SYNTHESIS: A solution of 33.2 g of veratraldehyde in 15.0 g
nitroethane was treated with 0.9 g of n-amylamine and placed in a dark
place at room temperature. In a day or so, separated H2O was apparent
and, after a couple of weeks, the mixture completely solidified. The
addition of 50 mL EtOH and heating effected complete solution and, on
cooling, this provided 1-(3,4-dimethoxyphenyl)-2-nitropropene as
yellow crystals, 29.0 g, with mp of 70-71 °C. The more conventional
reaction scheme, 6 h heating of a solution of the aldehyde and
nitroethane in acetic acid with ammonium acetate as catalyst, gave a
much inferior yield of product (33.2 g gave 14.8 g) of the same
purity. Recrystallization from MeOH increased the mp to 72-73 °C.
To a refluxing suspension of 7 g LAH in 600 mL anhydrous Et2O, stirred
and under an inert atmosphere, there was added 7.5 g
1-(3,4-dimethoxyphenyl)-2-nitropropene by allowing the returning
condensed ether to leach out the material as a warm solution from a
Soxhlet thimble. Following the completion of the addition of the
nitrostyrene, refluxing was maintained for 24 h, and the reaction
mixture allowed to stand several days at room temperature. The excess
hydride was destroyed by the cautious addition of 500 mL H2O
containing 40 g H2SO4, and the phases were separated. The aqueous
phase was washed with both Et2O and CH2Cl2. There was then added 200
g potassium sodium tartrate, and the pH brought above 9 by the
addition of aqueous NaOH. This clear solution was extracted with
3x150 mL CH2Cl2, the extracts were pooled, and the solvent removed
under vacuum to give a residual oil. This was dissolved in Et2O,
saturated with anhydrous HCl gas, and the resulting solids removed by
filtration. Recrystallization from 10 mL acetone gave 1.35 g
3,4-dimethoxyamphetamine hydrochloride (3,4-DMA) as beautiful white
crystals with a mp of 144-145 °C.
DOSAGE: a few hundred milligrams.
DURATION: unknown.
QUALITATIVE COMMENTS: (with 70 mg i.v.) [One patient received 0.004
mM/Kg of the hydrochloride salt intravenously and exhibited only
slight increase in psychiatric symptoms; a comparable dosage in a
second individual also elicited only insignificant changes.]
(with 700 mg i.v.) [When one of these patients was reinjected at a
later date with approximately 0.04 mM/Kg of 3,4-DMA a definite
`mescaline-like' state was induced. The symptoms included colored
hallucinations of geometric figures and occasional structured forms.
The other individual experienced visual distortions, notable
after-imagery, feelings of unreality, and paranoid ideas. Marked
mydriasis and gross body tremors also occurred but apparently no
hallucinations were experienced.]
EXTENSIONS AND COMMENTARY: These "Qualitative Comments" are not
explicit quotations from people who had taken 3,4-DMA. They are
written descriptions by the observers who had given 3,4-DMA to
psychiatric patients. This is one of the most outrageous chapters in
the books on military medicine. The chemical warfare group within the
U.S. Army explored many potential psychedelics by administering them
to innocent patients with not even a thought of obtaining informed
consent. These experiments took place at the New York State
Psychiatric Institute (amongst other places) in the early 1960's. The
Edgewood Arsenal code name for 3,4-DMA was EA-1316. A few
non-military studies have indicated that 3,4-DMA is orally active at
160 milligrams, and so probably its potency by this more conventional
route would fall midway between that of mescaline and of MDA. The
3-methoxy-4-other-than-methoxy things (such as hydroxy, ethoxy,
allyloxy and methyl) are mentioned in the recipe for MEPEA. The
alpha-ethyl homologue of 3,4-DMA,
2-amino-1-(3,4-dimethoxyphenyl)butane, and of other DMA's are
discussed under the recipe for ARIADNE.
There are a total of six possible amphetamine molecules with two
methoxyl groups attached. The 3,4-orientation has always been the
most appealing to the life scientists as this is the positional
substitution pattern found in the natural neuro-chemicals dopamine,
norepinephrine and epinephrine. These latter two are called
noradrenalin and adrenalin in England. Two adjacent hydroxy groups
represent the catechol in the well known word catecholamines. You
might read in a textbook, "This is where nature placed the groups when
she put the compounds in our brains. So that is where the groups
might be the most interesting in a psychedelic." Why? I have never
understood this kind of reasoning. If a possible psychedelic has just
the exact oxygen positioning of a neurotransmitter, then, voila,
that's why it is active. And if a possible psychedelic has some
positioning of these oxygen atoms that is different than that of a
neurotransmitter? Then voila again. That's why it is active. Both
sound equally reasonable to me, and neither one even begins to address
the fundamental question, how do the psychedelic drugs do what they
do? A study in the human animal of the intimate effects of one of
these neurotransmitter analogues might bring us a little bit closer to
answering this fundamental question. But maybe it wouldn't, after
all. Nothing has made much sense so far! Anyway, 3,4-DMA is one of
the ten essential amphetamines that can, in theory, arise from the ten
essential oils of the spice and herb trade. In this case, the origins
are methyl eugenol and methyl isoeugenol.
Two of these "different" isomers, 2,4-DMA and 2,5-DMA, have already
been discussed in their own separate recipes. And the remaining three
of the six possible DMA's that are "different" have been made and
studied pharmacologically in animals but not in man. These are the
2,3-DMA, 2,6-DMA and the 3,5-DMA isomers. The products of their
reaction with elemental bromine are discussed under META-DOB.
Both the 2,6- and the 3,5-isomers, as the N,N-dimethyl homologues,
have been looked at as potential radio-halogen recipients in the
search for positron-emitting brain blood-flow indicators, as discussed
in the recipe for IDNNA. Both were made from the appropriate
nitrostyrene via the corresponding phenylacetone.
The 2,6-isomer was derived from 2,6-dimethoxybenzaldehyde. This, in
nitroethane and ammonium acetate, gave the nitrostyrene as
canary-yellow crystals from MeOH that melted at 101.5-102.5 °C.
Elemental iron in acetic acid converted this nitrostyrene to
2,6-dimethoxyphenylacetone (a water-white oil with boiling point of
95-105 °C at 0.4 mm/Hg. Anal. (C11H14O3) C,H) and reductive amination
with dimethylamine and sodium cyanoborohydride gave
2,6-dimethoxy-N,N-di-methylamphetamine perchlorate (2,6-DNNA) with a
melting point of 109-110 °C. This base was readily fluorinated with
18F acetylhypofluorite and iodinated with chloramine-T-oxidized 122I
iodide ion. It was also halogenated with (non-radioactive) bromine
and iodine monochloride to give the corresponding 3-bromo-(and
3-iodo)-2,6-dimethoxy-N,N-dimethylamphetamines but these, in turn, did
not react with radioactive acetyl hypofluorite.
The 3,5-isomer followed precisely the same flow sheet.
3,5-Dimethoxybenzaldehyde gave the nitrostyrene (with a melting point
of 87-88 °C), the phenylacetone (with a boiling point of 110-130 °C at
0.3 mm/Hg) and the product 3,5-dimethoxy-N,N-dimethylamphetamine
perchlorate (3,5-DNNA) with a melting point of 100-101 °C. This also
reacted readily with 18F acetylhypofluorite and 122I-hypoiodite.
Several alpha-ethyl homologues of these compounds have also been
discussed in the recipe for ARIADNE.
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