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#69 gamma-DOM
Z-7; 2,6-DIMETHOXY-4-METHYLAMPHETAMINE
SYNTHESIS: To a
solution of
2,6-dimethoxy-4-methylbenzaldehyde (mp
92-93 °C from the
lithiation of
3,5-dimethoxytoluene followed by
reaction with N-
methylformanilide) in 10 mL
nitroethane, there was
added 0.1 g
anhydrous am-monium
acetate and the mixture was heated on
the steam bath for 16 h. Removal of the
solvent under vacuum gave a
slightly oily red-orange
crystalline mass which was finely ground
under 1 mL of MeOH. Filtration and a sparing wash with MeOH gave,
after air drying, 0.8 g of a light yellow
crystalline solid with a mp
of 121-122.5 °C. Re
crystallization from 4 mL boiling absolute
EtOH
gave 0.6 g of
1-(2,6-dimethoxy-4-methylphenyl)-2-nitropropene as very
light yellow platelets, which melted at 123-124 °C.
To a
solution of 0.25 g LAH in 25 mL refluxing THF, well stirred and
under He, there was added a
solution of 0.3 g
1-(2,6-dimethoxy-4-methylphenyl)-2-nitropropene in 5 mL dry THF. Upon
the completion of the addition, the reaction mixture was held at
reflux for 48 h. After cooling with an external ice bath there was
added, in sequence, 0.5 mL H2O, 0.5 mL 15%
NaOH, and finally 1.5 mL
H2O. The inorganic solids were removed by filtration, and the filter
cake washed with THF. The
solvent from the combined filtrate and
washings was removed under vacuum, and the residue (0.3 g) was a
crystal clear colorless oil with a high refractive index. This was
dissolved in 2 mL IPA, neutralized with concentrated HCl, and diluted
with 35 mL of
anhydrous Et2O. After a minute's standing, the
solution
became turbid, followed by the slow
deposition of very fine white
crystals. After standing 1 h at room tem
perature, these were removed
by filtration,
Et2O washed, and air dried to constant weight. There
was thus obtained 0.3 g
2,6-dimethoxy-4-methylamphetamine
hydrochloride (gamma-DOM) with a mp of 203 °C. sharp.
DOSAGE: 15 - 25 mg.
DURATION: 6 - 8 h.
QUALITATIVE COMMENTS: (with 14 mg) I am really quite spacey. I can
go from a train of thought straight up into thin air. Then, to get to
another one there must be a careful choice of words. Logic has
nothing to do with any of it. There is no trace of the
MDMA-like
magic. This is an interpretive drug, not simply an ASC
altered state
of consciousness opening.
(with 18 mg) There is a light-headedness, and a somewhat starry-eyed
stoned state. Nothing visual, and no body concern except for what
seems to be a very fine inner tremor. I think that with a little
more, things might very well begin to move in the visual field. But I
have no feeling of great concern about taking a somewhat higher
dosage.
(with 25 mg) I was at a +++ for about three hours, and it was a very
weird place. There were some visuals, but they were not at all
commensurate with the degree to which I was simply stoned. The erotic
does not knit, and it's hard to get involved with music. It is as if
you were going down some totally unknown street in a completely
familiar city. You know the territory, but yet it is strangely all
new. Eyes closed fantasy and shaped imagery was quite remarkable.
But some heart
arrhythmias and a pretty constant
diarrhea made the
experience less than totally ideal. My sleep was good and with good
dreams.
EXTENSIONS AND COMMENTARY: I can't remember the exact names of the
companies that went with the oil additives. STP was, I believe, it's
own thing, and originally stood for Scientifically Treated
Petroleum.
And F-310 was, I believe, a
Chevron Oil product. F-320 was, of
course, the product of the wild and happy chemists at the
Pharmaceutical Chemistry
Department at the University of
California in
San Francisco, playing with what they fondly called "funny drugs." And
when the
2,4,6-orientation became an obvious positional
isomer, the
Pennzoil Oil Company's additive, Z-7, was a natural to have its name
volunteered to the cause. There was one additional
isomer possible,
with the
methyl in the 2-position and the
methoxyl groups at the 4-
and 6-positions. This followed the more conventional
aldehyde made
from
3,5-dimethoxytoluene via the Vilsmeier process, with POCl3 and
N-
methylformanilide. This material
(
2,4-dimethoxy-6-methylbenzaldehyde with mp 64-65 °C from
cyclohexane
or from MeOH) is completely distinct from the
isomer used above
(
2,6-dimethoxy-4-methylbenzaldehyde with a mp of 92-93 °C from MeOH).
The
amphetamine from this
isomer is
2,4-dimethoxy-6-methylamphetamine,
and had been
christened by the chemistry crowd as Z-7.1.
