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#150 3-TE
3-THIOESCALINE; 4-ETHOXY-5-METHOXY-3-METHYLTHIOPHENETHYLAMINE
SYNTHESIS: A
solution of 10.4 g of
3-bromo-N-
cyclohexyl-4-ethoxy-5-
methoxybenzylidenimine (see under
3-TASB for its preparation) in 125 mL
anhydrous Et2O, in a He
atmosphere, was cooled with an external dry ice
acetone bath to -80 °C
with good stirring. To this clear pale yellow
solution there was
added 25 mL 1.6 M
butyllithium in hexane (about a 25% excess) which
produced a fine white
precipitate over the following 15 min. There
was then added 4.2 g
dimethyl disulfide. At the half-addition point,
the generated solids became so heavy that stirring became difficult,
but towards the end of the addition the reaction thinned out again and
became quite loose. The dry ice bath was removed and the reaction
allowed to come to room tem
perature, which again allowed the formation
of a heavy solid
phase while warming and, again, a loose and easily
stirred mixture when finally at room tem
perature. All was added to
400 mL H2O which had been strongly acidified with HCl. The two
phases
were separated, and the aqueous
phase (which contained a small amount
of yellow oily matter in
soluble in either
phase) was heated on the
steam bath for 0.75 h. On cooling, the oily component set to a yellow
solid, which was removed by filtration and washed with H2O. This
crude product, 5.9 g of yellow solid, was
distilled 115-125 °C at 0.3
mm/
Hg to give 4.9 g of
4-ethoxy-3-methoxy-5-(methylthio)benzaldehyde
as a pale yellow solid that had a mp of 43-45 °C. Re
crystallization
from MeOH gave a mp of 47-48 °C. Anal. (
C11H14O3S) C,H. This product
can also be prepared from the anion of 3-
thiosyringaldehyde (mp
141-143 °C as
crystals from MeOH) by reaction with
ethyl iodide in the
presence of
phase-transfer catalyst, but the yield is quite poor.
To a
solution of 4.4 g
4-ethoxy-5-methoxy-3-(methylthio)benzaldehyde
in 75 mL
nitromethane, there was added 0.5 g
anhydrous ammonium
acetate and the mixture was heated on the steam bath for 80 min. Care
must be taken in the length of time, and there must be frequent TLC
montoring, as there is a rapid scrudge buildup (see under
3-TSB for a
discussion of scrudge). The reaction mixture was stripped of
nitromethane under vacuum, and the
residual deep-yellow oil was
dissolved in 20 mL of boiling MeOH. This was decanted from a small
amount of in
soluble matter and, upon cooling,
deposited bright yellow
crystals of
4-ethoxy-5-methoxy-3-methylthio-beta-nitrostyrene. This was
removed by filtration and, after washing with cold MeOH and air
drying, weighed 2.4 g. The mp was ambiguous. The above crude
material melted at 92-93 °C, which is probably too high! Earlier
samples which melted in the low 80's appeared to have a mp, after
repeated re
crystallization from MeOH, of 87-88 °C. This latter was
the property of the
analytical sample. Anal. (
C12H15NO4S) C,H. The
mp of the TLC low-moving component is always quite high, and might
have been a factor in the assignment of this physical property.
