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(a.a-dideutero-3,4,5-tri-methoxyphenethylamine). I fully expect both 3,5-D and 2,6-D to be indistinguishable from mescaline in effect, since it is known that not much metabolism takes place in man at these locations of the molecule.
The last compound, a-D, could be quite a different matter. The principal metabolite of mescaline is 3,4,5-trimethoxyphenylacetic acid, and this product requires enzymatic attack at the exact position where the deuteriums will be located. To the extent that they are harder to remove (come off more slowly or to a lesser degree), to that extent the molecule will be more potent in man, and the dosage required for effects will be less. The compound will be easily made by the reduction of 3,4,5-trimethoxyphenylacetonitrile with lithium aluminum deuteride. And if there is a believable difference between a-D and mescaline, it will be necessary to synthesize each of the two optically active a-mono-deutero analogs. That will be quite a challenge.
Some years ago I performed a fascinating series of experiments with another isotopically labeled mescaline derivative. This was '-14C
labeled material, which I self-administered on three occasions, at three different levels. One dosage was with 350 milligrams, a second a few weeks later was with 4 milligrams, and a third was a few weeks later yet, with about 60 micrograms. In each case, exactly the same absolute quantity of radioactivity was administered, so the metabolic distribution was equally visible. Only the weight dosage was different. Urinary analysis was run for each experiment for the presence of unchanged mescaline, and for the primary metabolite, 3,4,5-trimethoxyphenylacetic acid. The smaller the dosage, the proportionately larger amount of mescaline was oxidized to the inactive acetic acid, and the smaller amount was excreted in an unchanged state. It seemed to me that there might be a finite capacity of the body to oxidatively deaminate mescaline, and at larger and larger dosages, this capacity became increasingly depleted.
Perhaps this is why mescaline requires such a large dosage to be effective in man.
52 DESOXY; 3,5-DIMETHOXY-4-METHYLPHENETHYLAMINE
SYNTHESIS: To a well-stirred solution of 31 g 2,6-dimethoxytoluene in 200 mL CH2Cl2 there was added 11 mL elemental bromine, a portion at a time. There was a copious evolution of HBr and the color gradually faded from deep red to straw. The reaction mixture was poured into 500 mL H2O, and the organic layer separated, washed first with dillute NaOH and finally with dilute HCl. The solvent was removed under vacuum, and the residue distilled at 85-90 !C at 0.4 mm/Hg to provide 44 g of 3-bromo-2,6-dimethoxytoluene as a white oil.
A well-stirred solution of 42 mL diisopropylamine in 100 mL petroleum ether was placed in a He atmosphere and cooled to 0 !C with an external ice-water bath. There was then added 120 mL of a 2.5 M
solution of n-butyllithium in hexane, producing a clear but viscous solution of the lithium amide. Maintaining this temperature, there was added 100 mL of anhydrous THF, followed by 10 mL dry CH3CN, which produced an immediate white precipitate. A solution of 23 g of 3-bromo-2,6-dimethoxytoluene in 75 mL anhydrous THF was then added which produced a light red color. The reaction mixture was allowed to come to room temperature. The color became progressively darkened, eventually becoming a deep red-brown. After 0.5 h, the reaction mixture was poured into 500 mL of dilute H2SO4, the layers were separated, and the aqueous layer extracted with 2x75 mL CH2Cl2. The organics were combined, the solvent removed under vacuum, and the residue distilled. Discarding a first fraction, the cut boiling at 125-165 !C at 0.3 mm/Hg was collected. This light yellow fraction spontaneously crystallized and weighed 11.0 g. Trituration under 20
mL petroleum ether provided 1.72 g of 3,5-dimethoxy-4-methylphenylacetonitrile as a yellowish solid.
A solution of LAH in anhydrous THF under nitrogen (20 mL of a 1.0 M
solution) was cooled to 0 !C and vigorously stirred. There was added, dropwise, 0.54 mL 100% H2SO4, followed by 1.5 g 3,5-dimethoxy-4-methylphenylacetonitrile as a solid. The reaction mixture was stirred at 0 !C for a few min, then brought to room temperature for 1 h, and finally to a reflux on the steam bath for 30
min. After cooling back to 0 !C there was added IPA until no more hydrogen was evolved, followed by sufficient 15% NaOH to produce a granular texture. The white solids were removed by filtration, and washed with THF. The filtrate and washes were stripped of solvent under vacuum, the residue added to 150 mL dilute H2SO4 and washed with 2x50 mL CH2Cl2. The aqueous phase was made basic with 25% NaOH, and extracted with 3x100 mL CH2Cl2. These extracts were pooled, the solvent removed under vacuum, and the residue distilled at 110-120 !C
at 0.45 mm/Hg to give a colorless viscous oil. This was dissolved in 10 mL of IPA, neutralized with 10 drops of concentrated HCl and diluted with 20 mL anhydrous Et2O. The product was removed by filtration, washed with Et2O, and air dried to give 0.55 g 3,5-dimethoxy-4-methylphenethylamine (DESOXY) as white crystals.
