SYNTHESIS: A solution of 7.0 g of 98% pure (by GC)
4-methoxy-2,3-methylenedioxybenzaldehyde (see under MMDA-3a for its
preparation) in 30 mL glacial acetic acid was treated with 5 mL
nitroethane and 3 g anhydrous ammonium acetate, and heated on the
steam bath for 3.5 h. H2Owas added to the hot solution to the point
of turbidity, then it was allowed to cool to room temperature with
occasional stirring. A modest crop of yellow crystals formed which
were removed by filtration, washed with aqueous acetic acid and air
dried to constant weight. There was obtauned 4.6 g of
1-(4-methoxy-2,3-methylenedioxphenyl)-2-nitropropene, with a mp of
95-102 °C. Recrystallization from EtOH tightened this to 97-101.5 °C.
The infra-red spectrum is completely different from that of its
positional isomer
1-(2-methoxy-3,4-methylenedioxyphenyl)-2-nitropropene.
A suspension of 7.0 g LAH in 1 L anhydrous Et2O under an inert
atmosphere was brought to a gentle reflux. The reflux condensate was
passed through a Soxhlet thimble containing 6.15 g
1-(4-methoxy-2,3-methylenedioxyphenyl)-2-nitropropene which was
effectively adding the nitropropene as a saturated solution. The
mixture was maintained at reflux for 16 h. After cooling to 0 °C with
an ice bath, the excess hydride was destroyed by the addition of 800
mL of 1.5 N H2SO4. The phases were separated, and the aqueous phase
washed with 2x100 mL Et2O. To this phase there was added 175 g
potassium sodium tartrate followed by sufficient 25% NaOH to raise the
pH >9. This was then extracted with 3x100 mL CH2Cl2, and the solvent
from the pooled extracts removed under vacuum. The residual off-white
oil weighed 5.4 g and was dissolved in 250 mL anhydrous Et2O and
saturated with anhydrous HCl gas. There was produced a crop of
slightly sticky white solids that finally became granular and loose.
These were removed by filtration, washed with Et2O, and air dried to
give 5.56 g of 4-methoxy-2,3-methylenedioxyamphetamine hydrochloride
(MMDA-3b) with a mp of 196-199 °C. A small sample from propanol had a
mp of 199-200 °C, and a sample from nitromethane/MeOH (5:1) had a mp
of 201-202 °C.
EXTENSIONS AND COMMENTARY: And that's all there is known as to the
activity of MMDA-3b in man. Very, very little. Nothing has ever been
tried in excess of 80 milligrams that I know of, and the above trials
were made over 20 years ago. There can be little argument that the 3b
is less effective than the 3a, but no one can say by how much. The
literature statement is that it is threefold less, but that was based
on the relative responses at just-above-threshold levels. The effects
here are hand-wavingly similar to those reported for MMDA-3a at 20
milligrams, but these are difficult to compare accurately as they were
reported by different people. There have been absolutely no animal
studies reported with MMDA-3b in the scientific literature. And
neither the 2-carbon nor the 4-carbon analogues of MMDA-3b has even
been prepared.
The remaining MMDA-analogue that has been prepared, is the
2,3,6-isomer. The flow diagram started with sesamol
(3,4-methylenedioxyphenol) which was methylated with methyl iodide,
converted to the aldehyde using butyllithium and N-methylformanilide
(putting the new group directly between the two oxygen atoms, giving
2,3-methylenedioxy-6-methoxybenzaldehyde), reaction with nitroethane
to the nitrostyrene, and its reduction with lithium aluminum hydride
in ether. The product, 6-methoxy-2,3-methylenedioxyamphetamine
hydrochloride (MMDA-5) is practically unexplored in man. I have heard
one report that 30 milligrams was modestly active, but not a
particularly pleasant experience. Another person told me that he had
tried 15 milligrams, but he neglected to mention if there had been any
effects. I have not tried it myself. But, I have succumbed to the
pressure of the experimental pharmacologists to give a number for the
"Y-axis" of their animal behavior studies. So I said to myself, if
this is active at 30 milligrams, and mescaline is active at 300
milligrams, why not say that it is 10x the activity of mescaline? So
I did. But I have absolutely no confidence in that number.
And if the information on MMDA-5 is sparse, look at the positional
isomer, MMDA-4, which I have discussed under its analogue TMA-4. Here
nothing is known at all, since the compound itself is unknown. No one
has yet found a way of making it.
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