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From: sender@mit.edu
Newsgroups: sci.med,sci.chem,alt.drugs
Subject: PiHKAL: The Chemical Story.  File 3 of 6

(I'm posting this for a friend.)

This is part 3 of 6 of the second half of PiHKAL: A Chemical Love
Story, by Alexander Shulgin and Ann Shulgin.  Please forgive any typos
or misprints in this file; further, because of ASCII limitations,
many of the typographical symbols in the original book could not be
properly represented in these files.

If you are seriously interested in the chemistry contained in these
files, you should order a copy of the book PiHKAL.  The book may be
purchased for $22.95 ($18.95 + $4.00 postage and handling) from
Transform Press, Box 13675, Berkeley, CA 94701.  California residents
please add $1.38 State sales tax.

At the present time, restrictive laws are in force in the United
States and it is very difficult for researchers to abide by the
regulations which govern efforts to obtain legal approval to do work
with these compounds in human beings....  No one who is lacking legal
authorization should attempt the synthesis of any of the compounds
described in these files, with the intent to give them to man.  To do
so is to risk legal action which might lead to the tragic ruination of
a life.  It should also be noted that any person anywhere who
experiments on himself, or on another human being, with any of the
drugs described herin, without being familiar with that drug's action
and aware of the physical and/or mental disturbance or harm it might
cause, is acting irresponsibly and immorally, whether or not he is
doing so within the bounds of the law.




#60 DMPEA; 3,4-DIMETHOXYPHENETHYLAMINE

SYNTHESIS: A solution of 33 g 3,4-dimethoxybenzaldehyde in 140 mL
acetic acid was treated with 23 mL nitromethane and 12.5 g anhydrous
ammonium acetate, and heated on the steam bath for 45 min.  To this
there was slowly added, with good stirring, 300 mL H2O, and the
resulting solids were removed by filtration.  The product was finely
ground under a small amount of MeOH, filtered again, and air dried to
give 13.5 g 3,4-dimethoxy-'-nitrostyrene with a mp of 142-143 !C.

To a stirred suspension of 12.0 g LAH in 500 mL anhydrous Et2O that
was at a gentle reflux and under an inert atmosphere, there was added
11.45 g 3,4-dimethoxy-'-nitrostyrene by leaching it from a thimble in
a modified Soxhlet condenser.  The addition took 2 h and the refluxing
was maintained for another 16 h.  After cool-ing to room temperature,
the excess hydride was destroyed by the cautious addition of 500 mL
1.5 N H2SO4.  The phases were separated, and to the aqueous phase
there was added 250 g potassium sodium tartrate.  The pH was brought
to >9, and the clear solution was extracted with 3x100 mL CH2Cl2.
Remo-val of the solvent from the combined extracts under vacuum gave
5.2 g of a pale yellow oil.  This was dissolved in 300 mL anhydrous
Et2O and saturated with anhydrous HCl gas, giving 5.0 g of a slightly
sticky off-white solid.  This was recrystallized from 75 mL of boiling
CH3CN to give 3.3 g 3,4-dimethoxyphenethylamine hydrochloride (DMPEA)
as beautiful white crystals.

DOSAGE: greater than 1000 mg.

DURATION: unknown.

QUALITATIVE COMMENTS: (with 500 mg) Nothing.

(with 1000 mg) Nothing.

(with 10 mg i.v.)  RNothing.

(with 1000 mg of 3,4-dimethoxyphenylacetic acid, a major human
metabolite of DMPEA) RNothing.

(with 500 mg of N-acetyl-3,4-dimethoxyphenethylamine, a major human
metabolite of DMPEA) RNothing.

EXTENSIONS AND COMMENTARY: Why all the interest?  Why keep pursuing a
compound that is so obviously without activity?  Or a metabolite that
is also without activity?  The answer is that these are totally
fascinating compounds just because they have no activity!  By the way,
in this instance, I actually made up most of the quotations.  I am not
sure that the subjects actually said, RNothing,S but they did report
that there were no effects.  In my own experiments, my notes record
the phrase, RNo effects whatsoever.

A little background: one of the transmitter heavyweights in the brain
is dopamine.  Dopamine is called dopamine because it is an amine that
comes from an amino acid that is 3,4-dihydroxyphenylalanine and this,
in German, is Di-Oxo-Phenyl-Alanine, or DOPA.  The levo-optical (or
L-) isomer of DOPA has rather cutely been called the punch-drunk
Spanish matador, or El Dopa.  But that is not part of the story.

The story is really about the RPink Spot of Schizophrenia.S Many years
ago, an observation was made in a biochemical laboratory on the East
Coast that stirred up a rolling controversy.  It had been found that
if the urines of schizophrenic patients (sloppily called
Rschizophrenic urinesS) were extracted in such and such a way, and the
extracts chromatographed, a pink spot would develop at a particular
place on the chromatogram.  Well, if this proved to be true with
urines of a sick population, and were this proved to be different from
the urines of a healthy population, it would constitute an objective
diagnosis of schizophrenia.  A simple chemical test to confirm a
pathology that had defied all efforts to achieve consensus amongst the
psychiatrists of the world.

The literature was suddenly filled with dozens of papers.  Researcher
A confirmed that the pink spot was found with schizophrenics, and not
with normal controls.  Researcher B found the pink spot in all urines,
regardless of pathology.  Researcher C found it in no urines at all.
Researcher D argued that it was a factor from the hospital diet.
Researcher E found that the pink spot reflected the time of day that
the urine sample was collected.  Researcher F drew a conclusion about
where truth might lie by tallying the number of papers that supported
argument A, B, C, D, or E.

The only confirmable fact that endured was that the pink spot was due
to DMPEA.  So a bright spotlight was directed towards its possible
role in mental illness.  And this expressed itself in the simple
question: would it produce schizophrenia in a normal subject?  No.
And in a way I am comforted that that did not evolve into a simple
litmus test for a schizophrenic diagnosis.  There are so many
cultural, political, and social factors that come to bear on the
assignment of a diagnosis of mental illness, that I would have been
forever skeptical of a neat biochemical marker.

A chemical modification of DMPEA that has been explored in this
question of pink spots, mental pathology, and diagnostic markers, is
the corresponding acetamide.  One of the metabolites of DMPEA was
found to be the N-acetyl deriva-tive, N-acetyl-3,4-
dimethoxyphenethylamine.  It was found to be demethylated in man, and
to have pharmacological activity in animals.  Maybe this was the
active compound that could be involved in the schizophrenic process.
But human trials with it, as with the principal metabolite
3,4-dimethoxyphenylacetic acid, showed nothing at all in man.

Another chemical modification is the beta-hydroxy analogue of DMPEA.
It has been explored separately, and is the subject of its own recipe,
in its own rights.  See DME.

Pink was not the only colorful spot associated with schizophrenia.
Somewhere at about this same time, a research paper from Canada
reported the observation of a mauve spot in the chromatographic
analysis of urines of schizophrenic patients.  This had nothing to do
with DMPEA.  I was working closely with a researcher at the
psychiatric institute and we were fascinated by, again, a possible
diagnostic marker.  We assayed the urines of the next 10 patients
being admitted as acute schizophrenics.  No trace of mauve.  We wrote
to Canada, and verified the analytical procedure.  We were told that
the whatzis should have been added after, rather than before, the
whosey, and that we should have heated for 30, not 10 minutes.  Okay.
We assayed the urines of the next 10 patients being admitted using
these new directions.  No trace of mauve.  Another call to Canada, and
we were informed that we still werenUt doing it right.  They were
consistently batting a 100% positive correlation between mauve spots
and schizophrenics, and 0% with healthy controls.  In fact, they
actually gave this positive test the name of a disease, Malvaria.

Then, that little burst of insight!  Aha!  What if, just what if, they
had been seeing something given to their schizophrenics?
Chlorpromazine was the popular treatment of the day.  We took a
whopping dose of chlorpromazine, and over the next couple of days did
manage (barely) to collect our urine samples.  Both of us were
positive Malvarians!  And three days later, we were again negative.
We were most likely seeing a metabolite of chlorpromazine.  One last
call to Canada with the ultimate question Q had you given any
medication to your schizophrenics before your urine analysis?  Of
course (came the answer) Q it would not be ethical to leave them
untreated.  Another color down the drain, and still no objective
measure for mental illness.

By the way, I cannot say I like the chlorpromazine trip.  There is no
real communication either with others or with yourself, with that
stuff.  You are a zombie, but if you are both schizophrenic and a
zombie, you cannot possibly be troublesome for anybody in the
emergency room.

 

 

 



#61 DOAM; 2,5-DIMETHOXY-4-(n)-AMYLAMPHETAMINE

SYNTHESIS: A solution of 110 g p-dimethoxybenzene and 102 g valeric
acid in 168 g polyphosphoric acid was heated on the steam bath for 3
h, giving a deep red homogeneous solution.  This was poured into 1 L
H2O with good stirring.  The strongly acidic, cloudy suspension was
extracted with 3x200 mL CH2Cl2, the extracts pooled, washed with 4x150
mL 5% NaOH, and finally once with dilute HCl.  The solvent was removed
under vacuum, and the residual amber oil cooled overnight at 0 !C.
Some 30 g of crystalline, unreacted dimethoxybenzene were removed by
filtration, and the 85 g of residual oil distilled at the water pump.
Another 15 g of di-methoxybenzene came over as an early cut, but the
fraction boil-ing at 184-192 !C (mostly 188-192 !C) weighed 53.0 g and
was reasonably pure 2,5-dimethoxyamylophenone.  The reaction of the
acid chloride of valeric acid with p-dimethoxybenzene and anhydrous
AlCl3 in CH2Cl2 (parallel to the preparation of the butyrophenone
analog, see DOBU) gave an inferior yield (23.2 g from 92 g
dimethoxybenzene), but did provide a sizeable sample (12.2 g) of
2-hydroxy-5-methoxyamylophenone from the basic washes of the crude
reaction mixture.  This pale yellow solid, after recrystallization
from MeOH, had a mp of 62-62.5 !C.  Anal. (C12H16O3) C,H.

To 360 g mossy zinc there was added a solution of 7.2 g mercuric
chloride in 200 mL warm H2O, and this was swirled periodically for 2
h.  The H2O was drained off, and the amalgamated zinc added to a 2 L
three-neck round-bottomed flask, treated with 200 mL concentrated HCl,
and heated with an electric mantle.  A solution of 53.0 g of
2,5-dimethoxyamylophenone in 107 mL EtOH containing 30 mL concentrated
HCl was added drop-wise over the course of 4 h accompanied by 330 mL
of concentrated HCl added batchwise over this same period.  The
mixture was held at reflux overnight and, after cooling, diluted with
sufficient H2O to allowed CH2Cl2 to be the lower phase.  The phases
were separated, and the aqueous phase was extracted with 2x200 mL
additional CH2Cl2.  These organic phases were combined, washed first
with 5% NaOH and then with H2O, and the solvent removed under vacuum.
Distillation at the water pump yielded two fractions.  The first
distilled from about 100-130 !C, weighed 8.8 g, had a faint smell of
apples and fennel, and was free of a carbonyl group in the infra-red.
It proved to be only 50% pure by GC, however, and was discarded.  The
major fraction was a pale amber oil distilling between 152-170 !C and
was substantially free of smell.  It weighed 18.9 g, and was (by GC)
90% pure 2,5-dimethoxy-(n)-amylbenzene.

A mixture of 36.3 g POCl3 and 40.9 g N-methylformanilide was allowed
to incubate for 0.5 h.  To this there was then added 18.5 g of
2,5-dimethoxy-(n)-amylbenzene and the mixture heated on the steam bath
for 2 h.  This mixture was poured into a large quantity of H2O and
stirred overnight.  The black oily product was extracted with 3x100 mL
CH2Cl2, and the extracts combined and stripped of solvent under
vacuum.  The black residue was distilled at 180-205 !C at 20 mm/Hg to
give 12.5 g of a pale amber oil that slowly set up to a crystalline
mass.  An analytical sample was recrystallized from MeOH to provide
2,5-dimethoxy-4-(n)-amylbenzaldehyde with a mp of 25-26 !C.  Anal.
(C14H20O3) H; C: calcd, 71.16: found, 71.92, 71.74.

A solution of 12.3 g 2,5-dimethoxy-4-(n)-amylbenzaldehyde in 50 mL
acetic acid was treated with 4.0 g anhydrous ammonium acetate and 12
mL nitroethane.  This mixture was heated on the steam bath for 4 h,
then poured into a large quantity of H2O.  This was extracted with
3x200 mL CH2Cl2, the extracts washed with H2O, and the solvent removed
to give a deep red oil that, on standing in the refrigerator, slowly
set to a crystalline mass weighing 13.5 g.  An analytical sample was
recrystallized from MeOH to provide
1-(2,5-dimethoxy-4-(n)-amylphenyl)-2-nitropropene as fine yellow
microcrystals with a mp of 44 !C sharp.  Anal. (C16H23NO4) C,H,N.

To a gently refluxing suspension of 10 g LAH in 500 mL anhydrous Et2O
under a He atmosphere, there was added by 13.2 g
1-(2,5-dimethoxy-4-(n)-butyl-phenyl)-2-nitropropene by allowing the
condensing ether drip into a Soxhlet thimble containing the
nitrostyrene which effectively added a warm saturated solution of it
dropwise to the reaction mixture.  Refluxing was maintained for 18 h,
and the cooled reaction flask stirred for several additional days.
The excess hydride was destroyed by the cautious addition of 1 L 8%
H2SO4.  When the aqueous and Et2O layers were finally clear, they were
separated, and the aqueous layer was washed with an additional 2x100
mL Et2O.  Removal of the solvent from the organic phase and washings
provided 4.7 g of a thick red oil that was discarded.  The aqueous
phase was then extracted with 2x200 mL CH2Cl2 which actually removed
the product as the sulfate salt.  This organic phase was washed with
2x100 mL 5% K2CO3 (removing the H2SO4) and with the evaporation of the
solvent there was obtained 6.2 g of an oily amber residue.  This was
dissolved in 200 mL Et2O and saturated with anhydrous HCl gas.  Fine
white crystals of 2,5-dimethoxy-4-(n)-amylamphetamine hydrochloride
(DOAM) separated, were removed by filtration, Et2O-washed and air
dried, and weighed 5.2 g.  The mp of 136-139 !C was increased to
145-146 !C by recrystallization from CH3CN. Anal. (C16H28ClNO2) C,H,N.

DOSAGE: greater than 10 mg.

DURATION: unknown.

QUALITATIVE COMMENTS: (with 10 mg) There was a clear threshold that
in no way interfered with my day's activities.  I was quite gay and
voluble at lunch and bubbled on into the afternoon with puns and high
spirits.  There may have been a little motor incoordination as noted
in handwriting, and there was a strange tenseness during driving.
There were no sequelae, there was no trouble sleeping, and with this
potency way down from the lower homologues, I have no pressing desire
to take this compound to a higher dose.

EXTENSIONS AND COMMENTARY: The actual procedure that was published for
the isolation of this final amine was a different one, one that would
certainly work, but which was based on the procedures tried and proven
with the lower homologues.  The process described above is just a bit
bizarre (a sulfate salt extracting into methylene chloride) but it was
the actual thing that was done.  The work was started towards two
additional compounds but these never got past the first Rketone and
phenolS stage.  p-Dimethoxybenzene was brought into reaction with
n-caproic acid with polyphosphoric acid (aiming towards
2,5-dimethoxy-4-(n)-hexylamphetamine, DOHE) but this was dropped when
DOAM proved to be down in potency.  And the reaction between
p-dimethoxybenzene and benzoyl chloride with anh. aluminum chloride
went well (aiming towards 2,5-dimethoxy-4-benzylamphetamine, DOBZ).  A
goodly amount of the phenol (2-hydroxy-5-methoxybenzophenone) was
obtained as fine yellow crystals, but this line of inquiry was also
dropped.

The preparation of DOAM was, as a matter of fact, the last of the
homol-ogous series of compounds actually completed, which stemmed from
the original discovery of DOM.  The RTen Classic LadiesS concept was
mentioned under ARIADNE, and the adding of a methyl group in the place
of a hydrogen atom at the 4-position-methyl led to the synthesis of
Ms. HECATE and gave rise to DOET.  The whole series of
methyl-ethyl-propyl-butyl-amyl compounds was appealing to me, in that
the potency seemed to increase initially as the chain got longer, and
then it abruptly dropped off.  WouldnUt it be nice, I thought, if I
could interest some pharmacologist in looking at this tight set of
drugs with some animal model, to see if there is some neurotransmitter
activity that would show a parallel action.

I learned of a curious young researcher in Washington who had an
elegant procedure for measuring serotonin agonist action using the
(otherwise) discarded sheep umbilical artery strips.  These become
available each year at lambing time, do not cost the life of anything,
and require very little compound.  He assayed my compounds and, lo and
behold, the serotonin activity also went through a maximum in the
middle of this series.  We published a short paper to this effect,
which served as a excellent vehicle to get the cogent human data into
the scientific literature.

I have never understood the reasons that there might be connection
between the twitching of a umbilical artery in a sheep and the
appearance of an insight in the mind of man.  And, I have never
personally met this pharmacologist.  Some day, I hope to do both.

 

 

 



#62 DOB; 2,5-DIMETHOXY-4-BROMOAMPHETAMINE

SYNTHESIS: To a well-stirred solution of 1.95 g of the free base of
2,5-dimethoxyamphetamine (2,5-DMA) in 12 mL glacial acetic acid, there
was added 1.8 g elemental bromine dissolved in 4 mL acetic acid over
the course of 5 min.  The slightly exothermic reaction was allowed to
stir for 3 h, and then added to about 200 mL H2O.  The cloudy solution
was washed with 2x100 Et2O, made basic with aqueous NaOH, and
extracted with 3x100 mL CH2Cl2.  Evaporation of the solvent from the
pooled extracts gave about 3 mL of a pale amber oil which was
dissolved in 250 mL anhydrous Et2O and saturated with anhydrous HCl
gas.  The fine white crystals of 2,5-dimethoxy-4-bromoamphetamine
hydrochloride, DOB, were removed by filtration, Et2O washed, and air
dried.  These weighed 1.7 g and had a mp of 195-196 !C.
Recrystallization from IPA brought this up to 207-208 !C.  Proton NMR
spectroscopy of the hydrochloride salt in D2O gave confidence that the
bromine atom had uniquely entered the 4-position, in that there were
only two unsplit aromatic hydrogen atoms present, at 6.97 and at 7.20
ppm downfield from external TMS.

DOSAGE: 1.0 - 3.0 mg.

DURATION: 18 - 30 h.

QUALITATIVE COMMENTS: (with 0.4 mg) There was a distinct enhancement
of visual perception, and some strengthening of colors.  A clean, cold
feeling of wind on the skin.  I felt an enriched emotional affect, a
comfortable and good feeling, and easy sleeping with colorful and
important dreams.

(with 2.0 mg) There was a continuous tremor at the physical level,
and an incredible Moebius strip representation of reality at the
intellectual level.  I was able to enter into personal problems
easily, and get out again when I chose to.  During the next day, there
were brief lapses of attention, or little fugue states, and it was not
until the following evening that I was completely myself again.

(with 2.8 mg) About three hours into this I had a severe cramp, and
had a near fainting response to the pain, and yet there was no pain!
I felt that I was very near a loss of consciousness, and this was most
disturbing.  There were flashes of depersonalization.  I saw rings
around the moon with prismatic colors, and there were long-lasting
Rafter-imagesS following any viewings of points of light.  I was still
a good plus 1 at 14 hours, but did manage to sleep.  It was the next
day before I was again at baseline.

(with 3.0 mg) This was a complex, but a very good day.  It involved
making a large pot of chicken-vegetable soup, and listening to H.L.,
my favorite Saturday morning fundamentalist Christian radio preacher,
bless Tim.  The Democrats are not exactly all anti-American dupes of
Moscow (or the Devil), but to H.L., they are practically, almost,
next-door to it.  The Rapture is supposed to happen tomorrow according
to a certain book, newly published (just in time, looks like) and he
is busy softening the possible disappointment of those who may find
themselves unchanged Monday morning.  Wunnerful.  It's been one heck
of a good experiment, and I canUt understand why we waited nine years
to try this gorgeous stuff.  Without going into the cosmic and
delicious details, let's just say itUs a great material and a good
level.

(with 0.5 mg of the RRS isomer) I am underway, and this is a smooth
intoxication.  I am completely functional, but still really a plus
two.  I would not choose to drive a car.  Not very far.  I felt a
rather quick dropping to a plus-one at the fifth hour, but there is a
residual stimulation still the following morning.

(with 1.0 mg of the RRS isomer) By the fourth hour I am absolutely a
+++ and am searching the kitchen for food.  But what I eat is only
so-so.  There is not the introspection or intensity of 2.0 milligrams
of the racemate material, but this is a rewarding place nonethless.
At the 18th hour, there was some fitful sleep, with bizarre dreams.
The next day I was still hungry for altered spaces, and successfully
challenged the residual plus one with LSD and, as is usually the case,
acid cut right through the detritus and allowed a direct shot up to a
+++ again.

(with 1.5 mg of the RRS isomer) This is a +++ but it is vaguely
irrational.  I feel a heavy body load, but then the temperature
outside is over a hundred degrees and I may not be in the best of all
physical environments.  I would not wish any higher dosage.  There
were cat-naps at the twelth hour, but most symptoms were still there
at the 18th hour.  A good experience.  It would be interesting to
compare this, some day, with 3.0 milligrams of the racemate.

(with 0.5 mg of the RSS isomer) There are no effects at all.

(with 1.0 mg of the RSS isomer) There is something warm and nice at a
couple of hours into this, but I am no more than threshold, and the
effects are very slight.  By the fifth hour there are no longer any
effects.

EXTENSIONS AND COMMENTARY: The stars had clearly lined up in favor of
making DOB and exploring its biological activity.  This preparation
had been completed in 1967 and the report of this compound and its
unprecedently high potency published in 1971.  And very shortly, two
additional papers appeared completely independently.  One described
DOB made via a different route, and describing high activity in rats.
The other described DOB and a couple of closely related brominated
amphetamines and their action in man.

This is one of the last of the experimental compounds within the
phenethylamine family on which any animal toxicity studies were
performed by me prior to human studies.  A mouse injected with 50
mg/Kg (ip) showed considerable twitching and was irritable.  Another,
at 100 mg/Kg (ip), had overt shaking at 20 minutes, which evolved into
persistent hyperactivity that lasted several hours.  Yet another, at
125 mg/Kg (ip), lost much of her righting reflex within 15 minutes,
entered into convulsions at 50 minutes, and was dead a half hour
later.  A fourth mouse, at 150 mg/Kg (ip), entered into spontaneous
convulsions within 10 minutes, and expired in what looked like an
uncomfortable death at 22 minutes following injection.  What was
learned?  That the LD/50 was somewhere between 100 and 125 mg/Kg for
the mouse.  And an effective dose in man of maybe 2 mg (for an 80 Kg
man) is equivalent to 25 ug/Kg.  Therefore the index of safety (the
therapeutic index, the lethal dose divided by the effective dose) is
well over a thousand.  I feel that two mice were killed without
anything of value having been received in return.

Actually, it is very likely that the damaging, if not lethal, level of
DOB in man is a lot lower than this ratio would imply.  There was a
report of a death of a young lady following the snorting of an amount
of DOB so massive, there was the actual recovery of over nine
milligrams of the drug from her body tissues in the post-mortem
examination.  It was said that she and her companion had thought that
the drug they were using was MDA and, taking a dosage appropriate for
this, effectively overdosed themselves.  He survived, following
convulsions and an extended period (several weeks) of being in a
comatose state.  Tragic examples have been reported that involve
arterial vascular spasm.  But in most overdose cases ascribed to DOB,
the identity of the drug has remained unestablished.

As with DOI, the presence of a heavy atom, the bromine atom, in DOB
makes the radioactive isotope labelled material a powerful research
tool.  Studies with DOB labelled with either 82Br or 77Br have been
used in human subjects to follow the distribution of the drug.  The
use of a whole body scanner permits the imaging of the intact body,
with the travelings of the radioactivity easily followed from outside.
A fascinating finding is that DOB goes first and foremost to the human
lung where it accumulates for a couple of hours.  It is only
afterwards that the brain level builds up.  There is a strong
implication that some metabolic conversion occurs in the lung, and it
is only after this that the truly active metabolite is available for
central action.  This is consistent with the relatively slow onset of
effect, and the very long duration of action.

As with all the other psychedelics which can and have been studied as
their optical isomers, it is the RRS isomer of DOB that is the more
active than the racemic mixture, and the RSS is certainly much less
active, but it has never been run up to fully active levels.  The
alpha-ethyl homologue of DOB is mentioned under ARIADNE.  The
positionally rearranged isomers of DOB are discussed under META-DOB.

 

 

 



#63 DOBU; 2,5-DIMETHOXY-4-(n)-BUTYLAMPHETAMINE

SYNTHESIS: A well stirred suspension of 140 g anhydrous AlCl3 in 400
mL CH2Cl2 was treated with 102 g butyryl chloride.  This mixture was
added in small portions, over the course of 20 min, to a well-stirred
solution of 110.4 g p-dimethoxybenzene in 300 mL CH2Cl2.  After an
additional 1 h stirring, the mixture was poured into 1 L H2O, and the
two phases separated.  The aqueous phase was extracted with 2x100 mL
CH2Cl2, and the organic fractions pooled.  These were washed with
4x125 mL 5% NaOH which removed both unreacted butyric acid as well as
a small amount of 2-hydroxy-4-methoxybutyrophenone.  Removal of the
CH2Cl2 under vacuum gave 156.7 g of a residue that was distilled at
170-178 !C at the water pump.  The isolated 2,5-dimethoxybutyrophenone
was a pale yellow oil that weighed 146 g and was about 85% pure by GC
analysis.  The principal impurity was unreacted dimethoxybenzene.  The
identical preparation with CS2 as a solvent, rather than CH2Cl2 gave a
somewhat smaller yield of product.