DOSAGE: 40 - 120 mg.
DURATION: 6 - 8 h.
QUALITATIVE COMMENTS: (with 40 mg) Initially I felt very chilled, so I lay down under a blanket. Eyes-closed imagery became very dream-like and my general state was felt as having lost my center.
Also, not much in touch with feelings, sense of strangeness, almost alien view of the world. Not through recog-nizable eyes. Neither pleasant nor unpleasant, just strange. Was able to drift into sleep very easily, or sleep-like trance state, with disconnected, far-out imagery. After 3 hours the nausea was gone, I was able to get up and explore. A little food went down well. No drive, no strong focus in any direction. Feel this was a quite fascinating experience.
Completely down by six hours. Would go a bit slowly because of slight hints of neurological sensitivity Q the instant chilling and a tendency to dart on going to sleep. The nervous system does not feel over-exposed, but all of a sudden there will be a millisecond of auditory hallucination, or an out-of-the-blue startle. So take it easy going up.S [Some 24 hours after this experiment had been completed, and a normal baseline re-established, a complex and psycho-logically disruptive syndrome occurred, that lasted for the better part of a week. The temporal juxtaposition between the use of desoxy and the subsequent Rspiritual crisisS initially suggested some possible connection, but in retrospect the events seem to be unrelated].
(with 40 mg) I have offered to be a control on an experiment where there had been a close relationship between a trial with desoxy and what might have been a psychotic break, or some kind of so-called spiritual emergency. These two events lay within a day of one another. I was aware of my 40 milligram dosage at about three-quarters of an hour into the experiment, and felt that there was no more in-tensification at the two-hour point. At that time I felt distinctly spaced but with a very good feeling, and I could see no reason not to increase the dosage at some future time. There was a good and mellow mood, and enjoyment in escapist reading. The only physical oddity that I noted was that there had been no urge to urinate, and only a small amount of quite concentrated urine was passed rather late in the experiment. I was at baseline at the fifth hour, and there was nothing unusual at any time during the following week.
(with 100 mg) The stuff has a sweet taste! There was a slight heart-push in the early awareness period, with a pulse up to 100 and a feeling of pressure in the chest. There were no apparent visual enhancements, but the eyes-closed imagery to music was noteworthy.
Thinking skills and conversation seemed to be fully under control, if not enhanced. There was none of the colorful psychedelic world of mescaline, but this might be just around the corner; perhaps with a larger dose. This is a comfortable in-between level. Sleep was not possible at the sixth hour, but two hours later, it was easy and very restful. There was no negative price to pay the next day.
EXTENSIONS AND COMMENTARY: All substituents that are involved with the several drugs being discussed in this writing are really things that are stuck like warts on the benzene ring that is central to every phenethylamine. Some of these warts are things attached with a oxygen atom; there are some of these in every single compound in this story.
But the removal of an oxygen atom (in those cases where there is more than one) can radically change the nature of the effects seen. This is the exact meaning of the term Rdesoxy.S RDesS, without, and RoxyS, the oxygen. Since this drug is simply the structure of mescaline with the oxygen at the 4-position plucked out of the picture, the first impulse was to abbreviate this compound as DOM for des-oxymescaline.
However, a long, long time ago, in a universe far, far away, a compound was synthesized that had a methoxy group replaced by a methyl, and it was already named DOM. This was the first of the STP
analogs, and the initials stood for desoxy (DO, losing an oxygen) and methyl (M, having it replaced with a methyl group). These are two different worlds. One M stands for Mescaline, and the other M stands for Methyl. Let's call it 4-desoxymescaline, or simply DESOXY, and be exact.
This drug is a prime example of a pharmacological challenge directed to the metabolic attack at the 4-position as a mechanism for the expression of biological activity. A methoxy group there would allow easy removal of the methyl group from the oxygen by some demethylation process, but a bare methyl group there cannot be removed by any simple process. It must be removed by a very difficult oxidation.
