SYNTHESIS: To a solution of 50 g 2,3,4-trimethoxybenzaldehyde in 157
mL glacial acetic acid which was well stirred and preheated to 25 °C
there was added 55.6 g 40% peracetic acid in acetic acid. The rate of
addition was adjusted to allow the evolved heat of the exothermic
reaction to be removed by an external ice bath at a rate that kept the
internal temperature within a degree of 25 °C. When the addition was
complete and there was no more heat being evolved, the reaction
mixture was diluted with 3 volumes of H2O, and neutralized with solid
K2CO3. All was extracted with 3x250 mL Et2O, and the removal of the
solvent from the pooled extracts under vacuum gave 42 g of residue
that appeared to be mainly phenol, with a little formate and aldehyde.
This was dissolved in 200 mL of 10% NaOH, allowed to stand for 2 h at
ambient temperature, washed with 2x75 mL CH2Cl2, acidified with HCl,
and extracted with 3x100 mL Et2O. The pooled extracts were washed
with saturated NaHCO3, and the solvent removed to give 34.7 g of
2,3,4-trimethoxyphenol as an amber oil which was used without further
purification. The infra-red spectrum showed no carbonyl group, of
either the formate or the starting aldehyde.
A solution of 11.4 g flaked KOH in 100 g EtOH was treated with 33.3 g
2,3,4-trimethoxyphenol and 21.9 g allyl bromide. The mixture was held
at reflux for 1.5 h, then poured into 5 volumes of H2O, made basic
with the addition of 25% NaOH, and extracted with 3x200 mL CH2Cl2.
Removal of the solvent from the pooled extracts gave about 40 g of a
crude 2,3,4-trimethoxy-1-allyloxybenzene that clearly had unreacted
allyl bromide as a contaminant.
A 39 g sample of crude 2,3,4-trimethoxy-1-allyloxybenzene in a
round-bottomed flask with an immersion thermometer was heated with a
soft flame. At 225 °C there was a light effervescence and at 240 °C
an exothermic reaction set in that raised the temperature immediately
to 265 °C. It was held there for 5 min, and then the reaction was
allowed to cool to room temperature. GC and IR analysis showed the
starting ether to be gone, and that the product was largely
2,3,4-trimethoxy-6-allylphenol. It weighed 34.4 g.
To a solution of 9.4 g KOH in 100 mL MeOH, there was added 33.3 g of
2,3,4-trimethoxy-6-allylphenol and 21.2 g methyl iodide and the
mixture was held on the steam bath for 2 h. This was poured into
aqueous base, and extracted with 3x100 mL CH2Cl2. Removal of the
solvent from the pooled extracts gave 30 g of an amber oil residue
that was distilled at 100-125 °C at 0.5 mm/Hg to provide 23.3 g of
nearly colorless 2,3,4,5-tetramethoxyallylbenzene.
The total distillation fraction, 23.3 g
2,3,4,5-tetramethoxyallylbenzene, was dissolved in a solution of 25 g
flaked KOH in 25 mL EtOH and heated at 100 °C for 24 h. The reaction
mixture was poured into 500 mL H2O, and extracted with 2x100 mL
CH2Cl2. The aqueous phase was saved. The pooled organic extracts
were stripped of solvent under vacuum to give 13.8 g of a fluid oil
that was surprising pure 2,3,4,5-tetramethoxypropenylbenzene by both
GC and NMR analysis. The basic aqueous phase was acidified, extracted
with 2x100 mL CH2Cl2, and the solvent stripped to give 7.5 g of an oil
that was phenolic, totally propenyl (as opposed to allyl), and by
infra-red the phenolic hydroxyl group was adjacent to the olefin
chain. This crude 2-hydroxy-3,4,5-trimethoxypropenylbenzene was
methylated with methyl iodide in alcoholic KOH to give an additional
5.6 g of the target 2,3,4,5-tetramethoxypropenylbenzene. This was
identical to the original isolate above. The distilled material had
an index of refraction, nD24 = 1.5409.
A well stirred solution of 17.9 g 2,3,4,5-tetramethoxypropenylbenzene
in 80 mL distilled acetone was treated with 6.9 g pyridine, and cooled
to 0 °C with an external ice bath. There was then added 14 g
tetranitromethane over the course of a 0.5 min, and the reaction was
quenched by the addition of a solution of 4.6 g KOH in 80 mL H2O. As
the reaction mixture stood, there was a slow deposition of yellow
crystals, but beware, this is not the product. This solid weighed 4.0
g and was the potassium salt of trinitromethane. This isolate was
dried and sealed in a small vial. After a few days standing, it
detonated spontaneously. The filtrate was extracted with 3x75 mL
CH2Cl2, and the removal of the solvent from these extracts gave a
residue of 20.8 g of crude
2-nitro-1-(2,3,4,5-tetramethoxyphenyl)propene which did not
crystallize.