To 150 g mossy zinc there was added a solution of 3 g mercuric
chloride in 60 mL H2O, and this was swirled periodically for 2 h.  The
H2O was drained off, and the amalgamated zinc added to a 1 L
three-neck round-bottomed flask, treated with 80 mL concentrated HCl,
and heated on the steam bath.  A solution of 20.8 g of
2,5-dimethoxybutyrophenone in 45 mL EtOH containing 10 mL concentrated
HCl was added in increments over a 4 h period.  During this period an
additional 140 mL of concentrated HCl was added periodically to the
ketone solution.  Heating was maintained for an additional 4 h.  After
cooling, the aqueous filtrate was extracted with 3x100 mL CH2Cl2 and
these pooled extracts washed with 2x200 mL 5% NaOH to remove a small
amount of phenolic impurity.  After removal of the solvent under
vacuum, the residual 16.1 g of clear oil was distilled over the
100-160 !C range (largely at 141-145 !C) at the water pump to give 10
g of 2,5-dimethoxy-(n)-butylbenzene as a white oil.  This was about
90% pure by GC analysis, and was used without further purification in
the next step.

A mixture of 98 mL POCl3 and 108 mL N-methylformanilide was allowed to
incubate for 0.5 h.  To this there was then added 47.3 g of
2,5-dimethoxy-(n)-butylbenzene and the mixture heated on the steam
bath for 1.5 h.  This mixture was poured into 1 L H2O and stirred
overnight.  The H2O was drained from the extremely gooey black
crystals that were formed, and extracted with 2x100 mL portions of
hexane.  The black residue was diluted with these extracts and, on
slow evaporation there was deposited 26.4 g of oily amber crystals.
Filtering these through a medium porous funnel and sucking the oily
phase away from the solids yielded 14.8 g of yellow crystals that
could be recrystallized from 50 mL MeOH to give, after filtration and
air drying to constant weight, 6.4 g of
2,5-dimethoxy-4-(n)-butylbenzaldehyde as pale yellow crystals with a
mp of 47-48 !C.  The recovery of all organic soluble things from the
above process gave, after removal of the extraction solvents and
making boiling hexane extractions of the residues, a second crop of
aldehyde of equal weight and of identical mp.  An analytical sample,
from hexane, had the same mp.  Anal. (C13H18O3) C,H.

A solution of 13.2 g 2,5-dimethoxy-4-(n)-butylbenzaldehyde in 50 mL
acetic acid was treated with 4.0 g anhydrous ammonium acetate and 10
mL nitroethane.  This mixture was heated on the steam bath for 4 h,
then poured into a large quantity of H2O.  This was extracted with
2x200 mL CH2Cl2, the extracts washed with H2O, and the solvent removed
to give 19 g of a deep red oil.  This was dissolved in 35 mL hot MeOH
and slowly cooled, depositing yellow-orange crystals.  These were
removed by filtration, washed with cold MeOH, and air-dried to
constant weight.  Thus there was obtained 11.8 g of
1-(2,5-dimethoxy-4-(n)-butylphenyl)-2-nitropropene with a mp of 54-56
!C.  Recrystallization of an analytical sample from MeOH tightened the
mp to 55-56 !C.  Anal. (C15H21NO4) C,H,N.

To a gently refluxing suspension of 8.5 g LAH in 300 mL anhydrous Et2O
under a He atmosphere, there was added 11.0 g
1-(2,5-dimethoxy-4-(n)-butylphenyl)-2-nitropropene by allowing the
condensing ether to drip into a Soxhlet thimble containing the
nitrostyrene, thus effectively adding a warm saturated solution of it
dropwise.  Refluxing was maintained overnight, and the cooled reaction
flask stirred for several additional days.  The excess hydride was
destroyed by the cautious addition of 600 mL H2O containing 55 g
H2SO4.  When the aqueous and Et2O layers were finally clear, they were
separated, and 250 g of potassium sodium tartrate was dissolved in the
aqueous fraction.  Aqueous NaOH was then added until the pH was above
9, and this was then extracted with 3x200 mL CH2Cl2.  Evaporation of
the solvent produced 12 g of an amber oil that gelatinized to a waxy,
amorphous mass.  This was leached as thoroughly as possible with
anhydrous Et2O which was clarified by filtration, then saturated with
anhydrous HCl gas.  After a few minutes delay, there commenced the
separation of fine white crystals of
2,5-dimethoxy-4-(n)-butylamphetamine hydrochloride (DOBU).  These
weighed, after filtration, Et2O washing, and air drying to constant
weight, 5.8 g.  Recrystallization from boiling CH3CN (this is an
unusually exothermic crystallization) yielded 5.4 g of a fluffy white
product with mp 151-152 !C.  Anal. (C15H26ClNO2) C,H,N.

DOSAGE: uncertain.

DURATION: very long.

QUALITATIVE COMMENTS: (with 2.2 mg) It was almost the fourth hour
before I noticed something.  Then I felt an increasing manic
intoxication, winding up tighter and tighter.  Sleep was impossible
until some 18 hours after the start of the trial.  There was some
paresthesia, but no mydriasis.  This might be a stimulant, but it is
not a psychedelic, at least at this level.  Go up slowly.

(with 2.8 mg) Nothing for over seven hours.  Then there was what
seemed to be an irritability and shortness of temper.  Mentally I am
completely clear, but no more alert than usual.  There was no sleep
that evening, and the next day there was a feeling of overall
depression.  Perhaps that was due to the lack of sleep, but there were
no signs of residual sleepiness.

EXTENSIONS AND COMMENTARY: It is not possible to give a dosage range
for DOBU.  There is no question but that whatever is occurring is slow
of onset, and very long lived.  In general, the effects resemble
stimulation more that anything else.

A butyl group has four carbons, and they can be interconnected in four
ways (as long as you donUt connect them in rings).  If all four of
them are in a straight chain, you have the so-called normal butyl (or
n-butyl) group, and this is the exact arrangement that is found in the
DOBU.  The atoms can be numbered #1 through #4, going outwards from
the point of attachment.  The chain can, however, be only three
carbons long, and the fourth or extra carbon attached on the #2 carbon
atom; this is called the iso-butyl (or i-butyl) group.  Or the extra
left-over carbon can be attached to the #1 carbon atom; this is called
the secondary butyl (or sec-butyl or s-butyl) group.  Or lastly, the
atoms can be all scrunched up, with the chain only two carbons long,
and the other two left-over methyl carbons attached to the #1 carbon
atom.  This isomer is called the tertiary butyl (or tert-butyl or
t-butyl) group.  In animal studies, and in preliminary human studies,
the activity of these compounds drops as the butyl group gets more and
more scrunched.

The isomer with the iso-butyl group has been synthesized by the
Friedel- Crafts reaction of isobutyryl chloride with
p-dimethoxybenzene, followed by reduction of the ketone to an alcohol,
dehydration to a dimethylstyrene, and final hydrogenation to a
hydrocarbon.  The formation of the benzaldehyde, reaction with
nitroethane, and final lithium aluminum hydride reduction to
2,5-dimethoxy-4-(2-methylpropyl)-amphetamine hydrochloride (DOIB, mp
164-166 !C) were completely conventional.  In drug discrimination
studies in rats, DOIB was only a third as active as DOM, and in humans
the activity falls in the 10 to 15 milligram area.  The isomer with
the sec-butyl group was made in a somewhat similar manner, from
2,5-dimeth-oxyacetophenone.  The addition of ethyl magnesium bromide
gave an alcohol which with dehydration yielded a pair of
dimethylstyrenes isomeric to the compound mentioned above.  From there
an identical sequence of steps (hydrogenation, benzaldehyde synthesis,
nitrostyrene, and lithium aluminum hydride reduction) produced
2,5-dimethoxy-4-(1-methylpropyl)amphetamine hydrochloride (DOSB, mp
168-170 !C.).  In the rat studies it was only a twelfth the potency of
DOM, and in man the active dose is in the 25 to 30 milligram area.  As
with the normal butyl compound, there is a strong stimulation factor,
with real and long-lasting sleep disturbance.

The last of the butyl isomers, the tert-butyl compound, was made from
a much more obvious starting material.  This is the commercially
available tert-butyl hydroquinone.  It was methylated in sodium
hydroxide with methyl iodide, and then carried through the above
sequence (benzaldehyde. mp 124 !C from cyclohexane, nitrostyrene,
yellow crystals from methanol, mp 95-96.5 !C, and lithium aluminum
hydride reduction) to give
2,5-dimethoxy-4-(1,1-dimethylethyl)amphetamine hydrochloride (DOTB, mp
168 !C).  Rats trained in a process called the Sidman Avoidance
Schedule gave behavior that suggested that DOTB had no activity at
all, and in human trials, doses of up to 25 milligrams were totally
without effect.

An effort was made to prepare a butyl analogue containing a ring, but
it was never completed.  This was the cyclopropylmethyl isomer,
2,5-dimethoxy-4-cyclo-propylmethylamphetamine hydrochloride, DOCPM.
Only the first step of its synthesis was complete (the reaction of
cyclopropylcarboxylic acid chloride with p-dimethoxybenzene) and even
it went badly.  The desired ketone (2,5-dimethoxyphenyl cyclopropyl
ketone) was most difficult to separate from the recovered starting
ether.  A promising approach would be the isolation of the phenol
(2-hydroxy-5-methoxyphenyl cyclopropyl ketone) which is a beautiful
yellow solid with a melting point of 99-100 !C from methanol.  Anal.
(C11H12O3) C,H.  It then could be methylated to the wanted
intermediate.  It is the major product when the reaction is conducted
with anhydrous aluminum chloride in methylene chloride.

The 2-carbon phenethylamine homologues of these compounds could all,
in principle be easily made by using nitromethane instead of
nitroethane with the intermediary benzaldehydes.  But, as of the
present time, none of them have been made, so their pharmacology
remains completely unknown.

 

 

 



#64 DOC; 2,5-DIMETHOXY-4-CHLOROAMPHETAMINE

SYNTHESIS: A solution of 6.96 g 2,5-dimethoxyamphetamine hydrochloride
(2,5-DMA) in 250 mL H2O was made basic with aqueous NaOH and extracted
with 3x75 mL CH2Cl2.  After removal of the solvent from the pooled
extracts under vacuum, the residual free base was dissolved in 36 g
glacial acetic acid and, with good stirring, cooled to 0 !C with an
external ice bath.  There was then added, with a Pasteur pipette, 3 mL
of liquid chlorine.  The generation of HCl was evident, and the
reaction was allowed to stir for an additional 3 h.  The mixture was
then poured into 300 mL H2O and washed with 3x100 mL Et2O.  The
aqueous phase was made basic with NaOH and extracted with 3x150 mL
CH2Cl2.  After removal of the solvent from the pooled extracts, the
residue was dissolved in Et2O and saturated with anhydrous HCl gas.
There was the formation of a heavy oily precipitate.  The ether
supernatent was decanted, and the residue was intimately mixed with
200 mL of fresh anhydrous Et2O.  Everything set up as an off-white
crystalline mass weighing 2.3 g.  This was dissolved in 12 mL of
boiling MeOH and diluted with 230 mL boiling Et2O.  The clear solution
was quickly filtered to give a clear, pale amber mother liquor, which
soon started depositing lustrous white crystals.  After filtering,
Et2O washing, and air drying to constant weight, there was obtained
1.4 g of 2,5-dimethoxy-4-chloroamphetamine hydrochloride (DOC) From
the mother liquors (from the original HCl saturation) an equal amount
of product could be obtained by exploiting the acetone insolubility of
the hydrochloride salt of the product.  The published mp of this salt,
from acetone/EtOH, is 187-188 !C.  A sample of this hydrochloride
salt, prepared from the amino analogue via diazotization and eventual
hydrolysis of an acetylated precursor, was recrystallized from
EtOH/ether and had a mp of 193-194.5 !C.

DOSAGE: 1.5 - 3.0 mg.

DURATION: 12 - 24 h.

QUALITATIVE COMMENTS: (with 1.6 mg) I was hit with a slightly light
head; the effects were quite real.  I was disconnected, and somehow
spacey, but this was a favorable spacey which was kind of fun.
Somewhere at about the sixth hour I realized that I was beginning to
drop off a bit, but six hours later yet, there was still a lot of
memory.  This is a long thing.

(with 2.4 mg) This is what I might call an archetypical psychedelic.
Everything is there in spades, with few if any of the subtle graces,
the Tgentle imagesU and Tgentle fantasiesU of the 2-carbon
phenethylamines.  This is the works.  There are visuals, and there are
interpretive problems with knowing just where you really are.  The
place where nothing makes sense, and yet everything makes sense.  I
have just slept for a few hours, and now I am awake and it has been
eighteen hours, and there is a lot still going on, although I have a
relaxed, good feeling.  Anyone who uses this had better have 24 hours
at their disposal.

(with 2.4 mg) Here I am at the sixth hour, and I am still roaring
along at a full plus three.  I have established that this material is
neither anti-erotic nor anorexic.  The body is very comfortable, and
so is the mind.  There is an interesting aspect, perhaps peculiar only
to this experiment and under these conditions.  With my eyes closed
the fantasy is a completely dark screen, lovely and seductive, subtle,
and yet light must be deliberately brought in.  This is not in any way
negative for being in the dark, but is just unusual.  I will have to
try this in the daylight next time, to see what the eyes-closed brings
to the mind-screen.  At 24 hours, I have found that my sleep was not
too great.  My dreams were tight, and I kept defending against
trouble; the nervous system was too alert.  I was in a good humor,
though, and I still am.  This is excellent stuff, but start early in
the day.

EXTENSIONS AND COMMENTARY: It is clear that the three halo-amphetamine
derivatives, DOI, DOB and DOC, are all pretty much of the same
potency.  And all of them very long lived.  The difference between the
various halogen atoms was brought up under the 2C-C discussion.  DOC
is clearly a long-lasting, dyed-in-the-wool psychedelic.

In the making of this, by the procedures that have been followed in
Canada, there are two chemical intermediates which might, some day, be
looked at as potential psychedelics under their own colors.  Reduction
of the compound that is called DON in this Book II
(2,5-dimethoxy-4-nitroamphetamine hydrochloride) with Pd/charcoal and
hydrogen, gives the 4-amino derivative.  This is
2,5-dimethoxy-4-aminoamphetamine dihydrochloride, DOA, which melts at
248-250 !C.  And the reduction of an oxime intermediate gives rise to
the acetamido analogue, 2,5-dimethoxy-4-acetamidoamphetamine
hydrochloride, DOAA, with a mp of 249-250 !C.  Neither compound has
been tasted, but someday this omission will be corrected.  DOA and
DOAA have a sinister ring to them, however, and some changes of
terminology might be needed.  DOA, in the coroner's vocabulary, means
Dead-On-Arrival.  But then, AMA (the American Medical Association)
just happens to also mean (in the jargon of emergency medicine)
Against-Medical-Advice.  Everything averages out, somehow.  Remember
that the amyl homolog (amyl at the 4-position) follows the 4-letter
convention of all of the DOM homo-logues, and has the code name of
DOAM.  Thus, DOA, amino; DOAA, acetamido, and DOAM, amyl.

One must learn to keep one's sense of humor.  The immortal humorist
Wavy Gravy once said, RIf you canUt laugh at life, it just isnUt funny
anymore.S The code name of this compound,
2,5-dimethoxy-4-chloroamphetamine is, after, all, DOC.  This should
certainly appeal to some physicians.

 

 

 



#65 DOEF; 2,5-DIMETHOXY-4-(2-FLUOROETHYL)-

AMPHETAMINE

SYNTHESIS: A well-stirred solution of 0.45 g free base DOB in 2 mL
CH2Cl2 was treated with 0.37 g triethylamine, cooled to 0 !C, and
there was then added a solution of 0.39 g
1,1,4,4-tetramethyl-1,4-dichlorodisilylethylene in 2 mL CH2Cl2.  The
reaction mixture was allowed to return to room temperature, with
stirring continued for 2 h.  The solvent was removed under vacuum, the
residue suspended in hexane, and the insoluble by-products removed by
filtration through celite.  Removal of the solvent under vacuum gave
0.60 g
1-(4-bromo-2,5-dimethoxyphenyl)-2-(1-aza-2,5-disila-2,2,5,5-tetramethylcyclopentyl)propane
as a gold-colored impure semi-solid mass which was used without
further purification.

To a solution of 0.60 g
1-(4-bromo-2,5-dimethoxyphenyl)-2-(1-aza-2,5-disila-2,2,5,5-tetramethylcyclopentyl)propane
in 10 mL anhydrous Et2O under an inert atmosphere and cooled to -78 !C
there was added 1.8 mL of a 1.7 M solution of t-butyl lithium in
hexane.  The resulting yellow solution was stirred for 20 min, and
then treated with 1.65 mL of a 1.4 M solution of ethylene oxide in
Et2O, the stirring was continued for 40 min, then the reaction mixture
allowed to come to room temperature over an additional 40 min.  There
was added 20 mL hexane, and the temperature increased to 50 !C for an
additional 2 h.  The reaction mixture was treated with 3 mL H2O and
diluted with 60 mL Et2O.  The organic phase was washed with saturated
NH4Cl, dried over anhydrous MgSO4, and after filtering off the
inorganic drying agent, the organic solvents were removed under
vacuum.  The gold-colored residual oil was dissolved in 10 mL MeOH and
treated with a 10% KOH.  This mixture was heated for 30 min on the
steam bath, returned to room temperature, and the volatiles removed
under vacuum.  The residue was dissolved in 3% H2SO4, washed twice
with CH2Cl2, brought to pH 12 with 25% NaOH, and extracted with 3x50
mL CH2Cl2.  The pooled extracts were combined, dried with anhydrous
Na2SO4, and the solvent removed under vacuum to give 0.24 g of
2,5-dimethoxy-4-(2-hydroxyethyl)amphetamine (DOEH) as a white solid
with a mp of 102-104 !C.

To a suspension of 0.94 g DOEH in ice-cold anhydrous Et2O containing
1.4 g triethylamine, there was added 2.4 g trifluoroacetic anhydride
dropwise over the course of 10 min.  The reaction mixture was brought
to reflux temperature, and held there with stirring for 1 h.  After
cooling, 60 mL of CH2Cl2 was added, and the organic phase washed with
saturated NaHCO3.  The solvent was removed under vacuum, providing a
gold-colored solid as a residue.  This was dissolved in 50 mL MeOH,
diluted with 30 mL H2O and, following the addition of 0.76 g solid
NaHCO3 the reaction mixture was stirred at room temperature for 3 h.
The excess MeOH was removed under vacuum, and the remaining solids
were suspended in CH2Cl2 and washed with H2O.  After drying the
organic phase with anhydrous Na2SO4 and removal of the solvent under
vacuum, there was obtained 1.34 g
1-(2,5-dimethoxy-4-(2-hydroxyethyl)phenyl)-2-(2,2,2-trifluoroacetamido)propane
as white solid with a mp of 129-131 !C.  Anal. (C15H20F3NO4) C,H.

A well-stirred solution of 0.09 g
1-(2,5-dimethoxy-4-(2-hydroxyethyl)phenyl)-2-(2,2,2-trifluoroacetamido)propane
in 15 mL CH2Cl2 was cooled to -78 !C and treated with 0.05 g
diethylaminosulfur trifluoride (DAST) added dropwise.  The pale yellow
reaction solution was stirred an additional 5 min and then brought up
to room temperature and stirred for 1 h.  There was then added
(cautiously) 3 mL H2O followed by additional CH2Cl2.  The phases were
separated, the organic phase washed with H2O, dried with anhydrous
Na2SO4 and, after filtering off the drying agent, stripped of solvent
under vacuum.  There was thus obtained 0.088 g of
1-[2,5-dimethoxy-4-(2-fluoroethyl)phenyl]-2-(2,2,2-trifluoroacetamido)propane
as a white solid with a mp of 102-104 !C.

A solution of 0.12 g
1-[2,5-dimethoxy-4-(2-hydroxyethyl)phenyl]-2-(2,2,2-trifluoroacetamido)propane
in a mixture of 5 mL CH2Cl2 and 5 mL IPA was treated with 0.2 mL 2 N
KOH, heated on the steam bath for 30 min, and then stripped of
solvents under vacuum.  The residue was suspended in CH2Cl2 and washed
with 20% NaOH.  The organic phase was dried with anhydrous Na2SO4
which was removed by filtration, and the combined filtrate and
washings stripped of solvent under vacuum.  The residual glass (0.08
g) was dissolved in IPA, neutralized with concentrated HCl and diluted
with anhydrous Et2O to provide
2,5-dimethoxy-4-(2-fluoroethyl)amphetamine hydrochloride (DOEF) as a
white crystalline solid with a mp of 205-208 !C.  Anal. (C13H21ClFNO2)
C,H.

DOSAGE: 2 - 3.5 mg.

DURATION: 12 - 16 h.

QUALITATIVE COMMENTS: (with 2.2 mg) Somewhere between the first and
second hour, I grew into a world that was slightly unworldly.  Why?
That is hard to say, as there was no appreciable visual component.  I
just knew that the place I was in was not completely familiar, and it
was not necessarily friendly.  But it was fascinating, and the music
around me was magical.  Time was moving slowly.  I had to drive across
the bay at about ten hours into this, and I was comfortable.  That
evening I slept well, but my dreams were pointless.

(with 3.0 mg) It took almost three hours to full activity.  The first
signs of effects were felt within a half hour, but from then on the
progress was slow and easy, without any discernible jumps.  There was
absolutely no body discomfort at all.  Completely comfortable.  There
was a general humorousness about my state of mind which is always a
good sign.  We went to the bedroom at the two and a half hour point,
and proceeded to establish that the material is far from anti-erotic.
Beautiful response, without a mention of any feeling of risk at
orgasm.  I myself was not able to reach orgasm until about 5th to 6th
hour, and then it was full and exceptionally delicious.  So was the
second one, a couple of hours later, if I remember correctly.  All
systems intact, body, mind and emotion.  Gentle.  Good for writing.
No dark corners apparent at all.  For me, not highly visual.  Would
take again, higher.

(with 3.0 mg) There was no body threat at any time Q very
comfortable.  Good eyes closed, with complex imagery to music, but not
too much with eyes-open.  My attention span is relatively short, and
easily diverted into new directions Q all quite reminiscent of DOI
both as to dosage and effect.  At 13 hours, I am still too alert to
sleep, but a couple of hours later, OK.  In the morning there is still
a trace of something going on.  This was a valid +++.

EXTENSIONS AND COMMENTARY: I was asked by a student of mine a while
ago, when I told him of this material, just why would anyone just
happen to place a fluorine atom at the end of the 4-ethyl group of
DOET?  It wasnUt the sort of thing that someone would just happen to
do.  If there were a rationale, then that's fine.  But by capricious
impulse, no.  But there is a rationale of sorts, which I just hinted
at in the discussion under 2C-T-21.

This argument of reason goes as follows.  Assume that I would like to
put a fluorine atom into a drug that does not normally have one.  Why
would I want to?  Because I want to have the molecule carry a
radioactive fluorine atom into some inner recess of the brain.  Why?
Because by using a positron-emitting fluorine I could possibly
visualize the area of the brain that the drug went to.  And if it went
there in some abnormal way, the exact measure of that abnormality
might give some clue as to potential brain misfunctioning.

But, if you put a fluorine atom on a drug, it becomes a totally new
drug and, quite reasonably, a pharmacologically different drug.
However, a body of evidence is being accumulated that if a halogen,
such as a bromine or an iodine atom, is replaced by a beta-fluoroethyl
group, the electronic and polar properties of the drug can be pretty
much the same.  So, what psychedelics have a bromo or an iodo group?
Obviously, DOB and DOI.  Thus, DOEF is a natural candidate for
fluorine-18 positron emission tomography, and also a natural candidate
for clinical trials.  And, voila, it is an active material.

And IUll bet you dollars to doughnuts, that if one were to make the
two-carbon analog 2,5-dimethoxy-4-(2-fluoroethyl)-phenethylamine, it
would be every bit as much a treasure and ally as is 2C-B or 2C-I.  In
fact, I am sure enough about this prediction that I am willing to name
the stuff 2C-EF.  It will be easily made from 2C-B by the same
reaction scheme that was used above for DOEF.  And I will even guess
that its activity level will be in the 20-30 milligram area.

 

 

 



#66 DOET; HECATE; 2,5-DIMETHOXY-4-ETHYLAMPHETAMINE

SYNTHESIS: To a solution of 19.7 g 2,5-dimethoxy-4-ethylbenzaldehyde
(see the recipe for 2C-E for its preparation) in 72 g glacial acetic
acid there was added 6.5 g anhydrous ammonium acetate and 10.2 g
nitroethane.  After heating for 1.75 h on the steam bath, the reaction
mixture was cooled in a wet ice bath, diluted with 10 mL H2O, and
seeded with a small crystal of product.  The yellow crystals were
removed by filtration (7.6 g wet with acetic acid) and another 2.25 g
was obtained from the mother liquors with additional H2O.  The
combined fractions were recrystallized from 25 mL boiling MeOH, to
give 6.5 g fine yellow crystals of
1-(2,5-dimethoxy-4-ethyl)-2-nitropropene, with a mp of 67.5-68.5 !C.
Anal. (C13H17NO4) C,H,N.

