2Cl2 and,
after pooling, the solvent was removed under vacuum leaving 4.91 g of
product as an oil. This was distilled at 145-160 °C at 0.4 mm/Hg
giving 3.91 g of a white oil. This was dissolved in 40 mL IPA and
neutralized with 35 drops of concentrated HCl. The beautiful white
solids that formed were removed by filtration, and washed with IPA.
All were suspended in, and ground under, 40 mL anhydrous Et2O,
refiltered and air dried. The final weight of
2,5-dimethoxy-4-(2-fluoroethylthio)phenethylamine hydrochloride
(2C-T-21) was 4.07 g of glistening white crystals.
DOSAGE 8 - 12 mg.
DURATION: 7 - 10 h.
QUALITATIVE COMMENTS: (with 6 mg) I noticed something undefined
within five minutes which went away. Within 15 minutes I noticed a
definite awareness of activity. There was a progressive increase in
awareness of something happening over the next two hours with a
plateau of perhaps an hour then occurring. The nature of the
happening, as usual, was not clear. During the experience I was more
talkative than I usually am. I seemed to be interacting with all
others. There was no euphoria but, then, there was no body load or
nausea, nor was there any nystagmus. I found a little mental
confusion at the peak and there was some searching in my memory bank
for the right chips at times. I lost the entire line of one of my
conversations at one point during the plateau and had to ask what I
was talking about. I tested my visual field on a painting and with
sufficient concentration I could get the center part to wiggle a
little. I didn't try to observe anything with my eyes closed. I feel
that there was something physical about the eyes. In the evening,
after-images were quite intense, and the next day my eyes seemed tired
or bothered. What can I say? The material was pleasant and I
certainly got the feeling of being high but not getting too much out
of it. There were no insights or "ah-hahs." I wonder if periodic and
frequent use (say twice a day) at the one or two milligram level would
be a positive mood enhancer?
(with 8 mg) Comes on very gradually and slowly. Takes about an hour
to feel. Reasonably intense in two hours, ++. Very pleasant
material, enhancing communication, clear thinking, good feeling.
There is a feeling of closeness; the bondedness with the group grows
steadily during the day, reaching a highly rewarding level. For me a
couple of firsts regarding food. I was hungry only two hours into it.
I usually don't want food 'til well down as I usually feel that it
interferes with the experience. And, also, I nibbled constantly as I
felt that there was nothing in my body. And I enjoyed it thoroughly,
feeling only the warmth and energy, with no contrary developments.
There was a nice feeling of inner strength and peace.
(with 8 mg) It was very difficult to fix the times of ascent or
descent. Some chilling during onset but not later. And there was
some yawning and ear-popping. It is easy on the body, in no way
threatening. This time I am very relaxed and somewhat lethargic; the
visuals are not too pronounced. Excellent sleep.
(with 10 mg) I find I can use it if I set my energy in a direction I
really want to go in. Otherwise I can just be stoned and
self-indulgent. Not out-of-body cosmic at all. But it's good
material, an ally, not presenting hidden negatives.
(with 12 mg) Well ... 12 milligrams is quite enough for a +3, which
was established within the first hour and plateau'd by the end of the
second. Body felt quite safe, again, but there was considerable push
of energy. I did not feel par-ticularly interested in doing anything
like writing and in fact preferred to watch television while rocking a
bit on the couch, to ease the push. Mood was faintly grim, but not
more than faintly. I noted something that I hadn't seen before with
this material: time slowing. The first two hours seemed to last a
very long time. There was no anorexia. It wasn't until 10 PM [fifth
hour] that the idea of writing had any appeal at all. By then, I was
still +3 but a lot more at ease. I wrote two letters and enjoyed the
process. Sleep was fine. My mood next day was slightly introverted,
not very spontaneous for a while. Late in the afternoon, it was a lot
better.
EXTENSIONS AND COMMENTARY: This is about as potent a phenethylamine as
they come. There are a couple in the 2C-G family that are similar in
potency, but they are much longer lived. The motivation for the use
of the beta-fluoroethyl group can be seen under the discussion of
DOEF, where there was an amalgamation of two lines of reasoning: the
imitation of potent serotonin agonists with a need of including an
atom (the fluorine) that is potentially labelable with a positron
emitter. And the mass-18 isotope of fluorine, with a half-life of
just under 2 hours, is ideal for many biological studies. In fact,
much of the research work being carried out by the Nuclear Medicine
group in Berkeley is based on the analogy between a halogen atom and a
beta-fluoroethyl group. There are some similarities in pharmacology
so that if there is a bromine or an iodo atom present in a drug, it is
a fair guess that the corresponding beta-fluoroethyl would also be
active. In a sense, the cute (and chemically impossible) idea of
putting a bromo atom on the sulfur of the 2C-T family is nicely
satisfied by using the beta-fluoroethyl group instead (which is
chemically completely possible).
