2-Thioisomescaline · 3,4-Dimethoxy-2-methylthiophenethylamine
SYNTHESIS: A short foreword to the synthetic portion is needed. First, although the required thioanisole, 2,3-dimethoxythioanisole, is now commercially available, it is of the utmost importance that it be free of the impurity, veratrole. I know that the material presently available from Aldrich Chemical Company is satisfactory, as I have had a hand in making it. But, if veratrole is present, there are very difficult separations encountered during these preparations. And secondly, the synthesis of 2-TIM and
A solution of 150 mL of 1.6 M butyllithium in hexane under N2 was vigorously stirred and diluted with 150 mL petroleum ether (30–60 °C) and then cooled with an external ice bath to 0 °C. The addition of 26.7 g of veratrole produced a flocculant white precipitate. Next, there was added a solution of 23.2 g of N,N,N′,N′-tetramethylethylenediamine in 100 mL anhydrous Et2O and the stirred reaction mixture was allowed to come to room temperature. The subsequent addition of 20.7 g of dimethyl disulfide over the course of several min produced an exothermic response, and this was allowed to stir for an additional 30 min. There was then added 10 mL EtOH followed by 250 mL of 5% NaOH. The organic phase was washed first with 150 mL 5% NaOH, followed by 2×100 mL portions of 5% dilute HCl. The removal of solvent and bulb-to-bulb distillation of the residue provided 2,3-dimethoxythioanisole boiling at 72–80 °C at 0.4 mm/Hg as a white oil. This product contained some 20% unreacted veratrole as a contaminant and the isolation of subsequent products from this impure material was extraordinarily difficult. The effort needed for careful purification at this point was completely justified. The product could be obtained in a pure state by distillation at 0.1 mm/Hg through a 6 cm Vigreaux column with collection of several fractions. Those that distilled at 84–87 °C were pure 2,3-dimethoxythioanisole. An analytical sample can be obtained by cooling a concentrated MeOH solution in dry ice, filtering the generated crystals, and washing with cold MeOH. This product melts at 36.5–37 °C. Anal. (C9H12O2S) C,H,S. The picrate can be formed by treatment with a saturated EtOH solution of picric acid. It formed orange crystals with a mp of 73–78 °C. Anal. (C15H15N3O9S) N.
To 18 mL of POCl3 there was added 25 mL N-methylformanilide and the solution allowed to stand at room temperature for 0.5 h, until the color had developed to a rich claret. There was then added 25.0 g of 2,3-dimethoxythioanisole and the mixture heated on the steam bath for 2.5 h. This was added to 500 mL H2O and stirred at ambient temperature for 2 h. The product was extracted with 4×150 mL CH2Cl2, the extracts combined, and the solvent removed under vacuum. The residue was distilled through a Vigreaux column under vacuum (0.1 mm/Hg) with the fraction boiling at 125–135 °C being richest in aldehydes, as determined by GC analysis. If the starting 2,3-dimethoxythioanisole contains appreciable veratrole as a contaminant, then this aldehyde fraction contains three components. There is present both 2,3-dimethoxy-4-(methylthio)benzaldehyde and 3,4-dimethoxy-2-(methylthio)benzaldehyde (the two desired precursors to
Although efforts to separate this mixture were not effective, one of the aldehydes could be isolated in small yield by derivative formation. This was too wasteful to be of preparative value, but it did allow the generation of seed that was of great value in the later separation of the mixed nitrostyrenes that were prepared. If a 1 g portion of this mixture was fused with 0.6 g p-anisidiine over an open flame and then cooled, the melt set up as a solid. Triturating under MeOH gave a yellow solid (0.45 g, mp 77–80 °C) which on recrystallization from hexane appeared to be a single one of the three possible Schiff’s bases that could theoretically be prepared. It had a mp of 80–81 °C. Anal. (C17H19NO3S) C,H. Hydrolysis with hot 3 N HCl freed the benzaldehyde which was isolated by quenching in H2O and extraction with CH2Cl2. The extracts were stripped of solvent under vacuum and the residue distilled bulb-to-bulb under vacuum to give white crystals of 3,4-dimethoxy-2-(methylthio)benzaldehyde (the 2-TIM aldehyde) with a mp of 23–24 °C. A micro-scale conversion of this to the corresponding nitrostyrene provided the seed that was effectively used in the large scale preparation described below.