A suspension of 6.5 g LAH in 500 mL well stirred anhydrous Et2O was
held at reflux under an inert atmosphere, with the return of the
condensed solvent passing through a Soxhlet thimble containing 6.5 g
1-(2,5-dimethoxy-4-ethylphenyl)-2-nitropropene.  After the addition of
the nitrostyrene was complete, the stirred suspension was maintained
at reflux for an additional 18 h, then cooled to room temperature.
The excess hydride was destroyed with 500 mL 8% H2SO4, added
cautiously until the hydrogen evolution ceased, then at a speed that
allowed the formed solids to disperse.  The phases were separated, the
aqueous phase washed once with Et2O, treated with 150 g potassium
sodium tartrate, and finally made basic (pH >9) with 5% NaOH.  This
was extracted with 3x100 mL CH2Cl2, the extracts pooled, and the
solvent removed under vacuum.  The residue, 7.9 g of a clear oil, was
dissolved in 100 mL anhydrous Et2O and saturated with anhydrous HCl
gas.  After standing at room temperature for 2 h, the crystalline
2,5-dimethoxy-4-ethylamphetamine hydrochloride (DOET) was removed by
filtration, washed with Et2O, and air dried to constant weight.  There
was obtained 5.9 g of lustrous white crystal with a mp of 190-191 !C.
Recrystallization from CH3CN or EtOAc increased the mp to 194-195 !C.
Anal. (C13H22ClNO2) C,H,N.

DOSAGE: 2 - 6 mg.

DURATION: 14 - 20 h.

QUALITATIVE COMMENTS: (with 1.0 mg) This was a very gentle, relaxing
level, but there were no psychedelic effects that were apparent.
Easy, and relaxed, and I am in no way intoxicated or turned on.  But I
was in the throes of my menstrual period, and the cramps (and the
accompanying irritability) were completely knocked out.  Perhaps this
is why I felt so relaxed and at peace.

(with 2.5 mg) There is much, too much, movement with my eyes closed.
And an awful lot there with my eyes open.  The movement on the
concrete floor in the basement when I went downstairs for wood for the
fireplace, was too much.  I felt almost sea-sick.  And I am having
reality problems Q I cannot seem to find my centering point of
reference.  There has to be a place to pin myself down to, and it is
not findable anywhere I look.  And my legs are twitching, and feeling
as if they are falling asleep, and I had a crawling sensation on my
body, so the body is not at peace either.  In the morning I was still
++, but there is a clear indication that I am repairing.  Anyway, I
survived the experience.  This is definitely not my thing.

(with 4 mg) Just after an hour into the experiment, I was surprised
by the awareness of some effects Q I had forgotten that I had taken
something.  At the second hour, it was real, but subtle.  As a
psychotomimetic or STP-like thing, there is very little there.  But as
a mood energizer, it is really a ++ or more.  The clinical literature
is right Q none of the hallucinogenic effects, but one brings into
play whatever one wants to.  Worked at cleaning up the office until 11
PM.  I slept well.  This has none of the LSD or STP seriousness.

(with 6 mg) The onset was slow, and subtle.  But the effects are
fully there in about three or so hours.  Everything I smelled was
vivid, as are all the colors and shapes; they are clean, beautiful,
serenely self-contained.  No visual movement.  The eyes-closed fantasy
images tend to take off on their own, however, and they are extremely
rich.  I donUt see any dark corners.  I believe it might well be
possible to be creative with this, and there is no suggestion of body
depletion, of body load.

(with 7 mg) A hot day.  Unbelievably lovely erotic-to-divine, deep
loving, open, not much visual, eyes-closed form-image-symbol.  Sleep
attempts very shallow, slight TthinnessU, with an anticipation of
darts.  Intellect and feeling-emotion area intact and functioning at
all times.  Next morning still at a plus one.  Incredible material.
Perhaps best at 6 to 7 milligrams, no higher due to body load.

EXTENSIONS AND COMMENTARY: The original code for this compound was
DOE, which was completely logical based on DOM being the methyl member
of this series (DO for the removal of the oxygen, desoxy, and M for
putting a methyl in its place).  And the putting of the ethyl thence
should be DOE.  This was fine until it was pointed out to me by a
close colleague that DOE was a classic abbreviation for
desoxyephedrine, a synonym for methamphetamine.  The pressure to add
the RTS of the RETS of the ethyl was heightened by looking ahead to
other members of the series.  DOA became DOAM, DOE became DOET, but
DOM was already too firmly set in popular usage.  And, anyway, DOME
really looked strange.

The original publications of the action of DOM clearly documented the
compound as being a psychedelic and one with a sizeable measure of
potential abuse.  And, it is not a surprise that it was quickly
shuffled into a legal classification that effectively precluded any
further study of it.  So, when this immediate homologue of DOM was
studied and discussed in the literature, all reported dosages were
those that were at the lowest levels, and no disturbing hints of
abusability were mentioned.  And this particular homologue has so far
escaped the attention and restrictive action of the drug enforcement
agencies, although the specific wording of the Controlled Substance
Analogue Enforcement Act of 1986 might make this point moot, at least
as far as human trials are concerned.  At modest levels, DOET has the
reputation of being a cognitive enhancer and is largely free of those
sensory distortions that would catch the attention of the authorities
who cannot tolerate drugs that distort the senses.  The higher levels
mentioned here have never been put into the published literature.  It
must be noted that there is a considerable variation of individual
responses to this material.  The effective dose range stated is quite
broad.  Some people are quite sensitive.  This is, after all, one of
the Classic Ladies, namely HECATE.

The young experimental subject who had the dramatic relief from
menstrual cramps at the one milligram dose tried the compound again
the following month, and again had complete relief.  But another
volunteer, also plagued with severe cramping at that particular time
of month, found no relief at all.  A 50% success rate.  No one else
has, to my knowledge, explored this particular property.

 

 

 



#67 DOI; 2,5-DIMETHOXY-4-IODOAMPHETAMINE

SYNTHESIS: A mixture of 14.8 g phthalic anhydride and 19.5 g of
2,5-dimethoxyamphetamine (2,5-DMA) as the free base was heated
gradually to about 150 !C with an open flame.  A single clear phase
was formed with the loss of H2O.  After the hot melt remained quiet
for a few moments, it was allowed to cool to about 50 !C and then
diluted with 100 mL of hot MeOH.  The solution was stirred until
homogenous, seeded with product, and then cooled in an ice bath to
complete the crystallization.  After removal of the product by
filtration, washing sparingly with MeOH, and air drying, there was
obtained 24.6 g of N-(1-(2,5-dimethoxyphenyl)-2-propyl)phthalimide as
off-white crystals, with a mp of 105-106 !C.  Anal. (C19H19NO4) C,H,N.

To a solution of 2.0 g N-(1-(2,5-dimethoxyphenyl)-2-propyl)phthalimide
in 15 mL warm acetic acid which was being vigorously stirred, there
was added a solution of 1.2 g iodine monochloride in 3 mL acetic acid.
This was stirred for 2 h at about 40 !C during which time there was a
definite lightening of color, but no solids formed.  The reaction
mixture was poured into 600 mL H2O which produced a reddish glob
floating in a yellow-orange opaque aqueous phase.  The glob was
physically removed, dissolved in 30 mL boiling MeOH which, on cooling
in an ice bath, deposited off-white crystals.  These were removed by
filtration, washed with MeOH, and air dried to give 1.5 g of
N-[1-(2,5-dimethoxy-4-iodophenyl)-2-propyl]phthalimide as fine white
crystals with a slight purple cast.  The mp was 103-105.5 !C and the
mixed mp with the starting non-iodinated phthalimide (mp 105-106 !C)
was depressed (85-98 !C).  Extraction of the aqueous phase, after
alkalinification, provided an additional 0.15 g product.  Anal.
(C19H18NO4) C,H,N.

A solution of 0.75 g
N-(1-(2,5-dimethoxy-4-iodophenyl)-2-propyl)phthalimide in 10 mL EtOH
was treated with 0.3 mL of hydrazine hydrate, and the clear solution
was held at reflux on the steam bath overnight.  After cooling, there
was a crystallization of 1,4-dihydroxyphthalizine that started as
small beads but finally became extensive and quite curdy.  These
solids were removed by filtration and had a mp of about 340 !C
(reference samples melted over a five to ten degree range in the area
of 335-350 !C).  The filtrate was dissolved in 100 mL CH2Cl2 and
extracted with 2x150 mL 0.1 N HCl.  The aqueous extracts were washed
once with CH2Cl2, made basic with 5% NaOH, and extracted with 3x100 mL
CH2Cl2.  Removal of the solvent under vacuum gave 0.5 g of a colorless
oil which was dissolved in 300 mL anhydrous Et2O and saturated with
anhydrous HCl gas.  There was obtained, after filtration, and air
drying, 0.35 g of 2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI)
as white crystals that melted at 200.5-201.5 !C.  This value did not
improved with recrystallization.  Anal. (C11H17ClINO2) C,H,N.

DOSAGE: 1.5 - 3.0 mg.

DURATION: 16 - 30 h.

QUALITATIVE COMMENTS: (with 0.6 mg) There was a nice spacey
light-headedness for a few hours, and time seemed to move quite
slowly.  Then a generic sadness came over me, as I reminisced about
earlier days (recalling pleasures now gone) and wondered if I would be
allowed to be here on the Farm when I am old and not important.  There
is so much to be done, and I cannot do it all, and no one else cares.
My mood became present-day and healthy by about the seventh hour.

(with 1.6 mg) The general nature of the experience was depressing,
with a sad view of life.  There was no way I could connect with my
emotions.  Even my sadness was vague.  At about the ninth hour I
decided that enough was enough, and this strangely disappointing
about-plus-two was aborted with 125 micrograms of LSD.  The emotions
became present and living within a half hour.  I was greatly relieved.
The erotic was not a mechanical attempt but a deeply involved feeling
with an archetype of orgasm easily available.  It was shaped like a
flower, richly colored, with an unusual RSS shape to it.  This was a
lovely end to a difficult day.

(with 3.0 mg) This is a clear, clean psychedelic.  The eyes-closed
imagery is excellent, with clearly delineated patterns, pictures, and
colors.  Perfect for an artist, and next time IUll devote some time to
painting.  Total ease for the body, but no help for my smoking
problem.  I still want to smoke.  And at sixteen hours into this I am
still at 1.5+ but IUll try to go to bed anyway, and sleep.

(with 3.5 mg) I was at a full crashing +++ for about three or four
hours.  There was none of the LSD sparkle, but there were moments of
Tlight-headednessU where one could move sideways with reality.  I
could leave where I was right over there, and come over here and get a
strange but authentic view of where the TthereU was that I had left.
It would be out-of-body, except that the body came over here with me
rather than staying there.  This doesnUt make sense now, but it sure
did then.  There was no trace of body impact, and I slept late that
evening, but with some guardedness due to the intense imagery.  This
was no more intense than with 3.0 milligrams, but it was a little bit
more to the unreal side.

(with 1.0 mg of the RRS isomer) There was a clear ++ from the second
to the eighth hour, but somehow there was not quite the elegance or
the push of the racemate.  I was sensible, and managed to do several
technical chores in a reasonable way.  Easy sleep at 15 hours into
it.

(with 2.3 mg of the RRS isomer) The water solution of the
hydrochloride salt has a slightly sweetish taste!  I was at a +++
without question, but there was a slight down mood towards the end.
And it lasted a really long time; I was distinctly aware of residual
stuff going on, well into the next day.

(with 6.3 mg of the RSS isomer) I was at a benign one-and-a-half plus
at about two hours, and finally flattened out at a ++.  Would I double
this dose?  Probably not, but half again (to 9 or 10 milligrams) would
feel safe for a plus 3.  By evening I was near enough baseline to
drive into town for a social obligation, but even when trying to sleep
later that night there was some residue of imagery; remarkably, it was
all in slow motion.  The fantasies were slow-paced and sluggish.  It
would have been interesting to have explored eyes-closed during the
day.

EXTENSIONS AND COMMENTARY: Again, as with every other psychedelic
amphetamine analogue which has a chiral center and has been explored
as the individual optical isomers, it is the RRS isomer that is the
more potent.  And again, the other isomer, the RSS isomer, still shows
some activity.  The same was true with DOB, and DOM, and MDA.  The
only exception was MDMA, but then that is more of a stimulant, and
there is virtually no psychedelic component to its action.  Rat
studies, where there is a measure of the discrimination of a test
compound from saline, have shown the RRS isomer to have about twice
the potency of the RSS isomer.  That the RRS is more potent is
certain, but the above reports would suggest that the factor would be
closer to times-four rather than times-two.

A number of studies with DOI in animal models have shown it to have an
extremely high binding capacity to what are called the 5-HT2
receptors.  Serotonin is a vital neurotransmitter in the brain, and is
strongly implicated in the action of all of the phenethylamine
psychedelics.  The place where it acts, at the molecular level, is
called its receptor site.  As an outgrowth of the cooperative studies
of the medicinal chemists working closely with the
neuropharmacologists, a number of compounds have emerged that interact
with these sites.  But this one interacts with these sites and not
those, and that one interacts with those sites and not these.  So,
there has developed a collection of sub-divisions and sub-subdivisions
of receptor sites, all related to serotonin, but each defined by the
particular compound that interacts most tightly with it.

Thus, there were serotonin R1S receptors, and then there were R1S and
R2S receptors, and then R1a and R1bS and R2aS and R2bS receptors, and
on and on.  These are called 5-HT receptors, since the chemical name
for serotonin is 5-hydroxytryptamine, and the scientist would never
want to let the layman know just what he is talking about.  DOI has
been synthesized with a variety of radioactive iodine isotopes in it,
and these tools have been of considerable value in mapping out its
brain distribution.  And by extrapolation, the possible localization
of other psychedelic compounds that cannot be so easily labelled.  A
small neurochemical research company on the East Coast picked up on
these properties of DOI, and offered it as a commercial item for
research experiments.  But I doubt that they are completely innocent
of the fact that DOI is an extremely potent psychedelic and that it is
still unrecognized by the Federal drug laws since, in their most
recent catalog, the price had almost doubled and a note had been added
to the effect that telephone orders cannot be accepted for this
compound.

The four-carbon butylamine homologue (the ARIADNE analogue) of DOI has
been synthesized.  A mixture of the free base of
1-(2,5-dimethoxyphenyl)-2-aminobutane (see preparation under DOB) and
phthalic anhydride was fused, cooled, and recrystallized from either
methanol or cyclohexane to give crystals of
N-[1-(2,5-dimethoxyphenyl)-2-butyl]phthalimide with a melting point of
76-77 !C and an analysis (C20H21NO4) C,H,N.  This was iodinated with
iodine monochloride in acetic acid to give
N-[1-(2,5-dimethoxy-4-iodophenyl)-2-butyl]phthalimide which was
chromatographically distinct from the uniodinated starting material
(silica gel, CH2Cl2 ), but which did not crystallize.  This was
treated with hydrazine hydrate in ethanol to provide
1-(2,5-dimethoxy-4-iodophenyl)-2-aminobutane hydrochloride which was
crystallized from CH3CN/EtOH to give white crystals with a mp of
217-218.5 !C and an analysis (C12H19CINO2) C,H,N.  This butyl homolog
of DOI has been assayed at up to four milligrams, and is without any
central effects whatsoever.  An experiment with 12.4 microcuries of
131I labelled material with the whole body scanner showed most of it
accumulating in the gut and liver, with almost none to the brain.

For those who find such statistics interesting, the parent compound
DOI vies with DOB as probably the most potent of the phenethylamine
psychedelics as of the moment, and certainly one of the most long
lived.

A very important, centrally pivotal, and completely paradoxical
compound in this area, is the N,N-dimethyl homologue of DOI, or
2,5-dimethoxy-N,N-dimethyl-4-iodoamphetamine (IDNNA).  This compound
was the starting point of the study of a large number of homologues
and it deserves, and has received, a separate recipe.

 

 

 



#68 DOM; STP; 2,5-DIMETHOXY-4-METHYLAMPHETAMINE

SYNTHESIS: To a solution of 54.9 g 2,5-dimethoxy-4-methylbenzaldehyde
(see the recipe for 2C-D for its preparation) in 215 g glacial acetic
acid there was added 19.5 g anhydrous ammonium acetate and 30.6 g
nitroethane.  This mixture was heated for 3 h on the steam bath, the
reaction mixture was cooled in a wet ice bath, allowing the
spontaneous formation of yellow crystals.  As much H2O as possible was
added (just short of a persistant cloudy oily character) and after a
few additional h standing, the crystalline
1-(2,5-dimethoxy-4-methylphenyl)-2-nitropropene was removed by
filtration and recrystallized from boiling acetic acid.  The yield,
after drying to constant weight, was 28.3 g and the mp was 87-88 !C.
Anal. (C12H15NO4) C,H,N.

A suspension of 9.5 g LAH in 750 mL well stirred anhydrous Et2O was
held at reflux under an inert atmosphere, with the return of the
condensed solvent passing through a Soxhlet thimble containing 9.5 g
1-(2,5-dimethoxy-4-methylphenyl)-2-nitropropene.  After the addition
of the nitrostyrene was complete, the stirred suspension was
maintained at reflux for an additional 4 h, then cooled to room
temperature and allowed to continue stirring overnight.  The excess
hydride was destroyed by the addition of 750 mL 8% H2SO4, cautiously,
until the hydrogen evolution ceased, then at a speed that allowed the
formed solids to disperse.  The phases were separated, the aqueous
phase washed once with Et2O, treated with 225 g potassium sodium
tartrate, and finally made basic (pH >9) with 5% NaOH.  This was
extracted with 3x150 mL CH2Cl2, the extracts pooled, and the solvent
removed under vacuum.  The residue was 9.6 g of a clear oil which
spontaneously formed crystals with a mp of 60.5-61 !C from hexane.
These solids were dissolved in 150 mL anhydrous Et2O, and saturated
with anhydrous HCl gas.  After standing at room temperature for 2 h,
the crystalline 2,5-dimethoxy-4-methylamphetamine hydrochloride (DOM)
was removed by filtration, washed with Et2O, and air dried to constant
weight.  There was obtained 8.25 g of glistening white crystals that
had a mp of 190.5-191.5 !C.  The sulfate had a mp of 131 !C.  Anal.
(C12H20ClNO2) C,H,N.

The above nitrostyrene may also be converted to the final amine
product through the intermediary of the corresponding phenylacetone.
To a well stirred suspension of 10.4 g powdered iron in 20 mL glacial
acetic acid held at reflux temperature, there was added 4.9 g
1-(2,5-dimethoxy-4-methylphenyl)-2-nitropropene as a solid.  Refluxing
was continued for 2 h and then all was filtered through wet Celite.
After washing with 300 mL H2O followed by 300 mL Et2O, the combined
filtrate and washes were separated, and the aqueous phase extracted
with 2x100 mL Et2O.  The organic phase and extracts were combined and
washed with 2x100 mL saturated K2CO3 and the solvent was removed under
vacuum yielding a reddish oil weighing 3.3 g.  This was distilled at
111-115 !C at 0.5 mm/Hg to give a pale green solid.  After
recrystallization from benzene, there was obtained 2.8 g
1-(2,5-dimethoxy-4-methylphenyl)-2-propanone as white crystals with a
mp of 57-59 !C.  This ketone has also been described as a pale-yellow
oil with a bp of 115-118 !C at 0.4 mm/Hg.  A solution of 0.7 g
1-(2,5-dimethoxyphenyl-4-methyl)-2-propanone in 20 mL MeOH was treated
with 6.0 g ammonium acetate, 0.3 g sodium cyanoborohydride, and 3 g
Linde 3 A molecular sieves.  The mixture was stirred overnight, the
solids removed by filtration, and the filtrate dissolved in 100 mL
H2O.  The solution was acidified with dilute H2SO4, and washed with
2x25 mL CH2Cl2.  The aqueous phase was made basic with aqueous NaOH,
and the product extracted with 2x25 mL CH2Cl2.  The solvent was
removed under vacuum, and the residue distilled (at 160 !C at 0.2
mm/Hg) to give colorless product which was dissolved in 3 mL IPA,
neutralized with concentrated HCl, and diluted with 50 mL anhydrous
Et2O.  There was obtained 0.18 g of 2,5-dimethoxy-4-methylamphetamine
hydrochloride (DOM) as a white solid with a mp of 187-188 !C.

The optical isomers of DOM have been prepared in two ways.  The
racemic base has been resolved as the ortho-nitrotartranilic acid salt
by recrystallization from EtOH.  The (+) acid provides the (+) or RSS
isomer of DOM preferentially.  Also, the above-mentioned
1-(2,5-dimethoxy-4-methylphenyl)-2-propanone can be reductively
aminated with optically active alpha-methyl benzylamine with Raney
Nickel.  This amine is isolated and purified by recrystallization of
the hydrochloride salt.  When optically pure, the benzyl group was
removed by hydrogenolysis with palladium on carbon.  The mp of either
of the optical isomers, as the hydrochloride salts, was 204-205 !C.

DOSAGE: 3 - 10 mg.

DURATION: 14 - 20 h.

QUALITATIVE COMMENTS: (with 1.0 mg) There is almost certainly an
effect.  Physically there is a slight dryness in the mouth, and my
eyes are noticeably dilated.  There is an eerie feeling overall.

(with 2.3 mg) Mood elevation at 2-3 hrs.  After 3 hours, emotional
effects become more pronounced, enhancement of color also.  Very
little distortion of perception, no disorientation, no creeping or
flowing, but color enhancement considerable.  The emotional content
and empathy for others was closer to mescaline than to amphetamine, a
welcome change.  No suggestion of nausea at any time.  Unable to sleep
at ten hours, so I took 3/4 grain Seconal.  Headache and listlessness
next morning, probably due to the Seconal.

(with 3 mg) In the middle of the experience I found that I was able
to separate components of complex things so as to evaluate them
separately.  There is no need to respect their normal purpose.  The
sharpness of observation is enhanced, but one can focus at every
different depth of a thing or a concept.  Colors are not just
brighter; there are more of them.  There is a profoundness of meaning
inherent in anything that moves.  A line of thought or a bit of
personal history ties the thinker to the objects that had been thought
of, or once experienced.  It is this relationship that will prove
productive.  Not like in a movie which is circular in its totalness,
but as in true life where the future is the result of your own
involvement with everything about you.

(with 4 mg) The first four hours were largely directed to the body.
There was a shuddering, and a tight jaw, and I am not particularly
motivated to talk to anyone.  It is more arousing (like amphetamine)
than depressing (like phenobarb).  I am feeling just a little sick at
the three hour point, but a bit of regurgitation clears this up.  Then
at the fourth hour, it went totally outside of me.  I saw the clouds
towards the west.  THE CLOUDS!!!  No visual experience has ever been
like this.  The meaning of color has just changed completely, there
are pulsations, and pastels are extremely pastel.  And now the oranges
are coming into play.  It is a beautiful experience. Of all past joys,
LSD, mescaline, cannabis, peyote, this ranks number one.  Normally I
have no color effects with mescaline.  A dynamic experience.  Feels
good, too.

(with 5 mg) There was the magnification of light, color and odors.
It was all very pleasant and beautiful, except that I had an
overwhelmingly negative feeling.  This at times grew to considerable
intensity, and I feel it was clearly due to anger.  At times the
negativity disappeared completely, and I broke into the most
enjoyable, even hilarious experiences.  I alternated about 50-50
between joy and discomfort.  As the evening drew on, I became
withdrawn and pensive.  It seemed clear that I had made all the wrong
decisions Q choice of partner, place to live, isolation, no meaningful
activity.  The greatest shocker was that my practice of meditation,
which is one of my central focuses, and which I thought had brought me
much peace and understanding, seemed to be a delusional solution to my
unhappiness and isolation.  The experience continued unabated
throughout the night with much tension and discomfort.  I was unable
to get any sleep.  I hallucinated quite freely during the night, but
could stop them at will.  While I never felt threatened, I felt I knew
what it was like to look across the brink to insanity.

(with 8 mg) The very quiet development picks up speed betweeen the
first and second hour.  There is a rich curly-imaged eyes-closed show
that interlocks closely with music.  It is occasionally an off-beat
fantasy and not directly knit together, and even occasionally
unenjoyable.  But always intense and completely appropriate to the
music.  There is a continuous thirst, and little urine.  Napping seems
OK at 16 hours, but real sleep must wait until the 20 hour point.
Overall a rolling +++, and I am looking forward to a repeat some day.

(with 10 mg) If on this page I shall have expressed it to you then it
is true that DOM has the glory and the doom sealed up in it.  All
that's needed to unseal it is to surround it with a warm living human
for a few hours.  For that human for those hours all the dark things
are made clear.

(with 12 mg) The first awareness was at 30 minutes and it was in the
tummy.  The development was extremely rapid, something more like LSD
than previously remembered.  The body tremor feels like poisoning,
there is no escaping the feeling of being disabilitated, but at least
there is no nausea.  This transition ended and the trauma cleared
completely at about the second hour.  The music was exceptional, the
erotic was exceptional, the fantasy was exceptional.  Listz's RA
Christmas Cantata #1,S part 1, with eyes closed was an experience
without precedent.  There were some residual effects still noted the
next day.  This may be a bit much for me.

(with 0.3 mg of the RRS isomer) Maybe slightly wiry?  No effects.

