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Book II of PiHKAL: A Chemical Love Story, by Alexander & Ann Shulgin #160: TMA-4
#160 TMA-4: 2,3,5-Trimethoxyamphetamine

#160 TMA-4 SYNTHESIS: To a solution of 68 g 2,4-dimethoxybenzaldehyde in 250 mL glacial acetic acid that had been warmed to 25 °C and well stirred, there was added, dropwise, 86 g of a 40% peracetic acid solution (in acetic acid). The reaction was exothermic, and the rate of addition was dictated by the need to maintain the internal temperature within a few degrees of 28 °C. External cooling was used as needed. The addition took 1 h, and when the reaction had clearly been completed (no further temperature rise) the entire reaction mixture was added to 3 volumes of H2O. The excess acid was neutralized with solid K2CO3 (283 g were required). This was extracted with 3×100 mL Et2O, the extracts pooled, and stripped of solvent under vacuum to give 66 g of crude 2,4-dimethoxyphenyl formate. This was suspended in 125 mL 10% NaOH, and the mixture heated on the steam bath for 1.5 h. On cooling, the reaction mixture set to a heavy black solid. This was removed by filtration, washed with H2O, and dissolved in 250 mL CH2Cl2. The organic phase was washed with dilute HCl, and then with aqueous NaHCO3, which removed much of the color. Removal of the solvent under vacuum gave a deep red goo that was dissolved in 200 mL anhydrous Et2O and filtered through paper. The resulting clear solution was stripped of solvent, yielding 34.4 g of 2,4-dimethoxyphenol as a red oil that crystallized on cooling. A 1.0 g sample in 4 mL pyridine was treated with 0.9 g benzoyl chloride and heated on the steam bath for a few min. The addition of H2O gave a pasty solid that was isolated by pressing on a porous plate. The yield of crude 2,4-dimethoxyphenyl benzoate was 1.1 g. Recrystallization from cyclohexane gave a white product with a mp of 86–87 °C. A second recrystallization from cyclohexane raised this to 89–90 °C, which is in agreement with the literature value.

To a solution of 31.0 g crude 2,4-dimethoxyphenol in 60 mL absolute EtOH there was added a solution of 11.25 g KOH in 90 mL boiling EtOH. To this, there was then added 28 g allyl bromide which produced an immediate white precipitate of KBr. The mixture was held at reflux for 2 h and then quenched in 3 volumes of H2O. Sufficient 10% NaOH was added to make the reaction strongly basic, and this was extracted with 3×100 mL Et2O. Removal of the solvent under vacuum gave 33.2 g of 1-allyloxy-2,4-dimethoxybenzene, shown to be free of phenol starting material by GC analysis. Analyses must be carried out at low column temperatures (below 180 °C) on an ethylene glycol succinate substrate. If a silicone column is used, even at these low temperatures, there is considerable Claisen rearrangement taking place on the column. Low temperature distillation can be used for further purification (107–110 °C at 1.0 mm/Hg).

A 31.0 g sample of 1-allyloxy-2,4-dimethoxybenzene was gently heated with a soft flame until the internal temperature reached 215 °C. An exothermic reaction took place, with the temperature rising to 270 °C. The residue left in the flask was largely 2-allyl-4,6-dimethoxyphenol, that contained perhaps 10% of 2,4-dimethoxyphenol which resulted from the pyrolytic loss of the allyl group. This mixture was methylated without further purification.

To a solution of 30 g impure 2-allyl-4,6-dimethoxyphenol in a little absolute EtOH there was added a boiling solution of 8.7 g KOH in 75 mL absolute EtOH followed, immediately, by 22.4 g methyl iodide in a little EtOH. The mixture was held at reflux for 3 h, then added to 4 volumes of H2O. Sufficient 10% NaOH was added to make the mixture strongly basic, and this was extracted with 4×100 mL Et2O. Removal of the solvent gave 28 g of 1-allyl-2,3,5-trimethoxybenzene. GC analysis showed some 10% of the expected impurity, 1,2,4-trimethoxybenzene.

To a solution of 26 g crude 1-allyl-2,3,5-trimethoxybenzene in an equal weight of absolute EtOH there was added 52 g of flaked KOH. The mixture was heated on the steam bath overnight, and then quenched with much H2O. This was extracted with 3×100 mL Et2O which, on removal under vacuum gave 24.6 g of product. This contained, by GC analysis, largely cis- and trans-1-propenyl-2,3,5-trimethoxybenzene and the expected 1,2,4-trimethoxybenzene. This mixture was dissolved in an equal volume of pentane, and cooled in dry ice. Quick filtration gave 9.2 g of an amber solid which had a melting point of 39–41.5 °C. Recrystallization from hexane provided pure trans-1-propenyl-2,3,5-trimethoxybenzene with a mp of 44–45 °C. Evaporation of the original pentane mother liquor provided an impure sample of mixed cis- and trans- isomers.

A solution of 7.2 g trans-1-propenyl-2,3,5-trimethoxybenzene in 41 g dry acetone was treated with 3.3 g dry pyridine and, with good stirring, cooled to 0 °C. There was then added 6.9 g of tetranitromethane over the course of 1 min, and the reaction mixture was allowed to stir for an additional 2 min. The reaction mixture was then quenched with a solution of 2.2 g KOH in 40 mL H2O. After the addition of more H2O, the product was extracted with 3×50 mL CH2Cl2. Removal of the solvent under vacuum yielded 7.0 g of an impure product which would not crystallize. This was distilled under vacuum to give four fractions, all of which crystallized spontaneously. Cuts #1 and #2 (bp 100–120 °C and 120–130 °C at 2 mm/Hg) were combined, weighed 0.8 g, and after crystallization from hexane yielded white crystals with a mp of 62–63 °C. The NMR spectrum (in CDCl3) was in agreement with 2,3,5-trimethoxybenzaldehyde, and the literature mp has been reported as being 62–63 °C. Cuts #3 and #4 (bp 130–170 °C and 170–175 °C at 2 mm/Hg with the bulk coming over in the latter fraction) were combined to give 3.0 g of yellow crystals. These were triturated under a little cold MeOH, and then recrystallized from MeOH to give 1.15 g of yellow crystals of 2-nitro-1-(2,3,5-trimethoxyphenyl)propene, with a mp of 87–88 °C. The forerun of the distillation contained considerable unreacted trans-1-propenyl-2,3,5-trimethoxybenzene and some 1,2,4-trimethoxybenzene, by GC analysis.

