SYNTHESIS: Apiole, as the crystalline essential oil
1-allyl-2,5-dimethoxy-3,4-methylenedioxybenzene, is isolated directly
from commercial Oil of Parsley, by careful fractional distillation.
It is the fraction that boils at 165-167 °C at 27 mm/Hg. A solution
of 19.8 g apiole in a mixture of 43 g KOH and 60 mL hot EtOH was
heated in the steam bath for 24 h. With vigorous stirring, it was
diluted with H2O, at a rate which the crystals that formed
spontaneously could accumulate from the turbidity that was generated.
When no more H2O could be added (there was persistent oiling out of
material) the reaction mixture was filtered to give 12.1 g of an amber
solid material. This was recrystallized from 20 mL boiling hexane,
which was filtered while hot to remove insolubles. From the cooled
filtrate, there was obtained 9.3 g of
2,5-dimethoxy-3,4-methylenedioxy-1-propenylbenzene, isoapiole, as pale
cream-colored solids.
A stirred solution of 8.8 g
2,5-dimethoxy-3,4-methylenedioxy-1-propenylbenzene and 3.9 g pyridine
in 45 mL acetone was cooled to ice-bath temperatures, and treated with
7.9 g tetranitromethane. This extremely dark reac-tion was stirred at
0 °C for 5 min, then quenched with a solution of 2.6 g KOH in 45 mL
H2O. With continued stirring, there appeared yellow crystals of
1-(2,5-dimethoxy-3,4-methylenedioxyphenyl)-2-nitropropene which, after
filtering, washing with 50% acetone and air drying, weighed 8.0 g and
had a mp of 110-111 °C.
To a well-stirred and gently refluxing suspension of 6.3 g LAH in 500
mL anhydrous Et2O, under an inert atmosphere, there was added 7.5 g
1-(2,5-dimethoxy-3,4-methylenedioxyphenyl)-2-nitropropene by leaching
out the nitrostyrene from a thimble in a modified Soxhlet condenser
apparatus. The addition took 1.5 h, and the refluxing was maintained
for an additional 3 h. After cooling, the excess hydride was
destroyed by the cautious addition of 300 mL of 1.5 N H2SO4. The
aqueous phase was brought to a pH of 6 with Na2CO3. This was heated
to 80 °C and clarified by filtration though paper. The addition of a
stochiometric amount of picric acid in boiling EtOH gave rise to
precipitation of the product picrate as globs that did not
crystallize. These were washed with cold H2O, then dissolved in 30 mL
5% NaOH. Extraction with 2x75 mL Et2O, and the stripping of the
solvent from the pooled extracts, gave 3.1 g of an oily residue which,
upon dissolving in 250 mL Et2O and saturation with anhydrous HCl gas,
gave white crystals. These were removed by filtration, Et2O-washed,
and air dried, to give 2.9 g of
2,5-dimethoxy-3,4-methylenedioxyamphetamine hydrochloride (DMMDA) that
melted in the 165-175 °C range.
DOSAGE: 30 - 75 mg.
DURATION: 6 - 8 h.
QUALITATIVE COMMENTS: (with 25 mg) The intoxication was there at an
hour and a quarter, and I was hit with nausea with no particular
warning. I am shaky, a little dilated in the eyes, and there is a
modest depersonalization (reminding me of LSD). Time might be
slightly slowed, and there is a mild ataxia in the legs. A couple of
hours later, all effects are going away fast. I ate an apple, but
maybe my mouth didn't work quite right. The apple was incredibly
noisy.
(with 32 mg) I am up to a 2 1/2 plus at something after two hours,
with no apparent visuals, no push, no erotic. And a few hours later
it is quietly slipping away. It felt completely safe, and without any
conspicuous psychedelic action, at least at this level.
(with 50 mg) I took graded doses of 10 milligrams every thirty
minutes for a total of 50 milligrams, and there were no effects at
all.
(with 50 mg) In the middle of this all, I found myself getting into
abstract thinking, and maybe some imagery as well. The effects were
disappointingly light.
(with 75 mg) This was equal to somewhere between 75 and 100
micrograms of LSD. I was caught up with the imagery, and there was an
overriding religious aspect to the day. The experience had an
esthetic value. I liked it.
EXTENSIONS AND COMMENTARY: DMMDA was the first of the tetraoxygenated
amphetamine derivatives that was ever explored in man, back in 1962.
And it is not easy to find an acceptable single phrase to describe its
action or an acceptable number to describe its potency. I have put
the value of 10 mescaline units (M.U.) into the literature and this
would imply that maybe 30 milligrams was an active dose. This is
probably too low, and some day I would like to run an experiment with
the entire research group with this compound to see just what it
really does.
The essential oil that corresponds to DMMDA is, of course, apiole from
the Oil of Parsley, which again ties together the spice world and the
amphetamine world. And there is isoapiole, also a natural thing.
This pair represents the ring-substitution pattern of one of the ten
essential oils and DMMDA is one of the ten essential amphetamines.
Several people have asked me what I thought about the potential
activity of a compound with a methyl group added to DMMDA. One of
these possibilities would be the N-methylated derivative,
2,5-dimethoxy-N-methyl-3,4-methylenedioxyamphetamine, or METHYL-DMMDA
(or DMMDMA for the dimethoxy-methylenedioxy-methamphetamine
nomenclature). It is a MDMA analogue, and is described in the recipe
for METHYL-MMDA-2.
The placement of an added methyl group onto the beta-position of DMMDA,
rather than on the nitrogen atom, produces a pair of stereoisomeric
homologues. These are the threo- (or-trans-) and erythro- (or
cis)-2,5-dimethoxy-beta-methyl-3,4-methylenedioxyamphetamines. They have
never been assigned trivial names (my original codes for them were
S-1495 and S-1496 which is not too intuitively informative). Their
chemically proper names would have the 2-amino-3-substituted
phenylbutane form. The synthesis of these DMMDA homologues started
with the reduction of the nitrosyrene to the ketone (see under
METHYL-MMDA-2 for this preparation), followed by methylation with
fresh sodium isopropoxide and methyl iodide, to give the beta-methyl
product. This formed the two possible oximes, one with a mp of 120
°C, and the other from MeOH with a mp of 146 °C. The 120 °C oxime,
with fresh sodium ethoxide gave
threo-2-amino-3-(2,5-dimethoxy-3,4-methylenedioxyphenyl)butane
hydrochloride. This salt had a mp of 247-249 °C. The 146 °C oxime
gave erythro-2-amino-3-(2,5-dimethoxy-3,4-methylenedioxyphenyl)butane
hydrochloride with a mp of 188-189 °C. The threo-isomer showed a
possible threshold effect at 80 milligrams, with hyperventilation and
perhaps some mental muddiness. The erythro-isomer showed no effects,
but it had been taken up only to 10 milligrams.
The only other beta-methyl homologue of an active material that was
explored chemically, was related to MDA. The ketone
(3,4-piperonylacetone, see under MDMA) was methylated with sodium
isopropoxide and methyl iodide, and a crystalline oxime was obtained.
Reduction with Zn dust gave what appeared to be
2-amino-3-(3,4-methylenedioxyphenyl)butane hydrochloride, but there
were sufficient uncertainties (possible dimethylation, only one oxime
isolated, the need of strong reducing conditions) that the entire
project was placed in, and still is in, an indefinite holding pattern.
The similar analogues for DOM are the two Classic Ladies, DAPHNE and
ELVIRA, and they, too, are for some time in the future.
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