(with 0.5 mg of the RRS isomer) There is a real effect, and it is
significant that the first effects of the racemate were noted at 1.0
milligram.  There is a trace of time slowing and in general a pretty
full manic state.  There is some mydriasis.  Everything had pretty
much cleared up by evening.

(with 2.0 mg of theSSS isomer) No effects.  There was an unexpected
slight tachycardia at the two hour point, but nothing suggesting
psychotropic action.

(with 2.6 mg of the RSS isomer) There are signs of both pulse
increase and blood pressure increase.  There is some teeth-rubbiness,
but still no psychological turn on at all.

EXTENSIONS AND COMMENTARY: The rationale for the design and making of
DOM has already been discussed.  One could predict that it could have
been, theoretically, a totally inactive compound and maybe an
effective blocker for whatever receptor sites are being occupied by
other psychoactive drugs and even for strange things that some
unbalanced people might actually make within their bodies, using their
own personal chemistry.  On the other hand, it could have been a
potent psychedelic in its own rights, and if so, probably long lived.
The latter Rcould have beenS proved to be so.

The very modest amount of study of the individual optical isomers
clearly indicates that the RRS isomer is the more active.  The sparse
comments suggest that some of the heavier physical aspects of the
racemate might be due to contributions from the RinactiveS RSS isomer.
It is, after all, the RSS isomer of amphetamine that carries the major
punch of that stimulant.  Maybe if that isomer were removed, and one
were to explore the pure RRS isomer of DOM, the dramatic visual
aspects of the larger dosages might not be complicated with a
troublesome physical component.

This compound, unbeknownst to me, was scattered widely and plentifully
in the heyday of the Haight-Ashbury in San Francisco, in mid-1967.  It
was distributed under the name STP, which was said to stand for
Serenity, Tranquility, and Peace.  It was also claimed to represent
Super Terrific Psychedelic, or Stop The Police.  The police called it:
Too Stupid to Puke.  Actually, the name was taken from the initials of
a motor additive which was completely unrelated chemically.
Incredibly, and sadly, one of the avowed experts in the area of the
Rsensuous drugsS actually stated that STP, the motor oil additive, was
really one and the same as STP, the highly dangerous psychedelic.  The
motor oil additive, he wrote in a book of his, had properties somewhat
related to those of LSD, mescaline, and the amphetamines.  How
fortunate that the love children of the time didnUt do much reading,
for they might have gotten into yet deeper pharmacological troubles
with drug raids on the local gasoline stations.

Two complications became apparent during this first appearance and
they led to serious difficulties.  One, there was no equation made
between STP and DOM.  No one knew what this drug was which had been
distributed in a cavalier way throughout the city.  There could be no
educated guess as to the best treatment of overdose emergencies.  And
secondly, the initial tablets that had been distributed apparently
contained 20 milligrams of DOM per tablet; later, it was dropped to 10
milligrams.  Either of these, in retrospect, is now known to be a
thoroughly whopping dose.  The overdose situation was aggravated by
the slow onset of DOM.  The user may be aware of some initial effects
at the half-hour point, there will be what might be called a + or ++
at the end of the first hour, and the full impact of the drug is not
appreciated until some two hours have elapsed.  But many of the
recipients of the free handouts of DOM were familiar with LSD which
can show its alert in 15 to 20 minutes, or even sooner with a large
dose, and there is already a deep and compelling intoxication felt at
the half-hour point.  They, quite reasonably, expected this familiar
activity pattern with STP and assumed, when there was little if any
activity noted at the half-hour point, that the potency was less than
expected.  They took one or even two additional dosage units.  Thus,
some of the overdose victims of that period may well have taken as
much as 30 mg of DOM.  The slow onset of action, coupled with the
remarkably long duration, caught many innocent users unprepared.

Clinical studies have documented the rapid tolerance development from
repeated exposures to DOM.  Five volunteers were given 6 milligrams
daily for three days.  Objectively, psychological tests showed a
decrease in responses.  Subjectively, all found extremely intense
effects on the first day, and all but one found it unpleasant.  By the
third exposure on the third day, all had diminished responses, ranging
from only Rmoderately strongS to Rfelt absolutely nothing.S One
actually slept during the experience on the third day.

The hexadeutero-analogue (deuterium atoms on the two methoxyl groups)
has been prepared as an internal standard for analytical work, but
there are no reports of its human pharmacology.  A study with this
sort of derivative would be a fine companion to the studies already
underway with the mescaline analogues that are similarly substituted.
A difference exists, however.  With mescaline, it is believed that the
loss of a methoxyl group is a step towards the inactivation of the
compound, whereas with DOM this loss may be associated with the
formation of an active metabolite.  The several fascinating questions
raised by possible differences in both the rates and the degree of
demethylation of these two compounds are well worth trying to answer.

A number of compounds related to DOM had been synthesized and studied
at the University of California at San Francisco, at about this time.
Two of these were simply the juggling of the two methoxyl groups and
the methyl group on the ring, still maintaining the 2,4,5-ness
relative to the amphetamine chain.  These are
2,4-dimethoxy-5-methylamphetamine and
4,5-dimethoxy-2-methylamphetamine.  Since the slang name for DOM in
and about the medical center was STP, and since STP was the name of a
motor oil additive, it is not unreasonable that the first of these to
be synthesized, the 2,4-dimethoxy-5-methyl isomer, was referred to by
the name of another motor oil additive popular at that time, F-310.
The Vilsmeier reaction between 2,4-dimethoxytoluene and the Vilsmeier
complex of POCl3 and N-methylformanilide gave the benzaldehyde (mp
117-118 !C) with a yellow malononitrile derivative from EtOH with a mp
of 193-194 !C.  The nitrostyrene from this and nitroethane formed
yellow crystals from CH3CN, with a mp 138-139 !C.  The amine formed
easily with LAH in ether, and the product F-310 (or 5-DOM) gave white
crystals from CH3CN with a mp of 182-183 !C.

And the other isomer, the 4,5-dimethoxy-2-methyl counterpart, became
known familiarly as F-320, or sometimes simply 2-DOM.  Its preparation
followed an identical procedure, starting from 3,4-dimethoxytoluene.
I have been told that F-310 is not active even at 20 milligrams in
man, which would make it several times less potent than DOM (STP).  I
know of no trials with F-320.  The use of the letter RFS does not
imply any relationship between these two compounds and the series
described elsewhere with the RFS code followed by other numbers, such
as F-2 and F-22.  These latter are F's because they are furans, not
motor oil additives.  And yet another oil additive, well known at the
time as Z-7, became associated with the synthesis of the DOM (STP)
isomer with its groups in the 2,4,6-positions.  This is entered
separately under y-DOM.

 

 

 



#69 Y-DOM; Z-7; 2,6-DIMETHOXY-4-METHYLAMPHETAMINE

SYNTHESIS: To a solution of 2,6-dimethoxy-4-methylbenzaldehyde (mp
92-93 !C from the lithiation of 3,5-dimethoxytoluene followed by
reaction with N-methylformanilide) in 10 mL nitroethane, there was
added 0.1 g anhydrous am-monium acetate and the mixture was heated on
the steam bath for 16 h.  Removal of the solvent under vacuum gave a
slightly oily red-orange crystalline mass which was finely ground
under 1 mL of MeOH.  Filtration and a sparing wash with MeOH gave,
after air drying, 0.8 g of a light yellow crystalline solid with a mp
of 121-122.5 !C.  Recrystallization from 4 mL boiling absolute EtOH
gave 0.6 g of 1-(2,6-dimethoxy-4-methylphenyl)-2-nitropropene as very
light yellow platelets, which melted at 123-124 !C.

To a solution of 0.25 g LAH in 25 mL refluxing THF, well stirred and
under He, there was added a solution of 0.3 g
1-(2,6-dimethoxy-4-methylphenyl)-2-nitropropene in 5 mL dry THF.  Upon
the completion of the addition, the reaction mixture was held at
reflux for 48 h.  After cooling with an external ice bath there was
added, in sequence, 0.5 mL H2O, 0.5 mL 15% NaOH, and finally 1.5 mL
H2O.  The inorganic solids were removed by filtration, and the filter
cake washed with THF.  The solvent from the combined filtrate and
washings was removed under vacuum, and the residue (0.3 g) was a
crystal clear colorless oil with a high refractive index.  This was
dissolved in 2 mL IPA, neutralized with concentrated HCl, and diluted
with 35 mL of anhydrous Et2O.  After a minute's standing, the solution
became turbid, followed by the slow deposition of very fine white
crystals.  After standing 1 h at room temperature, these were removed
by filtration, Et2O washed, and air dried to constant weight.  There
was thus obtained 0.3 g 2,6-dimethoxy-4-methylamphetamine
hydrochloride (y-DOM) with a mp of 203 !C. sharp.

DOSAGE: 15 - 25 mg.

DURATION: 6 - 8 h.

QUALITATIVE COMMENTS: (with 14 mg) I am really quite spacey.  I can
go from a train of thought straight up into thin air.  Then, to get to
another one there must be a careful choice of words.  Logic has
nothing to do with any of it.  There is no trace of the MDMA-like
magic.  This is an interpretive drug, not simply an ASC [altered state
of consciousness] opening.

(with 18 mg) There is a light-headedness, and a somewhat starry-eyed
stoned state.  Nothing visual, and no body concern except for what
seems to be a very fine inner tremor.  I think that with a little
more, things might very well begin to move in the visual field.  But I
have no feeling of great concern about taking a somewhat higher
dosage.

(with 25 mg) I was at a +++ for about three hours, and it was a very
weird place.  There were some visuals, but they were not at all
commensurate with the degree to which I was simply stoned.  The erotic
does not knit, and it's hard to get involved with music.  It is as if
you were going down some totally unknown street in a completely
familiar city.  You know the territory, but yet it is strangely all
new.  Eyes closed fantasy and shaped imagery was quite remarkable.
But some heart arrhythmias and a pretty constant diarrhea made the
experience less than totally ideal.  My sleep was good and with good
dreams.

EXTENSIONS AND COMMENTARY: I canUt remember the exact names of the
companies that went with the oil additives.  STP was, I believe, itUs
own thing, and originally stood for Scientifically Treated Petroleum.
And F-310 was, I believe, a Chevron Oil product.  F-320 was, of
course, the product of the wild and happy chemists at the
Pharmaceutical Chemistry Department at the University of California in
San Francisco, playing with what they fondly called Rfunny drugs.S And
when the 2,4,6-orientation became an obvious positional isomer, the
Pennzoil Oil Company's additive, Z-7, was a natural to have its name
volunteered to the cause.  There was one additional isomer possible,
with the methyl in the 2-position and the methoxyl groups at the 4-
and 6-positions.  This followed the more conventional aldehyde made
from 3,5-dimethoxytoluene via the Vilsmeier process, with POCl3 and
N-methylformanilide.  This material
(2,4-dimethoxy-6-methylbenzaldehyde with mp 64-65 !C from cyclohexane
or from MeOH) is completely distinct from the isomer used above
(2,6-dimethoxy-4-methylbenzaldehyde with a mp of 92-93 !C from MeOH).
The amphetamine from this isomer is 2,4-dimethoxy-6-methylamphetamine,
and had been christened by the chemistry crowd as Z-7.1.

Much effort had been put forth in research by this medical school
group of graduate students and graduate advisors, to try to explain
the biological activity of the 2,4,5-things such as TMA-2 and DOM
(STP).  And a considerable investment had been made in the attempt to
tie together the amphetamine world of psychedelics with the indole
world of psychedelics.  The convenience of having two methoxy groups
para to one another was a clear invitation to speculate upon the
formation of a benzoquinone intermediate of some kind, and this would
require the loss of the methyl groups which were already known to be
metabolically labile.  This Rquinone-likeS intermediate was the
cornerstone of a Rhydroquinone hypothesis,S as it allowed further
condensation within the molecule itself involving the primary amine
group, to form something called an indolene which, with some arcane
electron pushing and removal, could eventually become an indole.
There.  We now have a tie-in to the tryptamine world, and to
serotonin, and that entire neurotransmitter magic.

There was only one small fly in the ointment.  No matter how the
2,4,5-things were explained, none of the proposed mechanisms could
allow for the 2,4,6-things to also be active.

How can one accommodate such blasphemy?  The first and obvious
approach was the simplest.  Denial.  The 2,4,6-things arenUt really
active at all.  Placebo stuff.  There is a commonly used phrase, Rbad
scienceS which is an in-famous term used to belittle findings that do
not fit with one's theories or purposes.  But that simply didnUt wash,
because I knew, as did a few others who chose not to identify
themselves too publicly, that TMA-2 and TMA-6 were both fully active
in the 40 to 50 milligram area.  And although not as potent as DOM,
the compound of this recipe, y-DOM or Z-7, was certainly an active
one.  So, since approach number one didnUt work, try approach number
two.  Make the shoe fit the wearer, without respect to the size of his
foot.  One single size shoe fits all.  One single mechanistic
hypothesis explains all.  It was obvious that for the RhydroquinoneS
hypothesis to survive, Z-7 would have to undergo some metabolic
oxidation Q phenol formation Q in the 3-position.

And guess who was actually euchred into embarking onto the synthesis
of this hypothetical metabolic Lucy [that's the anthropological-type,
not the LSD-type Lucy]?  Moi!  On to a new methoxylated amphetamine
which would be called Z-7.2.  Oxidation of the above
2,4-dimethoxy-6-methylbenzaldehyde with metachloroperoxybenzoic acid
gave 2,4-dimethoxy-6-methylphenol which smoothly methylated (KOH,
CH3I) to give 2,3,5-trimethoxytoluene as a white oil, bp 59-62 !C at
0.1 mm/Hg.  This formed the anion between the meta-methoxy groups with
butyllithium, and N-methylformanilide gave the new compound
2,3,6-trimethoxy-4-methylbenzaldehyde, also an oil (bp 130-140 !C at
0.7 mm/Hg) with an excellent NMR spectrum.  This formed the 3-carbon
nitrostyrene with nitroethane, as bright yellow crystals from methanol
with a mp 67-68.5 !C (and excellent NMR and microanalysis, C,H,N).
Lithium aluminum hydride reduction gave rise to what I was assuming
would be the target amphetamine, 4-methyl-2,3,6-trimethoxyamphetamine
or Z-7.2.  This formed a hydrochloride salt which, although
analytically excellent, insisted in remaining as an ether and
chloroform-soluble oil which had an excellent NMR spectrum.  This was
certainly MY target compound, but it was not THEIR target compound.
The upper echelons who were running the show were serious about this
hydroquinone thing.  Therefore, this product Z-7.2, that should have
been entered into human evaluation, was instead processed further by
the substitution of a t-BOC on the amine group, oxidation to the
quinone with ceric ammonium nitrate, reduction to the hydroquinone
with dithionite, and finally deprotection of the blocking t-BOC group
by hydrochloric acid.  The final product,
2,5-dihydroxy-6-methoxy-4-methylamphetamine hydrochloride, was an
extremely light-sensitive solid which was looked at by NMR (excellent
spectrum in D2O) and by cyclic voltimetry (destructive and
uninformative) but which would have been totally worthless to have
tasted.

In fact, the whole 2,4,6 substitution concept is just now beginning to
explode.  Fully half of the drugs described in this Book II are of the
classical 2,4,5-trisubstitution pattern, and it is becoming evident
that every one of them will have a 2,4,6-trisubstituted counterpart
that bids fair to be an active psychedelic.  Diligence could thus
easily double the number of known psychedelics.  The nickname RpseudoS
is really the Greek letter RpsiS which looks like a candelabrum
standing on the table holding up three candles.  If I can find the
type in some font, I will simply precede each known drug with this
letter, to indicate that the 2,4,5-ness has become a 2,4,6-ness.
Therefore, Z-7 is also pseudo-DOM.

Z-7.2 might have been an interesting compound to taste.  But the
academic climate was not appropriate at that time (early 1977) for
such honesty.  The Rhydro-quinone hypothesisS is now not much more
than a minor bit of history.  And anyhow, it was just about this time
that I had uncovered a slick way of getting a sulfur atom into the
amphetamine molecule.  I quickly lost interest in the pursuit of other
people's hypotheses that didnUt seem to lead anywhere.  Maybe,
someday, some single earth-shaking mechanism will emerge to explain
everything.  But in the meantime, the best contribution I can make to
this Rgrand unified theory of psychedelic activityS is to continue to
make new and unexpected things which, if they are active, will
effectively destroy any hypothesis that just happens to be popular at
the moment.  It is a lot more exciting, too.

 

 

 



#70 DON; 2,5-DIMETHOXY-4-NITROAMPHETAMINE

SYNTHESIS: A solution of 8.4 g 2,5-dimethoxyamphetamine base in 40 mL
acetic acid was added dropwise over the course of 0.5 h to 43 mL of
50% nitric acid which was well stirred and cooled with an external ice
bath.  The resulting solution was quenched with ice water, made basic
with aqueous NaOH, and extracted with a benzene-ether mixture.  The
residue that remained after the removal of the solvent was dissolved
in dilute HCl which, upon evaporation of the H2O, yielded a nearly
colorless residue.  Recrystallization from an ethanol/ether mixture
gave, after drying, 10.5 g of 2,5-dimethoxy-4-nitroamphetamine
hydrochloride (DON) with a mp of 206-207 !C.  The acetamide derivative
melted at 166-168 !C.  The formamide derivative was easily hydrolyzed
with 3N HCl.  And the R-isomer of DON hydrochloride had a mp of
231-232 !C.

DOSAGE: 3.0 - 4.5 mg.

DURATION: 8 - 15 h.

QUALITATIVE COMMENTS: (with 3.0 mg) There was an amphetamine-like
stimulation that was apparent an hour into it, and considerable
anxiety.  I had stomach cramps, but there were indications that there
might be something hallucinogenic at a higher dose.

(with 4.5 mg) An enhancement of color perception, and some auditory
distortion, that was still noticeable some eight hours into the
experience.  The visual changes were intense.  I felt I was running a
slight fever, and was restless, but there was almost no physical
malaise.  I was still somewhat wound up even at the 14th hour.

EXTENSIONS AND COMMENTARY: These qualitative comments are not true
quotations, but have been reconstructed from the published summaries
of the human trials reported by several South American researchers.  I
have personally never tasted DON and have only these fragments from
which to create a portrait of activity.  A brief quotation, from a
note published by these researchers in a bulletin that is restricted
to forensic scientists serving law enforcement agencies, is certainly
subject to a number of interpretations.  It reads as follows: RThis
action [a strong stimulant action reminiscent of amphetamine] seems to
reduce the incidence of insightful, and therefore potentially
unpleasant experiences, and thus [DON seems likely] to appear on the
market as an illicit recreational drug.S I must admit that I have
tried, and I am still not able, to interpret this quotation.

 

 

 



#71 DOPR; 2,5-DIMETHOXY-4-(n)-PROPYLAMPHETAMINE

SYNTHESIS: A suspension of 285 g mossy zinc in 285 mL H2O containing
5.7 g mercuric chloride was treated with 285 mL concentrated HCl and
shaken as needed to effect amalgamation.  The H2O was then drained
off, the zinc washed with fresh water and drained again.  There was
added a solution of 74 g 2,5-dimethoxypropiophenone (from the reaction
of propionic acid and p-dimethoxybenzene in the presence of
polyphosphoric acid, see under DOAM for an effective general
procedure) in 140 g EtOH.  The reaction mixture was held at reflux for
24 h with the periodic addition of concentrated HCl.  It was then
cooled, diluted with H2O and CH2Cl2, and the organic phase separated.
The aqueous phase was extracted with 2x100 mL additional CH2Cl2.  The
combined organic phases were washed with 5% NaOH until the washes
remained basic, once with H2O, and then the solvent was removed under
vacuum.  The residue was distilled at the water pump, giving an early
fraction quite rich in starting p-dimethoxybenzene, and a second
fraction (61 g, bp 140-160 !C) which was free of carbonyl group by
infra-red, and which was largely 2,5-dimethoxypropylbenzene.  It was
used without further purification in the following aldehyde synthetic
step.

A mixture of 124 g N-methylformanilide and 140 g POCl3 was allowed to
stand until there was the development of a strong red color.  There
was then added 60 g of the above 2,5-dimethoxypropylbenzene and the
mixture was held on the steam bath for 2 h.  The mixture was added to
2 L H2O and stirred until the excess acid chloride had completely
decomposed.  The mixture was extracted with 3x100 mL CH2Cl2 and, after
the removal of the solvent from the combined extracts, the residue was
extracted with 3x100 mL boiling hexane.  Removal of the solvent gave
the product 2,5-dimethoxy-4-propylbenzaldehyde as an oil, 23 g, which
was characterized as its malononitrile derivative.  Equal weights of
the product and malononitrile in EtOH with a catalytic amount of
triethylamine gave yellow crystals which, on recrystallization from
toluene, had a mp of 113-114 !C.

A solution of 21.5 g of the above crude
2,5-dimethoxy-4-propylbenzaldehyde in 75 g acetic acid, was treated
with 10.4 g nitroethane and 6.6 g anhydrous ammonium acetate.  This
was heated on the steam bath for 1.75 h, then cooled and diluted with
H2O to the point of turbidity.  With long standing and scratching,
there finally was the deposition of crystals which were removed by
filtration and sucked as dry as possible.  This 23 g of crude product
cake was triturated under MeOH, filtered again, and air dried to give
11 g of dull orange crystals.  Recrystallization from boiling MeOH
gave 1-(2,5-dimethoxy-4-(n)-propylphenyl)-2-nitropropene as fine
orange crystals which weighed, after filtering, washing, and drying,
7.4 g, and which had a mp of 94-96 !C.

To a suspension of 6.0 g LAH in 500 mL anhydrous Et2O, which was being
stirred and also held as a gentle reflux, there was added a saturated
solution of (2,5-dimethoxy-4-(n)-propylphenyl)-2-nitropropene in warm
THF.  The reaction mixture was held at reflux for 24 h, then cooled to
room temperature.  The excess hydride was destroyed by the cautious
addition of 500 mL dilute H2SO4.  The phases were separated, and the
aqueous phase washed with additional Et2O.  There was then added 150 g
potassium sodium tartrate, and the pH was brought to >9 with aqueous
NaOH.  The product was extracted with Et2O and, after removal of the
solvent, the residue was dissolved in 200 mL anhydrous Et2O and
saturated with anhydrous HCl gas.  The solids that formed were removed
by filtration, giving 6.15 g 2,5-dimethoxy-4-(n)-propylamphetamine
hydrochloride (DOPR) as an electrostatic, white crystalline powder,
with a mp of 182.5-183 !C.  This was not improved by recrystallization
from either IPA or CH3CN.

DOSAGE: 2.5 - 5.0 mg.

DURATION: 20 - 30 h.

QUALITATIVE COMMENTS: (with 2.0 mg) The onset is slower than any
other thing I can think of.  There was nothing at all at the end of an
hour, and only a threshold a half hour later.  By the middle of the
third hour, I was up to 1+, and that seemed to be about as high as it
intended to take me.  Attempts to sleep at the ninth hour were not
successful, as there were strange patterns of not-quite logical
thinking going on.  Stuff like: TThe block events (like a babyUs
rectangular building blocks) that were gotten, along with other
things, from the full octaves of the left hand in Listz's Hungarian
Rhapsody, events that allowed an easy recognition of the odds of
achieving successful re-entry from any of several erotic codes.U
Clearly this was not a baseline state.  After six hours of successful
sleep, I was still off-baseline , and on into the following day.  Go
on up with curiosity but with caution.

(with 3.6 mg) Imagery that was constructed in response to the music
turned out to be necessary to organize and contain it. The trio is the
nucleus that transforms the written to the heard, but it has created
its own bubble without connections to the real world, and must play on
and on and on to keep itself afloat and never touching the stage
again.

(with 5.0 mg) I am now at midnight, and still strongly +++.  This is
certainly maximum dosage, at least for a long time.  There are faint
intimations of nervous system scrungies.  You know, the kind of thing
that makes you figure it's going to be a while before youUll try to
relax into sleep.  This material, like all the other DOUs, is a heavy
duty psychedelic, the kind that says to you, 'Forget all that stuff
about screening out visuals,' and then proceeds to prove it.  Sort of
indole-like in that way.  Your body as well as your mind tells you
youUre into it, baby, and better relax and enjoy the trip, because
youUve left the shore way behind.  When it was time for bed, I got to
sleep with surprising ease, and slept for only about six hours.  My
dreams were excellent, balancing, and good humored.  But the next day
I realized I was still carrying the DOPR in me, and that baseline was
definitely not there.  But it was OK.  No problems except for
sleepiness.  The next evening I went to bed at unheard-of hour of 9 PM
and slept for 13 hours, give or take.  Fascinating compound, but I
wonUt go out of my way to take it again soon.

EXTENSIONS AND COMMENTARY: There is a thread of disconnection and of
inconsistent reference that pervades most of the reports that I have
received concerning the use of DOPR.  The word that comes to mind is
hypnogogic.  There is a drifting into that place that lies between a
not-quite-awake and a not-quite-asleep state seems to characterize
this compound.  There is no question but that it is very potent, and
that it is very long-lived.  But there is a nagging suggestion of the
out-of-body, out-of-center character that is the hallmark of the
anesthetic and delusional drugs such as scopolamine or ketamine.  With
them, the psychedelic effects become clouded with touches of amnesia.
If DOPR shows this with it's three carbon alkyl group, thereis every
reason to pay close attention as the chain becomes longer.

