SYNTHESIS: A stirred solution of 8.3 g 3,5-dimethoxy-1-chlorobenzene
and 7.2 g isopropylsulfide in 100 mL anhydrous Et2O was cooled with an
external ice bath, and then treated with 67 mL 1.5 M lithium
diisopropylamide in hexane which was added over the course of 10 min.
The reaction mixture was allowed to return to room temperature and the
stirring was continued for 0.5 h. The mixture was poured into dilute
H2SO4, the organic layer was separated, and the aqueous phase
extracted with 3x75 mL EtOAc. The organic phases were combined, dried
over anhydrous K2CO3, and the solvent removed under vacuum. The
resulting 4.54 g of almost colorless oil was distilled at 85-95 °C at
0.1 mm/Hg to give 4.2 g of 3,5-dimethoxyphenyl isopropyl sulfide as a
colorless oil, showing a single spot on TLC with no indication of
starting chlorobenzene. The product formed a picrate salt, but this
had an unsatisfactory mp character (partly melting at 45-47 °C, and
then completely at about 80-90 °C). The microanalysis for this picrate
was low in the carbon value, although the hydrogen and nitrogen were
excellent. Anal. (C17H19N3O9S) H,N; C: calcd, 46.25; found, 44.58,
44.45.
To a well-stirred solution of 4.1 g 3,5-dimethoxyphenyl isopropyl
sulfide and 3.5 mL N,N,N',N'-tetramethylethylenediamine in 25 mL
anhydrous Et2O that had been cooled to -78 °C with a dry-ice/acetone
bath, there was added 10 mL 2.5 M hexane solution of butyllithium.
The mixture was allowed to return to room temperature, and there was
added 3.5 mL DMF which caused the yellow color to progressively
darken. The reaction mixture was poured into dilute H2SO4, the Et2O
layer was separated, and the aqueous phase extracted with 3x75 mL
EtOAc. The solvent was removed from the combined organic phases, and
the residue distilled at 0.15 mm/Hg to give two fractions. One,
boiling at 120-140 °C, was 0.98 g of a pale yellow mobile liquid,
which was part starting sulfide and part product aldehyde by TLC. The
second cut, boiling at 160-180 °C, was a viscous liquid, weighed 1.66
g, and was largely 2,6-dimethoxy-4-(i-propylthio)benzaldehyde. This
formed a crystalline anil with 4-methoxyaniline (by fusing equimolar
amounts of the two with a flame) which, after recrystallization from
MeOH, gave fine yellow crystals with a mp of 87.5-89 °C. Anal.
(C19H23NO3S) C,H.
A solution of 0.8 g 2,6-dimethoxy-4-(i-propylthio)benzaldehde in 10 mL
nitromethane was treated with 0.2 g anhydrous ammonium acetate and
heated on the steam bath for 1 h. The excess reagent/solvent was
removed under vacuum, and the residue spontaneously solidified. This
was recrystallized from 5 mL MeOH to give 0.70 g
2,6-dimethoxy-beta-nitro-4-(i)-propylthiostyrene as a pale yellow fluffy
solid, with a mp of 83-84.5 °C. Anal. (C13H17NO4S) C,H.
A solution of LAH (20 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 0.54 mL 100% H2SO4 dropwise, to minimize charring. This was
followed by the addition of 0.54 g
2,6-dimethoxy-beta-nitro-4-(i)-propylthiostyrene in a small volume of
anhydrous THF. The color was discharged immediately. After a few
minutes further stirring, the temperature was brought up to a gentle
reflux on the steam bath for about 10 min, and then all was cooled
again to 0 °C. The excess hydride was destroyed by the cautious
addition of IPA 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 well with THF. The filtrate was stripped of solvent under
vacuum and the residue dissolved in 100 mL of dilute H2SO4. This was
washed with 2x50 mL CH2Cl2 (the washes were saved, see below), made
basic with aqueous NaOH, and then extracted with 2x50 mL CH2Cl2. The
residue remaining after the removal of the solvent was distilled at
130-140 °C at 0.05 mm/Hg to give 0.11 g of a white oil. This was
dissolved in 10 mL IPA, neutralized with 5 drops of concentrated HCl
and diluted with 50 mL anhydrous Et2O. After filtration of the formed
crystals, Et2O washing, and air drying, there was obtained 80 mg of
2,6-dimethoxy-4-(i)-propylthiophenethylamine hydrochloride (gamma-2C-T-4)
as fine white crystals. The removal of the solvent from the CH2Cl2
washes of the dilute H2SO4 solution gave a H2O-soluble white solid
that proved to be the sulfate salt of the product. This provided,
after making the H2O solution basic, extraction with CH2Cl2, and
solvent removal, the free base that was converted, as described above,
to a second crop of the hydrochloride salt.