A logical extension of 2C-T-21 is the three carbon amphetamine
analogue which should be, by comparing structures and activities, a
very potent and in-teresting material in its own rights. This would
be 2,5-dimethoxy-4-(2-fluoroethylthio)amphetamine or, following the
nomenclature used with the earlier members of this series, ALEPH-21.
A solution of 2,5-dimethoxy-4-(2-fluoroethylthio)benzaldehyde (see
earlier in this recipe) in nitroethane with ammonium acetate gave
1-(2,5-dimethoxy-4-(2-fluoroethylthio)phenyl)-2-nitropropene as
yellow-orange crystals from MeOH with a melting point of 102-104 °C.
And that is where the project now stands. It has not yet been reduced
to the amine.
This phenethylamine, 2C-T-21, was the last of the 2C-T's to be
completed. A couple of other sulfur analogues have been given
numbers, and have been started, but the syntheses are still at some
intermediate state.
The (n)-butyl compound, named 2C-T-19, has been taken to the
nitrostyrene stage. Reaction between 2,5-dimethoxythiophenol and
(n)-butylbromide with KOH gave 2,5-dimethoxyphenyl (n)-butyl sulfide
as a colorless oil. This, with phosphorus oxychloride and
N-methylformanilide, provided
2,5-dimethoxy-4-(n-butylthio)benzaldehyde as pale orange solids from
MeOH, with a melting point of 78-79 °C. This, with nitromethane and
ammonium acetate, gave 2,5-dimethoxy-4-(n-butylthio)-beta-nitrostyrene,
with a melting point of 133-134 °C from either IPA or acetonitrile.
The 2,2,2-trifluoroethyl compound, which I have named 2C-T-22, has
been taken to the benzaldehyde stage. Reaction between
2,5-dimethoxythiophenol and 2,2,2-trifluoroethyliodide with KOH gives
2,5-dimethoxyphenyl 2,2,2-trifluoroethyl sulfide as a very pale amber
oil. This, with phosphorus oxychloride and N-methylformanilide
provided 2,5-dimethoxy-4-(2,2,2-trifluoroethyl)benzaldehyde as
crystals that proved to be exceedingly difficult to purify. Yellow
solids can be obtained from several solvents, and they melt in the 70
°C area. The initially isolated fraction melted at 69-72 °C and
showed three major spots by both TLC and GCMS. The largest GC peak
was the correct product with a parent peak of 280 m/e, and cracking
fragments at 154 and 234 m/e. A small sample was finally obtained
from hexane with a melting point of 78-79 °C but I am not sure that
even it is particularly pure. Not surprisingly, the reaction of this
crude benz-aldehyde with nitromethane and ammonium acetate gave a
nitrostyrene product that was a complex mixture. And there that
project also rests.
A couple of additional efforts warrant comment. The reaction between
trifluoromethyliodide and 2,5-dimethoxythiophenol should have produced
2,5-dimethoxyphenyl trifluoromethyl sulfide, but it didn't produce
anything. And one more. What about a bare thio group at the
4-position in this 2C-T-family? Maybe this can be protected through
everything as the disulfide, and be reduced at the last step! The
disulfide, 2,5-dimethoxyphenyl disulfide (see under 2C-T-15) was aimed
towards the needed bis-aldehyde with phosphorus oxychloride and
N-methylformanilide, but all that came out of this were black oils and
tars. This has also been abandoned for now.
And it has just occurred to me that there is yet another effort that
is certain-ly worth making, inspired by the observation that
2,2-difluoroethyl iodide is commercially available and not
prohibitively expensive. It, with 2,5-dimethoxythiophenol, and
following the obvious steps to the aldehyde, the nitrostyrene, and the
final amine, would produce
2,5-dimethoxy-4-(2,2-difluoroethylthio)phenethylamine hydrochloride.
It lies exactly half way between the highly potent 2C-T-21 (the
mono-fluoro), and the yet to be finished 2C-T-22 (the trifluoro).
Let's be weird, and call it 2C-T-21.5. I will wager mucho that it
will be very potent.
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