There had been quite a bit of speculation in the literature that the
metabolic attack on DOM was at the 4-position, and this was an
oxidation process.  In a moment of inspiration, I decided to explore a
similar oxidation step in DOPR, since it is probably the most potent
of the DO-series.  Why not make the compound which would be the first
step in this oxidation, the 1-hydroxypropyl analogue?  This I did, by
using the phthalimide derivative of 2,5-dimethoxyamphetamine
(described in the synthesis of DOI) and making the propiophenone using
propionic acid as both reagent and solvent, and polyphosphoric acid as
the condensing agent.  The ketone product (a white crystalline solid
from methanol) was dissolved in warm methanol and reduced to the
alcohol with sodium borohydride.  This product, also a white
crystalline solid, was stripped of the phthalimide blocking group with
overnight refluxing with hydrazine in ethanol.  The product,
2,5-dimethoxy-4-(1-hydroxypropyl)-amphetamine (hydroxy-DOPR) had a mp
of 148-150 !C from IPA.  Its activity is not yet known, but there were
no effects at all at trials, orally, of up to 200 micrograms.

But this is all with the normal-propyl compound.  There is a rich
collection of misinformation and potential discovery that is
associated with the isopropyl isomer.  This structural isomer,
2,5-dimethoxyl-4-(i)-propylamphetamine is properly called DOIP for
des-oxy-iso-propyl.  It has been synthesized and explored in animals
and, to a modest extent, in man.  The synthesis has proceeded from
2,5-dimethoxyacetophenone by the addition of a methyl group to the
carbonyl followed by reduction to the hydrocarbon.  Aldehyde
formation, nitropropene synthesis with nitroethane, and lithium
aluminum hydride reduction are uneventful, providing the hydrochloride
salt DOIP, which has a mp of 183-184 !C as an analytical sample.
Animal tests (such as rabbit hyperthermia assays), have indicated that
the isopropyl compound DOIP is less potent than the propyl prototype,
DOPR, by between one and two orders of magnitude.  In man, a dose of
four milligrams, a rousing dose of DOPR, is without any effects.  At
10 milligrams, there is some disturbance but substantially no effects.
I have been told that with doses in the 20 to 30 milligram range there
are valid changes in mental state, but I have not been told the nature
of these changes.

A fascinating red herring had been drawn across all of these exacting
lines by a strange visitor to this research project.  An olive-faced
M.D., Ph.D., passed through this confusing scene briefly, and when he
left, a small supply of DOPR left with him.  He promptly published in
an obscure journal some animal behavioral responses which he ascribed
to the isopropyl analogue, DOIP.  But what he had studied could only
have been DOPR since DOIP, at that time, had not yet been synthesized
either by me, or by either of the other two active synthesists of that
moment.  It was not yet a known material.  We all made it some time
later, but by that time our olive-face had disappeared.  There is a
magnificent French phrase that applies here as nowhere else; Il a
foutu le camp.  Its idiomatic meaning is equivalent to our, RHe took
off,S or RHe split the scene,S but the literal translation is, RHe
fucked the camp.

 

 

 



#72 E; ESCALINE; 3,5-DIMETHOXY-4-ETHOXYPHENETHYLAMINE

SYNTHESIS: To a solution of 72.3 g 2,6-dimethoxyphenol in 400 mL MeOH,
there was added 53.3 g of a 40% solution of aqueous dimethylamine
folowed by 40 g of a 40% aqueous solution of formaldehyde.  The dark
solution was heated under reflux for 1.5 h on a steambath.  The
volatiles were then removed under vacuum yielding a dark oily residue
of 2,6-dimethoxy-4-dimethylaminomethylphenol.  This residue was
dissolved in 400 mL of IPA, to which there was added 50 mL of methyl
iodide.  The spontaneously exothermic reaction deposited crystals
within 3 min, and was allowed to return to room temperature and
occasionally stirred over the course of 4 h.  The solids were removed
by filtration, washed with cold IPA, and allowed to air dry yielding
160 g of the methiodide of 2,6-dimethoxy-4-dimethylaminomethylphenol
as a cream-colored crystalline solid.

A suspension of 155 g of the above methiodide of
2,6-dimethoxy-4-dimethylaminophenol in 600 mL H2O was treated with a
solution of 130 g KCN in 300 mL H2O.  The reaction mixture was heated
on a steam bath for 6 h during which time there was a complete
dissolving, the development of a brownish color with a bright blue
film on the surface and the walls of the flask, and the gentle
evolution of fine gas bubbles.  The hot reaction mixture was poured
into 1.2 L H2O and acidified with concentrated HCl (careful, HCN
evolution).  The aqueous solution was extracted with 3x150 mL CH2Cl2,
the extracts pooled, washed with saturated NaHCO3 which removed much
of the color.  The solvent was removed under vacuum yielding about 70
g of a viscous black oil.  This was distilled at 0.4 mm/Hg at 150-160
!C to provide 52.4 g of homosyringonitrile
(3,5-dimethoxy-4-hydroxyphenylacetonitrile) as a white oil that
spontaneously crystallized to lustrous white crystals that melted at
57-58 !C.

A solution of 5.75 g of homosyringonitrile and 12.1 g ethyl iodide in
50 mL dry acetone was treated with 6.9 g finely powdered anhydrous
K2CO3 and held at reflux for 18 h.  The mixture was diluted with 100
mL Et2O, filtered, and the filtrate solvent removed under vacuum The
residue was recrystallized from Et2O/hexane to yield 5.7 g
3,5-dimethoxy-4-ethoxyphenylacetonitrile with a mp 57-58 !C.  Anal.
(C12H15NO3) C,H,N.

A solution of 2.21 g 3,5-dimethoxy-4-ethoxyphenylacetonitrile in 25 mL
EtOH containing 2.5 mL concentrated HCl and 400 mg 10% palladium on
charcoal, was shaken in a 50 lb/sq.in. atmosphere of hydrogen for 24
h.  Celite was added to the reaction suspension and, following
filtration, the solvents were removed under vacuum.  The residue was
recrystallized from IPA/Et2O to yield 2.14 g
3,5-dimethoxy-4-ethoxyphenethylamine hydrochloride (E) with a mp of
166-167 !C.

Synthesis from syringaldehyde: A well-stirred suspension of 21.9 g
syringaldehyde in 45 mL H2O was heated to reflux in a heating mantle.
There was then added a solution of 15 g NaOH in 60 mL H2O.  The
heating and stirring was continued until the generated solids
redissolved.  Over a period of 10 min, there was added 23 g diethyl
sulfate, then refluxing was continued for 1 h.  Four additional
portions each of 5 g diethyl sulfate and of 6 mL 20% NaOH were
alternately added to the boiling solution over the course of 2 h.  The
cooled reaction mixture was extracted with Et2O, the extracts pooled
and dried over anhydrous MgSO4, decolorized with Norite, and stripped
of solvent.  The crude 3,5-dimethoxy-4-ethoxy-benzaldehyde weighed
21.8 g and melted at 51-52 !C.

A solution of 14.7 g 3,5-dimethoxy-4-ethoxybenzaldehyde and 7.2 mL
nitromethane in 50 mL glacial acetic acid was treated with 4.4 g
anhydrous am-monium acetate and held at reflux for 30 min.  Cooling
the reaction allowed the formation of yellow crystals which were
removed by filtration and washed sparingly with cold acetic acid.  The
dried 3,5-dimethoxy-4-ethoxy-'-nitrostyrene weighed 11.5 g and melted
at 108-109 !C after recrystallization from EtOH Anal. (C12H15NO5) C,H.
Alternately, this product may be prepared from 3.9 g.
3,5-dimethoxy-4-ethoxybenzaldehyde in 60 mL nitromethane containing
0.7 g ammonium acetate and heated on a steam bath for 1 h.  The
solvent was removed under vacuum, and the residue dissolved in a
minimum of hot MeOH.  Cooling provided, after filtration and air
drying, 2.3 g of bright yellow crystals of
3,5-dimethoxy-4-ethoxy-'-nitrostyrene, with a mp of 105-107 !C.

A solution of 2.25 g LAH in 45 mL anhydrous THF was vigorously stirred
and cooled to 0 !C under He.  There was added 1.5 mL 100% H2SO4
dropwise, followed by 2.3 g 3,5-dimethoxy-4-ethoxy-'-nitrostyrene in
anhydrous THF.  After the addition was complete, the mixture was
allowed to stir for 30 min, and then brought to room temperature.  The
unreacted hydride was decomposed with 2.3 mL H2O in THF, followed by
the addition of 9.2 mL of 15% NaOH.  The white suspension was
filtered, the filter cake was washed with THF, the filtrate and
washings combined, and the solvent removed under vacuum.  The residue
was dissolved in 300 mL dilute H2SO4, washed with 2x75 mL CH2Cl2, made
basic with 25% NaOH, and the product extracted with 3x75 mL CH2Cl2.
After removal of the solvent, the residue was distilled at 110-120 !C
at 0.3 mm/Hg yielding 1.4 g of a colorless oil.  A solution of this
oil in 20 mL IPA was neutralized with 17 drops of concentrated HCl and
diluted with 100 mL anhydrous Et2O.  After a few minutes there was the
spontaneous formation of white crystals of
3,5-dimethoxy-4-ethoxyphenethylamine hydrochloride (E) which was
recrystallized from 40 mL boiling EtOAc containing 1 mL MeOH.  The mp
was 165-166 !C.

DOSAGE: 40 - 60 mg.

DURATION: 8 - 12 h.

QUALITATIVE COMMENTS: (with 40 mg) This is a powerful and complex
intoxicant Q I could not have coordinated any rational muscular
activity.  I could not walk; I could not tie my shoe-laces.  There is
analgesia and an incoordination that I cannot shake.  My menstrual
flow started a bit ahead of time, but it was light.

(with 50 mg) I felt that the body tensions outweighed the
psychological and sensory rewards, in that I had a lot of dehydration
and my sleep had a nightmare quality.  This pretty much offset the few
virtues that I felt I had obtained.

(with 60 mg) There is a quality of rational analysis and insight that
is totally impressive.  Many subtle factors in my life can be viewed
with insight, and usefully dissected.  I got into a deep discussion,
but I was not argumentative or even defensive and I remained detached
and kept a tone of cool impersonality.  I had a good appetite.  But I
also had some tachycardia and muscular tension.  There was
unquestionable sensory enhancement, but without an intellectual
component.  Overall it was most pleasant.

EXTENSIONS AND COMMENTARY: In an isolated situation, there is easy
fantasy, but little synthesis of external sensory inputs such as music
or visual stimulae.  A gradual decline brings the subject back to a
restful baseline somewhere before the 12th hour.  The following day is
often seen as one of tiredness and low energy.  An anonymous flyer
appeared in the California drug community in 1984 stating an effective
range to be 50 to 100 milligrams, but it described the drug as the
sulfate.  The above data all pertain to the hydrochloride salt.

The replacement of that one methyl group with an ethyl group leads to
a nice jeu de mots.  The play on words depends on a remarkable
coincidence.  The name of the alkaloid mescaline stems from an ancient
Nahuatl word for a drink (Mexcalli) which also provided the source of
the term Mescal (an Agave of entirely different pharmacology).  The
prefix for the simplest, the one carbon organic radical, is methyl.
This is from the Greek word RmethyS and represents wine from wood.
Such is, indeed, methyl alcohol, or methanol, or wood alcohol, the
simplest one-carbon drink and a rather dangerous one for the human
animal.  And this is the group that is on the central oxygen of
mescaline.

It is customary to refer to homologs (bigger-by-one) of methanol by
their classical chemical names, so the natural extension of methyl is
ethyl, and that of mescaline would be escaline.  One carbon-chain on
the 4-position oxygen becoming a two-carbon chain.  This is all
entymologically appealing, but there is no botanical support for any
of it.  The ethyl group is much more rare in nature.  It is just a
happy coincidence that mescaline (the plant), and methyl (the alkyl
group involved), and methoxy (the group on the 4-position of the
aromatic ring) all happen to start with the letter RMS.

Very few of the homomescaline phenethylamines have been synthesized as
their three-carbon chain counterparts, the corresponding analogues of
amphetamine.  And only three of them have been explored in man (four,
if you count the amphetamine analogue of mescaline itself, TMA).  The
obvious names for these compounds have, unfortunately, already been
used.  It would be logical to use the letter M for a methoxy, and the
letter E for ethoxy, etc. and simply read the groups from around the
ring.  But this is the naming system for the 2,4,5-trisubstituted
amphetamines.  MEM is, for example, 2,5-dimethoxy-4-ethoxyamphetamine
(in sequence, methoxy, ethoxy, methoxy reading around the ring, and a
fascinating compound talked about at length in this book), so this
term cannot represent 3,5-dimethoxy-4-ethoxyamphetamine.

A truly simple code employs the length of the carbon chain.  The
phenethylamine chain is two carbons long, and the amphetamine chain is
three carbons long.

If a drug has been initially developed (and initially named) as an
amphetamine derivative (three carbon chain) then the two-carbon chain
analogue will use the original name (or a symbolic part of it) with
the term 2C ahead of it.  The two-carbon analogue of DOB (a
three-carbon chain compound) will become 2C-B.  DOI becomes 2C-I, DON
becomes 2C-N, and DOET becomes 2C-E.  Each of these is a substituted
amphetamine derivative lacking one carbon atom, thus becoming a
phenethylamine derivative.  Most of these have 2,4,5-substitution
patterns.

And if a drug has been initially developed (and initially named) as a
phenethylamine derivative (two carbon chain) then the three-carbon
chain analogue will use the original name with the term 3C ahead of
it.  The three carbon analogue of E (escaline, a two-carbon chain
compound) will become 3C-E.  P becomes 3C-P and CPM becomes 3C-CPM.
Most of these have 3,4,5-substitution patterns.

Thus, R2-CS implies that a known amphetamine drug has been shortened
to a phenethylamine, and R3-CS inplies that a known phenethylamine has
been lengthened to an amphetamine.  A great number of the former have
been made and have proven to be most rewarding.  Only a few of the
latter are known, but most of them will eventually prove to be potent
psychedelics.

 

 

 



#73 EEE; 2,4,5-TRIETHOXYAMPHETAMINE

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.

 

 

 



#74 EEM; 2,4-DIETHOXY-5-METHOXYAMPHETAMINE

SYNTHESIS: To a solution of 12.3 g 3-ethoxy-4-methoxyphenol (see
recipe for MEM for the preparation of this phenol) in 20 mL MeOH,
there was added a warm solution of 4.8 g KOH in 100 mL MeOH.  There
was then added 8.2 g ethyl bromide, and the mixture held at reflux on
the steam bath.  Within 0.5 h, severe bumping ensued.  An additional 3
g ethyl bromide were added, refluxing continued for another 0.5 h,
then the reaction mixture was allowed to come to room temperature and
to stand overnight.  It was poured into 3 volumes H2O which produced
crystals spontaneously.  There was added additional base, and the
mixture was extracted with 3x150 mL CH2Cl2.  Removal of the solvent
from the pooled extracts under vacuum gave 6.4 g of
2,4-diethoxyanisole as tan crystals with a mp of 48-48.5 !C.

A mixture of 10.9 g N-methylformanilide and 12.3 g POCl3 was allowed
to stand at room temperature for 0.5 h producing a deep red claret
color.  There was then added 6.2 g 2,4-diethoxyanisole and the mixture
was heated on the steam bath for 2 h.  All was poured into 200 g
chipped ice, and stirred mechanically.  The dark viscous gummy oil
gradually became increasingly granular and finally appeared as
jade-green solids.  These were removed by filtration and washed with
H2O, giving a wet cake weighing 18 g and having a mp (from a porous
plate) of 95.5-96.5 !C.  The entire crop was recrystallized from 75 mL
boiling MeOH which gave, after filtering, washing lightly with cold
MeOH, and air drying, 5.4 g of 2,4-diethoxy-5-methoxybenzaldehyde with
a mp of 98-99 !C.  A solution of 0.2 g of this aldehyde, and 0.3 g
malononitrile in 2.0 mL warm EtOH was treated with a drop of
triethyl-amine.  There was an immediate generation of crystals which
were removed by filtration, EtOH-washed, and dried to constant weight.
The bright yellow needles of 2,4-diethoxy-5-methoxybenzalmalononitrile
weighed 0.15 g and had a mp of 172-172.5 !C.

A solution of 5.0 g 2,4-diethoxy-5-methoxybenzaldehyde in 16 g glacial
acetic acid was treated with 2.7 g nitroethane followed by 1.7 g
anhydrous ammonium acetate.  The mixture was heated for 2.5 h on the
steam bath, then removed and diluted with a equal volume of H2O.  With
cooling there was the generation of a heavy crop of orange crystals
which was removed, washed with 50% acetic acid, and sucked as dry as
possible.  The product had a mp of 97-104 !C, and there was
spectrographic evidence of some unreacted starting aldehyde.  A small
sample was recrystallized from boiling MeOH, with considerable loss,
to give an analytical sample of
1-(2,4-diethoxy-5-methoxyphenyl)-2-nitropropene as orange-yellow
crystals with a mp of 112-113 !C.  Anal. (C14H19NO5) C,H.  The
unpurified first crop was employed in the following synthesis of the
corresponding amphetamine.

To a gently refluxing suspension of 2.9 g LAH in 400 mL anhydrous Et2O
under a He atmosphere, there was added 4.0 g of impure
1-(2,4-diethoxy-5-methoxyphenyl)-2-nitropropene by allowing the
condensing ether to drip into a shunted Soxhlet thimble apparatus
containing the nitrostyrene.  This effectively added a warm saturated
solution of the nitrostyrene dropwise over the course of 1 h.
Refluxing was maintained for 5 h and the reaction mixture was cooled
with an external ice bath with the stirring continued.  The excess
hydride was destroyed by the cautious addition of 400 mL of 1.5 N
H2SO4.  When the aqueous and Et2O layers were finally clear, they were
separated, and 100 g of potassium sodium tartrate was dissolved in the
aqueous fraction.  Aqueous NaOH was then added until the pH was above
9, and this was then extracted with 3x150 mL CH2Cl2.  Removal of the
solvent under vacuum produced 2.7 g of a pale amber oil that was
dissolved in 300 mL anhydrous Et2O and saturated with anhydrous HCl
gas.  After a few minutes delay, there commenced the separation of
fine white crystals of 2,4-diethoxy-5-methoxyamphetamine hydrochloride
(EEM).  After the crystallization was complete, these were removed by
filtration, washed with Et2O and air dried, providing 2.55 g of a fine
white crystalline solid with mp 158-159 !C.  Anal. (C14H24ClNO3)
C,H,N.

DOSAGE: unknown.

DURATION: unknown.

EXTENSIONS AND COMMENTARY: This particular identity and arrangement of
the alkoxy groups on the amphetamine molecule, EEM, is a totally
unexplored molecule.  It is reasonable to assume that it would be way
down in potency, but there is no way of guessing what the nature of
its activity might be at the dosage that would be active.

 

 

 



#75 EME; 2,5-DIETHOXY-4-METHOXYAMPHETAMINE

SYNTHESIS: To a solution of 14.0 g 4-ethoxy-3-methoxyphenol (see the
recipe for MME for the preparation of this starting material) in an
equal volume of EtOH, there was added a solution of 5.3 g KOH in 100
mL hot MeOH.  This was followed with 9.1 g ethyl bromide, and the
mixture was held at reflux for 2 h.  The first deposition of KBr was
apparent in 5 min, and there was rather severe bumping by the end of
the reaction.  The mixture was diluted with 3 volumes H2O and 1 volume
5% NaOH, and extracted with 2x200 mL Et2O.  The extracts were pooled,
and the solvent removed under vacuum, yielding 14.3 g of a pale amber
oil that set to crystals of 2,5-diethoxyanisole with a mp of 44-45 !C.
The compound had been reported in the literature from the action of
diethyl sulfate on methoxyhydroquinone.

To a mixture of 24.1 g N-methylformanilide and 27.3 g POCl3 that had
been allowed to stand at room temperature until strongly red-colored
(about 0.5 h) there was added 13.8 g solid 2,5-diethoxyanisole and the
mixture was heated on the steam bath for 2 h.  The black, thick
reaction product was poured over chipped ice and, with continuous
stirring, the color lightened and there was the formation of a
yellowish powder.  After a few h standing, this was removed by
filtration and sucked as dry as possible.  The 32 g of damp product
showed the presence of isomeric contaminatiion by GC, and the aqueous
mother liquor, upon extraction with CH2Cl2 and concentration, showed
yet more aldehyde-like impurities.  The isolated solids were
recrystallized from 125 mL boiling MeOH giving 15.8 g yellowish
crystals (wet weight) that still showed detectable impurities by GC.
A second recrystallization from 100 mL boiling MeOH gave off-white
fluffy crystals of 2,5-diethoxy-4-methoxybenzaldehyde which weighed,
after air drying, 8.5 g.  The mp was 109-110 !C.  The combined mother
liquors from the two MeOH crystallizations were stripped of solvent,
and the resulting solid mass crystallized again from MeOH to give a
second crop of aldehyde, 5.7 g, with a mp of 110-111 !C.  A solution
of 1.0 g of this aldehyde and 0.7 g malononitrile in 40 mL warm
absolute EtOH was treated with a few drops of triethylamine.  In a
minute or so, there was the formation of crystals.  These were removed
by filtration, washed with EtOH, and air dried, giving 0.6 g of
2,5-diethoxy-4-methoxybenzalmalononitrile as brilliant yellow crystals
with a mp of 156.5-158 !C.

A solution of 6.7 g 2,5-diethoxy-4-methoxybenzaldehyde in 21 g glacial
acetic acid was treated with 3.1 g nitroethane and 1.93 g anhydrous
ammonium acetate, and heated on the steam bath for 2.5 h.  The
addition of a small amount of H2O to the hot reaction mixture
instituted crystallization of an orange product which, after the
mixture had come to room temperature and stood for several h, was
removed by filtration, H2O washed, and air dried.  The product,
1-(2,5-diethoxy-4-methoxyphenyl)-2-nitropropene, was dull orange in
color, weighed 3.0 g and had a mp of 84-86 !C.  An analytical sample
from toluene had a mp of 85-86 !C.  Anal. (C14H19NO5) C,H.

To a gently refluxing suspension of 2.0 g LAH in 250 mL anhydrous Et2O
under a He atmosphere, there was added 2.8 g
1-(2,5-diethoxy-4-methoxyphenyl)-2-nitropropene by allowing the
condensing Et2O to drip into a shunted Soxhlet thimble containing the
nitrostyrene.  This effectively added a warm saturated solution of the
nitrostyrene dropwise.  The addition took 1 h and the refluxing was
continued for an additional 6 h.  The reaction mixture was brought
down to ice-bath temperature, and the excess hydride was destroyed by
the cautious addition of 150 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 >9, and this was then
extracted with 3x150 mL CH2Cl2.  Removal of the solvent under vacuum
produced 2.3 g of a clear white oil that was dissolved in 300 mL
anhydrous Et2O and saturated with anhydrous HCl gas.  At first the
solution remained completely clear, and finally there was the start of
the formation of fine white crystals.  When the crystallization was
complete, these solids were removed by filtration, Et2O washed, and
air dried.  There was thus obtained 2.2 g of
2,5-diethoxy-4-methoxyamphetamine hydrochloride (EME) with a mp of
162-164 !C with prior softening at 154 !C.  Anal. (C14H24ClNO3) C,H,N.

DOSAGE: unknown.

DURATION: unknown.

EXTENSIONS AND COMMENTARY: This is another of the collection of all
possible ethoxy homologues of TMA-2.  The latter and heavier members
of this series were synthesized and completed before the directions of
biological activity had become evident from the earlier ones.  This
compound has never been assayed, and it is a reasonable guess that it
will have a very low potency, with hints of toxicity at higher dose
levels.  I suspect that it will never be assayed, certainly not by me.

 

 

 



#76 EMM; 4,5-DIMETHOXY-2-ETHOXYAMPHETAMINE

SYNTHESIS: A solution of 166 g 3,4-dimethoxybenzaldehyde in 600 mL
acetic acid was well stirred, and brought up to an internal
temperature of exactly 25 !C.  There was added, in very small
portions, a 40% solution of peracetic acid in acetic acid.  The
evolved heat was removed with an external ice bath, and the rate of
addition was dictated by the requirement that the internal temperature
should not exceed 25 !C.  A total of 210 g of the 40% peracetic acid
was used.  The reaction mixture was poured into 3 L H2O, and the
acetic acid neutralized by the addition of solid K2CO3.  The neutral
aqueousphase was extracted with 5x150 mL Et2O, and the solvent from
the pooled extracts was removed under vacuum.  To the red-colored
residue there was added 300 mL 10% NaOH, and the mixture was heated
for 1 h on the steam bath.  This was cooled, washed once with CH2Cl2,
acidified with HCl, and extracted with 5x150 mL Et2O.  The pooled
extracts were washed once with saturated NaHCO3 (which removed most of
the color) and the removal of the solvent under vacuum gave 105 g of
3,4-dimethoxyphenol as an amber oil that slowly set up to crystals.

The above crude 3,4-dimethoxyphenol was dissolved in 200 mL EtOH, and
treated with a solution of 38.1 g KOH in 300 mL hot EtOH.  The clear
solution of the potassium salt was a deep red color, and was promptly
treated with 94.3 g allyl bromide, at a rate commensurate with the
exothermic reaction.  The mixture was held at reflux for 2 h.  This
was then added to 1 L H2O and extracted with 5x100 mL Et2O.  The
extracts were pooled, and removal of the solvent under vacuum gave a
residue of 98 g of a black oil.  This was distilled at 104-108 !C at
0.7-1.0 mm/Hg to give 59.3 g 1-allyloxy-3,4-dimethoxybenzene as a pale
yellow oil with a greenish cast.