To a refluxing and stirred suspension of 1.1 g LAH in 150 mL anhydrous Et2O and under an inert atmosphere, there was added a solution of 1.1 g 2-nitro-1-(2,3,5-trimethoxyphenyl)propene in 50 mL anhydrous Et2O. The creamy mixture was held at reflux for 4 h, cooled, and then the excess hydride cautiously destroyed by the addition of 1.5 N H2SO4. There was then added 20 g potassium sodium tartrate followed by sufficient aqueous NaOH to raise the pH to >9. The Et2O phase was separated, and the remaining aqueous phase extracted with 3×75 mL CH2Cl2. The organic phase and extracts were combined, and the solvent removed under vacuum yielding 0.9 g of a colorless oil. This was dissolved in 200 mL anhydrous Et2O which was saturated with anhydrous HCl gas. There was generated a thick oil that did not crystallize. The Et2O was decanted from this, and allowed to stand for several days in a sealed container at room temperature. There was the deposition of fine white needles of 2,3,5-trimethoxyamphetamine hydrochloride (TMA-4) weighing, after Et2O washing and air drying, 0.31 g. The mp was 118–119 °C. Anal. (C12H20ClNO3) C,H. The residual oil was dissolved in H2O, made basic with NaOH, and extracted with CH2Cl2. Evaporation of the solvent gave 0.40 of a white oil which was dissolved in a little MeOH containing 0.22 g oxalic acid. There was the immediate deposition of crystals of the oxalate salt of 2,3,5-trimethoxyamphetamine, with a mp of about 110 °C.

DOSAGE: greater than 80 mg.

DURATION: perhaps 6 h.

QUALITATIVE COMMENTS: (with 80 mg) “I was concerned about life issues, with much introspection, for about 6 hours. There were no subjective physical symptoms. It was comparable to about 50 micrograms of LSD, or to 120 milligrams TMA, for me.”

EXTENSIONS AND COMMENTARY: That is the sum total of the knowledge of subjective effects that exist. There was such a precious small amount of the final hydrochloride salt that, by the time the needed build-up of dosage had been completed, there was just enough left for this single trial, which was conducted in South America. Based upon the volunteered comparisons to LSD and TMA, a potency for this compound has been published that states that it is 4× the potency of mescaline, or 4 M.U. The material must be re-synthesized, and re-evaluated with the now-accepted protocol.

In the future re-synthesis, there will be a considerable improvement made with the several steps that are described above. The products from the preparations of the phenol, the allyl ether, the Claisen rearrangement, the methylation of the new phenol, and the isomerization to the mixture of cis- and trans-propenylbenzenes were all conducted without the benefit of a Kugel-Rohr apparatus. The products became progressively thick and blacker, and it was only by the grace of getting a solid at the trans-propenyl stage that some degree of purity could finally be obtained. All of the intermediates are certainly white oils, and when this preparation is repeated, they will be distilled at each and every stage.

This 2,3,5-orientation of the methoxy groups on the aromatic ring is far and away the most difficult tri-substitution pattern known to chemists. There just isn’t any simple way to put it together. The 2-carbon phenethylamine (2,3,5-trimethoxyphenethylamine) had been synthesized quite a while ago. Its role as a substrate for liver amine oxidase in in vitro studies has been explored, but it has never been tried in man. Even more bizarre is the amphetamine with this oxygenation pattern, in which a methylenedioxy ring has replaced the two adjacent methoxyl groups. This is the material 2,3-methylenedioxy-5-methoxyamphetamine, or MMDA-4. Despite its theoretical appeal (being one of the six possible MMDA derivatives) and it’s synthetic challenge (as with the 2,3,5-trimethoxy things above, everything is simply in the wrong position) the compound is of unknown pharmacology. This follows, quite logically, from the fact that it has never been synthesized. No one has yet put together a workable procedure that would make it. In the course of making all possible positional isomers of MMDA explicitly Schedule I drugs, the DEA has named this compound, and since it was specifically named, it was entered into the Chemical Abstracts. So it is listed in the literature, at least it is in the Chem. Abstracts. But it is in reality completely unknown. Some day, some one somewhere will have a light bulb go on over his head, and find a synthetic process that will make it. Of course, the moment it is made, an illegal act will have occurred, at least in the United States as long as the present laws remain unchanged, as it is currently a Schedule I drug.

Needless to say, the 2-carbon analog of MMDA-4, 2,3-methylenedioxy-5-methoxyphenethylamine (would 2C-MMDA-4 be a reasonable name?) is also unknown.

Page updated 30 March 2012 · This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License ·

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. Still others remain to be added.

I have tried here to expunge any artifacts introduced by the earlier transcriptions and restore most of the typographic niceties found in the printed edition. I’ve also made minor changes to some chemical names in line with current nomenclature practice, and in the hope of aligning with more readers’ searches. Typically the change is little more than expanding a prefix and setting it in italics. The errata and changes page has further details.

Cautionary Note

“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.”

Alexander T. Shulgin

Copyright Notice

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.

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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.

Although 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.

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