This is not the first time that oxygen atoms have been removed from the mescaline molecule. Both the 3,5-dideoxymescaline (3,5-dimethyl-4-methoxyphenethylamine) and 3,4,5-trideoxymescaline (also called desoxymescaline in the literature, but really tri-desoxymescaline or 3,4,5-trimethylphenethylamine) have been studied in the cat, and have shown extraordinary pharmacological profiles of CNS action. The trimethyl compound showed behavior that was interpreted as being intense mental turmoil, accompanied by a startling rise in body temperature. The significance is hard to determine, in that LSD gave similar responses in the cat, but mescaline was without effects at all. No human studies have been made on these compounds, just animal studies. But they might prove upon trial in man to be most revealing. They would have to be performed with exceptional care.
The 3-carbon chain amphetamines that correspond to these mescaline look-alikes with one or more methoxy groups replaced with methyl groups, are largely untested and would require independent and novel syntheses. The 3,4,5-trimethylamphetamine is known, and is known to be very hard on experimental cats.
A mescaline analogue with a bromo atom in place of the 4-methoxyl group is an analogue of mescaline in exactly the same way that DOB (a very potent am-phetamine) is an analog of TMA-2 (the original trisubstituted amphetamine). This analogue, 3,5-dimethoxy-4-bromoamphetamine, has been found to be a most effective serotonin agonist, and it is a possibility that it could be a most potent phenethylamine. But, as of the present time, it has never been assayed in man.
53 2,4-DMA; 2,4-DIMETHOXYAMPHETAMINE
SYNTHESIS: To a solution of 10 g 2,4-dimethoxybenzaldehyde in 50 mL
nitroethane there was added 0.5 g anhydrous ammonium acetate, and the mixture was heated on the steam bath for 2 h. The excess solvent/reagent was removed under vacuum, and the residue oil dissolved in 25 mL boiling MeOH. On cooling, this deposited yellow crystals of 1-(2,4-dimethoxyphenyl)-2-nitropropene that, after filtering, MeOH washing, and air drying, weighed 10.2 g and had a mp of 78-79 !C.
A magnetically stirred suspension of 6.0 g LAH in 300 mL anhydrous Et2O was brought up to a gentle reflux under a He atmosphere. A total of 8.5 g 1-(2,4-dimethoxyphenyl)-2-nitropropene was introduced into the reaction mixture by allowing the condensed Et2O to leach it from a modified Soxhlet condenser. After the addition was complete, the reaction was held at reflux for an additional 24 h. After cooling with an external ice bath, the excess hydride was destroyed by the cautious addition of H2O. When the exothermic reaction had subsided, there was added 500 mL H2O, 150 g potassium sodium tartrate, and sufficient base to bring the pH above 9. The phases were separated, the organic phase dried over anhydrous MgSO4, the drying agent removed by filtration, and the clear filtrate then saturated with anhydrous HCl gas to produce white crystals of 2,4-dimethoxyamphetamine hydrochloride (2,4-DMA) with a mp of 146-147 !C.
DOSAGE: greater than 60 mg.
DURATION: short.
QUALITATIVE COMMENTS: (with 60 mg) This is definitely threshold, or even a bit more. There is a lot of amphetamine-like component, and a certain blush of euphoria. There is also a diffusion of association, so it's more than just amphetamine, no question about it. At the three-hour point, it is definitely quieting down.
EXTENSIONS AND COMMENTARY: What can one say as to the active dosage of 2,4-DMA? Nothing. What can one say as to the duration? Probably short. The 60 milligram report given above is the highest level that I personally know of having been tried in man, and there is no hint as to what might be found at a fully active dose, or just where that dose might be. It might be fully speedy. It might be fully psychedelic.
It might give a cardiovascular push that would be scary. Studies of 2,4-DMA on vascular strips (associated with serotonin action) were not impressive in comparison with structurally related psychedelics, and it seems as if its action might involve norepinephrine release. It is a reasonable guess that there would be cardio-vascular activity at higher levels. But it will only be with human trials, someday, that the answer will be known for sure.
The meta-orientation of the two methoxyl groups does, however, greatly increase the susceptibility of the aromatic ring to electrophilic attack. This is one of the three possible meta-dimethoxy substituted amphetamines, and it is the best studied one in the pursuit of potential radio-halogen substituted brain blood-flow agents. This strategy is discussed under IDNNA; the other two meta-compounds are discussed under 3,4-DMA.