DOSAGE: above 12 mg.
DURATION: probably short.
QUALITATIVE COMMENTS: (with 8 mg) I might actually be up to a plus 1,
and with a very good feeling. But I cannot say how long it lasted,
and it was probably pretty short. It just sort of faded away.
(with 12 mg) At the 25 minute point I am reminded of the experiment,
and in another quarter hour I am into something. Will this be another
forever threshold? I feel very good, but there is no sparkle.
EXTENSIONS AND COMMENTARY: Here is another example of the presentation
of a compound for which there has not yet been an effective level
determined. Why? For a very good reason. This is an example of a
whole class of compounds that I have called the pseudos, or the
gamma-compounds. Pseudo- as a prefix in the literary world generally
stands for "false." A pseudopod is a thing that looks like a foot, but
isn't one. A pseudonym is a fictitious name. But in chemistry, it
has quite a different meaning. If something has a common name, and
there is a second form (or isomer, or shape, or orientation) that is
possible and it doesn't have a common name, it can be given the name
of the first form with a Rpseudo-S attached. Ephedrine is the
erythro-isomer of N-methyl-beta-hydroxyamphetamine. There is a second
stereoisomer, the threo- isomer, but it has no trivial name. So it is
called pseudoephedrine, or the "Sudafed" of sinus decongestant fame.
The pseudo-psychedelics are the 2,4,6-trisubstituted counterparts of
the 2,4,5-trisubstituted psychedelics. Almost all of the
2,5-dimethoxy-4-something-or-other compounds are active and
interesting whether they be phenethylamines or amphetamines, and it is
an exciting fact that the 2,6-dimethoxy-4-something-or-other compounds
are going be just as active and just as interesting. A number of
examples have already been mentioned. TMA-2 is
2,4,5-trimethoxyamphetamine (a 2,5-dimethoxy-substituted compound with
a methoxyl at the 4-position). The pseudo- analogue is TMA-6
(2,4,6-trimethoxyamphetamine) and it is every bit as potent and
fascinating. Z-7 could be called pseudo-DOM, and although it is quite
a bit down in potency, it is an active drug and will both demand and
receive much more clinical study some day.
Will the other 2,4,5-things spawn 2,4,6-things that are active?
Without a shadow of a doubt. Chemically, they are much more difficult
to synthesize. The 2,5-dimethoxy orientation made the 4-position a
natural and easy target. The 2,6-dimethoxy orientation pushes for
3-substitution, and the 4-position is completely unnatural. Tricks
are needed, but tricks have now been found. The above synthesis of
pseudo-2C-T-4 shows one such trick. This is, in my opinion, the
exciting chemistry and psychopharmacology of the next decade. Well
over half of all the psychedelic drugs mentioned in Book II are
2,4,5-trisubstituted compounds, and every one of them has a
(potentially active) 2,4,6-pseudo-counterpart.
It goes yet further. The antidepressant series of "Ariadne" compounds
are 1-phenyl-2-aminobutanes. But the 1-phenyl is again a
2,4,5-trisubstituted compound. The 2,4,6-isomer will give rise to a
pseudo-Ariadne family, and I will bet that they too will be
antidepressants. The 1-phenyl-2-aminobutane analog of gamma-2C-T-4 is the
2,4,6-analogue and it has been prepared as far as the nitrostyrene.
It has not yet been reduced, so it is not yet been evaluated, but it
could be a most remarkable psycho-pharmacological probe.
And it goes yet yet further. Think back to the six possible TMA's.
TMA and TMA-3 were relatively inactive. And TMA-2 and TMA-6 were the
interesting ones. The first gave rise to the last twenty years of
psychedelic chemistry, and the other (as speculated upon above) will
give rise to the forthcoming ten years. But what of TMA-4 and TMA-5?
Both showed activity that was more than TMA but less than that of the
-2 or -6 isomers. Could they, some day, provoke yet other families of
psychedelics? Maybe the 3-position of these two might be focal points
of leverage as to psychological activity. What are the letters that
follow y in the Greek alphabet? If I remember correctly, the next
letter is the last letter, omega. So, I guess that Nature is trying
to tell us something, that the -4 and -5 isomers will not engender
interesting families. What a pity. The chemistry is so unthinkably
difficult that it would have been a true challenge. My next
incarnation, maybe?
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