A total of 59 g of the neat 1-allyloxy-3,4-dimethoxybenzene was
provided with an internal thermometer, and heated with an open flame.
The color quickly became purple, then lightened to a red at 70 !C, and
finally to a pale pink by 210 !C.  At 240 !C an exothermic reaction
set in with the temperature going up to almost 290 !C.  It was held in
the 270-280 !C range for several min, then allowed to return to room
temperature.  GC analysis showed two peaks, the second and major one
being the desired 1,2,4,5-isomer.  A small sample was caught by
prep-GC, and it successfully seeded the crude Claissen rearrangement
product.  The isolated 2-allyl-4,5-dimethoxyphenol, pressed on a
porous plate, had a mp of 39.5-40.5 !C which was improved to 41.5-42
!C by recrystallization from hexane.

To a solution of 9.7 g 2-allyl-4,5-dimethoxyphenol in a few mL EtOH,
there was added a solution of 2.8 g KOH in 25 mL boiling EtOH followed
by 5.5 g ethyl bromide.  The mixture was held at reflux for 3.5 h and
then poured into 200 mL H2O and extracted with 3x100 mL CH2Cl2.
Pooling the extracts and removal of the solvent under vacuum gave a
residue of 10.4 g of 4,5-dimethoxy-2-ethoxy-1-allylbenzene as a clear,
mobile oil.  It was substantially a single component by GC and was
used in the following isomerization step without further purification.

A solution of 9.4 g 4,5-dimethoxy-2-ethoxy-1-allylbenzene in 10 mL
EtOH was treated with 20 g flaked KOH, and heated on the steam bath.
The progress of the isomerization was followed by the assay of
isolates by GC.  After 5 h, the reaction mixture was poured into 250
mL H2O which immediately generated a pasty solid.  This was sucked
free of solvent and other liquids on a sintered funnel, giving 5.5 g
of trans-4,5-dimethoxy-2-ethoxy-1-propenylbenzene as an amber solid
with a mp of 65-67 !C.  A small analytical sample from hexane had a mp
of 68 !C.

A solution of 5.0 g trans-4,5-dimethoxy-2-ethoxy-1-propenylbenzene in
27 g acetone that contained 2.2 g pyridine was magnetically stirred
and cooled to 0 !C.  There was then added 4.5 g tetranitromethane and,
after 2 minutes stirring at this temperature, the reaction mixture was
quenched with a solution of 1.5 g KOH in 26 mL H2O.  The reaction
mixture remained a clear deep orange color, and additional H2O was
required to institute crystallization.  There was the slow deposition
of bright yellow crystals of
1-(4,5-dimethoxy-2-ethoxyphenyl)-2-nitro-propene which weighed, after
EtOH washing and air drying to constant weight of 4.4 g.  The mp was
75-76 !C.

To a gently refluxing suspension of 3.5 g LAH in 250 mL anhydrous Et2O
under a He atmosphere, there was added 3.9 g
1-(4,5-dimethoxy-2-ethoxyphenyl)-2-nitropropene by allowing the
condensing Et2O to drip into a shunted Soxhlet apparatus with the
thimble containing the nitrostyrene.  This effectively added a warm
saturated solution of the nitrostyrene dropwise; the nitrostyrene was
very soluble in Et2O.  Refluxing was maintained for 2.5 h and the
reaction continued to stir at room temperature for an additional 3.5
h.  The excess hydride was destroyed by the cautious addition of 225
mL 1.5 N H2SO4.  When the aqeous and Et2O layers were finally clear,
they were separated, and 75 g of potassium sodium tartrate was
dissolved in the aqueous fraction.  Aqueous NaOH was then added until
the pH was >9, and this was then extracted with 3x100 mL CH2Cl2.
Evaporation of the solvent under vacuum produced 2.8 g of a clear,
almost colorless oil that was dissolved in anhydrous Et2O and
saturated with anhydrous HCl gas.  This initially generated a solid
that then oiled out.  After a few minutes stirring, this began to
solidify again and it finally transformed into a loose fine white
solid.  This was recrystallized by dissolution in 50 mL warm IPA
followed by dilution with 300 mL Et2O.  After a few minutes, crystals
of 4,5-dimethoxy-2-ethoxyamphetamine hydrochloride (EMM) formed which
were removed by filtration, Et2O washed, and air dried.  These weighed
2.7 g and had a mp of 171-172 !C.  Anal. (C13H22ClNO3) C,H,N.

DOSAGE: greater than 50 mg.

DURATION: unknown.

QUALITATIVE COMMENTS: (with 50 mg) There were no effects.

EXTENSIONS AND COMMENTARY: This was the first of the ethoxy homologues
of TMA-2, and it was immediately (well, within a couple of months) run
up from an initial dab to 25 milligrams.  This was in early 1963, and
the lack of activity of EMM was keenly disappointing.  This was a
level at which the prototype, TMA-2, was very active, and the
conclusion was that maybe any change on the molecule would result in a
loss of activity.  So this approach was shelved for a while, and all
efforts were directed into the relocation, rather than the elongation,
of the methoxy groups.  A few months later, the ethoxy question was
addressed again, and the discovery of MEM rekindled full interest in
this ethoxy question.

 

 

 



#77 ETHYL-J; 2-ETHYLAMINO-1-(3,4-METHYLENEDIOXYPHENYL)BUTANE;

N-ETHYL-1-(1,3-BENZODIOXOL-5-YL)-2-BUTANAMINE

SYNTHESIS: A stirred solution of 9.0 g
1-(3,4-methylenedioxyphenyl)-2-butanone (see the recipe for J for its
preparation) in 150 mL MeOH was treated with 9.0 g ethylamine
hydrochloride, 4.0 g anhydrous NaOAc, and 3.0 g sodium
cyanoborohydride.  The pH was maintained between 6 and 7 by the
periodic addition of HCl.  After the base formation had stabilized,
there was added an additional 9.0 g ethylamine hydrochloride, 9.0 g
NaOAc and 2.0 g sodium cyanoborohydride.  With continuous stirring,
there was HCl added over the course of 1 h until the final pH was
approximately 2.  The reaction mixture was poured into 700 mL dilute
NaOH, and extracted with 3x75 mL CH2Cl2.  These extracts were pooled,
and back-extracted with dilute H2SO4.  This was washed with 2x50 mL
CH2Cl2, then made basic with dilute NaOH and extracted with 2x75 mL
CH2Cl2.  Removal of the solvent under vacuum gave a 0.81 g residue
which was dissolved in 10 mL IPA.  Neutralization with concntrated HCl
formed white crystals spontaneously.  These were diluted with Et2O,
filtered, Et2O washed and air dried to provide 0.85 g
2-ethylamino-1-(3,4-methylenedioxy-phenyl)butane hydrochloride
(ETHYL-J), with mp of 176-177 !C.  Anal. (C13H20ClNO2) C,H.  The
neutral fraction that remained in the organic phase following the
dilute sulfuric acid extraction, was recovered by removal of the
solvent under vacuum.  There was obtained about 5 g of an amber liquid
that was largely 2-hydroxy-1-(3,4-methylenedioxyphenyl)butane.

DOSAGE: greater than 90 mg.

DURATION: probably short.

QUALITATIVE COMMENTS: (with 65 mg) Perhaps aware at 20 minutes.
Definitely aware at 45 minutes.  Diffusing to nothing at 3-4 hours.

(with 90 mg) I am somewhere between 1 and +.  And everything became
lost in the evening with a couple of glasses of wine and talk that
went on to 3 AM.

EXTENSIONS AND COMMENTARY: And nothing higher has ever been looked at.
If the analogy with the amphetamine counterparts (J with MDA, METHYL-J
with MDMA, and this, with MDE) were to hold up (a drop of about a
third in potency with the lengthening of the chain by a carbon atom),
one might guess that this compound would be an interesting intoxicant,
but probably not until you got up into the area at or above a 200
milligram dose.  And that is a lot of chemical for the body to have to
handle.  Some day, maybe.

 

 

 



#78 ETHYL-K; 2-ETHYLAMINO-1-(3,4-METHYLENEDIOXYPHENYL)PENTANE;

N-ETHYL-1-(1,3-BENZODIOXOL-5-YL)-2-PENTYLAMINE

SYNTHESIS: A solution of 120 mg mercuric chloride in 160 mL H2O was
poured over 4.7 g aluminum foil (Reynolds Wrap, regular weight, cut
into 1 inch squares) and allowed to stand until the amalgamation was
well underway (about 30 min).  The H2O was then drained and the foil
washed with 2x200 mL H2O with thorough draining.  There was then
added, in sequence and with good swirling and agitation between each
addition, 8.5 g ethylamine hydrochloride dissolved in 7 mL H2O, 21 mL
IPA, 17 mL 25% NaOH, 7.1 g 1-(3,4-methylenedioxyphenyl)-2-pentanone
(see the recipe for METHYL-K for its preparation), and finally 40 mL
IPA.  The reaction mixture was periodically heated on the steam bath
to keep the reaction moving and active.  After all the metal had been
consumed, the mixture was filtered, and the filter cake washed with
MeOH.  The solvent was removed from the combined filtrate and
washings, and the residue suspended in 800 mL dilute HCl.  This was
washed with 3x100 mL Et2O, made basic with 25% NaOH, and extracted
with 3x100 mL CH2Cl2.  The pooled extracts were stripped of solvent
under vacuum yielding a residue of 6.3 g of an amber oil.  This was
distilled at 115-125 !C at 0.4 mm/Hg to give 5.61 g of an almost white
liquid which was dissolved in 28 mL IPA, neutralized with concentrated
HCl, and diluted with 100 mL anhydrous Et2O.  The resulting clear
solution became cloudy, then set up in a cottage cheese texture, and
then all broke up to a beautiful loose solid.  This was filtered, Et2O
washed and air dried to give 5.99 g
2-ethylamino-1-(3,4-methylenedioxyphenyl)pentane hydrochloride
(ETHYL-K) with a mp of 157-158 !C.  Anal. (C14H22ClNO2) C,H.

DOSAGE: (greater than 40 mg).

DURATION: unknown.

QUALITATIVE COMMENTS: (with 40 mg) There was a paresthetic twinge in
my shoulder area at about an hour Q other than that, absolutely
nothing.

EXTENSIONS AND COMMENTARY: And that is as high a dose as has
apparently ever been tried with ETHYL-K.  The compounds with the
hexane chain (L-series) rather than the pentane chain of the K-series
have been made, but they have been spun into the recipe for METHYL-K.

 

 

 



#79 F-2; 2-M;
6-(2-AMINOPROPYL)-5-METHOXY-2-METHYL-2,3-DIHYDROBENZOFURAN

SYNTHESIS: To a solution of 43.2 g KOH pellets in 250 boiling EtOH
there was added 96 g 4-methoxyphenol followed by the slow addition of
131.2 g allyl bromide, and the mixture was held under refluxing
conditions for 16 h.  After cooling, the reaction was added to 1.6 L
H2O, and made strongly basic with 25% NaOH.  This was extracted with
3x100 mL CH2Cl2, the extracts pooled, washed once with dilute NaOH and
then once with dilute HCl.  Removal of the solvent under vacuum gave
93.8 g of 4-allyloxyanisole as a pale amber oil, which was used in the
following reaction without further purification.

A round-bottomed flask containing 93 g crude 4-allyloxyanisole was
equipped with an immersed thermometer and heated with an external
flame until an exothermic reaction set in at 230 !C.  The temperature
rose to 270 !C and it was maintained there with the flame for five
minutes.  After cooling to room temperature, the reaction mix was
poured into 2 L H2O and made strongly basic with the addition of 25%
NaOH.  This dark aqueous phase was washed with 2x200 mL CH2Cl2, and
then acidified with HCl.  This was then extracted with 2x200 mL
CH2Cl2, and the pooled extracts washed first with saturated NaHCO3 and
then with H2O.  Removal of the solvent under vacuum gave 65.6 g of
2-allyl-4-methoxyphenol as a clear, amber oil.  To a solution of 1.66
g of this crude phenol in 5 mL hexane with just enough CH2Cl2 added to
effect a clear solution, there was added 1.3 g phenyl isocyanate
followed with three drops of triethylamine.  An exothermic reaction
ensued which spontaneously deposited white crystals.  These was
removed and hexane washed to give 2-allyl-4-methoxyphenyl N-phenyl
carbamate, with a mp of 88-89 !C.  The acetate ester, from the phenol
and acetic anhydride in pyridine, did not crystallize.

To a solution of 37.7 g 2-allyl-4-methoxyphenol in 125 mL glacial
acetic acid there was added 19 g zinc chloride followed with 63 mL
concentrated HCl.  The mixture was held at reflux temperature for 40
min, then cooled to room temperature, diluted with 300 mL H2O, and
extracted with 2x200 mL CH2Cl2.  The pooled extracts were washed
repeatedly with 8% NaOH until the washings remained basic.  Removal of
the solvent under vacuum gave a clear pale yellow oil that was
distilled at the water pump.  A fraction boiling at 150-165 !C was
5-methoxy-2-methyl-2,3-dihydrobenzofuran which weighed 25 g and which
was a highly refractive colorless oil.  The infra-red spectrum
indicated that some small amount of hydroxy group was present, but the
NMR spectrum was in complete accord with the benzofuran structure.  A
higher cut in this distillation gave 4.5 g of a phenolic product
tentatively assigned the structure of 4-methoxy-2-propenylphenol.  The
target dihydrobenzo-furan has also been synthesized from the open-ring
o-allyl phenol in acetic acid solution with the addition of a
catalytic amount of concentrated H2SO4.

To a half-hour pre-incubated mixture of 69 g POCl3 and 60 g
N-methylformanilide there was added 29.0 g
5-methoxy-2-methyl-2,3-dihydrobenzofuran and the mixture was heated on
the steam bath for 2 h.  The reaction mixture was poured into 1 L H2O,
and allowed to stir overnight.  The brown gummy solids were removed by
filtration, and air dried as completely as possible.  These weighed 32
g and were shown by GC on OV-17 to consist of two benzaldehyde isomers
in a ratio of 7:2.  This was triturated under 18 mL MeOH, and the
undissolved solids removed by filtration and washed with 6 mL
additional MeOH.  The mother liquor and washings were saved.  The 17.8
g of dull yellow solids that were obtained were repeatedly extracted
with 75 mL portions of boiling hexane (4 extracts were required) and
each extract, on cooling, deposited yellow crystals of the major
aldehyde.  The dried crystals of
6-formyl-5-methoxy-2-methyl-2,3-dihydrobenzofuran were combined (9.5
g) and had a mp of 80-82 !C.  The methanol washes saved from above
were stripped of solvent, and the sticky, orange solids that remained
were enriched in the minor aldehyde isomer (3:2 ratio).  Several
injections of this crude material into a preparative GC OV-17 column
gave sufficient quantities of the RwrongS isomer for NMR
characterization.  The 2-methyl group was intact (eliminating the
possibility of a dihydrobenzopyran isomer) and the ring meta-proton
splitting required that the formyl group be in the benzofuran
7-position.  This crystalline solid was, therefore,
7-formyl-5-methoxy-2-methyl-2,3-dihydrobenzofuran.

A solution of 9 g of 6-formyl-5-methoxy-2-methyl-2,3-dihydrobenzofuran
in 35 mL glacial acetic acid was treated with 6 mL of nitroethane
followed with 3.1 g anhydrous ammonium acetate.  This mixture was
heated on the steam bath for 4 h, diluted with half its volume with
warm H2O, and seeded with a bit of product that had been obtained
separately.  The slightly turbid solution slowly crystallized as it
cooled, and was finally held at 0 !C for several h.  The deep orange
product was removed by filtration, washed with 50% acetic acid, and
air dried to constant weight.  There was thus obtained 7.0 g
5-methoxy-2-methyl-6-(2-nitro-1-propenyl)-2,3-dihydrobenzofuran with a
mp of 89-90 !C from MeOH.

A suspension of 5.0 g LAH in 500 mL of well stirred anhydrous Et2O at
a gentle reflux, was treated with a warm, saturated solution of 7.0 g
5-methoxy-2-methyl-6-(2-nitro-1-propenyl)-2,3-dihydrobenzofuran in
Et2O added dropwise.  The mixture was kept at reflux temperature for
36 h, allowed to stand 2 days, and then the excess hydride destroyed
by the cautious addition of 500 mL 6% H2SO4.  The phases were
separated, and the aqueous phase washed with 2x200 mL CH2Cl2.  A total
of 125 g potassium sodium tartrate was added to the aqueous phase, and
sufficient 25% NaOH added to bring the pH to about 10.  This phase was
extracted with 3x150 mL CH2Cl2, and the pooled extracts were stripped
of solvent under vacuum.  The residual oil (4.8 g, amber in color) was
dissolved in 300 mL anhydrous Et2O which, upon saturation with
anhydrous HCl gas gave a clear solution that suddenly deposited white
crystals.  The hydrochloride salt of
6-(2-aminopropyl)-5-methoxy-2-methyl-2,3-dihydrobenzofuran weighed 2.3
g and was not satisfactory as a solid derivative, but it appears that
the oxalate salt is both nonhygroscopic and quite stable.  It (F-2)
had a mp of 216-218 !C and it displayed a textbook NMR.

DOSAGE: greater than 15 mg.

DURATION: unknown.

EXTENSIONS AND COMMENTARY: This material, which is certainly a mixture
of two diastereoisomeric pairs of racemates since there are two chiral
centers present, showed no effects at levels of up to 15 milligrams
orally.  Doses of 100 mg/Kg were without effects in mice following
i.p. injections, although half again this amount proved to be lethal.
In rats trained to discriminate LSD from saline, F-2 proved to be
about 40 times less potent than the reference compound DOM, requiring
some 5 mg/Kg for positive responses.  But the human trials were only
up to about 0.2 mg/Kg.

This was the prototype compound that was originally put together to
justify giving a paper at a marijuana conference in Sweden, in 1968.
Although I had never done much with marijuana or with its principal
ingredients, I thought maybe I could bend the topic a bit to embrace
some potentially active phenethylamines.  There is a story of an
international conference held in Geneva a few years earlier to discuss
the worrisome decrease in the elephant population.  A German zoologist
invested a full eight-hour day in a summary of his 21 volume treatise
on the anatomy and the physiology of the elephant.  A French
sociologist presented a lively slide show on the mating rituals and
rutting behavior of the elephant.  And a rabbi from Tel Aviv entitled
his talk: RElephants and the Jewish Problem.S My Swedish talk should
have been named RMarijuana and the Psychedelic Amphetamines.S The
memorable story of meeting the chief of the Swedish equivalent of the
Bureau of Narcotics, and ending up playing Mozart sonatas in the attic
of his home, has been spun out elsewhere in the book.

The original concept was a grand plan to imitate two of the three
rings of tetrahydrocannabinol.  There is an aromatic ring (with an
alkyl group and two oxygens on it) and it is fused to a pyran ring
with a couple of methyl groups on it.  So, if one were to tie the
methyl group at the 4-position of DOM around with a short carbon chain
into the oxygen atom at the five position, one could squint and say
that the resulting amphetamine was kinda something like an analogue of
THC.  Thus, the resulting six-membered ring (a pyran) or five-membered
ring (a furan) could be peppered with methyl groups at different
locations (and up to two per location).  If the ring was a
five-membered structure, then the parent system would be a benzofuran,
and the location of methyl groups on the ring would be indicated by
the appropriate numbers following the letter RFS which would stand for
RfuranS.  And if it were to be a six-membered ring, the resulting
benzopyran would be indicated with a RPS for pyran, and again the
methyl group or groups would be indicated by the substitution
position.  This code would cover all polymethylated homologues with
codes that would look like F-22 and P-2234.  If any of them showed up
with fascinating activities, I would extend methyls to ethyls, and
work out some whole new naming code at some future time.  An early
system, naming this compound 2-M for a methyl group on the 2-position
of the furan ring, was abandoned when it became apparent that the
pyran world would screw everything up.

The isolation of characterizable quantities of
7-formyl-5-methoxy-2-methyl-2,3-dihydrobenzofuran from the
benzaldehyde recipe above gave a fleeting fantasy of a whole new
direction that this little project might go.  If this unexpected
benzaldehyde were to be converted to the corresponding amphetamine,
one would have
7-(2-aminopropyl)-5-methoxy-2-methyl-2,3-dihydrobenzofuran.  Suddenly
here would be a 2,3,5-trisubstituted thing with a ring at the
2,3-position, similar to the still unmade MMDA-4.  The temptation to
be diverted in this way lasted, fortunately, only a few minutes, and
the project was shelved.  Someday, when there are buckets of spare
time or hosts of eager graduate students, some fascinating chemistry
might lie this way, and maybe some fascinating pharmacology, even.

The plain furan analogue, without any methyl groups on it, has been
made.  Five-methoxybenzofuran formed the 6-formyl derivative (the
aldehyde) with a mp of 79-80 !C and from it the nitrostyrene (orange
needles, mp 89-91 !C) and the final amphetamine (white solids, as the
methane sulfonate, mp 141-144 !C) were prepared in a manner similar to
the preparation of F-2 above.  In the rat studies, it was three times
more potent than F-2, but still some 15 times less potent than DOM.
And in initial human trials (of up to 30 milligrams) there were again
no effects noted.  Naming of this material is easy chemically
(6-(2-aminopropyl)-5-methoxy-2,3-dihydrobenzofuran) but tricky as to
code.  If the numbers that follow the RFS give the location of the
methyl groups, then this material, without any such groups, can have
no numbers following, and should properly be simply RF.S OK, it is
RF.S The preparation or the attempted preparations of other homologues
such as F-23 and F-233 are outlined under the recipe for F-22.

 

 

 



#80 F-22;
6-(2-AMINOPROPYL)-2,2-DIMETHYL-5-METHOXY-2,3-DIHYDROBENZOFURAN

SYNTHESIS: To a solution of 43.2 g flaked KOH in 250 mL hot EtOH there
was added 96 g 4-methoxyphenol followed by 90 g 2-methylallyl chloride
over the course of 2 h.  The mixture was held at reflux for 24 h, then
added to 1.6 L H2O.  There was sufficient 25% NaOH added to make the
phase strongly basic, and this was then extracted with 3x200 mL
CH2Cl2.  The pooled extracts were washed with H2O, and the solvent
removed under vacuum.  The residue, 125 g of a pale amber oil, was
crude 4-(2-methylallyloxy)anisole and was used without further
purification in the following reaction.

In a round-bottomed flask containing an internal thermometer, there
was placed 125 g of unpurified 4-(2-methylallyloxy)anisole, and this
was heated with an open flame.  At an internal temperature of 190 !C
an exothermic reaction set in, raising the temperature to 250 !C,
where it was held for an additional 2 min.  After the reaction mixture
had cooled to room temperature, it was poured into 500 mL H2O, made
strongly basic with 25% NaOH, and extracted repeatedly with 100 mL
portions of CH2Cl2 until the extracts were essentially colorless.
These extracts were pooled and the solvent removed to provide 80.0 g
of a deeply colored oil that proved to be largely the appropriately
substituted dihydrobenzofuran.  The aqueous residue from above was
acidified with concentrated HCl, and again extracted with CH2Cl2.
Removal of the solvent gave 17.7 g of
4-methoxy-2-(2-methylallyl)phenol as an amber oil which eventually set
down as white crystals with a mp of 52.5-54 !C.

A solution of 17 g of 4-methoxy-2-(2-methylallyl)phenol in 56 g acetic
acid was treated with 8.4 g zinc chloride followed with 28 mL
concentrated HCl.  This mixture was heated at reflux temperature with
a mantle for 1 h.  After cooling, this was poured into H2O and
extracted with 2x150 mL CH2Cl2.  The pooled extracts were washed with
several portions of 8% NaOH, until the extracts were colorless.  The
organic fraction was then washed with H2O, and the solvent removed to
yield 5.8 g of 2,2-dimethyl-5-methoxy-2,3-dihydrobenzofuran as a pale
amber oil with a pungent smell.  This was purified by distillation,
giving a fraction of an off-white oil with a bp of 136-138 !C at 33
mm/Hg.

To a mixture of 8.0 g N-methylformanilide and 9.2 g POCl3 which had
been allowed to stand for 0.5 h, there was added 4.0 g
2,2-dimethyl-5-methoxy-2,3-dihydrobenzofuran, and the mixture held at
the steam bath temperature for 2.5 h.  This was then poured into 200
mL H2O which produced a black oily phase that gave no hint of
crystallization.  This mixture was extracted with 3x150 mL CH2Cl2 and
the solvent was removed from the pooled extracts under vacuum.  The
residual oil (which was shown by GC to contain approximately equal
quantities of two isomeric benzaldehydes A and B) was extracted with
three 75 mL portions of boiling hexane, each of which on cooling
deposited a reddish oil that partially crystallized.  A fourth hexane
extract gave nothing more.  The solvent was decanted from these three
extracts, and the semi-solid residues were ground under 3.0 mL MeOH
giving 1.4 g of pale yellow crystals of
2,2-dimethyl-6-formyl-5-methoxy-2,3-dihydrobenzo-furan, isomer RBS.
After recrystallization from MeOH, the color was almost white, and the
mp was 79.5-80.5 !C.  The combined mother liquors were enriched in
isomer RAS which proved, following preparative GC separation and NMR
analysis, to be the 7-formyl isomer.  The 80 g of impure
dihydrobenzofuran isolated from the Claisen rearrangement above was
distilled and a fraction (43.8 g) that boiled from 138-153 !C at 30
mm/Hg was processed as described here to the aldehyde mixture.
Following similar hexane extractions, a yield of 4.0 g of a 95% pure
isomer RBS was finally obtained.  The remaining components of this
fraction were not determined, but it is possible that there were some
that contained the six-membered benzopyran ring system.

