SYNTHESIS: A solution of 20 g methylamine hydrochloride in 150 mL hot
MeOH was treated with 10.0 g 4-methoxyphenylacetone and stirred
magnetically. After returning to room temperature, there was added
5.0 g sodium cyanoborohydride, followed by cautious addition of HCl as
required to maintain the pH at about 6. The reaction was complete
after a few days, and the mixture was poured into 800 mL H2O. This
was acidified with HCl (HCN evolution!) and washed with 3x75 mL
CH2Cl2, which removed most of the yellow color. There was 25% NaOH
added to make the reaction mixture strongly basic, and this was
extracted with 3x75 mL CH2Cl2. The solvent was removed from the
pooled extracts under vacuum, and the 10.3 g of residue distilled at
0.3 mm/Hg. The 9.7 g of colorless oil that distilled at 75-90 °C was
dissolved in 50 mL IPA, neutralized with 4.5 mL concentrated HCl, and
then diluted with 100 mL anhydrous Et2O. There were generated
glistening crystals of 4-methoxy-N-methylamphetamine hydrochloride
(METHYL-MA or DOONE) that weighed, after washing with Et2O and air
drying to constant weight, 11.0 g and which had a mp of 177-178 °C.
The same base can be made by the action of ethyl chloroformate on 4-MA
in the presence of triethylamine to make the carbamate, or the action
of formic acid to make the formamide. These can then be reduced with
LAH to this same end product.
DOSAGE: greater than 100 mg.
DURATION: short.
QUALITATIVE COMMENTS: (with 110 mg) One hour into it, my pulse was up
over 100, and I was compulsively yawning. There was some eye muscle
disturbance, a little like the physical side of MDMA, but there was
none of its central effects. But all the hints of the cardiovascular
are there. By the fourth hour, I am pretty much back to baseline, but
the yawning is still very much part of it. I might repeat this, at
the same level, but with continuous close monitoring of the body.
EXTENSIONS AND COMMENTARY: Why would there be interest in this
particular compound? The track record from the comparison of active
compounds that are primary amines, and their N-methyl homologues, has
shown that, in general, the stimulant component might be maintained,
but the "psychedelic" contribution is generally much reduced. MDMA
is, of course, an exception, but then, that particular compound is a
one-of-a-kind thing which simply defies all the rules anyway, and I
drop it from this kind of reasoning. And as 4-MA is a pretty pushy
stimulant with little if any sensory sparkle, why bother with the
N-methyl compound at all?
For a completely silly and romantic reason. When the MDMA story
became front-page news back in mid-1985, the cartoonist-author of
Doonesbury, Gary Trudeau, did a two-week feature on it, playing it
humorous, and almost (but not quite) straight, in a hilarious sequence
of twelve strips. On August 19, 1985 he had Duke, president of Baby
Doc College, introduce the drug design team from USC in the form of
two brilliant twins, Drs. Albie and Bunny Gorp. They vividly
demonstrated to the enthusiastic conference that their new drug
"Intensity" was simply MDMA with one of the two oxygens removed.
"Voila," said one of them, with a molecular model in his hands, "Legal
as sea salt." And what is MDMA with one oxygen atom removed? It is
4-methoxy-N-methylamphetamine or METHYL-MA which, according to the
twins, should give the illusion of substance to one's alter ego. So,
I called it Doonesamine, or simply RDOONES for short. Maybe that was
also a homonym for Frank Herbert's science fiction book, "Dune,"
wherein the magical drug "spice" provided a most remarkable alteration
of the user's state of consciousness.
This comic strip presentation was the first nationally distributed
allusion to the term "designer drugs," and perhaps it lent unexpected
support for the passage, just a year later, of the Controlled
Substances Analogue Enforcement Act of 1986. This intentionally vague
piece of legislation makes the giving of, or the taking of, or even
the possession with the intent to take, any drug that in any way
alters your state of consciousness, a felony. A shameful and
desperate effort by the governmental authorities to maintain the image
of control in a lost situation.
Enough editorial. Back to historic technicalities. In truth,
METHYL-MA is a well studied drug, at least in animals. In both mice
and rats, it is an exceptionally potent agent in creating the state of
catatonia. Animal studies, prompted by the clandestine synthesis of
METHYL-MA, have shown that there is indeed locomotor stimulation and
some central effects, but these effects are somehow different than
those of a simple amphetamine-like agent. The experimenter's
conclusions, based on its structural resemblance to 4-MA and its
proclivity to produce catatonia in some animal species and the
ever-present possibility that there might be unsuspected neurochemical
changes to be seen with its use, are that human experimentation should
be discouraged. I have come to the same conclusion, but in my case
this is based on a much more succinct observation: I tried it and I
didn't like it.
A brief comment on two of the N,N-dimethylhomologues of
methoxyamphetamine. One was 4-methoxy-N,N-dimethylamphetamine,
4-MNNA. This material, made by the reductive amination of
4-methoxyphenylacetone with dimethylamine, was a colorless oil, which
distilled at 70-85 °C at 0.3 mm/Hg. The corresponding
2-methoxy-N,N-dimethylamphetamine was similarly made. 2-MNNA was also
a colorless oil and had the same bp. Both of them were fluorinated
with 18F labelled acetyl hypofluorite (3% and 6% yields respectively)
but neither of them was pursued any further in the search for a brain
blood flow indicator.
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