SYNTHESIS: A solution of 30 g piperonal in 25 mL cyclohexylamine was
brought to a boil on a hot plate, until there was no more water
apparently being evolved. The resulting melt was distilled giving 45
g of N-cyclohexyl-3,4-methylenedioxybenzylideneimine boiling at
114-135 °C at 0.2 mm/Hg as a light yellow oil.
In 400 mL anhydrous Et2O there was dissolved 40.3 g
N-cyclohexyl-3,4-methylenedioxybenzylidenimine and 30 mL
N,N,N',N'-tetramethylethylenediamine (TMEDA). This solution was put
under an inert atmosphere, and with good stirring brought to -78 °C
with an external dry ice/acetone bath, which produced a light white
crystalline precipitate. There was then added 120 mL of 1.55 M
butyllithium, which produced an immediate darkening and a dissolving
of the fine precipitate. After 10 min stirring, there was added 20 mL
of dimethyl disulfide. The color immediately vanished and there was
the formation of a white precipitate. The temperature was allowed to
return to ice bath temperature, and then all volatiles were removed
under vacuum. The residue was poured into 500 mL H2O and acidified
with HCl. After heating for 1 h on the steam bath, the reaction
mixture was cooled, producing a gummy solid that was shown to be a
complex mixture by TLC. But there was a single fluorescent spot that
was the product aldehyde and it was pursued. Extraction with 3x75 mL
CH2Cl2 gave, after pooling and stripping of the solvent, a residue
which was extracted with four separate passes, each with 75 mL boiling
hexane. The deposited crystals from each were separated, and all
recrystallized from boiling MeOH to give 3.3 g of
3,4-methylenedioxy-2-(methylthio)benzaldehyde, with a mp of 77-80 °C.
To a solution of 3.0 g 3,4-methylenedioxy-2-(methylthio)benzaldehyde
in 25 mL IPA there was added 2 mL nitroethane, 0.11 mL ethylenediamine
and 0.1 mL acetic acid. This was held at reflux temperature for 18 h,
and the solvents removed under vacuum. The residue showed a total of
eight spots on TLC analysis, extending from the origin to the spot of
the product nitrostyrene itself. Trituration of this residue under 25
mL MeOH gave a crude nitrostyrene which was, after separation,
recrystallized from 20 mL of boiling MeOH. The final isolation of
1-(3,4-methylenedioxy-2-methylthiophenyl)-2-nitropropene gave 0.5 g of
a product that had a mp of 94-95 °C. The mixed mp with the
nitrostyrene from piperonal (mp 97-98 °C) was soundly depressed (mp
67-79 °C).
A solution of AH was prepared by the treatment of a solution of 0.5 g
LAH in 10 mL THF, at 0 °C and under He, with 0.32 mL 100% H2SO4. A
solution of 0.45 g
1-(3,4-methylenedioxy-2-methylthiophenyl)-2-nitropropene in 10 mL THF
was added dropwise, and the stirring was continued for 1 h. After a
brief period at reflux, the reaction mixture was returned to room
temperature, and the excess hydride destroyed by the addition of IPA.
The salts were converted to a filterable mass by the addition of 5%
NaOH, and after filtering and washing with IPA, the combined filtrate
and washings were stripped of solvent under vacuum. The residue was
dissolved in dilute H2SO4 which was washed with 3x75 mL CH2Cl2. After
alkalinification with 25% aqueous NaOH, the product was extracted with
2x75 mL CH2Cl2. The extracts were pooled, and the solvent removed
under vacuum. Distillation of the residue gave a fraction that boiled
at 137-150 °C at 0.3 mm/Hg and weighed 0.3 g. This was dissolved in
1.6 mL IPA, neutralized with 6 drops of concentrated HCl, warmed to
effect complete solution, and diluted with 4 mL of anhydrous Et2O.
The formed crystals were collected by filtration, and after Et2O
washing and air drying to constant weight, gave 0.3 g
3,4-methylenedioxy-2-methylthioamphetamine hydrochloride (2T-MMDA-3a).
DOSAGE: greater than 12 mg.
DURATION: unknown.
EXTENSIONS AND COMMENTARY: And visions of sugar-plums danced through
their heads. There are many trisubstituted amphetamine analogues that
have been documented with varying degrees of activity. There are six
TMA's and if one were to systematically make every possible
thio-analogue of each of these, there would be a total of sixteen
thio-analogues of the TMA. Let's go for it, said I to myself. Let's
get the 16 thio analogues in hand. That is where the action's at.
But hold on a minute. Each and every MMDA isomer has, by definition,
three possible thio analogues, so there are eighteen more possible
thio compounds just with them. Sure, let's make them all! It will be
an unprecedented coup for students of structure-activity
relationships. Let's whip out some 34 compounds, and test them all,
and maybe we will begin to understand just why those which are active
are, indeed, active. And maybe not.
Anyway, this was the most manic of all manic programs ever, involving
thio-analogues. And it was totally compelling. Another synthetic
clue stemmed from the fact that vanillin also formed the cyclic
carbonate with sodium thiocyanate and it could, in principle, be
brought around in time to 3-methoxy-5,4-methylenethiooxyamphetamine,
or 5T-MMDA. That made two of the magic analogues, and only some 32 to
go. What a marvelous task for a graduate student. (What a horribly
dull task for a graduate student.) But in any case there was no
graduate student, and this appeared to be the end of the line. Some
day, let's make all these possibilities. A magnificent tour-de-force,
but at the present time, not worth the effort. Other directions are
more exciting and more appealing.
A last note of simple humor. One of the compounds used in this
preparation was N,N,N',N'-tetramethylethylenediamine, which has been
abbreviated TMEDA. There is a pattern, within any active inner clique
of research chemists intently pursuing a goal, to begin condensing
complex comcepts into deceptively simple terms. We "MOM-ed the
hydroxy group of the T-BOC-ed amine." I have recently heard the above
tetramethyl monster referred to in the chemist's jargon as a
pronounced, rather than a spelled out, word. It sounds very much like
"tomato" spoken by a native of the Bronx.
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