SYNTHESIS: To a solution of 68 g 2,4-dimethoxybenzaldehyde in 250 mL
glacial acetic acid that had been warmed to 25 °C and well stirred,
there was added, dropwise, 86 g of a 40% peracetic acid solution (in
acetic acid). The reaction was exothermic, and the rate of addition
was dictated by the need to maintain the internal temperature within a
few degrees of 28 °C. External cooling was used as needed. The
addition took 1 h, and when the reaction had clearly been completed
(no further temperature rise) the entire reaction mixture was added to
3 volumes of H2O. The excess acid was neutralized with solid K2CO3
(283 g were required). This was extracted with 3x100 mL Et2O, the
extracts pooled, and stripped of solvent under vacuum to give 66 g of
crude 2,4-dimethoxyphenyl formate. This was suspended in 125 mL 10%
NaOH, and the mixture heated on the steam bath for 1.5 h. On cooling,
the reaction mixture set to a heavy black solid. This was removed by
filtration, washed with H2O, and dissolved in 250 mL CH2Cl2. The
organic phase was washed with dilute HCl, and then with aqueous
NaHCO3, which removed much of the color. Removal of the solvent under
vacuum gave a deep red goo that was dissolved in 200 mL anhydrous Et2O
and filtered through paper. The resulting clear solution was stripped
of solvent, yielding 34.4 g of 2,4-dimethoxyphenol as a red oil that
crystallized on cooling. A 1.0 g sample in 4 mL pyridine was treated
with 0.9 g benzoyl chloride and heated on the steam bath for a few
min. The addition of H2O gave a pasty solid that was isolated by
pressing on a porous plate. The yield of crude 2,4-dimethoxyphenyl
benzoate was 1.1 g. Recrystallization from cyclohexane gave a white
product with a mp of 86-87 °C. A second recrystallization from
cyclohexane raised this to 89-90 °C, which is in agreement with the
literature value.
To a solution of 31.0 g crude 2,4-dimethoxyphenol in 60 mL absolute
EtOH there was added a solution of 11.25 g KOH in 90 mL boiling EtOH.
To this, there was then added 28 g allyl bromide which produced an
immediate white precipitate of KBr. The mixture was held at reflux
for 2 h and then quenched in 3 volumes of H2O. Sufficient 10% NaOH
was added to make the reaction strongly basic, and this was extracted
with 3x100 mL Et2O. Removal of the solvent under vacuum gave 33.2 g
of 1-allyloxy-2,4-dimethoxybenzene, shown to be free of phenol
starting material by GC analysis. Analyses must be carried out at low
column temperatures (below 180 °C) on an ethylene glycol succinate
substrate. If a silicone column is used, even at these low
temperatures, there is considerable Claisen rearrangement taking place
on the column. Low temperature distillation can be used for further
purification (107-110 °C at 1.0 mm/Hg).
A 31.0 g sample of 1-allyloxy-2,4-dimethoxybenzene was gently heated
with a soft flame until the internal temperature reached 215 °C. An
exothermic reaction took place, with the temperature rising to 270 °C.
The residue left in the flask was largely 2-allyl-4,6-dimethoxyphenol,
that contained perhaps 10% of 2,4-dimethoxyphenol which resulted from
the pyrolytic loss of the allyl group. This mixture was methylated
without further purification.
To a solution of 30 g impure 2-allyl-4,6-dimethoxyphenol in a little
absolute EtOH there was added a boiling solution of 8.7 g KOH in 75 mL
absolute EtOH followed, immediately, by 22.4 g methyl iodide in a
little EtOH. The mixture was held at reflux for 3 h, then added to 4
volumes of H2O. Sufficient 10% NaOH was added to make the mixture
strongly basic, and this was extracted with 4x100 mL Et2O. Removal of
the solvent gave 28 g of 1-allyl-2,3,5-trimethoxybenzene. GC analysis
showed some 10% of the expected impurity, 1,2,4-trimethoxybenzene.
To a solution of 26 g crude 1-allyl-2,3,5-trimethoxybenzene in an
equal weight of absolute EtOH there was added 52 g of flaked KOH. The
mixture was heated on the steam bath overnight, and then quenched with
much H2O. This was extracted with 3x100 mL Et2O which, on removal
under vacuum gave 24.6 g of product. This contained, by GC analysis,
largely cis- and trans-1-propenyl-2,3,5-trimethoxybenzene and the
expected 1,2,4-trimethoxybenzene. This mixture was dissolved in an
equal volume of pentane, and cooled in dry ice. Quick filtration gave
9.2 g of an amber solid which had a melting point of 39-41.5 °C.
Recrystallization from hexane provided pure
trans-1-propenyl-2,3,5-trimethoxybenzene with a mp of 44-45 °C.
Evaporation of the original pentane mother liquor provided an impure
sample of mixed cis- and trans- isomers.
A solution of 7.2 g trans-1-propenyl-2,3,5-trimethoxybenzene in 41 g
dry acetone was treated with 3.3 g dry pyridine and, with good
stirring, cooled to 0 °C. There was then added 6.9 g of
tetranitromethane over the course of 1 min, and the reaction mixture
was allowed to stir for an additional 2 min. The reaction mixture was
then quenched with a solution of 2.2 g KOH in 40 mL H2O. After the
addition of more H2O, the product was extracted with 3x50 mL CH2Cl2.
