SYNTHESIS: A solution of 13.3 g 3,4-diethoxyphenol (see the recipe for
MEE for its preparation) in 20 mL MeOH, and a solution of 4.8 g KOH in
100 mL hot MeOH were combined. There was added 8.2 g ethyl bromide
and the mixture was held at reflux on the steam bath for 2 h. The
reaction was quenched by the addition of three volumes H2O, made
strongly basic by the addition of 10% NaOH, and extracted with 3x150
mL CH2Cl2. The solvent was removed from the pooled extracts under
vacuum giving a residue of 9.1 g 1,2,4-triethoxybenzene that
solidified to a crystalline mass. The mp was 28.5-29.5 °C, but the
infra-red analysis showed the presence of unreacted phenol. The
CH2Cl2 solution was again washed thoroughly with 10% NaOH and, after
removal of the solvent, the solidified residue weighed 6.0 g and
appeared free of impurities. The mp of this sample was 33-34 °C.
To a mixture of 10.5 g N-methyl formanilide and 11.9 g POCl3 that had
incubated at room temperature for 0.5 h (it had become quite red in
color) there was added 6.4 g of the solid ether,
1,2,4-triethoxybenzene. The mixture was heated on the steam bath for
2.5 h, then poured into 500 mL of shaved ice. After a few minutes
stirring, crystals appeared. The reaction was allowed to stand for a
few h, then filtered and sucked as dry as possible. The damp 14.4 g
of slate-green crude solids were dissolved in 30 mL boiling MeOH, and
allowed to cool to room temperature overnight. Filtration of the
cream-colored product, and air drying, gave 6.1 g of
2,4,5-triethoxybenzaldehyde with a mp of 94-95 °C. A solution
containing 0.5 g of this aldehyde and 0.4 g malononitrile in 7 mL
absolute EtOH was treated with three drops of triethylamine. There
was an immediate formation of granular yellow crystals of
2,4,5-triethoxybenzalmalononitrile which, on filtering and air drying,
weighed 0.4 g and had a mp of 169-170 °C.
A solution of 5.0 g 2,4,5-triethoxybenzaldehyde and 2.6 g nitroethane
in 14.8 g glacial acetic acid was treated with 1.6 g anhydrous
ammonium acetate and heated on the steam bath for 2 h. The addition
of an equal volume of H2O gave a slightly turbid solution which, upon
the administration of a small amount of externally developed seed,
smoothly set up as orange crystals as the reaction mix returned to
room temperature. The product was removed by filtration, washed with
a little 50% acetic acid, and allowed to air dry to constant weight.
There was thus obtained 2.5 g of fluffy yellow-orange (almost yellow)
crystals of 2-nitro-1-(2,4,5-triethoxyphenyl)propene with a mp of
91-92.5 °C. Anal. (C15H21NO5) C,H.
To a gently refluxing suspension of 1.7 g LAH in 200 mL anhydrous Et2O
under a He atmosphere, there was added 2.5 g
2-nitro-1-(2,4,5-triethoxyphenyl)propene by allowing the condensing
Et2O to drip into a shunted Soxhlet thimble containing the
nitrostyrene, thus effectively adding a warm saturated solution of the
nitrostyrene dropwise. Refluxing was maintained for 5 h, and then the
reaction mixture was cooled with an external ice bath. The excess
hydride was destroyed by the cautious addition of 300 mL 1.5 N H2SO4.
When the aqueous and Et2O layers were finally clear, they were
separated, and 50 g of potassium sodium tartrate were dissolved in the
aqueous fraction. Aqueous NaOH was then added until the pH was above
9, and this was extracted with 3x200 mL CH2Cl2. Removal of the
solvent under vacuum produced an amber oil that was dissolved in
anhydrous Et2O and saturated with anhydrous HCl gas. After a few min
delay, there com-menced the separation of fine white crystals of
2,4,5-triethoxyamphetamine hydro-chloride, (EEE). These weighed,
after filtration, Et2O washing, and air drying to constant weight,
1.75 g and had a mp of 167-168 °C, with prior softening at 162 °C.
Anal. (C15H26ClNO3) C,H,N.
DOSAGE: unknown.
DURATION: unknown.
EXTENSIONS AND COMMENTARY: This amphetamine, the final item on the
ethoxy homologue of TMA-2 project, has never been tried in man. I do
not know how it tastes, but I suspect that it is probably bitter. An
interesting sidelight concerning this project, and one which can serve
as a measure of the enthusiasm that went into it, is that (except for
the 2-ethoxy homologue EMM) all of the possible ethoxy homologues of
TMA-2, including MEM, MME, EEM, EME, MEE and EEE, their precursor
nitrostyrenes, the precursor aldehydes (and their malononitrile
derivatives), the precursor ethers, and the precursor phenols, for a
total of 33 compounds, were all synthesized, purified, and
characterized within a period of just over three weeks. Actually it
was 23 days, and that was a magically exciting time.
And there were two true treasures that came out of it all. The
compound MEM, and the knowledge that the 4-position was where the
action is.
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