SYNTHESIS: A solution of 13.4 g
3-bromo-N-cyclohexyl-4-methoxy-5-ethoxybenzylidenimine (see under ME
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 the formation of a granular precipitate.
There was then added 28 mL of 1.6 N butyllithium in hexane over the
course of 5 min, and the mixture (which had turned quite creamy) was
stirred for 15 min. This was followed by the addition of 5.5 g
diethyl disulfide over the course of 1 min. The mixture was allowed
to come to room temperature over the course of 1 h, and then added to
100 mL of dilute HCl. The Et2O phase was separated and the solvent
removed under vacuum. The residue was dissolved in 50 mL MeOH,
combined with the original aqueous phase, and the entire mixture
heated on the steam bath for 0.5 h. The aqueous solution was cooled
to room temperature, extracted with 3x100 mL CH2Cl2, the extracts
pooled, and the solvent removed under vacuum. The residue was
distilled at 132-140 °C at 0.3 mm/Hg to yield 9.1 g of
3-ethoxy-5-ethylthio-4-methoxybenzaldehyde as a white oil that, on
standing for several months, spontaneously crystallized. A small bit
of the crystalline solid was wastefully recrystallized from MeOH to
provide white crystals with a mp of 31.5-32.5 °C. Anal. (C12H16O3S)
C,H. The crude distillate was used in the following reactions.
Several attempts were made to prepare the nitrostyrene from this
aldehyde and nitromethane. The most successful, but still inadequate,
procedure is described here. A solution of 1.0 g
3-ethoxy-5-ethylthio-4-methoxybenzaldehyde in 10 mL nitromethane was
treated with about 150 mg of anhydrous ammonium acetate and heated on
the steam bath. The course of the reaction was followed by TLC. The
bulk of the aldehyde had disappeared in 45 min, and there were several
UV-absorbing spots visible. Removal of the excess nitromethane under
vacuum gave an orange oil which, when rubbed under cold MeOH, gave 200
mg of yellow solids. This was (by TLC) a mixture of nitrostyrene,
starting aldehyde, and several slow-moving scrudge impurities.
Recrystallization from MeOH gave a poor recovery of a yellow solid
with a mp of 102.5-104 °C but this was still contaminated with the
same impurities. Several repetitions of this synthetic procedure gave
little if any of the desired
3-ethoxy-5-ethylthio-4-methoxy-beta-nitrostyrene.
A suspension of 5.4 g methyltriphenylphosphonium bromide in 30 mL
anhydrous THF was placed under a He atmosphere, well stirred, and
cooled with an external water bath. There was then added 10 mL of 1.6
N butyllithium in hexane which resulted in the generation of a bright
pumpkin color. The initial heavy solids changed into a granular
precipitate. There was then added 2.4 g of
3-ethoxy-5-ethylthio-4-methoxybenzaldehyde in a little THF. An
initial gummy phase became granular with patient swirling and
stirring. After 30 min, the reaction was quenched in 500 mL H2O, the
top hexane layer separated, and the aqueous phase extracted with 2x75
mL of petroleum ether. The organic fractions were combined, washed
with H2O, dried over anhydrous K2CO3, and the solvents removed under
vacuum to give the crude 3-ethoxy-5-ethylthio-4-methoxystyrene as a
yellow mobile liquid.
A solution of 2 mL of borane-methyl sulfide complex (10 M BH3 in
methyl sulfide) in 20 mL THF was placed in a He atmosphere, cooled to
0 °C, treated with 4.2 mL of 2-methylbutene, and stirred for 1 h while
returning to room temperature. To this there was added a solution of
the impure 3-ethoxy-5-ethylthio-4-methoxystyrene in a little anhydrous
THF. This was stirred for 1 h. The excess borane was destroyed with
1 mL MeOH, followed by the addition of 3.8 g elemental iodine,
followed in turn by a solution of 0.8 g NaOH in hot MeOH added over
the course of 5 min. The color gradually faded, and became a pale
lime green. This was added to 300 mL dilute aqueous sodium
thiosulfate which was extracted with 2x100 mL petroleum ether. The
extracts were pooled, and the solvent evaporated under vacuum to
provide crude 1-(3-ethoxy-5-ethylthio-4-methoxyphenyl)-2-iodoethane as
a residue.
