Book II of PiHKAL: A Chemical Love Story. Alexander & Ann Shulgin #8: ARIADNE
4C-DOM; BL-3912; Dimoxamine; 1-(2,5-Dimethoxy-4-methylphenyl)-2-aminobutane; 2,5-Dimethoxy-α-ethyl-4-methylphenethylamine
SYNTHESIS: In 50 mL of benzene there was dissolved 31.6 g 2,5-dimethoxy-4-methylbenzaldehyde (see recipe for 13H17NO4) 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 (+)-2′-nitrotartranilic acid (to give the “S” isomer) or with (+)-2′-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 (+)-α-methyl benzylamine followed by the hydrogenolysis of the benzyl group.
DOSAGE: as psychedelic, unknown.
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
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 (
Some of these analogues I had made, and sent in for animal screening. The high potency of 12H15NO4) 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
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
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, 3CN as fine yellow crystals, and this was reduced with AH in cold THF to
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
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 structure of
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
The two beta-hydrogen atoms of
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
3 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.
About PiHKAL • info
This version of Book II of PiHKAL is based on the Erowid online version, originally transcribed by Simson Garfinkle and converted into HTML by Lamont Granquist. I drew also on “Tyrone Slothrop’s” (Unfinished) Review of PIHKAL to enumerate the many analogues mentioned in PiHKAL but not described at length. Many, many others have since been added.
I have tried here to expunge any artifacts introduced by the earlier transcriptions and restore the typographic niceties found in the printed edition. I’ve also made minor changes to some chemical names in line with current nomenclature practice. Typically the change is little more than expanding a prefix or setting it in italics. The errata and changes page has further details.
“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 herein, 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.”
The copyright for Book I of PiHKAL has been reserved in all forms and it may not be distributed. Book II of PiHKAL may be distributed for non-commercial reproduction provided that the introductory information, copyright notice, cautionary notice and ordering information remain attached.
PiHKAL is the extraordinary record of the authors’ years exploring the chemistry and transformational power of phenethylamines. This book belongs in the library of anyone seeking a rational, enlightened and candid perspective on psychedelic drugs.
Though Sasha and Ann have put Book II of PiHKAL in the public domain, available to anyone, I strongly encourage you to buy a copy. We owe them — and there’s still nothing quite like holding a real book in your hands.
PiHKAL (ISBN 0-9630096-0-5) is available for US$24.50 (plus $10 domestic first-class shipping) from Transform Press.Transform Press,
Berkeley, CA 94701
510 · 934 · 4930 (voice)
510 · 934 · 5999 (fax)