SYNTHESIS: In 50 mL of benzene there was dissolved 31.6 g
2,5-dimethoxy-4-methylbenzaldehyde (see recipe for 2C-D for its
preparation), 20.2 mL 1-nitropropane, and 6 mL cyclohexylamine. This
solution was held at reflux in a Dean Stark apparatus for 24 h,
effectively removing the water of reaction. Upon cooling, there was
deposited 19.6 g of 1-(2,5-dimethoxy-4-methylphenyl)-2-nitro-1-butene
as brilliant orange crystals. The mp, after recrystallization from
MeOH, was 114-115 °C and a second recrystallization increased the mp
another 2 °C. Anal. (C13H17NO4) C,H,N.
A suspension of 12.5 g LAH in 600 mL anhydrous THF was stirred
magnetically, and brought up to a reflux. To this there was added,
dropwise, 15.0 g 1-(2,5-dimethoxy-4-methylphenyl)-2-nitro-1-butene
dissolved in 150 mL THF. Refluxing was continued for 15 h and, after
cooling, the excess hydride was decomposed by the addition of 12.5 mL
H2O. The inorganic salts were made loose and granular by the addition
of 12.5 mL 15% NaOH followed by an additional 37.5 mL H2O. These
solids were removed by filtration, and the filter cake was washed with
THF. The combined filtrate and washings were stripped of solvent
under vacuum. The residue was dissolved in anhydrous Et2O, and
treated with hydrogen chloride gas, yielding
1-(2,5-dimethoxy-4-methylphenyl)-2-aminobutane hydrochloride (ARIADNE)
as white crystals which, after recrystallization from IPA, weighed
11.4 g and had a mp of 232.5-234.5 °C. Anal. (C13H22ClNO2) C,H,N,Cl.
The racemic mixture was resolved into its optical isomers by the
formation of salts with (+)-2beta-nitrotartranilic acid (to give the "S"
isomer) or with (+)-2beta-chlorotartranilic acid (to give the "R"
isomer). The "R" isomer can also be prepared by the reductive
amination of 1-(2,5-dimethoxy-4-methylphenyl)-2-butanone (from the
above nitrostyrene and elemental iron) with (+)-a-methyl benzylamine
followed by the hydrogenolysis of the benzyl group.
DOSAGE: as psychedelic, unknown.
DURATION: short.
QUALITATIVE COMMENTS: (with 12 mg) I believe that my mood has
distinctly improved, and my sleep that evening was excellent. This is
physically benign.
(with 32 mg) There was some sort of threshold that lasted for a
couple of hours.
(with 25 mg of the "R" isomer) There is the alert of a psychedelic,
with none of the rest of the package. Perhaps a bit of paranoia. And
by the fifth hour everything is largely gone.
EXTENSIONS AND COMMENTARY: How does one discover a new drug for a
malady that does not exist in experimental animals? Drugs that
interfere with sleep, or with appetite, or with some infecting
bacterium, are naturals for animal screening, in that animals sleep,
eat, and can be easily infected. But there are lots of syndromes that
involve a state of mind, and these are uniquely human. Many of the
psychopharmacological anti-this or anti-that agents address ailments
such as anxiety, psychosis, paranoia, or depression, which are only
known in man. So how does one discover a new drug in areas such as
these? If one has in hand a drug that is known to be effective in one
of these human ailments, an animal assay can be set up to give some
measurable response to that specific drug, or a biochemical property
can be rationalized as being related to a mechanism of action. And
with the known drug as a calibration, and restricting your search to
structurally related compounds, you can find structural relatives that
give the same responses.