A solution of 9.0 g of a mixture of 3,4-dimethoxy-2-(methylthio)benzaldehyde and 2,3-dimethoxy-4-(methylthio)benzaldehyde in 50 mL of nitromethane was treated with 1.5 g anhydrous ammonium acetate and held at reflux for 5 h. The excess nitromethane was removed under vacuum to yield 10.4 g of a dark orange oil which, upon dissolving in 40 mL hot MeOH and being allowed to cool and slowly evaporate at ambient temperatures, provided dark colored crystals. Filtration (save the mother liquors!) and recrystallization from 40 mL MeOH provided 6.3 g of a yellow crystalline solid. A second recrystallization from 50 mL MeOH gave 5.0 g of lemon yellow plates 3,4-dimethoxy-2-methylthio-β-nitrostyrene with a mp of 102–103.5 °C. An analytical sample, from IPA, had a mp of 103–104 °C and a single spot on TLC with CHCl3, with an Rf of 0.54. Anal. (C11H13NO4S) C,H. When there had been veratrole left as a contaminant in the original 2,3-dimethoxythioanisole, the nitrostyrene that was isolated by this method had, after recrystallization, a mp of 93–95 °C. This substance acted as a single compound through a number of recrystallization trials, but on TLC analysis always gave two components (silica gel, chloroform) with Rf’s of 0.54 and 0.47. It proved to be a mixture of 3,4-dimethoxy-2-methylthio-β-nitrostyrene and 3,4-dimethoxy-β-nitrostyrene in an exact molecular ratio of 2:1. This latter nitrostyrene is the precursor to 32H37N3O12S2) C,H. The mother liquor above is the source of the
A solution of 4.2 g LAH in 70 mL anhydrous THF was cooled to 0 °C under He and with stirring. There was added, dropwise, 2.8 mL of 100% H2SO4, followed by 4.4 g of 3,4-dimethoxy-2-(methylthio)-β-nitrostyrene dissolved in 25 mL THF. Stirring was continued for a few min as the reaction returned to room temperature, and then it was heated to a reflux for 10 min on the steam bath. The reaction was cooled again, and 25% NaOH was added dropwise until a white granular precipitate was obtained. This was removed by filtration, and the filter cake was washed with 2×50 mL Et2O. The filtrate was extracted into 100 mL dilute H2SO4 which was, in turn, made basic again and extracted with 2×100 mL CH2Cl2. The extracts were pooled, and the solvent removed under vacuum to give a residue of crude product. This was distilled from 100–115 °C at 0.3 mm/Hg yielding 3.2 g of a clear white oil. This was dissolved in 25 mL IPA, neutralized with 23 drops of concentrated HCl, and diluted with 75 mL anhydrous Et2O. There was a deposition of beautiful white platelets of 3,4-dimethoxy-2-methylthiophenethylamine hydrochloride (2-TIM) which were removed by filtration, washed with ether, and air dried. This hydrochloride salt contained a quarter mole of H2O of crystallization. The mp was 183–184 °C. Anal. (C11H18ClNO2S·1/4 H2O) C,H,N.
DOSAGE: greater than 240 mg.
QUALITATIVE COMMENTS: (with 160 mg) “There was perhaps some awareness in an hour or so, but in another hour there was absolutely nothing. A small amount of wine in the evening was quite intoxicating.”
(with 240 mg) “No effects of any kind.”
EXTENSIONS AND COMMENTARY: The problems that might be associated with the making of the three amphetamines that correspond to 2-TIM,
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 history 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.”
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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.
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.
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