To this crude 1-(3-ethoxy-5-ethylthio-4-methoxyphenyl)-2-iodoethane
there was added a solution of 3.7 g potassium phthalimide in 50 mL
anhydrous DMF, and all was heated on the steam bath. The reaction
seemed to be complete after 15 min (as seen by TLC) and the addition
of a second batch of potassium phthalimide in DMF produced no further
change. After adding to 500 mL of dilute NaOH, the aqueous phase was
extracted with 2x75 mL Et2O. These extracts were combined, washed
first with dilute NaOH and then with dilute H2SO4, dried over
anhydrous K2CO3, and the solvent removed under vacuum which provided
an amber oil as residue. This was triturated under cold MeOH giving
white solids which were recrystallized from 20 mL MeOH. Thus there
was obtained 0.9 g of
1-(3-ethoxy-5-ethylthio-4-methoxyphenyl)-2-phthalimidoethane as white
crystals that melted at 79-80.5 °C. A small sample was recrystallized
from EtOH to give large flat needles with a mp of 81-82 °C. Anal.
(C21H23NO4S) C,H.
A suspension of 0.8 g of the crystallized
1-(3-ethoxy-5-ethylthio-4-methoxyphenyl)-2-phthalimidoethane in 25 mL
of n-butanol was treated with 2 mL of 66% hydrazine, and the mixture
was heated on the steam bath for 0.5 h. Initially all went into
solution, and then there was the separation of solids that resembled
cottage cheese. The reaction mixture was added to 150 mL dilute
H2SO4. The solids were removed by filtration, and the filtrate was
washed with 3x50 mL CH2Cl2. These washes were discarded. The H2O
phase was then made basic with aqueous NaOH, extracted with 2x75 mL
CH2Cl2, and the solvent from these pooled extracts removed under
vacuum. The residue was distilled at 135-155 °C at 0.3 mm/Hg to give
0.45 g of a colorless oil. This was dissolved in 2.5 mL IPA,
neutralized with 5 drops of concentrated HCl, and diluted with 10 mL
anhydrous Et2O. The solution became cloudy, and then deposited
lustrous white plates. These were removed by filtration, washed with
additional Et2O, and air dried to give 0.4 g of
3-ethoxy-5-ethylthio-4-methoxyphenethylamine hydrochloride (3-TSB)
with a mp of 153.5-154.5 °C. Anal. (C13H22ClNO2S) C,H.
DOSAGE: greater than 200 mg.
DURATION: unknown.
QUALITATIVE COMMENTS: (with 200 mg) No effects whatsoever, neither
mental nor physical.
EXTENSIONS AND COMMENTARY: The elephant labored and brought forth a
mouse. A lot of work for a material without activity.
I have used the term "scrudge" in this and other recipes, without
defining it. With this aldehyde, as with most aldehydes in this
nitrostyrene synthesis reaction where there is no ortho-substituent on
the benzaldehyde, the reaction progress should be carefully followed
by thin-layer chromatography. As the aldehyde disappears from the
reaction mixture, the nitrostyrene appears, but there is usually the
development of one or more slower moving components as seen by TLC.
Such a wrong-product is called scrudge. The reaction should be
continuously titrated, and stopped when there is a favorable balance
between the aldehyde being mostly gone, the nitrostyrene being mostly
made, and the slower-moving scrudge components being not yet too
plentiful. Methylene chloride is an excellent solvent to try first,
with silica gel plates and UV detection. The nitrostyrene is always
the fastest moving component of the reaction mixture and often
fluoresces a dull purple. The starting aldehyde is the second spot
and usually fluoresces white or pale yellow. The scrudge spots then
occur in a cascade from the aldehyde to the origin. A maddening
property is that they are yellow or brown colored, and in the probe
mass spectrograph they can crack to give rise to what appears to be
the right nitrostyrene. Usually, they are high melting.
In this preparation, there was not one but several scrudges, and
little if any nitrostyrene. The same was true for the other of the
diethyl compounds such as 3-TASB, 5-TASB and 3-T-TRIS. Thus, it is
preferable to circumvent this usual synthetic step by using the Wittig
reaction instead, as described here.
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