SYNTHESIS: To a solution of 10 g 2,4-dimethoxybenzaldehyde in 50 mL
nitroethane there was added 0.5 g anhydrous ammonium acetate, and the
mixture was heated on the steam bath for 2 h. The excess
solvent/reagent was removed under vacuum, and the residue oil
dissolved in 25 mL boiling MeOH. On cooling, this deposited yellow
crystals of 1-(2,4-dimethoxyphenyl)-2-nitropropene that, after
filtering, MeOH washing, and air drying, weighed 10.2 g and had a mp
of 78-79 °C.
A magnetically stirred suspension of 6.0 g LAH in 300 mL anhydrous
Et2O was brought up to a gentle reflux under a He atmosphere. A total
of 8.5 g 1-(2,4-dimethoxyphenyl)-2-nitropropene was introduced into
the reaction mixture by allowing the condensed Et2O to leach it from a
modified Soxhlet condenser. After the addition was complete, the
reaction was held at reflux for an additional 24 h. After cooling
with an external ice bath, the excess hydride was destroyed by the
cautious addition of H2O. When the exothermic reaction had subsided,
there was added 500 mL H2O, 150 g potassium sodium tartrate, and
sufficient base to bring the pH above 9. The phases were separated,
the organic phase dried over anhydrous MgSO4, the drying agent removed
by filtration, and the clear filtrate then saturated with anhydrous
HCl gas to produce white crystals of 2,4-dimethoxyamphetamine
hydrochloride (2,4-DMA) with a mp of 146-147 °C.
DOSAGE: greater than 60 mg.
DURATION: short.
QUALITATIVE COMMENTS: (with 60 mg) This is definitely threshold, or
even a bit more. There is a lot of amphetamine-like component, and a
certain blush of euphoria. There is also a diffusion of association,
so it's more than just amphetamine, no question about it. At the
three-hour point, it is definitely quieting down.
EXTENSIONS AND COMMENTARY: What can one say as to the active dosage of
2,4-DMA? Nothing. What can one say as to the duration? Probably
short. The 60 milligram report given above is the highest level that
I personally know of having been tried in man, and there is no hint as
to what might be found at a fully active dose, or just where that dose
might be. It might be fully speedy. It might be fully psychedelic.
It might give a cardiovascular push that would be scary. Studies of
2,4-DMA on vascular strips (associated with serotonin action) were not
impressive in comparison with structurally related psychedelics, and
it seems as if its action might involve norepinephrine release. It is
a reasonable guess that there would be cardio-vascular activity at
higher levels. But it will only be with human trials, someday, that
the answer will be known for sure.
The meta-orientation of the two methoxyl groups does, however, greatly
increase the susceptibility of the aromatic ring to electrophilic
attack. This is one of the three possible meta-dimethoxy substituted
amphetamines, and it is the best studied one in the pursuit of
potential radio-halogen substituted brain blood-flow agents. This
strategy is discussed under IDNNA; the other two meta-compounds are
discussed under 3,4-DMA.
The homologues of 2,4-DMA that were iodinated (or occasionally
fluor-inated) were mono- or di-alkylated on the nitrogen, and the
precursor that was common to all was the corresponding acetone. The
above nitrostyrene, 1-(2,4-dimethoxyphenyl)-2-nitropropene, was
reduced in acetic acid with elemental iron, and the base-washed
extracts stripped of solvent and distilled (125-145 °C at 0.5 mm/Hg)
to give 2,4-dimethoxyphenylacetone as a water-white oil. The
principal reductive amination product of this, the one that was most
thoroughly explored with various halogenation schemes, was obtained by
the reaction of 2,4-dimethoxyphenylacetone with dimethylamine and
sodium cyanoborohydride. This product,
2,4-dimethoxy-N,N-dimethylamphetamine or 2,4-DNNA, distilled at
105-115 °C at 0.4 mm/Hg and formed a perchlorate salt that melted at
98-98.5 °C. This could be iodinated with the radio-iodide anion, when
oxidized with chloramine-T in buffered sulfuric acid, to give the
iodinated analogue (2,4-dimethoxy-N,N-dimethyl-5-iodoamphetamine) in
an excellent yield. Radio-fluorination with acetyl hypofluorite gave
the 5-fluoroanalogue (2,4-dimethoxy-N,N-dimethyl-5-fluoroamphetamine)
in an acceptable yield. Both compounds went into a rat's brain to a
pretty good extent, but both of them washed out too rapidly to be
clinically interesting.
A large family of other N-substituted homologues of 2,4-DMA were
similarly prepared from the above ketone and sodium cyanoborohydride.
Methylamine, ethylamine, propylamine, isopropylamine and hexylamine
gave the corresponding N-alkyl homologues. The N,N-diethyl homologue
was made from the primary amine, 2,4-DMA itself, with acetaldehyde and
sodium cyanoborohydride but the product,
N,N-diethyl-2,4-dimethoxyamphetamine, could not be converted into a
crystalline hydrochloride salt.
Yet another variation on these structures was launched, again with the
design of making radio-iodination targets which are not psychedelic
and thus might be useful clinically. In this variation, the nitrogen
atom substitution pattern was held constant, with two methyl groups,
as were the ring locations of the two oxygen atoms. But the
identities of the alkyl groups on these oxygen atoms were varied. The
synthetic procedure followed was to make the appropriate
2,4-dialkoxybenzaldehyde, convert it to the nitrostyrene with
nitroethane, reduce this to the phenylacetone with elemental iron, and
then reductively aminate this ketone with dimethylamine. Following
this reaction scheme, five amphetamine homologues of 2,4-DMA were
made, three with the 4-methoxy group maintained but the 2-position
extended, and two with both groups extended symmetrically. These are:
(1) N,N-dimethyl-2-ethoxy-4-methoxyamphetamine; (2)
2-(n)-butyloxy-N,N-dimethyl-4-methoxy-amphetamine; (3)
2-(n)-decyloxy-N,N-dimethylamphetamine; (4)
2,4-diethoxy-N,N-dimethylamphetamine; and (5)
N,N-dimethyl-2,4-di-(i)-propoxyamphetamine. I believe that most of
these have been iodinated and assayed in rats, and several of them
appear quite promising. But none of them have been assayed in man,
yet. The bromination product of 2,4-DMA
(5-bromo-2,4-dimethoxyamphetamine, 5-Br-2,4-DMA) is way down in
activity (see its recipe, separately). Since all iodo analogues are
of about the same potency as the bromo counterparts, and since the
addition of two methyl groups on the nitrogen does not appear to
enhance central activity, I feel the iodination products of these
N,N-dialkyl-dialkoxyamphetamines would not have any interesting
psychopharmacology.
There is something vaguely counterproductive, in my evaluation of
things, when the goal of a research project is to avoid activity
rather than to create it. Although this chemistry was completely
fascinating and could have produced the world's best
positron-emitting, brain-scanning diagnostic compound, I feel it quite
unlikely that it would have produced the world's best
insight-revealing, empathy-enhancing psychedelic, so this research
direction never totally caught my fancy. I went on to other things.
Back]
]