But how does one find a new class? One way is to kind of stumble into
it as a side-line of human experimentation with new psychedelics. But
it is really difficult to pick up the clues as to what will be a good
anti-depressant if you are not depressed. This compound, to which I
had given the name of ARIADNE as the first of my ten "classic ladies"
(I'll say more about them later), was not really a stimulant of any
kind, certainly it was not a psychedelic, and yet there was something
there. It had been explored rather extensively as a potential
psychotherapeutic ally by a friend of mine. He said that there seemed
to be some value in a few of his patients who had some underlying
depression, but not much of anything with the others. So, I decided
to call it an anti-depressant. I had mentioned some of this history
one time when I was giving an address at a conference on the East
Coast, and my host (who happened to be the research director at a
large pharmaceutical house) asked if I would send him a sample. His
company did many animal tests, one of which showed that it was not
hallucinogenic (a cat whose tail erected dramatically with DOM did
nothing with ARIADNE) and another that showed re-motivation (some old
maze-running monkeys who had decided not to run any more mazes changed
their minds with ARIADNE).
So patents were obtained for the "R" isomer, the more effective
isomer, covering its use for such things as the restoring of
motivation in senile geriatric patients. And a tradename of
Dimoxamine was assigned it, despite several voices that held out for
Ariadnamine. But it didn't have what was needed to make it all the
way to the commercial market
Many, many analogues of ARIADNE have been made, and for a variety of
reasons. In the industrial world there is research backup carried
out, not only for the discovery of new things, but also for patent
protection of old things. Several dozen analogues of ARIADNE have
been made and pharmacologically evaluated, and some of them have been
put into the published literature. The major points of variation have
been two: keep the 4-position methyl group intact, and make the
variations on the alpha-carbon (propyl, butyl, dimethyl, phenyl,
benzyl, phenethyl, etc.--an extensive etc.) or: keep the
alpha-position ethyl group intact and make the variations on the
4-position (chloro, iodo, methylthio, carboxy, etc.--again, an
extensive etc.).
Some of these analogues I had made, and sent in for animal screening.
The high potency of DOB suggested the bromo-counterpart of ARIADNE.
The making of this entailed the proteo counterpart,
1-(2,5-dimethoxyphenyl)-2-aminobutane. Reaction of
2,5-dimethoxybenzaldehyde with nitropropane in benzene in a Dean Stark
apparatus with cyclohexylamine as a catalyst produced
1-(2,5-dimethoxyphenyl)-2-nitrobutene, which crystallized as orange
crystals from MeOH with a mp of 47-47.5 °C. Anal. (C12H15NO4) C,H,N.
This was reduced to the amine 1-(2,5-dimethoxyphenyl)-2-aminobutane
with LAH in ether, and this gave a hydrochloride salt with a mp of
172-174 °C after recrystallization from acetonitrile. The free base
of this compound was brominated in acetic acid to give
1-(2,5-dimethoxy-4-bromophenyl)-2-aminobutane which yielded a white
hydrochloride salt with a mp of 204-206 °C following recrystallization
from IPA. The isomeric non-brominated analogue,
1-(3,4-dimethoxyphenyl)-2-aminobutane was made and explored by the
Chemical Warfare group at Edgewood Arsenal; its code number is
EA-1322.
Several of the alpha-ethyl analogues of ARIADNE were N,N-dialkylated,
and were target compounds for halogenation with radio-iodine or
radio-fluorine, for evaluation as potential brain blood-flow
indicators. In these studies. all examples followed a common flow
diagram. The reaction of the appropriate benzaldehyde and
nitropropane, using N,N-dimethylethylenediamine as a catalyst and
following recrystallization from MeOH, gave the corresponding
1-aromatic-2-nitro-1-butene (the nitrostyrene) which, by reduction
with elemental iron, gave the corresponding 2-butanone (which was
distilled at about 0.3 mm/Hg). This led, by reductive amination with
dimethylamine hydrochloride and sodium cyanoborohydride, to the
corresponding N,N-dimethyl product which was distilled at about 0.3
mm/Hg and which, in no case, either formed a solid HCl salt or reacted
with carbon dioxide from the air. From 2,4-dimethoxybenzaldehyde, the
nitrostyrene appeared as yellow crystals, the ketone as a white oil,
and the product N,N-dimethyl-1-(2,4-dimethoxyphenyl)-2-aminobutane as
a white oil. From 2,5-dimethoxybenzaldehyde, the nitrostyrene formed
bright yellow crystal, the ketone was an off-white oil, and the
product N,N-dimethyl-1-(2,5-dimethoxyphenyl)-2-aminobutane was a white
oil. From 3,5-dimethoxybenzaldehyde, the nitrostyrene formed pale
yellow crystals that discolored on exposure to the light, the ketone
was an off-white clear oil, and the product
N,N-dimethyl-1-(3,5-dimethoxyphenyl)-2-aminobutane was a white oil.