The homologues of 2,4-DMA that were iodinated (or occasionally fluor-inated) were mono- or di-alkylated on the nitrogen, and the precursor that was common to all was the corresponding acetone. The above nitrostyrene, 1-(2,4-dimethoxyphenyl)-2-nitropropene, was reduced in acetic acid with elemental iron, and the base-washed extracts stripped of solvent and distilled (125-145 !C at 0.5 mm/Hg) to give 2,4-dimethoxyphenylacetone as a water-white oil. The principal reductive amination product of this, the one that was most thoroughly explored with various halogenation schemes, was obtained by the reaction of 2,4-dimethoxyphenylacetone with dimethylamine and sodium cyanoborohydride. This product, 2,4-dimethoxy-N,N-dimethylamphetamine or 2,4-DNNA, distilled at 105-115 !C at 0.4 mm/Hg and formed a perchlorate salt that melted at 98-98.5 !C. This could be iodinated with the radio-iodide anion, when oxidized with chloramine-T in buffered sulfuric acid, to give the iodinated analogue (2,4-dimethoxy-N,N-dimethyl-5-iodoamphetamine) in an excellent yield. Radio-fluorination with acetyl hypofluorite gave the 5-fluoroanalogue (2,4-dimethoxy-N,N-dimethyl-5-fluoroamphetamine) in an acceptable yield. Both compounds went into a rat's brain to a pretty good extent, but both of them washed out too rapidly to be clinically interesting.
A large family of other N-substituted homologues of 2,4-DMA were similarly prepared from the above ketone and sodium cyanoborohydride.
Methylamine, ethylamine, propylamine, isopropylamine and hexylamine gave the corresponding N-alkyl homologues. The N,N-diethyl homologue was made from the primary amine, 2,4-DMA itself, with acetaldehyde and sodium cyanoborohydride but the product, N,N-diethyl-2,4-dimethoxyamphetamine, could not be converted into a crystalline hydrochloride salt.
Yet another variation on these structures was launched, again with the design of making radio-iodination targets which are not psychedelic and thus might be useful clinically. In this variation, the nitrogen atom substitution pattern was held constant, with two methyl groups, as were the ring locations of the two oxygen atoms. But the identities of the alkyl groups on these oxygen atoms were varied. The synthetic procedure followed was to make the appropriate 2,4-dialkoxybenzaldehyde, convert it to the nitrostyrene with nitroethane, reduce this to the phenylacetone with elemental iron, and then reductively aminate this ketone with dim
ethylamine. Following this reaction scheme, five amphetamine homologues of 2,4-DMA were made, three with the 4-methoxy group maintained but the 2-position extended, and two with both groups extended symmetrically. These are: (1) N,N-dimethyl-2-ethoxy-4-methoxyamphetamine; (2) 2-(n)-butyloxy-N,N-dimethyl-4-methoxy-amphetamine; (3) 2-(n)-decyloxy-N,N-dimethylamphetamine; (4) 2,4-diethoxy-N,N-dimethylamphetamine; and (5) N,N-dimethyl-2,4-di-(i)-propoxyamphetamine. I believe that most of these have been iodinated and assayed in rats, and several of them appear quite promising. But none of them have been assayed in man, yet. The bromination product of 2,4-DMA (5-bromo-2,4-dimethoxyamphetamine, 5-Br-2,4-DMA) is way down in activity (see its recipe, separately). Since all iodo analogues are of about the same potency as the bromo counterparts, and since the addition of two methyl groups on the nitrogen does not appear to enhance central activity, I feel the iodination products of these N,N-dialkyl-dialkoxyamphetamines would not have any interesting psychopharmacology.
There is something vaguely counterproductive, in my evaluation of things, when the goal of a research project is to avoid activity rather than to create it. Although this chemistry was completely fascinating and could have produced the world's best positron-emitting, brain-scanning diagnostic compound, I feel it quite unlikely that it would have produced the world's best insight-revealing, empathy-enhancing psychedelic, so this research direction never totally caught my fancy. I went on to other things.
54 2,5-DMA; DMA; 2,5-DIMETHOXYAMPHETAMINE
SYNTHESIS: A solution of 10.0 g 2,5-dimethoxybenzaldehyde in 50 mL
glacial acetic acid was treated with 6.8 g of nitroethane and 4.0 g of anhydrous ammonium acetate. This mixture was heated on the steam bath for 3 h and then the reagent/solvent was removed under vacuum. The residue was suspended in H2O and extracted with CHCl3. Removal of the solvent from the pooled extracts yielded 11.2 g of an impure 1-(2,5-dimethoxyphenyl)-2-nitropropene which, on recrystallization from 75 mL boiling MeOH, gave 6.7 g of product with a mp of 73-75 !C.