A solution was made of 20.3 g of the crude
2-nitro-1-(2,3,4,5-tetramethoxyphenyl)propene in 200 mL anhydrous
Et2O, and this was filtered to remove some 2.7 g of insoluble material
which appeared to be the potassium salt of trinitromethane by
infra-red analysis. A suspension of 14 g LAH in 1 L anhydrous Et2O
was stirred, placed under an inert atmosphere, and brought up to a
gentle reflux. The above clarified ether solution of the propene was
added over the course of 1 h, and the mixture was held at reflux for
24 h. After cooling, the excess hydride was destroyed by the cautious
addition of 1 L 1.5 N H2SO4 (initially a drop or two at a time) and
when the two phases were complete clear, they were separated. The
aqueous phase was treated with 350 g potassium sodium tartrate, and
brought to a pH >9 with base. This was extracted with 3x150 mL
CH2Cl2, and the removal of the solvent from the pooled extracts gave a
residue that was dissolved in 200 mL anhydrous Et2O, and saturated
with anhydrous HCl gas. An Et2O-insoluble oil was deposited and,
after repeated scratching with fresh Et2O, finally gave a granular
white solid. This product was recrystallized from acetic anhydride,
giving white crystals that were removed by filtration, Et2O washed,
and air dried. The yield of 2,3,4,5-tetramethoxyamphetamine
hydrochloride (TA) was 1.9 g and had a mp of 135.5-136.5 °C.
DOSAGE: probably above 50 mg.
DURATION: unknown.
QUALITATIVE COMMENTS: (with 30 mg) Definite threshold. There was eye
dilation, and some unusual humor--a completely wild day with
chi-square calculations on the PDP-7 that were on the edge of bad
taste. But I was definitely baseline in the afternoon during the
Motor Vehicle Department interactions.
(with 35 mg) I had some gastric upset, but nonetheless there was a
distinct intoxication. The next morning I had a foul headache.
EXTENSIONS AND COMMENTARY: This is pretty thin stuff from which to go
out into a world that is populated by pharmacological sharks and stake
out claims as to psychedelic potency. The structure of this molecule
has everything going for it. It is an overlay of TMA (active) and
TMA-2 (even more active) so it is completely reasonable that it should
be doing something at a rational dosage. But that dosage might well
be in the many tens of milligrams.
Tens of milligrams. Now there is a truly wishy-washy phrase. There
is an art to the assignment of an exact number or, as is sometimes
desperately needed, a fuzzy number, to a collection of things. In my
youth (somewhere way back yonder in the early part of the century) I
had been taught rules of grammer that were unquestionably expected of
any well-educated person. If you used a Latin stem, you used a Latin
prefix. And if you used a Greek stem, you used a Greek prefix.
Consider a collection of things with simple geometric sides (a side is
a latus in Latin). One would speak of a one-sided object as being
unilateral, and a bilateral object has two sides. A trilateral, and
quadrilateral, and way up there to multilateral objects, are referred
to as having three or four or a lot of sides, respectively. Just the
opposite occurs with geometric objects with faces. A face is a hedra
in Greek, so one really should use the Greek structure. If one has
just one face, one has a monohedron, a dihedron has two faces, and
there are trihedron, tetrahedron, and polyhedron for things that have
three, four, or a lot of faces. Actually, the prefix "poly" swings
both ways. It was initially a Greek term, but as was the fate of many
Greek words, it wandered its way from East to West, and ended up as a
Latin term as well.
But back to the problem of how to refer to something that is more than
one or two, but not as much as a lot? If you know exactly how many,
you should use the proper prefix. But what if you don't know how
many? There are terms such as "some." And there is "several." There
is a "few" and a "number of" and "numerous" and "a hand full." One
desperately looks for a term that is a collective, but which carries
the meaning of an undefined number. There are English gems such as a
pride of lions and a host of daffodils. But without a specific animal
or plant of reference, one must have a target collective that is
appropriate, to let the term "many" or "few" imply the proper size.
There were many hundreds of persons (a few thousands of persons) at
the rally. Several dozen hunters (a few score hunters) were gathered
at the lake. A wonderful prefix is "oligo" which means a few, not a
lot, and it means that I am not sure just how many are meant. Say,
for example, that you have synthesized something in a biochemical
mixture that contains three or four peptides. Di-and tri- and
tetrapeptides are exact terms, but they do not describe what you have
done. Polypeptide is way too big. However, an oligopeptide means
that there are a few peptide units, I'm not sure how many. This may
well be the most accurate description of just what you have.
I love the British modesty that is shown by hiding a person's physical
weight by referring to it with the dimension known as the stone. This
is, as I remember, something like 14 pounds. So, if stones were the
weight equivalent of 10 milligrams, the activity of TA would be
several stone. And since the synthetic intermediate
1-allyl-2,3,4,5-tetramethoxybenzene is one of the ten essential oils,
the amination step from our hypothetical reaction in the human liver
would make TA one of the so-called Ten Essential Amphetamines.
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