Much effort had been put forth in research by this medical school
group of graduate students and graduate advisors, to try to explain
the
biological activity of the
2,4,5-things such as TMA-2 and DOM
(STP). And a considerable investment had been made in the attempt to
tie tog
ether the
amphetamine world of
psychedelics with the
indole
world of
psychedelics. The convenience of having two methoxy groups
para to one another was a clear invitation to speculate upon the
formation of a
benzoquinone intermediate of some kind, and this would
require the loss of the
methyl groups which were already known to be
metabolically labile. This "
quinone-like" intermediate was the
cornerstone of a "
hydroquinone hypothesis," as it allowed further
condensation within the molecule itself involving the primary
amine
group, to form something called an
indolene which, with some arcane
electron pushing and removal, could eventually become an
indole.
There. We now have a tie-in to the
tryptamine world, and to
serotonin, and that entire
neurotransmitter magic.
There was only one small fly in the ointment. No matter how the
2,4,5-things were explained, none of the proposed mechanisms could
allow for the
2,4,6-things to also be active.
How can one accommodate such
blasphemy? The first and obvious
approach was the simplest. Denial. The
2,4,6-things aren't really
active at all. Placebo stuff. There is a commonly used phrase, "bad
science" which is an in-famous term used to belittle findings that do
not fit with one's theories or purposes. But that simply didn't wash,
because I knew, as did a few others who chose not to identify
themselves too publicly, that TMA-2 and TMA-6 were both fully active
in the 40 to 50 milligram area. And although not as potent as DOM,
the compound of this recipe, gamma-DOM or Z-7, was certainly an active
one. So, since approach number one didn't work, try approach number
two. Make the shoe fit the wearer, without respect to the size of his
foot. One single size shoe fits all. One single mechanistic
hypothesis explains all. It was obvious that for the "
hydroquinone"
hypothesis to survive, Z-7 would have to undergo some
metabolic
oxidation--
phenol formation--in the 3-position.
And guess who was actually euchred into embarking onto the synthesis
of this
hypothetical metabolic Lucy
that's the anthropological-type,
not the LSD-type Lucy? Moi! On to a new
methoxylated
am
which would be called Z-7.2. Oxidation of the above
2,4-dimethoxy-6-methylbenzaldehyde with
metachloroperoxybenzoic acid
gave
2,4-dimethoxy-6-methylphenol which smoothly
methylated (KOH,
CH3I) to give
2,3,5-trimethoxytoluene as a white oil, bp 59-62 °C at
0.1 mm/
Hg. This formed the anion between the meta-methoxy groups with
butyllithium, and N-
methylformanilide gave the new compound
2,3,6-trimethoxy-4-methylbenzaldehyde, also an oil (bp 130-140 °C at
0.7 mm/
Hg) with an excellent
NMR spectrum. This formed the 3-
carbon
nitrostyrene with
nitroethane, as bright yellow
crystals from
methanol
with a mp 67-68.5 °C (and excellent
NMR and microanalysis, C,H,N).
Lithium
aluminum hydride reduction gave rise to what I was assuming
would be the target
amphetamine,
4-methyl-2,3,6-trimethoxyamphetamine
or Z-7.2. This formed a
hydrochloride salt which, although
analytically excellent, insisted in remaining as an
ether and
chloroform-
soluble oil which had an excellent
NMR spectrum. This was
certainly MY target compound, but it was not THEIR target compound.
The upper echelons who were running the show were serious about this
hydroquinone thing. Therefore, this product Z-7.2, that should have
been entered into human evaluation, was instead processed further by
the
substitution of a t-BOC on the
amine group,
oxidation to the
quinone with ceric
ammonium nitrate, reduction to the
hydroquinone
with
dithionite, and finally deprotection of the blocking t-BOC group
by
hydrochloric acid. The final product,
2,5-dihydroxy-6-methoxy-4-methylamphetamine hydrochloride, was an
extremely light-sensitive solid which was looked at by
NMR (excellent
spectrum in D2O) and by
cyclic voltimetry (destructive and
uninformative) but which would have been totally worthless to have
tasted.
In fact, the whole 2,4,6
substitution concept is just now beginning to
explode. Fully half of the drugs described in this Book II are of the
classical
2,4,5-trisubstitution pattern, and it is becoming evident
that every one of them will have a
2,4,6-trisubstituted counterpart
that bids fair to be an active
psychedelic.
Diligence could thus
easily double the number of known
psychedelics. The nickname "pseudo"
is really the Greek letter "psi" which looks like a candelabrum
standing on the table holding up three candles. If I can find the
type in some font, I will simply precede each known drug with this
letter, to indicate that the
2,4,5-ness has become a
2,4,6-ness.
Therefore, Z-7 is also pseudo-DOM.
Z-7.2 might have been an interesting compound to taste. But the
academic climate was not appropriate at that time (early 1977) for
such honesty. The "hydro-
quinone hypothesis" is now not much more
than a minor bit of history. And anyhow, it was just about this time
that I had uncovered a slick way of getting a
sulfur atom into the
amphetamine molecule. I quickly lost interest in the pursuit of other
people's hypotheses that didn't seem to lead anywhere. Maybe,
someday, some single earth-shaking mechanism will emerge to explain
everything. But in the meantime, the best contri
bution I can make to
this "grand unified theory of
psychedelic activity" is to continue to
make new and unexpected things which, if they are active, will
effectively destroy any hypothesis that just happens to be popular at
the moment. It is a lot more exciting, too.
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