Removal of the solvent under vacuum yielded 7.0 g of an impure product
which would not crystallize. This was distilled under vacuum to give
four fractions, all of which crys-tallized spontaneously. Cuts #1 and
#2 (bp 100-120 °C and 120-130 °C at 2 mm/Hg) were combined, weighed
0.8 g, and after crystallization from hexane yielded white crystals
with a mp of 62-63 °C. The NMR spectrum (in CDCl3) was in agreement
with 2,3,5-trimethoxybenzaldehyde, and the literature mp has been
reported as being 62-63 °C. Cuts #3 and #4 (bp 130-170 °C and 170-175
°C at 2 mm/Hg with the bulk coming over in the latter fraction) were
combined to give 3.0 g of yellow crystals. These were triturated
under a little cold MeOH, and then recrystallized from MeOH to give
1.15 g of yellow crystals of
2-nitro-1-(2,3,5-trimethoxyphenyl)propene, with a mp of 87-88 °C. The
forerun of the distillation contained considerable unreacted
trans-1-propenyl-2,3,5-trimethoxybenzene and some
1,2,4-trimethoxybenzene, by GC analysis.
To a refluxing and stirred suspension of 1.1 g LAH in 150 mL anhydrous
Et2O and under an inert atmosphere, there was added a solution of 1.1
g 2-nitro-1-(2,3,5-trimethoxyphenyl)propene in 50 mL anhydrous Et2O.
The creamy mixture was held at reflux for 4 h, cooled, and then the
excess hydride cautiously destroyed by the addition of 1.5 N H2SO4.
There was then added 20 g potassium sodium tartrate followed by
sufficient aqueous NaOH to raise the pH to >9. The Et2O phase was
separated, and the remaining aqueous phase extracted with 3x75 mL
CH2Cl2. The organic phase and extracts were combined, and the solvent
removed under vacuum yielding 0.9 g of a colorless oil. This was
dissolved in 200 mL anhydrous Et2O which was saturated with anhydrous
HCl gas. There was generated a thick oil that did not crystallize.
The Et2O was decanted from this, and allowed to stand for several days
in a sealed container at room temperature. There was the deposition
of fine white needles of 2,3,5-trimethoxyamphetamine hydrochloride
(TMA-4) weighing, after Et2O washing and air drying, 0.31 g. The mp
was 118-119 °C. Anal. (C12H20ClNO3) C,H. The residual oil was
dissolved in H2O, made basic with NaOH, and extracted with CH2Cl2.
Evaporation of the solvent gave 0.40 of a white oil which was
dissolved in a little MeOH containing 0.22 g oxalic acid. There was
the immediate deposition of crystals of the oxalate salt of
2,3,5-trimethoxyamphetamine, with a mp of about 110 °C.
DOSAGE: greater than 80 mg.
DURATION: perhaps 6 h.
QUALITATIVE COMMENTS: (with 80 mg) I was concerned about life issues,
with much introspection, for about 6 hours. There were no subjective
physical symptoms. It was comparable to about 50 micrograms of LSD,
or to 120 milligrams TMA, for me.
EXTENSIONS AND COMMENTARY: That is the sum total of the knowledge of
subjective effects that exist. There was such a precious small amount
of the final hydrochloride salt that, by the time the needed build-up
of dosage had been completed, there was just enough left for this
single trial, which was conducted in South America. Based upon the
volunteered comparisons to LSD and TMA, a potency for this compound
has been published that states that it is 4x the potency of mescaline,
or 4 M.U. The material must be re-synthesized, and re-evaluated with
the now-accepted protocol.
In the future re-synthesis, there will be a considerable improvement
made with the several steps that are described above. The products
from the preparations of the phenol, the allyl ether, the Claisen
rearrangement, the methylation of the new phenol, and the
isomerization to the mixture of cis- and trans-propenylbenzenes were
all conducted without the benefit of a Kugel-Rohr apparatus. The
products became progressively thick and blacker, and it was only by
the grace of getting a solid at the trans-propenyl stage that some
degree of purity could finally be obtained. All of the intermediates
are certainly white oils, and when this preparation is repeated, they
will be distilled at each and every stage.
This 2,3,5-orientation of the methoxy groups on the aromatic ring is
far and away the most difficult tri-substitution pattern known to
chemists. There just isn't any simple way to put it together. The
2-carbon phenethylamine (2,3,5-trimethoxyphenethylamine) had been
synthesized quite a while ago. Its role as a substrate for liver
amine oxidase in in vitro studies has been explored, but it has never
been tried in man. Even more bizarre is the amphetamine with this
oxygenation pattern, in which a methylenedioxy ring has replaced the
two adjacent methoxyl groups. This is the material
2,3-methylenedioxy-5-methoxyamphetamine, or MMDA-4. Despite its
theoretical appeal (being one of the six possible MMDA derivatives)
and it's synthetic challenge (as with the 2,3,5-trimethoxy things
above, everything is simply in the wrong position) the compound is of
unknown pharmacology. This follows, quite logically, from the fact
that it has never been synthesized. No one has yet put together a
workable procedure that would make it. In the course of making all
possible positional isomers of MMDA explicitly Schedule I drugs, the
DEA has named this compound, and since it was specifically named, it
was entered into the Chemical Abstracts. So it is listed in the
literature, at least it is in the Chem. Abstracts. But it is in
reality completely unknown. Some day, some one somewhere will have a
light bulb go on over his head, and find a synthetic process that will
make it. Of course, the moment it is made, an illegal act will have
occurred, at least in the United States as long as the present laws
remain unchanged, as it is currently a Schedule I drug.
Needless to say, the 2-carbon analog of MMDA-4,
2,3-methylenedioxy-5-methoxyphenethylamine (would 2C-MMDA-4 be a
reasonable name?) is also unknown.
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