SYNTHESIS: A solution of 11.5 g
3-bromo-N-cyclohexyl-4,5-diethoxybenzylidinimine (see under ASB for
its preparation) in 150 mL anhydrous Et2O was placed in a He
atmosphere, well stirred, and cooled in an external dry ice/acetone
bath to -80 °C. There was light formation of fine crystals. There
was then added 25 mL of 1.6 N butyllithium in hexane and the mixture
stirred for 15 min. This was followed by the addition of 4.3 mL
dimethyldisulfide over the course of 20 min, during which time the
solution became increasingly cloudy and then thinned out again. The
mixture was allowed to come to room temperature over the course of an
additional h, and then added to 400 mL of dilute HCl. There was the
generation of a lot of yellow solids, and the Et2O phase was almost
colorless. This was separated, the solvent removed under vacuum, and
the residue combined with the original aqueous phase. This phase was
then heated on the steam bath for 2 h. The aqueous solution was
cooled to room temperature, extracted with 3x100 mL CH2Cl2, the
extracts pooled, washed with H2O, and the solvent removed under vacuum
to yield 9.4 g of an amber oil which spontaneously crystallized. This
was distilled at 125-132 °C at 0.2 mm/Hg to yield 7.1 g of
3,4-diethoxy-5-(methylthio)benzaldehyde as a white oil that
spontaneously crystallized. The crude product had a mp of 73-74 °C
that actually decreased to 72-73 °C after recrystallization from MeOH.
Anal. (C12H16O3S) C,H.
A solution of 16.2 g methyltriphenylphosphonium bromide in 200 mL
anhydrous THF was placed under a He atmosphere, well stirred, and
cooled to 0 °C with an external ice water bath. There was then added
30 mL of 1.6 N butyllithium in hexane which resulted in the generation
of a clear yellow solution. The reaction mixture was brought up to
room temperature, and 7.0 g 3,4-diethoxy-5-(methylthio)benzaldehyde in
50 mL THF was added dropwise, dispelling the color, and the mixture
was held at reflux on the steam bath for 1 h. The reaction was
quenched in 800 mL H2O, the top hexane layer separated, and the
aqueous phase extracted with 2x75 mL of petroleum ether. The organic
fractions were combined and the solvents removed under vacuum to give
12.0 g of the crude 3,4-diethoxy-5-methylthiostyrene as a pale
amber-colored oil.
A solution of 6.0 mL of borane-methyl sulfide complex (10 M BH3 in
methyl sulfide) in 45 mL THF was placed in a He atmosphere, cooled to
0 °C, treated with 12.6 g of 2-methylbutene, and stirred for 1 h while
returning to room temperature. To this there was added a solution of
the impure 3,4-diethoxy-5-methylthiostyrene in 25 mL THF. This was
stirred for 1 h during which time the color deepened to a dark yellow.
The excess borane was destroyed with about 2 mL MeOH (all this still
in the absence of air). There was then added 11.4 g elemental iodine
followed by a solution of 2.4 g NaOH in 30 mL of boiling MeOH, added
over the course of 10 min. This was followed by sufficient 25% NaOH
to discharge the residual iodine color (about 4 mL was required). The
reaction mixture was added to 500 mL water, and sodium hydrosulfite
was added to discharge the remaining iodine color (about 4 g). This
was extracted with 3x100 mL petroleum ether, the extracts pooled, and
the solvent removed under vacuum to provide 25.9 g of crude
1-(3,4-diethoxy-5-methylthiophenyl)-2-iodoethane as a pale yellow
fluid oil. Thin layer chromatographic analysis of this material on
silica gel plates (using a 90:10 mixture of CH2Cl2/methylcyclopentane
as solvent) showed largely the iodo-product (Rf 0.9) with no visible
starting aldehyde (Rf 0.7).
To this crude 1-(3,4-diethoxy-5-methylthiophenyl)-2-iodoethane there
was added a solution of 12 g potassium phthalimide in 90 mL anhydrous
DMF, and all was held at reflux in a heating mantle. The reaction
progress was followed by TLC, and at 1.5 h it was substantially
complete. After adding to 500 mL 5% NaOH, the organic phase was
separated, and the aqueous phase was extracted with 2x75 mL Et2O. The
organic fractions were combined, and the solvent removed under vacuum
providing 19.3 g of an amber oil. The residual volatiles were removed
by distillation up to 170 °C at 0.2 mm/Hg. The distillate weighed 7.0
g and contained little if any phthalimide by TLC. The pot residue was
a viscous amber oil, and also weighed 7.0 g. About half of this was
employed in the following hydrolysis step, and the rest was rubbed
under an equal volume of MeOH providing
1-(3,4-diethoxy-5-methylthiophenyl)-2-phthalimidoethane as a white
solid. A small sample was recrystallized from an equal volume of MeOH
to give white crystals with a mp of 79.5-81 °C. Re-recrystallization
from MeOH produced an analytical sample with a mp of 83-84 °C. Anal.
(C21H23NO4S) C,H.
A solution of 3.2 g of the impure
1-(3,4-diethoxy-5-methylthiophenyl)-2-phthalimidoethane in 150 mL of
n-butanol there was added 20 mL of 66% hydrazine, and the mixture was
heated on the steam bath for 2 h. This was added to 600 mL of dilute
H2SO4, and the two layers were separated. The butanol layer was
extracted with 2x100 mL dilute H2SO4. These extracts were added to
the original aqueous phase, and this was washed with 3x75 mL CH2Cl2.
This was then made basic with 5% NaOH, extracted with 3x75 mL CH2Cl2,
and the solvent from these pooled extracts removed under vacuum. The
residue (which weighed 9.7 g and contained much butanol) was distilled
at 140-145 °C at 0.3 mm/Hg to give 0.7 g of a colorless oil. This was
dissolved in 3.0 mL IPA, neutralized with concentrated HCl, and
diluted with 12 mL anhydrous Et2O to give a solution that immediately
crystallized to provide white crystals of
3,4-diethoxy-5-methylthiophenethylamine hydrochloride (5-TASB). These
weighed 0.7 g after washing with Et2O and drying to constant weight.
The mp was 182-183 °C, and an analytical sample was dried at 100 °C
for 24 h. Anal. (C13H22ClNO2S) C,H.
DOSAGE: about 160 mg.
DURATION: about 8 h.
QUALITATIVE COMMENTS: (with 120 mg) Maybe there is something at about
hour 5. My talking with innocent people had hints of strangeness.
And there was the slightest suggestion of some physical effect. Call
it an overall (+).
(with 160 mg) I am immediately warm at the extremities. An awareness
grows upon me for a couple of hours. I am a little light-headed, and
I feel that there is more physical than there is mental, and it is not
all entirely nice. I am slightly hyperreflexive, and there is a touch
of diarrhea. I am happy that I held this at 160 milligrams. I am
mentally flat at the eighth hour, although there are some physical
residues. The effects are real, but I don't want to go higher. Some
trace physical memory seems to stay with me as a constant companion.
EXTENSIONS AND COMMENTARY: There is a ponderousness about adding a
couple of ethyl groups and a sulfur that seems to say, Rno fun.
5-TASB has something going for it (but not much) and 3-TASB is quite a
bit more peppy and, actually, 4-TASB has quite a bit of life. But
there is a sense of "why bother?" There were a couple of bouts of
light-headedness, but there was no unexpected excitement discovered in
this methodical study. No surprises. Keep the chain lengths down.
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