AH was prepared in the usual manner from a suspension of 2.0 g LAH in
75 mL
anhydrous THF, cooled to 0 °C, well stirred in an inert
atmosphere of He, and treated with 1.33 mL of 100% H2SO4 added
dropwise. There was added, dropwise and over the course of 10 min, a
solution of 2.4 g
4-ethoxy-5-methoxy-3-methylthio-beta-nitrostyrene in 15
mL
anhydrous THF. The reaction was exothermic, and was heated on the
steam bath at reflux for an additional 10 min. After cooling again,
there was added enough IPA to decompose the excess
hydride and
sufficient 10%
NaOH to convert the
aluminum oxide solids to a white,
easily filterable mass. This was filtered, the filter cake washed
with additional IPA, the filtrate and washes combined, and the
solvent
removed under vacuum. This was
dissolved in 100 mL of dilute H2SO4
which was washed with 2x50 mL
CH2Cl2. The aqueous
phase was made
basic with
NaOH, extracted with 2x50 mL
CH2Cl2, and the extracts
pooled and the
solvent removed under vacuum to yield a residue of a
colorless oil. This
distilled at 118-122 °C at 0.4 mm/
Hg producing
1.9 g of a colorless oil. This was
dissolved in 10 mL IPA,
neutralized with 30 drops of concentrated HCl and, with good stirring,
diluted with 20 mL
anhydrous Et2O. The product
4-ethoxy-5-methoxy-3-methylthiophenethylamine hydrochloride (3-TE) was
removed by filtration, washed with
Et2O, and air dried to provide a
white solid that weighed 1.0 g and melted at about 180 °C. Anal.
(
C12H20ClNO2S) C,H.
DOSAGE: 60 - 80 mg.
DURATION: 8 - 12 h.
QUALITATIVE COMMENTS: (with 60 mg) There may well be time slowing. I
noticed that the voices on the radio seemed to be of a deeper pitch.
And with music there is a most easy flight of fantasy. I tried to
keep a logical conversation going on the telephone, but I am pretty
sure there were problems. I found myself down sooner than I would
have liked.
(with 70 mg) I found myself in a good, rich place, and thoroughly
enjoyed my introspection. I didn't want to talk and interact, and
that seemed just fine with everyone else. Several of the others
seemed restless, but I lay back and let them do their thing. My
appetite was fine towards the end, and I might have actually
overeaten. I was able to drive home that evening, but there seemed to
be some slight
residual something after waking in the morning. I
would certainly repeat without hesitation.
(with 80 mg) Art interpretation and imagery with music are
remarkable. This material touches on the
psychedelic--rather than
just being stoned. The body is higher than the mind, but where the
mind is makes it all OK. It's worth the cost. My getting to sleep
was easy that evening, but sleep was not too restful and there was
something strange about it.
EXTENSIONS AND COMMENTARY: There is a good lesson to be learned in the
attempts to predict the potency of 3-TE before it was actually
explored. All
pharmacological prediction follows pretty much a single
mechanism. Find things that are close in some way, and arrange them
in a manner that allows comparison. A relates to B in this way, and A
relates to C in that way, and since D incorporates both this and that
of each, it will probably be such-and-such. The Roman square.
Here is the square with the horizontal arrow adding a
sulfur in the
3-position and the vertical arrow adding an
ethyl group in place of a
methyl group at the 4-position:
Mescaline x 3.5 3-TM
200-400 mg ------------------------> 60-100 mg
| |
| x 6 |
V V
Escaline 3-TE "x20"
40-60 mg ------------------------> = 10-20 mg
and one would predict a potency of some 20x that of mescaline, or
something in the range of 15 mg.
Here is an equally likely square, based on the horizontal arrow
relocating a
sulfur from the 4-position to the 3-position, and the
vertical arrow again adding an
ethyl group in place of a
methyl group
in the 4-position:
Thiomescaline x 0.3 3-Thiomescaline
20-30 mg ------------------------> 60-100 mg
| |
| x 1 |
V V
Thioescaline 3-TE "x0.3"
20-30 mg ------------------------> = 60-100 mg
and one would predict a potency of some one third of that of
thiomescaline, or something in the range of 80 milligrams.
This latter square gave a prediction that was very close to the
observed potency, but it would be careless, and probably wrong, to
assume that the latter relationships had any more significance than
the former ones. As one accumulates the potencies of many compounds
it is tempting to draw complex relationships such as these, and to be
seduced into believing that they must explain things. And,
especially, beware the multivariable power of the
computer which can
explore monstrous numbers of variables at breakneck speeds, and spew
forth fantastic correlations with marvelous ease.
But nothing can ever
substitute for the simple art of tasting
something new.
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