From 2,6-dimethoxybenzaldehyde, the nitrostyrene was obtained as
orange crystals, and was not pursued further.
A number of ARIADNE analogues have been made, or at least started,
purely to serve as probes into whatever new areas of
psychopharmacological activity might be uncovered. One of these is a
HOT compound, and one is a TOM compound, and a couple of them are the
pseudo (or near-pseudo) orientations. The HOT analogue was made from
the nitrostyrene precursor to ARIADNE itself, reduced not with LAH or
AH (which would give the primary amine), but rather with sodium
borohydride and borane dimethylsulfide. The product,
1-(2,5-dimethoxy-4-methylphenyl)-N-hydroxy-2-aminobutane
hydrochloride, was a white crystalline material. The 5-TOM analogue
got as far as the nitrostyrene. This was made from
2-methoxy-4-methyl-5-(methylthio)benzaldehyde (see under the 5-TOM
recipe for its preparation) and nitropropane in acetic acid, and gave
bright yellow crystals. The true pseudo-analogue is the
2,4,6-trimethoxy material based on TMA-6, which is the "real"
pseudo-TMA-2. The nitrostyrene from 2,4,6-trimethoxybenzaldehyde and
nitropropane crystallized from MeOH/CH3CN as fine yellow crystals, and
this was reduced with AH in cold THF to
1-(2,4,6-trimethoxyphenyl)-2-aminobutane which was a bright, white
powder.
And the near-pseudo analogue?
First, what is near-pseudo? I have explained already that the
"normal" world of substitution patterns is the 2,4,5. Everyone knows
that that is the most potent pattern. But, the 2,4,6 is in many ways
equipotent, and has been named the pseudo-stuff. The "real," or
"true" pseudo-stuff. So what is the "near" pseudo-stuff? I am
willing to bet that the rather easily obtained 2,3,6-trisubstitution
pattern, and the much more difficult to obtain 2,3,5-substitution
pattern, will produce treasures every bit as unexpected and remarkable
as either the 2,4,5- or the 2,4,6- counterparts. These are neither
"real" nor "pseudo," but something else, and I will find a name for
them when the time comes, something weird from the Greek alphabet.
And this will double again the range of possible exploration. The
TMA-5 analogue mentioned came from 2,3,6-trimethoxybenzaldehyde and
nitropropane using cyclohexylamine as a catalyst (yellow-orange
solids) which was reduced to the amine with AH. This hydrochloride
salt is an air-stable white powder. All of these materials remain
unexplored.
Somewhere in the wealth of compounds implicit in the many structural
variables possible (the normal versus the pseudo versus the
near-pseudo patterns, coupled with the wide variety of promising
substituents that can be placed on the 4-position, together with the
availability of the the unexplored members of the Ten Classic Ladies
harem), it would seem inescapable that interesting compounds will
emerge.
Just what is this all about the ten "Classic Ladies?" In the chemical
struc-ture of DOM, there is a total of nineteen hydrogen atoms. Some
of these are indis-tinguishable from others, such as the three
hydrogen atoms on a methyl group. But there are exactly ten "types"
of hydrogen atoms present. And, not having much, if any, intuition as
to just why DOM was so powerful a psychedelic, I decided to
systematically replace each of the ten unique hydrogens, one at a time
of course, with a methyl group. And I planned to give the resulting
materials the names of famous ladies, alphabetically, as you walk
around the molecule.
