SYNTHESIS: To a solution of 50 g 3,4-dihydroxy-5-methoxybenzaldehyde
in 100 mL distilled acetone there was added 70 g ethylene bromide and
58 g finely powdered anhydrous K2CO3. The mixture was held at reflux
for 5 days. This was then poured into 1.5 L H2O and extracted with
4x100 mL CH2Cl2. Removal of the solvent from the pooled extracts gave
a residue which was distilled at 19 mm/Hg. Several of the fractions
taken in the 203-210 °C range spontaneously crystallized, and they
were pooled to give 18.3 g of 3-methoxy-4,5-ethylenedioxybenzaldehyde
as white solids with a mp of 80-81 °C. A small sample with an equal
weight of malononitrile in EtOH treated with a few drops of
triethylamine gave 3-methoxy-4,5-ethylenedioxybenzalmalononitrile as
pale yellow crystals from EtOH with a mp of 153-154 °C.
A solution of 1.50 g 3-methoxy-4,5-ethylenedioxybenzaldehyde in 6 mL
acetic acid was treated with 1 mL nitroethane and 0.50 g anhydrous
ammonium acetate, and held on the steam bath for 1.5 h. To the cooled
mixture H2O was cautiously added until the first permanent turbidity
was observed, and once crystal-lization had set in, more H2O was added
at a rate that would allow the generation of additional crystals.
When there was a residual turbidity from additional H2O, the addition
was stopped, and the beaker held at ice temperature for several h.
The product was removed by filtration and washed with a little 50%
acetic acid, providing 0.93 g
1-(3-methoxy-4,5-ethylenedioxyphenyl)-2-nitropropene as dull yellow
crystals with a mp of 116-119 °C. Recrystallization of an analytical
sample from MeOH gave a mp of 119-121 °C.
A stirred suspension of 6.8 g LAH in 500 mL anhydrous Et2O under an
inert atmosphere was brought up to a gentle reflux. A total of 9.4 g
1-(3-methoxy-4,5-ethylenedioxyphenyl)-2-nitropropene in warm Et2O was
added over the course of 0.5 h. Refluxing was maintained for 6 h, and
then the reaction mixture was cooled and the excess hydride destroyed
by the cautious addition of 400 mL 1.5 N H2SO4. The two clear phases
were separated, and the aqueous phase was brought to pH of 6 by the
addition of a saturated Na2CO3 solution. This was filtered free of a
small amount of insolubles, and the clear filtrate was heated to 80
°C. To this there was added a solution of 9.2 g picric acid (90%
material) in 100 mL boiling EtOH, and the clear mixture allowed to
cool in an ice bath. Scratching generated yellow crystals of the
picrate salt. This salt was filtered free of the aqueous environment,
treated with 50 mL of 5% NaOH, and stirred until the picric acid was
totally in the form of the soluble sodium salt. This was then
extracted with 3x100 mL CH2Cl2, the extracts pooled, and the solvent
removed under vacuum. The residue weighed 6.0 g, and was dissolved in
100 mL anhydrous Et2O, and saturated with dry HCl gas. The white
solids that formed were filtered free of the Et2O, and ground up under
50 mL of slightly moist acetone, providing 4.92 g of
3-methoxy-4,5-ethylenedioxyamphetamine hydrochloride monohydrate
(MEDA) as white crystals.
DOSAGE: greater than 200 mg.
DURATION: unknown.
EXTENSIONS AND COMMENTARY: There are times when the Gods smile in
unexpectedly nice ways. Having found the activity of MMDA, the
"scientific" thing to do would be to compare it against the other
"psychotomimetic" amphetamine that was known at that time (this was
1962), namely TMA. Comparing their structures, the only difference of
any kind was that two of the adjacent methoxyl groups of TMA were
replaced with a 5-membered ring, called the methylenedioxy ring.
Where does one go next? Some perverse inspiration suggested
increasing the size of this ring to a 6-membered ring, the
ethylenedioxy (or dioxene) homologue. Well, if you thought that
getting myristicinaldehyde was a difficulty, it was nothing compared
to getting this 6-membered counterpart. But I huffed and I puffed,
and I did make enough to taste and to evaluate. And it was here that
I got the divine message! No activity!! So, rather than being
condemned forever a la Sisyphus to push ever larger rings up my
psyche, I gave myself permission to pursue another path. The message
was: "Don't change the groups. Leave them as they are, but relocate
them instead." And that led directly to TMA-2 and its story.
A couple of diversions may be mentioned here. Before the blessed
inactivity of MEDA was established, the 7-membered ring counterpart,
3-methoxy-4,5-trimethylenedioxyamphetamine (MTMA) was prepared by
essentially the same procedure. The above
3-methoxy-4,5-dihydroxybenzaldehyde with trimethylene bromide gave
3-methoxy-4,5-trimethylenedioxybenzaldehyde, white solids, with a
malononitrile derivative with a mp of 134-135 °C; the aldehyde with
nitroethane gave the nitropropene with a mp of 86-87 °C; and this with
LAH gave MTDA as the hydrochloride (mp 160-161 °C) again isolated
first as the picrate. It had been tasted at up to an 8 milligram
dosage (no activity, but none expected) before being abandoned. And,
an initial effort was made to synthesize a five-member ring
(methylenedioxy) with a methyl sticking out from it. This ethylidine
homologue got as far as the aldehyde stage. The reaction between
3,4-dihydroxy-5-methoxybenzaldehyde and 1,1-dibromoethane in acetone
containing anhydrous potassium carbonate gave a minuscule amount of a
product that was a two-component mixture. This was resolved by dozens
of separate injections into a preparatory gas chromatography system,
allowing the isolation of the second of the two components in a
quantity sufficient to demonstrate (by NMR spectroscopy) that it was
the desired 3-methoxy-4,5-ethylidinedioxybenzaldehyde. Starting with
the pre-prepared dipotassium salt or the lead salt of the
catecholaldehyde gave nothing. With no activity being found with
MEDA, all was abandoned.
There are some comments made under MDA for successful chemistry (using
a different approach) alo#ng these lines when there is no methoxyl
group present. These are the compounds EDA and IDA. But the
pharmacology was still not that exciting.
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