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#160 TMA-4
2,3,5-TRIMETHOXYAMPHETAMINE
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 tem
perature 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 tem
perature 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. Re
crystallization from
cyclohexane gave a white
product with a mp of 86-87 °C. A second re
crystallization 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 tem
peratures (below 180 °C) on an
ethylene glycol succinate
substrate. If a
silicone column is used, even at these low
tem
peratures, there is considerable
Claisen rearrangement taking place
on the column. Low tem
perature 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 tem
perature reached 215 °C. An
exothermic reaction took place, with the tem
perature 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.
Re
crystallization 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 re
crystallized 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 tem
perature. 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 tog
ether. 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 M
MDA-4.
Despite its
theoretical appeal (being one of the six possible M
MDA 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 tog
ether a
workable procedure that would make it. In the course of making all
possible positional
isomers of M
MDA 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 M
MDA-4,
2,3-methylenedioxy-5-methoxyphenethylamine (would 2C-M
MDA-4 be a
reasonable name?) is also unknown.
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