ARIADNE was the first of these, the methyl for a hydrogen atom on the
methyl group of the amphetamine chain. It was Ariadne who gave the
long piece of thread to Theseus to guide him through the mazes of the
Labyrinth so he could escape after killing the Minotaur. The record
is fuzzy as to whether, after the successful killing, she went with
him, or let him go on alone. A methyl group on the nitrogen atom
produced BEATRICE. There is the legendary Beatrijs of the Dutch
religious literature of the 14th century, and there is the Beatrice
from Beatrice and Benedict (of Berlioz fame). But the one I had in
mind was the lady from Florence whom Dante immortalized in the Divina
Commedia, and she is entered under her own name in this footnote.
Replacing the alpha-hydrogen of DOM with a methyl group would give the
phentermine analogue which is named CHARMIAN. You may be thinking of
Cleopatra's favorite attendant, but I was thinking of the sweet wife
of a very dear friend of mine, a lady who has been in a state of
gentle schizophrenia for some forty years now. The MDA analogue of
CHARMIAN has been described in this foornote under the code name of
MDPH. CHARMIAN, herself, has been synthesized and is of very much
reduced potency in animals, as compared to DOM. It has not been tried
in man as far as I know.
The two beta-hydrogen atoms of DOM are distinct in that, upon being
replaced with methyl groups, one would produce a threo-isomer, and the
other an erythro-isomer. I have named them DAPHNE (who escaped from
Apollo by becoming a laurel tree which was, incidentally, named for
her) and ELVIRA (who might not be too well known classically, but
whose name has been attached to Mozart's 21st piano concerto as its
slow movement was used as theme music for the movie Elvira Madigan).
I don't know if either of this pair has been made--I started and got
as far as the cis-trans mixture of adducts betweeen nitroethane and
2,5-dimethoxy-4-methylacetophenone. Whoever finally makes them gets
to assign the names. I had made and tested the corresponding
homologues of DMMDA that correspond to these two ladies.
And there are five positions (2,3,4,5 and 6) around the aromatic ring,
each of which either carries a hydrogen atom or a methyl group that
has a hydrogen atom. There is the 2-methoxy group which can become a
2-ethoxy group to produce a compound called FLORENCE. Her name is the
English translation of the Italian Firenze, a city that, although
having a female name, has always seemed thoroughly masculine to me.
There is the 3-hydrogen atom which can become a 3-methyl group to
produce a compound called GANESHA. This is a fine elephant-headed
Indian God who is the symbol of worldly wisdom and also has been seen
as the creator of obstacles. Here I really blew it; the Classic Lady
turned out to be a Classic Gentle-man; not even the name is feminine.
There is the 4-methyl group which can become a 4-ethyl group to
produce a compound called HECATE who presided over magic arts and
spells. There is the 5-methoxy group which can become a 5-ethoxy
group to produce a compound called IRIS, who is the Goddess of the
rainbow. And there is the 6-hydrogen atom which can become a 6-methyl
group to produce a compound called JUNO, who is pretty much a lady's
lady, or should I say a woman's woman.
GANESHA, 2,5-dimethoxy-3,4-dimethylamphetamine has been made, and has
proven to be an extraordinary starting point for a large series of
potent phenethylamines and amphetamines which are described in this
book. HECATE was given a synonym early in this process, and is now
known as DOET (2,5-dimethoxy-4-ethylamphetamine). IRIS has also been
entered under her name, and the other ethoxy homologue, FLORENCE,
would be easily made based on the preparation of the phenethylamine
analogue, 2CD-2ETO. Perhaps it has already been made somehow,
somewhere, as I have noted that I have claimed its citrate salt as a
new compound in a British patent. And, finally, JUNO
(3,6-dimethoxy-2,4-dimethylamphetamine) has been made (from
2,5-dimethoxy-m-xylene, which was reacted with POCl3 and
N-methylformanilide to the benzaldehyde, mp 53-54 °C, and to the
nitrostyrene with nitroethane, mp 73-74 °C from cyclohexane, and to
the final amine hydrochloride with LAH in THF). Rather amazingly, I
have had JUNO on the shelf for almost 14 years and have not yet gotten
around to tasting it.
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