To a solution of 5.2 g of
2,2-dimethyl-6-formyl-5-methoxy-2,3-dihydro-benzofuran in 20 mL
glacial acetic acid there was added 3 mL nitroethane followed by 1.6 g
anhydrous ammonium acetate.  This mixture was heated for 4 h on the
steam bath, and then a small amount of H2O was added to the hot
solution.  This instigated the formation of a copious deposition of
brick-red crystals which were, after cooling, removed by filtration,
and recrystallized from 50 mL boiling MeOH.  After air drying there
was thus obtained 2.7 g of day-glo yum-yum orange crystals of
2,2-dimethyl-5-methoxy-6-(2-nitro-1-propenyl)-2,3-dihydrobenzofuran.
An additional 0.6 g of product was obtained by working the mother
liquors.

A suspension of 2.5 g LAH in 300 mL refluxing anhydrous Et2O was
treated with a solution of 3.1 g
2,2-dimethyl-5-methoxy-6-(2-nitro-1-propenyl)-2,3-dihydrobenzofuran in
Et2O.  The mixture was held at reflux temperature for 18 h.  After
cooling, the excess hydride was destroyed by the cautious addition of
400 mL H2O which contained 15 g H2SO4.  The aqueous phase was
separated, washed once with Et2O, and then once with CH2Cl2.  There
was then added 60 g potassium sodium tartrate, and the pH was brought
to above 10 by the addition of 25% NaOH.  This was extracted with
3x250 mL CH2Cl2, the extracts pooled, and the solvent removed under
vacuum.  There remained 2.8 g of an amber oil with an ammoniacal
smell.  This was dissolved in 200 mL anhydrous Et2O, and saturated
with anhydrous HCl gas.  There was the immediate formation of an oil,
from which the supernatent Et2O was decanted.  The residual oil was
resuspended in a second 200 mL anhydrous Et2O, again decanted, and
finally a third 200 mL Et2O effected the dissolving of the remaining
oil to give a clear solution.  All three solutions became gelatinous
over the following few h, and each deposited a crop of white crystals
over the following few days.  From the first there was obtained 1.4 g
of product with a mp of 153-154 !C; from the second, 0.2 g with a mp
of 153-154 !C; and from the third, 1.2 g with a mp of 155-156 !C.
These crops were combined, and recrystallized from 10 mL of boiling
CH3CN to give 1.7 g
6-(2-aminopropyl)-2,2-dimethyl-5-methoxy-2,3-dihydrobenzofuran
hydrochloride (F-22) as a white crystalline solid which had a mp of
154-155 !C.  This material, even when dry, showed a tendency to
discolor with time.

DOSAGE: greater than 15 mg.

DURATION: unknown.

EXTENSIONS AND COMMENTARY: And here is yet another dihydrobenzofuran
which is not of a very high potency if, indeed, it is active at all.
This particular dihydrobenzofuran analogue, F-22, had sort of tickled
my fancy as being an especially good candidate for activity.  It had a
certain swing to it.  F-22, like LSD-25.  And here it was finished,
just five days before I had to deliver a paper concerning the
syntheses (and activities!) of all these dihydrobenzofurans to the
marijuana congress.  Could this possibly be another LSD?  I was
sufficiently convinced that the possibility was real, that I actually
started the screening process at a most unusually low level of 10
micrograms.  Two days later, I upped this to a dose of 25 micrograms
(no activity again) and three days after that, at 1 AM on the polar
flight to Copenhagen, I swallowed the RmonstrousS dose of 50
micrograms.  Shoot the works.  If I were to blossom all over the
tourist section of the SAS plane, well, it would be quite a paper to
give.  If not, I could always say something like, RThe active level
has not yet been found.S No activity.  Another Walter Mitty fantasy
down the tubes.

And, as it turned out, the entire project pretty much ran out of
steam.  A number of clever analogs had been started, and would have
been pursued if there had been any activity promised of any kind with
any of these dihydrobenzofurans.  The RotherS benzaldehyde described
above, could have been run in a manner parallel to that proposed for
the counterpart with F-2, to make the eventual amphetamine,
7-(2-aminopropyl)-2,2-dimethyl-5-methoxy-2,3-dihydrobenzofuran.  Great
strides had been made towards F-233 (I have discussed the naming
system under F-2, with the F standing for the furan of benzofuran and
the 2 and 3 and 3 being the positions of the methyl groups on it).
The reaction of 4-methoxyphenol with 1-chloro-3-methyl-2-butene gave
the ether which underwent the thermal Claisen rearrangement to
2-(1,1-dimethylallyl)-4-methoxyphenol with a bp of 148-157 !C at 30
mm/Hg.  This was cyclized to the intermediate cycle
2,3,3-trimethyl-2,3-dihydrobenzofuran which, after distillation, was
shown to be only 80% pure by GC analysis.  This was, nonetheless, (and
with the hope that is in the very fiber of a young innocent chemist),
pushed on to the benzaldehyde stage (and there were a
not-too-surprising four benzaldehydes to be found in the oil that was
produced, which refused to crystallize).  And then (when sheer
desperation replaced hope) these were condensed with nitroethane to
form an even worse mixture.  Maybe something might crystallize from
it?  Nothing ever did.  Junk.  Everything was simply put on the shelf
where it still rests today, and F-233,
6-(2-aminopropyl)-5-methoxy-2,3,3-trimethyl-2,3-dihydrobenzofuran,
remains the stuff of speculation.

And a start towards F-23,
6-(2-aminopropyl)-2,3-dimethyl-5-methoxy-2,3-dihydrobenzofuran, got
just as far as the starting ether, when it occurred to me that the
final product would have an unprecedented three chiral centers, and so
a total of four racemic pairs of diastereoisomers.  And then I
discovered that the starting allyl halide, crotyl chloride, was only
80% pure, with the remaining 20% being 3-chloro-1-butene.  This would
have eventually produced a 2-ethyl-analogue,
6-(2-aminopropyl)-2-ethyl-5-methoxy-2,3-dihydrobenzofuran, with its
two chiral centers and two more pairs of stereoisomers (not to speak
of the need to devise an entirely new coding system).  Unless
something were to fall into my lap as a crystalline intermediate, the
final mess could have had at least six discreet compounds in it, not
even considering optical isomers.  And I havenUt even begun to think
of making the six-membered dihydrobenzopyrans which were the THC
analogues that presented the rationale that started the whole project
in the first place.  A recent issue of the Journal of Medicinal
Chemistry has just presented an article describing the reaction of
6-methoxytetrahydrobenzopyran with dichloromethyl methyl ether, and
approximately equal amounts of all three of the possible isomers were
obtained.  That would have been the first step towards making the
prototypic compound 7-(2-aminopropyl)
6-methoxy-1,2,3,4-tetrahydrobenzopyran.  Just as the benzofurans were
all named as F-compounds, this, as a benzopyran, would have been a P
compound, but P also is used for proscaline, and there would have been
some repair-work needed for these codes.

Time to abandon ship.  The fact that I had just synthesized and
discovered the strange activity of ARIADNE at about this time, made
the ship abandonment quite a bit easier to accept.

 

 

 



#81 FLEA; N-HYDROXY-N-METHYL-3,4-METHYLENEDIOXYAMPHETAMINE

SYNTHESIS: (from 3,4-methylenedioxyphenylacetone) A solution of 2.1 g
N-methylhydroxylamine hydrochloride and 4.4 g
3,4-methylenedioxyphenylacetone in 5.5 mL MeOH was added to a
suspension of 4.5 g NaHCO3 in 30 mL boiling MeOH.  There was added
about 5 mL H2O (which gave a clear solution) followed by another 50 mL
H2O which produced a pale yellow color.  To this solution of the
unisolated nitrone there was added 1.7 g sodium cyanoborohydride,
which generated a goodly amount of foaming.  There was HCl added as
needed to maintain the pH at about neutrality.  The reaction appeared
to have stopped after a day or two, so all was poured into 500 mL H2O,
acidified with HCl, and washed with 2x75 mL CH2Cl2.  The addition of
base brought the pH >9, and this was then extracted with 3x75 mL
CH2Cl2.  Removal of the solvent from the pooled extracts gave a
residue of 1.65 g of crude
N-hydroxy-N-methyl-3,4-methylenedioxyamphetamine.  Efforts to obtain
solid seed samples of the salts with hydrochloric acid, perchloric
acid, sulfuric acid, phosphoric acid, and with a number of organic
acids, all failed.  The salt formation from this free-base will be
discussed below.

(from MDOH) A solution of 0.75 g crystalline free-base MDOH in a few
mL MeOH was treated with a solution of 0.4 g sodium cyanoborohydride
in 10 mL MeOH, and there was then added 2 mL of 35% formaldehyde.  The
stirred reaction mixture was kept at a neutral pH with the occasional
addition of HCl.  After several days (when additional acid was no
longer required) the excess solvent was removed under vacuum, and the
residue poured into dilute H2SO4.  This was washed with 2x75 mL CH2Cl2
and then, following the addition of base, this was extracted with 3x75
mL CH2Cl2.  Removal of the solvent from the pooled extracts gave a
viscous oil residue of 0.53 g.  The free-base product from these
preparations was distilled at 110-120 !C at 0.2 mm/Hg to give the
N-hydroxy-N-methyl product as a white oil.  An alternate methylation
procedure used a solution of MDOH in a 4:1 MeOH/acetic acid solution
containing formaldehyde which was reduced with sodium borohydride at
dry ice temperatures.  Its work-up is identical to that involving
sodium cyanoborohydride.

The distilled product was dissolved in an equal volume of MeOH, and
treated with a half-equivalent of oxalic acid dihydrate, dissolved in
10 volumes of MeOH.  This combination gave the slow deposition of
crystals of the full oxalate salt (one acid, two bases) as a white
crystalline product.  The mp of the crude salt was in the 130-150 !C
range, and after recrystallization from CH3CN,
N-hydroxy-N-methyl-3,4-methylenedioxyamphetamine oxalate (FLEA) had a
mp of 146-147 !C.

DOSAGE: 100 - 160 mg.

DURATION: 4 - 8 h.

QUALITATIVE COMMENTS: (with 90 mg) The material tastes terrible, like
grapefruit juice that has stayed in the can too long.  There was no
nausea, no feeling of difficulty in swallowing at any time during the
day.  I felt a dry mouth and was thirsty Q sipped water throughout the
day.  At the beginning of the experiment, there was a glimmer of the
MDMA warmth, but later I felt separated and a bit isolated.  I was
just floating around, seeing the beauty of colors and objects in the
house and outdoors and listening first to this conversation, then to
that one.  All senses seemed enhanced.  I found the material pleasant.
I was happy with the amount I took but would not be afraid to take
more or to take a supplement.  I found it similar to, but not the same
as, MDMA.

(with 110 mg) We found this very similar to MDMA, but perhaps
slightly slower.  I plateauUd at 2:30 hours and had a very gradual
descent.  My friend had a marvelous and private 'cone of silence' that
was to him unique to MDMA or to 2C-T-8.  Teeth problems were minor,
and the descent from the top of the experience showed less
interactive, and more contemplative action, than with MDMA.  Very
similar to MDMA, but with its own character.

(with 110 mg) The onset was at about a half-hour.  The come-on was
more gradual and much easier than with MDMA, and it seemed to be more
head than body oriented.  I had about two hours of very complex and
personal self-evaluation, and I am not at peace in putting all of it
down here in writing.  Overall I like it, and I would be interested to
see if there's a difference in conjunction with MDMA.  Thanks very
much.

(with 110 mg + 35 mg) I saw my onset at 20 minutes, and it was
subtle, and very pleasant, and had a mild amphetamine-like elevation
for me (body lightness, cognitive functions seemed clear and clean,
heightened visual awareness and with some enhancement of color).  It
seemed as if I were on the fringe of LSD-like visual changes, but that
never materialized.  The affect was very good, communicative,
friendly, accepting, but without the profound emotional bonding of
MDMA.  The following day felt very much like a post-LSD day; we felt
great.  The body was light, energy good, emotions high, several
insights throughout the day, interactions clear and open Q a
magnificent gift of a day.  I started a menstrual period the day of
the experience and it lasted 6 to 7 days; all of this was a couple of
weeks early.  I have a very favorable impression of FLEA although the
body penalty seems high.

EXTENSIONS AND COMMENTARY: Most people who were involved with the
evaluation of FLEA quite logically compared it with MDMA, as it was
presented as being a very close analogue which might share some of the
latter's properties.  And to a large measure, the comparison was
favorable.  The dosages are almost identical, the chronological course
of action is almost identical, and there are distinct similarities in
the effects that are produced.  If there is a consensus of
similarities and differences it would be that it is not quite as
enabling in allowing a closeness to be established with others.  And
perhaps there is more of a move towards introspection.  And perhaps a
slightly increased degree of discoordination in the thought processes.
But also, part of this same consensus was that, were MDMA unknown,
this material would have played its role completely.

And from the scientific point of view, it lends more weight to a
hypothesis that just might be a tremendous research tool in
pharmacology.  I first observed the intimate connection between an
amine and a hydroxylamine with the discovery that N-hydroxy-MDA (MDOH)
was equipotent and of virtually identical activity to the
non-hydroxylated counterpart (MDA).  And I have speculated in the
recipe for MDOH about the possible biological interconversions of
these kinds of compounds.  And here, the simple addition of a hydroxyl
group to the amine nitrogen atom of MDMA produces a new drug that is
in most of its properties identical to MDMA.  The concept has been
extended to 2C-T-2, 2C-T-7, and 2C-T-17, where each of these three
active compounds was structurally modified in exactly this way, by the
addition of a hydroxyl group to the amine nitrogen atom.  The results,
HOT-2, HOT-7 and HOT-17 were themselves all active, and compared very
closely with their non-hydroxylated prototypes.

Just how general might this concept be, that an N-hydroxyl analog of
an active amine shall be of similar action and duration as the parent
drug?  What if it really were a generality!  What havoc it would wreak
in the pharmaceutical industry!  If I could patent the concept, then I
would be able to make parallel best sellers to all of the primary and
secondary amines out there in the industry.  Perhaps 90% of all the
commercially available drugs that are concerned with the human mental
state are amines.  And a goodly number of these are primary or
secondary amines.  And each and every one of these could be converted
to its N-hydroxyl analogue, effectively by-passing the patent
protection that the originating corporation so carefully crafted.  An
example, just for fun.  A run-away best seller right now is an
antidepressant called fluoxetine, with the trade name Prozac.  I will
make a small wager that if I were to synthesize and taste
N-hydroxy-N-methyl-3-phenyl-3-((a,a,a-trifluoro-p-tolyl)oxy)propylamine,
I would find it to be an active antidepressant.  Remember, Mr. Eli
Lilly and Company; you read about it first, right here!

Of course, I was asked, why call it FLEA?  The origin was in a classic
bit of poetry.  A commonly used code name for MDMA was ADAM, and I had
tried making several modest modifications of the MDMA structure in the
search for another compound that would maintain its particular music
without the annoying tooth-grinding and occasional nystagmus, or
eye-wiggle, that some users have mentioned.  One of these was the
6-methyl homologue which was, with some perverse logic, called MADAM.
And, following this pattern, the 6-fluoroanalogue was to be FLADAM.
So, with the N-hydroxy analogue, what about HADAM?  Which brought to
mind the classic description of Adam's earliest complaint, an
infestation of fleas.  The poem was short and direct.  RAdam had Uem.
So, in place of HAD UEM, the term FLEA jumped into being.

 

 

 



#82 G-3; 2,5-DIMETHOXY-3,4-(TRIMETHYLENE)AMPHETAMINE;

5-(2-AMINOPROPYL)-4,7-DIMETHOXYINDANE

SYNTHESIS: A solution of 3.7 g of
2,5-dimethoxy-3,4-(trimethylene)benzaldehyde (see preparation under
2C-G-3) in 15 mL nitroethane was treated with 0.7 g anhydrous ammonium
acetate and heated on the steam bath for 2.5 h.  The excess solvent
was removed under vacuum leaving some 5 mL of a deep orange-red oil
which on cooling, spontaneously crystallized.  This was finely ground
under 10 mL MeOH, filtered, washed sparingly with MeOH, and air dried
to give 3.6 g of orange crystals with a strong smell of old acetamide.
The mp was 92-93 !C.  All was recrystallized from 30 mL boiling MeOH
to give, after filtering and drying, 2.9 g of
1-(2,5-dimethoxy-3,4-(trimethylene)phenyl)-2-nitropropene as yellow
crystals with a mp of 93-94 !C.  Anal. (C14H17NO4) C,H,N.

Fifty milliliters of 1 M LAH in THF was placed in an inert atmosphere,
well stirred, and cooled to 0 !C with an external ice-bath.  There was
added, dropwise, 1.35 mL of 100% H2SO4 at a rate slow enough to
minimize charring.  There was then added, dropwise, 2.8 g
1-(2,5-dimethoxy-3,4-(trimethylene)phenyl)-2-nitropropene in 15 mL
THF.  At the end of the addition, the stirring was continued for an
additional 0.5 h, and then the reaction mixture was held at reflux on
the steam bath for another 0.5 h.  After cooling again to ice-bath
temperature, the excess hydride was destroyed with the addition of 11
mL IPA, followed by 5.5 mL 5% NaOH which converted the inorganic mass
through a cottage cheese stage into a loose, filterable texture.  The
solids were removed by filtration, washed with additional THF, and the
combined filtrates and washes stripped of solvent under vacuum.  There
was obtained 2.51 g of a white oil that was distilled at 115-135 !C at
0.2 mm/Hg to give 1.83 g of a clear colorless oil.  This was dissolved
in 8 mL IPA, neutralized with 28 drops of concentrated HCl, and
diluted with 140 mL anhydrous Et2O.  In about 0.5 h there started a
slow snowfall of fine fluffy white crystals which was allowed to
continue until no additional crystals appeared.  After filtering, Et2O
washing and air drying, there was obtained 1.81 g of
2,5-dimethoxy-3,4-(trimethylene)amphetamine hydrochloride (G-3) with a
mp of 157-159 !C.  Anal. (C14H22ClNO2) C,H.

DOSAGE: 12 - 18 mg.

DURATION: 8 - 12 h.

QUALITATIVE COMMENTS: (with 12 mg) There was a warmth, a mellowness,
as things developed.  No body disturbance at all, but then there were
no visuals either which, for me on this particular occasion, was
disappointing.  The day was consumed in reading, and I identified
completely with the character of my fictional hero.  It was a
different form of fantasy.  I think I prefer music as a structural
basis for fantasy.

(with 18 mg) I am at a plus three, but I am not at all sure of why it
is a plus three.  With my eyes closed, there are puffy clouds, but no
drama at all.  Music was not exciting.  There could well have been
easy eroticism, but there was no push in that direction.  No great
amount of appetite.  Not much of anything, and still a plus three.
Simply lying still and surveying the body rather than the visual scene
gave some suggestions of neurological sensitivity, but with getting up
and moving about and doing things, all was fine.  The next morning I
was perhaps moving a bit more slowly than usual.  I am not sure that
there would be reward in going higher.

EXTENSIONS AND COMMENTARY: In a comparison between the 2-carbon
compound (2C-G-3) and the 3-carbon compound (G-3) the vote goes
towards the phenethylamine (the 2-carbon compound).  With the first
member of this series (2C-G versus GANESHA) this was a stand-off, both
as to quantitative effects (potency) and qualitative effects (nature
of activity).  Here, with the somewhat bulkier group located at the
definitive 3,4-positions, the nod is to the shorter chain, for the
first time ever.  The potency differences are small, and maybe the
amphetamine is still a bit more potent.  But there are hints of
discomfort with this latter compound that seem to be absent with the
phenethylamine.  The more highly substituted compounds (q.v.) more
clearly define these differences.

 

 

 



#83 G-4; 2,5-DIMETHOXY-3,4-(TETRAMETHYLENE)AMPHETAMINE;
6-(2-AMINOPROPYL)-5,8-DIMETHOXYTETRALIN

SYNTHESIS: A solution of
1,4-dimethoxy-5,6,7,8-tetrahydro-'-naphthaldehyde (see preparation
under 2C-G-4) in 20 mL nitroethane was treated with 0.13 g anhydrous
ammonium acetate and heated on the steam bath overnight.  The
volatiles were removed under vacuum and the residue, on cooling,
spontaneously crystallized.  This crude rust-colored product (1.98 g)
was recrystallized from 15 mL boiling MeOH yielding, after filtering
and air drying to constant weight, 1.33 g of
1-(2,5-dimethoxy-3,4-(tetramethylene)phenyl)-2-nitropropene as dull
gold-colored crystals.  The mp was 94-94.5 !C.  Anal. (C15H19NO4) C,H.

DOSAGE: unknown.

DURATION: unknown.

EXTENSIONS AND COMMENTARY: The discussion that appeared in the
commentary section under 2C-G-4 applies here as well.  The major
struggles were in the preparation of the aldehyde itself.  And
although the final product has not yet been made, this last synthetic
step should be, as Bobby Fischer once said in his analysis of a
master's chess game following a blunder by his opponent, simply a
matter of technique.

As with the phenethylamine counterpart, G-4 has a structure that lies
intermediate between G-3 and G-5, both potent compounds.  It is
axiomatic that it too will be a potent thing, and all that now needs
be done is to complete its synthesis and taste it.

 

 

 



#84 G-5; 3,6-DIMETHOXY-4-(2-AMINOPROPYL)BENZONORBORNANE

SYNTHESIS: A solution of 3.70 g 3,6-dimethoxy-4-formylbenzonorbornane
(see under 2C-G-5 for its preparation) in 20 g nitroethane was treated
with 0.88 g anhydrous ammonium acetate and held at steam bath
temperature overnight.  The excess solvent and reagent was removed
under vacuum to yield a residual yellow oil.  This was allowed to
stand at ambient temperature for a period of time (about 3 years) by
which time there was a spontaneous crystallization.  The dull yellow
crystals were removed by filtration and, after air drying, weighed
4.28 g.  A small sample was recrystallized repeatedly from MeOH to
provide a pale yellow analytical sample of
3,6-dimethoxy-4-(2-nitropropenyl)benzonorbornane with a mp of 90-91
!C.  Anal. (C16H19NO4) C,H.

A solution of LAH (50 mL of 1 M solution in THF) was cooled, under He,
to 0 !C with an external ice bath.  With good stirring there was added
1.32 mL 100% H2SO4 dropwise, to minimize charring.  This was followed
by the addition of 4.1 g
3,6-dimethoxy-4-(2-nitropropenyl)benzonorbornane in 20 mL anhydrous
THF over the course of 10 min.  The reaction mixture was stirred and
brought to room temperature over the course of 1 h.  This was then
brought to a gentle reflux on the steam bath for 0.5 h, and then all
was cooled again to 0 !C.  The excess hydride was destroyed by the
cautious addition of 10 mL IPA followed by 5 mL 5% NaOH and sufficient
H2O to give a white granular character to the oxides.  The reaction
mixture was filtered, and the filter cake washed with THF.  The
filtrate was stripped of solvent under vacuum providing a pale amber
oil that was distilled at 125-140 !C at 0.2 mm/Hg to give 2.5 g of an
almost white oil.  This was dissolved in 10 mL IPA, neutralized with
25 drops of concentrated HCl, and then diluted with 140 mL anhydrous
Et2O.  There appeared, after about two minutes, white crystals of
3,6-dimethoxy-4-(2-aminopropyl)benzonorbornane hydrochloride (G-5)
which, after filtration and air drying, weighed 2.47 g.

DOSAGE: 14 - 20 mg.

DURATION: 16 - 30 h.

QUALITATIVE COMMENTS: (with 15 mg) As part of the audience at the San
Francisco conference, Angels, Aliens and Archtypes, I could simply
listen and observe without having to participate.  Each speaker stood
in a cone of light that was beautifully bright and colorful, casting
everything else on the stage into obscurity.  Maybe angels really are
illuminated from above, and the aliens lurk out of sight until it is
their turn.  Where does one look for the archetypes?  A half of a
cream cheese sandwich was all I could eat, and even at dinner that
evening I was not hungry.  Sleep that evening was difficult.

(with 20 mg) Very slow to come on, but then it was up there all of a
sudden.  There is an unexpected absence of visual activity despite
being at a full +++.  The mental activity is excellent, with easy
writing and a positive flow of ideas.  But an absence of the bells and
whistles that are expected with a psychedelic in full bloom.  There is
a real drop by the 16th hour and the next day was free of effect
except for occasional cat-naps.

(with 20 mg) The transition period, which usually lasts for most
compounds for the first hour or two, with this seems to be much
longer.  This presages a long-acting material, as usually the slow-in
slow-out rule applies.  But there are exceptions.  There is an
indifference towards the erotic, but no separation at all from
personal interactions and emotions.  I believe in integration, not
separation of all parts of ourselves, distrusting any drug states
(particularly those that have the reputation of being strongly
Tcosmic)U which divorce the consciousness from the body.  And with
this material there is no separation from feelings, only from my
particular color language.

