SYNTHESIS: A solution of 15.4 g 2,5-dimethoxy-3,4-dimethylbenzaldehyde
(see under 2C-G for the preparation) in 50 mL nitroethane was treated
with 3 g anhydrous ammonium acetate and heated on the steam bath for
12 h. The excess nitroethane was removed under vacuum, and the
residual oil was diluted with a equal volume of MeOH. There was the
slow generation of deep red cottage-cheese-like crystals which were
removed by filtration and air-dried to constant weight (9.3 g) with a
mp 71-74 °C. Recrystal-lization from MeOH (10 ml/g) gave an
analytical sample of
1-(2,5-dimethoxy-3,4-dimethylphenyl)-2-nitropropene with a mp of 82 °C
sharp. Anal. (C13H17NO4) C,H,N. The NMR spectra (in CDCl3) and CI
mass spectrograph (MH+ = 252) were proper.
To a suspension of 3.3 g LAH in 200 mL refluxing THF, well stirred and
maintained under an inert atmosphere, there was added 4.2 g
1-(2,5-dimethoxy-3,4-dimethylphenyl)-2-nitropropene in 25 mL THF. The
mixture was held at reflux for 48 h. After cooling, 3.3 mL H2O was
added cautiously to decompose the excess hydride, followed by 3.3 mL
15% NaOH and finally another 10 mL H2O. The inorganic solids were
removed by filtration, and washed with additional THF. The combined
filtrate and washes were stripped of solvent under vacuum, and the
residue (4.7 g of a deep amber oil) dissolved in dilute HCl. This was
washed with CH2Cl2 (3x75 mL), then made basic with 5% NaOH and
extracted with CH2Cl2. Removal of the solvent under vacuum yielded an
amber oil that was distilled (105-115 °C at 0.4 mm/Hg) to give 1.2 g
of a white oil. This was dissolved in 8 mL IPA, neutralized with 15
drops of concentrated HCl, and diluted with 250 mL anhydrous Et2O.
After a period of time, there was a spontaneous appearance of white
crystals which were removed by filtration, Et2O washed, and air dried.
Thus was obtained 1.0 g of 2,5-dimethoxy-3,4-dimethylamphetamine
hydrochloride (GANESHA) with a mp of 168-169 °C. This was not
improved by recrystallization from either EtOAc or nitroethane. Anal.
(C13H22ClNO2) N.
DOSAGE: 20 - 32 mg.
DURATION: 18 - 24 h.
QUALITATIVE COMMENTS: (with 24 mg) There was a slow buildup to a ++
or more over the course of about three hours. Extremely tranquil, and
no hint of any body toxicity whatsoever. More than tranquil, I was
completely at peace, in a beautiful, benign, and placid place. There
was something residual that extended into the sleep period, and was
possibly still there in the morning. Probably I was simply tired from
an inadequate sleep.
(with 32 mg) A rapid and full development. Lying down with music,
the eyes-closed visuals were quite something. There was sudden
awareness of a potential toe cramp which I possibly exaggerated, but
it kept spinning itself into my awareness, and somehow locked in with
my visual imagery. It was not easy to keep the visual/somatic/
cognitive worlds in their proper places. The almost-cramp went away
and I forgot about it. There was a back spasm somewhere in this
drama, and it really didn't matter either. This dosage may be a bit
much for good housekeeping, though! Towards the end of the
experiment, I looked at a collection of photos from a recent trip to
Europe, and the visual enhancement was wonderful. A rolling +++
.
EXTENSIONS AND COMMENTARY: This compound was the seventh of the ten
possible Classic Ladies. I have mentioned the concept already under
the discussions on ARIADNE. This is the teutonic replacement of each
of the distinguishable hydrogen atoms of DOM with a methyl group. The
findings with GANESHA were a total surprise. The extension of a
hydrogen in the 3-position of DOM with a methyl group should have a
minor influence on its steric association with whatever receptor site
might be involved. A much greater impact might come not from the size
of the group but from its location. This, coupled with a full order
of magnitude of decrease in potency, seemed to call for an involvement
of that particular position as being one that is affected by
metabolism. And since the activity is decreased, the obvious role is
in the blocking of the metabolic promotion of DOM-like things to
active intermediates.
The remarkable point being emphasized here is that the placement of a
dull methyl group at a dull position of the DOM molecule actually
inactivated (for all intents and purposes) the activity of DOM. It is
not the presence of the methyl that has decimated the potency, but the
removal of the hydrogen atom.
How can such a hypothesis be explored? A historic premise of the
medicinal chemist is that if a structure gives an unusual response in
a receptor, vary it slightly and see how the response varies. This is
exactly the principle that led to the ten Classic Ladies, and with
this particular Lady (who actually turned out to be a gentleman), the
same concept should hold. There are two involved methyl groups in
GANESHA, one at the 3-position and one at the 4-position. Why not
homologate each to an ethyl group, and as a wrap up make both of them
into ethyl groups. Look at the differences along two lines of
variation; the effects of the homologation of the 3- and 4-positions,
coupled with the effects of the homologation intrinsic in the
comparison of the two-carbon chain of the phenethylamine with the
three-carbon chain of the amphetamine.
There are thus six compounds involved in such a study. And they have
been named (as have all the other GANESHA analogues) in accordance
with the collective carbon inventory in and about these two ring
positions. The first two compounds are related to DOET and to 2C-E.
Maintain the methyl group at the 3-position but homologate the
4-position to an ethyl. The ring pattern would become
2,5-dimethoxy-4-ethyl-3-methyl, and the phenethylamine and amphetamine
would be called 2C-G-12 and G-12 respectively (a one carbon thing, the
methyl, at position-3 and a two carbon thing, an ethyl, at
position-4). Reversal of these groups, the 3-ethyl homologues of 2C-D
and DOM would thus become 2C-G-21 and G-21. And, finally, the diethyl
homologues would be 2C-G-22 and G-22. In each of these cases, the
paired numbers give the lengths of the chains at the two positions,
the 3- and the 4-positions that are part of the GANESHA concept. And
this code is easily expandable to longer things such as 2C-G-31 and
2C-G-41, which would be the 3-propyl-4-methyl, and the
3-butyl-4-methyl homologues, resp.
Unfortunately, these six initially proposed compounds have so far
resisted all logical approaches to synthesis, and are at present still
unknown. What has been successfully achieved, the building up of a
big bulky hydrocarbon glob at these positions, has rather unexpectedly
led to a remarkable enhancement of potency. As with all true
exploration into areas of the unknown, the deeper you get, the less
you understand.
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