EXTENSIONS AND COMMENTARY: This is as potent as any of the
three-carbon Ganesha compounds, but it somehow lacks a little
something that would have made it a completely favorite winner.
Perhaps it is the generally commented upon absence of visual and
related sensory entertainment.  There seems to be no bodily threat to
discourage further exploration, but there simply was not the drive to
explore it much.  The comments concerning the enlargement of the ring
system (mentioned under 2C-G-5) are equally valid here.  The
RshrubberyS that is the hallmark of the Ganesha family is, with G-5,
about as bulky as has ever been put onto a centrally active molecule.
The norbornane group has a one carbon bridge and a two carbon bridge
sticking out of it at odd angles.  The replacement of the one-carbon
bridge with a second two-carbon bridge would make the compound G-6.
It would be makeable, but is there really a driving reason to do so?
There is a simplification intrinsic in this, in that G-5 actually has
two centers of asymmetry (the a-carbon atom on the amphetamine chain,
and the norbornyl area itself) and so it is really a mixture of two
racemic diastereoisomers.  G-6 would still be a racemate, but it would
be only a single compound, as are all the other substituted
amphetamine derivatives.

Someday I may try making G-6, but it's not a high priority right now.

 

 

 



#85 GANESHA; G; 2,5-DIMETHOXY-3,4-DIMETHYLAMPHETAMINE

SYNTHESIS: A solution of 15.4 g 2,5-dimethoxy-3,4-dimethylbenzaldehyde
(see under 2C-G for the preparation) in 50 mL nitroethane was treated
with 3 g anhydrous ammonium acetate and heated on the steam bath for
12 h.  The excess nitroethane was removed under vacuum, and the
residual oil was diluted with a equal volume of MeOH.  There was the
slow generation of deep red cottage-cheese-like crystals which were
removed by filtration and air-dried to constant weight (9.3 g) with a
mp 71-74 !C.  Recrystal-lization from MeOH (10 ml/g) gave an
analytical sample of
1-(2,5-dimethoxy-3,4-dimethylphenyl)-2-nitropropene with a mp of 82 !C
sharp.  Anal. (C13H17NO4) C,H,N.  The NMR spectra (in CDCl3) and CI
mass spectrograph (MH+ = 252) were proper.

To a suspension of 3.3 g LAH in 200 mL refluxing THF, well stirred and
maintained under an inert atmosphere, there was added 4.2 g
1-(2,5-dimethoxy-3,4-dimethylphenyl)-2-nitropropene in 25 mL THF.  The
mixture was held at reflux for 48 h.  After cooling, 3.3 mL H2O was
added cautiously to decompose the excess hydride, followed by 3.3 mL
15% NaOH and finally another 10 mL H2O.  The inorganic solids were
removed by filtration, and washed with additional THF.  The combined
filtrate and washes were stripped of solvent under vacuum, and the
residue (4.7 g of a deep amber oil) dissolved in dilute HCl.  This was
washed with CH2Cl2 (3x75 mL), then made basic with 5% NaOH and
extracted with CH2Cl2.  Removal of the solvent under vacuum yielded an
amber oil that was distilled (105-115 !C at 0.4 mm/Hg) to give 1.2 g
of a white oil.  This was dissolved in 8 mL IPA, neutralized with 15
drops of concentrated HCl, and diluted with 250 mL anhydrous Et2O.
After a period of time, there was a spontaneous appearance of white
crystals which were removed by filtration, Et2O washed, and air dried.
Thus was obtained 1.0 g of 2,5-dimethoxy-3,4-dimethylamphetamine
hydrochloride (GANESHA) with a mp of 168-169 !C.  This was not
improved by recrystallization from either EtOAc or nitroethane.  Anal.
(C13H22ClNO2) N.

DOSAGE: 20 - 32 mg.

DURATION: 18 - 24 h.

QUALITATIVE COMMENTS: (with 24 mg) There was a slow buildup to a ++
or more over the course of about three hours.  Extremely tranquil, and
no hint of any body toxicity whatsoever.  More than tranquil, I was
completely at peace, in a beautiful, benign, and placid place.  There
was something residual that extended into the sleep period, and was
possibly still there in the morning.  Probably I was simply tired from
an inadequate sleep.

(with 32 mg) A rapid and full development.  Lying down with music,
the eyes-closed visuals were quite something.  There was sudden
awareness of a potential toe cramp which I possibly exaggerated, but
it kept spinning itself into my awareness, and somehow locked in with
my visual imagery.  It was not easy to keep the visual/somatic/
cognitive worlds in their proper places.  The almost-cramp went away
and I forgot about it.  There was a back spasm somewhere in this
drama, and it really didnUt matter either.  This dosage may be a bit
much for good housekeeping, though!  Towards the end of the
experiment, I looked at a collection of photos from a recent trip to
Europe, and the visual enhancement was wonderful. A rolling +++.

EXTENSIONS AND COMMENTARY: This compound was the seventh of the ten
possible Classic Ladies.  I have mentioned the concept already under
the discussions on ARIADNE.  This is the teutonic replacement of each
of the distinguishable hydrogen atoms of DOM with a methyl group.  The
findings with GANESHA were a total surprise.  The extension of a
hydrogen in the 3-position of DOM with a methyl group should have a
minor influence on its steric association with whatever receptor site
might be involved.  A much greater impact might come not from the size
of the group but from its location.  This, coupled with a full order
of magnitude of decrease in potency, seemed to call for an involvement
of that particular position as being one that is affected by
metabolism.  And since the activity is decreased, the obvious role is
in the blocking of the metabolic promotion of DOM-like things to
active intermediates.

The remarkable point being emphasized here is that the placement of a
dull methyl group at a dull position of the DOM molecule actually
inactivated (for all intents and purposes) the activity of DOM.  It is
not the presence of the methyl that has decimated the potency, but the
removal of the hydrogen atom.

How can such a hypothesis be explored?  A historic premise of the
medicinal chemist is that if a structure gives an unusual response in
a receptor, vary it slightly and see how the response varies.  This is
exactly the principle that led to the ten Classic Ladies, and with
this particular Lady (who actually turned out to be a gentleman), the
same concept should hold.  There are two involved methyl groups in
GANESHA, one at the 3-position and one at the 4-position.  Why not
homologate each to an ethyl group, and as a wrap up make both of them
into ethyl groups.  Look at the differences along two lines of
variation; the effects of the homologation of the 3- and 4-positions,
coupled with the effects of the homologation intrinsic in the
comparison of the two-carbon chain of the phenethylamine with the
three-carbon chain of the amphetamine.

There are thus six compounds involved in such a study.  And they have
been named (as have all the other GANESHA analogues) in accordance
with the collective carbon inventory in and about these two ring
positions.  The first two compounds are related to DOET and to 2C-E.
Maintain the methyl group at the 3-position but homologate the
4-position to an ethyl.  The ring pattern would become
2,5-dimethoxy-4-ethyl-3-methyl, and the phenethylamine and amphetamine
would be called 2C-G-12 and G-12 respectively (a one carbon thing, the
methyl, at position-3 and a two carbon thing, an ethyl, at
position-4).  Reversal of these groups, the 3-ethyl homologues of 2C-D
and DOM would thus become 2C-G-21 and G-21.  And, finally, the diethyl
homologues would be 2C-G-22 and G-22.  In each of these cases, the
paired numbers give the lengths of the chains at the two positions,
the 3- and the 4-positions that are part of the GANESHA concept.  And
this code is easily expandable to longer things such as 2C-G-31 and
2C-G-41, which would be the 3-propyl-4-methyl, and the
3-butyl-4-methyl homologues, resp.

Unfortunately, these six initially proposed compounds have so far
resisted all logical approaches to synthesis, and are at present still
unknown.  What has been successfully achieved, the building up of a
big bulky hydrocarbon glob at these positions, has rather unexpectedly
led to a remarkable enhancement of potency.  As with all true
exploration into areas of the unknown, the deeper you get, the less
you understand.

 

 

 



#86 G-N; 1,4-DIMETHOXYNAPHTHYL-2-ISOPROPYLAMINE

SYNTHESIS: To a solution of 3.9 g 1,4-dimethoxy-2-naphthaldehyde (see
under 2C-G-N for the preparation) in 13.5 mL nitroethane there was
added 0.7 g anhydrous ammonium acetate, and the mixture heated on the
steam bath for 5 h.  The deep orange reaction mixture was stripped of
excess solvent under vacuum.  The residue was a red oil that, upon
dilution with two volumes MeOH, immediately set to orange crystals.
This crude product (mp 115-118 !C) was recrystallized from 70 mL EtOH
to yield, after filtering and air drying, 3.3 g of
1-(1,4-dimethoxy-2-naphthyl)-2-nitropropene as gold-orange crystals,
with a mp of 121-123 !C.  Recrystallization from MeOH gave a
gold-colored product with a mp of 119-120 !C.  Anal. (C15H15NO4)
C,H,N.

A solution of LAH (50 mL of 1 M solution in THF) was cooled, under He,
to 0 !C with an external ice-bath.  With good stirring there was added
1.32 mL 100% H2SO4 dropwise, to minimize charring.  This was followed
by the addition of 3.12 g 1-(1,4-dimethoxy-2-naphthyl)-2-nitropropene
in 40 mL anhydrous THF.  After stirring for 1 h, the temperature was
brought up to a gentle reflux on the steam bath for 0.5 h, and then
all was cooled again to 0 !C.  The excess hydride was destroyed by the
cautious addition of 16 mL IPA followed by 6 mL 5% NaOH to give a
white, filterable, granular character to the oxides, and to assure
that the reaction mixture was basic.  The reaction mixture was
filtered, and the filter cake washed with additional THF.  The
combined filtrate and washes were stripped of solvent under vacuum
providing 3.17 g of a deep amber oil.  Without any further
purification, this was distilled at 140-160 !C at 0.3 mm/Hg to give
1.25 g of a pale yellow oil.  This was dissolved in 8 mL IPA,
neutralized with 20 drops of concentrated HCl, and diluted with 60 mL
anhydrous Et2O which was the point at which the solution became
slightly turbid.  After a few min, fine white crystals began to form,
and these were eventually removed, washed with Et2O, and air dried to
provide 1.28 g 1,4-dimethoxynaphthyl-2-isopropylamine hydrochloride
(G-N) as the monohydrate salt.  The mp was 205-206 !C.  Even after 24
h drying at 100 !C under vacuum, the hydrate salt remained intact.
Anal.  (C15H20ClNO2aH2O) C,H.

DOSAGE: unknown.

DURATION: unknown,

EXTENTIONS AND COMMENTARY: The evaluation of this compound is not yet
complete.  An initial trial at the 2 milligram level showed neither
central action, nor toxicity.  It could be guessed from the activity
of the two-carbon counterpart, that an active level will be found in
the tens of milligrams area.  But, as of the moment, this level is not
known to anyone, anywhere, because no one has yet defined it.  And
when the potency is finally found out, the nature of the activity will
also have been found out, all the result of a magical interaction of a
virgin compound with a virgin psyche.  At the immediate moment, the
nature of G-N is not only unknown, it has not yet even been sculpted.
There can be no more exciting area of research than this, anywhere in
the sentient world.

 

 

 



#87 HOT-2; 2,5-DIMETHOXY-4-ETHYLTHIO-N-HYDROXYPHENETHYLAMINE

SYNTHESIS: A solution of 5.50 g
2,5-dimethoxy-4-ethylthio-'-nitrostyrene (see under 2C-T-2 for its
preparation) was made in 80 mL boiling anhydrous THF.  On cooling,
there was some separation of a fine crystalline phase, which was kept
dispersed by continuous stirring.  Under an inert atmosphere there was
added 3.5 mL of a 10 M borane dimethylsulfide complex, followed by 0.5
g sodium borohydride as a solid.  There was a slight exothermic
response, and the color slowly faded.  Stirring was continued for a
week.  There was then added 40 mL H2O and 20 mL concentrated HCl, and
the reaction mixture heated on the steam bath for 15 minutes, with the
THF at reflux.  After cooling again to room temperature, all was
poured into 1 L H2O and washed with 3x75 mL CH2Cl2, which removed all
of the color but little of the product.  The aqueous phase was made
basic with 25% NaOH, and extracted with 3x75 mL CH2Cl2.  The extracts
were pooled and the solvent removed under vacuum to give a residue of
3.88 g of an amber oil.  This was dissolved in 30 mL IPA, acidified
with concentrated HCL to a bright red on universal pH paper, and then
diluted with 200 mL anhydrous Et2O.  After a short period of time,
crystals started to form.  These were removed by filtration, washed
with Et2O, and air dried to constant weight.  Thus was obtained 2.86 g
2,5-dimethoxy-4-ethylthio-N-hydroxyphenethylamine hydrochloride
(HOT-2) as off-white crystals, with a melting point of 122 !C with
decomposition.  Anal. (C12H20ClNO3 S) H; C: calcd, 49.05; found,
50.15, 49.90.

DOSAGE: 10 - 18 mg.

DURATION: 6 - 10 h.

QUALITATIVE COMMENTS: (with 12 mg) Tastes OK.  Some activity noticed
in 30 minutes.  Very smooth rise with no body load for next two hours.
At that time I noted some visuals.  Very pleasant.  The bright spots
in the painting over the fireplace seemed to be moving backwards (as
if the clouds were moving in the painting).  Upon concentrating on any
item, there was perceptual movement with a little flowing aspect.  The
visuals were never all that strong, but could not be turned off during
the peak.  At hour three there was still some shimmering, and it was
hard to focus when reading.  Additionally, there was difficulty
concentrating (some mental confusion).  The material seemed to allow
erotic actions; there was no problem about obtaining an erection.  I
ate very well, some crazy dips, as well as a fabulous cake.  A very
gentle down trend and I became close to baseline by 6 or 7 PM.  I had
no trouble driving.  The dosage was good for me.  I did not want more
or less.

(with 12 mg) Comes on smoothly, nicely.  In 40 minutes I feel nice
euphoria, feel home again.  Then I begin to get uncomfortable
feelings.  Gets more and more uncomfortable, feel I am sitting on a
big problem.  Blood pressure, pulse, go up considerably.  Have hard
time communicating, lie down for a while, get insight that most
important thing for me to do is learn to listen, pay attention to what
is going on.  I do this the rest of the day, at first with
considerable difficulty, then easier and easier.  Discomfort stays
with me for several hours, and although I get more comfortable towards
the end of the day, I am never animated or euphoric.  I feel very
humbled, that I have a great deal to work out in my life.  The next
day I find myself very strong and empowered.  I see that all I have to
do is let things be as they are!  This feels marvelous, and a whole
new way to be Q much more relaxed, accepting, being in the moment.  No
more axes to grind.  I can be free.

(with 18 mg) I found myself with complete energy.  I was completely
centered with an absolute minimum of the dark edges that so often
appear as components of these experiences.  The ease of talking was
remarkable.  There was some blood-pressure run-up in the early part of
the day, but that quickly returned to normal.  I would repeat without
hesitation.

EXTENSIONS AND COMMENTARY: Again, a case of where the potency range of
the Rhot,S or hydroxylated compound (HOT-2, 10 to 18 milligrams) is
very similar to that of the non-hydroxylated prototype (2C-T-2, 12-25
milligrams).  It seems to be a well tolerated, and generally pleasant
material, with a mixture of sensory as well as insightful aspects.
Something for everyone.

 

 

 



#88 HOT-7; 2,5-DIMETHOXY-N-HYDROXY-4-(n)-PROPYLTHIOPHENETHYLAMINE

SYNTHESIS: A well-stirred solution of 1.77 g
2,5-dimethoxy-'-nitro-4-(n-propylthio)styrene (see under 2C-T-7 for
its preparation) in 20 mL anhydrous THF was placed in an He atmosphere
and treated with 1.5 mL of 10 M borane-dimethyl sulfide complex.  This
was followed by the addition of 0.2 g sodium borohydride, and the
stirring was continued at room temperature for a week.  The volatiles
were removed under vacuum, and the residue was treated with 20 mL
dilute HCl and heated on the steam bath for 30 min.  The cooled yellow
solution set up as solids.  The addition of H2O was followed by
sufficient K2CO3 to make the aqueous phase basic.  All efforts to work
with an acidified aqueous phase resulted in terrible emulsions.  The
basic phase was extracted with 3x75 mL CH2Cl2, and the pooled extracts
washed with H2O, then stripped of solvent under vacuum.  The residual
yellow oil was dissolved in 20 mL IPA, neutralized with 15 drops of
concentrated HCl, and then diluted with 50 mL anhydrous Et2O.  After a
few minutes stirring, a white crystalline solid separated.  This was
removed by filtration, washed with Et2O, and air dried to constant
weight to provide 0.83 g of
2,5-dimethoxy-N-hydroxy-4-(n)-propylthiophenethylamine hydrochloride
(HOT-7).

DOSAGE: 15 - 25 mg.

DURATION: 6 - 8 h.

QUALITATIVE COMMENTS: (with 15 mg) I am lightheaded, and maybe a
little tipsy.  I am well centered, but I donUt want to go outside and
meet people.  Shades of alcohol woozy.  The effects were going already
by the fifth hour and were gone by the seventh hour.  I would call it
smoothly stoning.

(with 22 mg) The transition into the effects was a bit difficult,
with a faint awareness in the tummy.  But by the second hour it was
quite psychedelic, and the body was not thought of again, except in
terms of sexual fooling around.  Very rich in eyes-closed imagery, and
very good for interpretive and conceptual thinking.  But the eyes-open
visuals were not as much as they might have been.  At the seventh
hour, drifted into an easy sleep.

(with 22 mg) The experience was very positive, but at each turn there
seemed to be a bit of sadness.  Was it a complete plus three
experience?  Not quite.  But it didnUt miss by much.  The erotic
explorations somehow just failed to knit by the thinnest of margins.
It was a truly almost-magnificent experience.

EXTENSIONS AND COMMENTARY: There is a working hypothesis that has been
growing in substance over the last few years in this strange and
marvelous area of psychedelic drugs.  It all was an outgrowth of the
rather remarkable coincidence that I had mentioned in the discussion
that followed MDOH.  There, an assay of what was thought to be MDOH
gave a measure of activity that was substantially identical to MDA,
and it was later found out that the material had decomposed to form
MDA.  So, MDA was in essence rediscovered.  But when the true, valid,
and undecomposed sample of MDOH was actually in hand, and assayed in
its own rights, it was found to have a potency that really was the
same as MDA.  So, the working hypothesis goes something like this:

AN N-HYDROXY AMINE HAS APPROXIMATELY THE SAME POTENCY AND THE SAME
ACTION AS ITS N-HYDROGEN COUNTERPART.

Maybe the N-hydroxy compound reduces to the N-H material in the body,
and the latter is the intrinsically active agent.  Maybe the N-H
material oxidizes to the N-hydroxy material in the body, and the
latter is the intrinsically active agent.  Either direction is
reasonable, and there is precedent for each.  The equivalence of MDA
and MDOH was the first suggestion of this.  And I have made a number
of NH vs. NOH challenges of this hypothesis.  The interesting 2C-T-X
series has provided a number of amines that are amenable to
N-hydroxylation, and this is the first of them.  And, after all, if
you put a hydroxy (HO) group on a thio material (T), you have a HOT
compound.

So, as far as nomenclature is concerned, the family of N-hydroxy
analogues of N-H amines is known as the HOT family.

How does HOT-7 compare with 2C-T-7?  They are almost identical.  The
same range of dose (centering on 20 milligrams) and if anything,
perhaps slightly less long lived.  Lets try some other N-hydroxys!



#89 HOT-17; 2,5-DIMETHOXY-4-(s)-BUTYLTHIO-N-HYDROXYPHENETHYLAMINE

SYNTHESIS: To a well-stirred solution of 6.08 g
2,5-dimethoxy-4-(s)-butylthio-'-nitrostyrene (see under 2C-T-17 for
its preparation) in 80 mL anhydrous THF under a He atmosphere, there
was added 3.5 mL 10 M borane dimethylsulfide complex, followed by 0.5
g of sodium borohydride.  As the stirring continued, the slightly
exothermic reaction slowly faded from bright yellow to pale yellow,
and eventually (after three days stirring) it was substantially
colorless.  There was then added 80 mL of 3 N HCl and the mixture
heated on the steam bath for 1 h, and then allowed to return to room
temperature.  An additional 600 mL H2O was added (there was a
combination of crystals and globby chunks in the aqueous phase) and
this was then extracted with 3x75 mL CH2Cl2.  The color went
completely into the organic phase.  This was washed with 2x50 mL
aqueous K2CO3, yielding a rusty-red colored CH2Cl2 solution, which on
removal of the solvent, yielded 4.5 g of a red oil.  A side effort to
make the sulfate salt at this stage with H2O and a little H2SO4,
indeed gave solids, but all of the color remained in the sulfate salt.
The red oil was dissolved in 45 mL IPA and neutralized with
concentrated HCl to bright red, not yellow, on universal pH paper.
The addition of 350 mL anhydrous Et2O instituted the slow
precipitation of white crystals.  After filtering and air drying,
there was obtained 1.32 g
2,5-dimethoxy-4-(s)-butylthio-N-hydroxyphenethylamine hydrochloride
(HOT-17).  The aqueous phase from above was just neutralized with 25%
NaOH (cloudy, slightly pink color) and then made basic with K2CO3 (the
color becomes green).  This was extracted with 3x75 mL CH2Cl2, the
extracts pooled, and the solvent removed to yield 0.5 g of a white
oil.  This was dissolved in 5 mL IPA, neutralized with concentrated
HCl, and diluted with a equal volume of Et2O.  An additional 0.36 g of
product was thus obtained.

DOSAGE: 70 - 120 mg.

DURATION : 12 - 18 h.

QUALITATIVE COMMENTS: (with 70 mg) There was a light feeling, a
little off-the-ground feeling, which made walking about a most
pleasant experience.  No distortion of the senses.  And there was no
sense of the beginning of a drop of any kind until about the eighth
hour.  Sleeping was a bit tricky but it worked out OK (at the twelfth
hour of the experience).  A completely valid ++.

(with 120 mg) HOT-17 has an unbelievably GRIM taste Q not bitter, but
simply evil.  There is a steady and inexorable climb for three hours
to a sound and rolling plus three.  There was absolutely no body
difficulty, but there was still something going on upstairs well into
the next day.  Writing was surprisingly easy; I was completely content
with the day, and would be interested in exploring it under a variety
of circumstances.

(with 120 mg) This is my first time with this material.  It is 4:45
PM.  Small nudge at 30 minutes, but not too real.  At one hour,
threshold, quite real.  6:15 to a +1.  By 7:25, +3 about.  7:45, no
doubt +3.  Possibly still climbing; I hope so.  No body discomfort at
all, no apparent body push.  This aspect of it is similar to the easy
body of the HOT-2.  However, it's at times like these that I reflect
on just exactly how hard-headed we two are.  I mean, +3 is no longer
the out-of-body, nearly loss of center state it used to be, four years
ago.  The question intrudes: would a novice experience this as a very
scary, ego-disintegrating kind of experiment, or not?  Silly question
which answers itself.  Yes, of course.  At 3 hours, aware of some mild
time-distortion.  More a tendency to not think in terms of clock-time,
than actual distortion.  The mind lazy when attempting to keep track
of clock time.  Feel it would be quite easy and pleasant to continue
writing.  The energy could very well go in that direction.  However,
the idea of the erotic is also quite agreeable.  This is, so far, a
good-humored Buddha area of the self.

EXTENSIONS AND COMMENTARY: Two virtues sought by some users of
psychedelic drugs are high intensity and brief action.  They want a
quicky.  Something that is really effective for a short period of
time, then lets you quickly return to baseline, and presumably back to
the real world out there.

Intensity is often (but not always) regulated by dose.  The
pharmacological property of dose-dependency applies to many of these
drugs, in that the more you take, the more you get.  If you want more
intensity, take a second pill.  And often, you get a longer duration
as an added property.  But it is instructive to inquire into the
rationale that promotes brevity as a virtue.  I believe that it says
something concerning the reasons for using a psychedelic drug.  A
trade off between learning and entertainment.  Or between the
achieving of something and the appearance of achieving something.  Or,
in the concepts of the classics, between substance and image.

In a word, many people truly believe that they cannot afford the time
or energy required for a deep search into themselves.  One has to make
a living, one has to maintain a social life, one has a multitude of
obligations that truly consume the oh-so-few hours in the day.  I
simply cannot afford to take a day off just to indulge myself in
such-and-such (choose one: digging to the bottom of a complex concept,
giving my energies to those whom I can help, to search out my inner
strengths and weaknesses) so instead I shall simply do such-and-such
(choose one: read the book review, go to church on Sunday morning, use
a short-acting psychedelic).  The world is too much with us.  This may
be a bit harsh, but there is some merit to it.

HOT-17 is by no means a particularly potent compound.  The hundred
milligram area actually has been the kiss of death to several
materials, as it is often at these levels that some physical concerns
become evident.  And it certainly is not a short lived compound.  But,
as has been so often the case, the long lived materials have proven to
be the most memorable, in that once the entertainment aspect of the
experience is past you, there is time for dipping deeply into the rich
areas of the thought process, and the working through of ideas and
concepts that are easily available.  And when this access is coupled
to the capability of talking and writing, then a rewarding experience
is often the result.

As with the parent compound, 2C-T-17 itself, the presence of an
asym-metric carbon atom out there on the (s)-butyl side chain will
allow the separation of HOT-17 into two components which will be
different and distinct in their actions.  The activity of the racemic
mixture often is an amalgamation of both sets of properties, and the
separate assay of each component can often result in a fascinating and
unexpected fractionation of these properties.