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Book II of PiHKAL: A Chemical Love Story, by Alexander & Ann Shulgin #177: 4-TSB
#177 4-TSB: 4-Thiosymbescaline; 3,5-Diethoxy-4-methylthiophenethylamine

#177 4-TSB SYNTHESIS: A solution of 12.1 g N,N,N′,N′-tetramethylethylenediamine and 16.6 g of 1,3-diethoxybenzene was made in 200 mL 30–60 °C petroleum ether. This was stirred vigorously under a N2 atmosphere and cooled to 0 °C with an external ice bath. There was added 66 mL of 1.6 M butyllithium in hexane. The stirred reaction mixture became a little cloudy and then gradually formed a white granular precipitate. This was brought to room temperature, stirred for 0.5 h, and returned again to 0 °C. There was added 9.45 g of dimethyl disulfide which converted the loose precipitate to a creamy texture. The reaction was exothermic. After being held 0.5 h at reflux temperature, the reaction mixture was added to 600 mL dilute H2SO4. There was the immediate formation of white solids which were insoluble in either phase. The petroleum ether phase was separated, and the aqueous phase extracted with 3×100 mL Et2O. The organics were combined, and the solvents removed under vacuum. There was obtained as residue 24.8 g of a slightly oily crystalline solid that, after trituration under 30 mL cold hexane, filtering, and air drying, weighed 16.9 g. This product, 2,6-diethoxythioanisole, had a mp of 71–72 °C which was not improved by recrystallization from methylcyclopentane. Anal. (C11H16O2S) C,H.

To a stirred solution of 16.7 g of 2,6-diethoxythioanisole in 175 mL CH2Cl2 there was added 13 g elemental bromine dissolved in 100 mL CH2Cl2. After stirring at ambient temperature 1 h, the dark solution was added to 150 mL H2O containing 1 g of sodium dithionite. Shaking immediately discharged the residual bromine color, and the organic phase was separated. The aqueous phase was extracted once with 100 mL CH2Cl2, the pooled extracts washed first with H2O, and then with saturated brine. Removal of the solvent under vacuum provided 28.6 g of a pale yellow oil with several globs of H2O present. This wet product was distilled at 118–125 °C at 0.25 mm/Hg to yield 3-bromo-2,6-diethoxythioanisole as a white oil weighing 21.5 g. It could not be crystallized. Anal. (C11H15BrO2S) C,H.

To a solution of 19.3 g diisopropylamine in 75 mL hexane under a He atmosphere there was added 100 mL of 1.6 M butyllithium. The viscous mixture was loosened by the addition of 200 mL anhydrous THF, and this stirred mixture was cooled with an external ice bath. There was then added 4.0 mL of dry CH3CN, and 11.6 g of 3-bromo-2,6-diethoxythioanisole (which had been diluted with a little anhydrous THF). The deep red brown reaction mixture was stirred for 0.5 h, and then poured into 1 L dilute H2SO4. This was extracted with 3×75 mL CH2Cl2, the extracts pooled, washed with H2O, dried with anhydrous K2CO3, and the solvent was removed under vacuum. The residue was distilled at 0.3 mm/Hg yielding two fractions. The first fraction boiled at 120–140 °C and weighed 1.2 g. This fraction partially crystallized, but was not investigated further. The second fraction was 3,5-diethoxy-4-methylthiophenylacetonitrile, which came over at 135–160 °C, was a yellow liquid, weighed 3.2 g, but did not crystallize.

A solution of LAH in anhydrous THF (30 mL of a 1.0 M solution) under N2 was cooled to 0 °C and vigorously stirred. There was added, dropwise, 0.78 mL 100% H2SO4, followed by 3.0 g 3,5-diethoxy-4-methylthiophenylacetonitrile diluted with a little anhydrous THF. The reaction mixture was stirred at 0 °C for a few min, then brought to reflux on the steam bath for 1.5 h. After cooling back to room temperature, there was added IPA to destroy the excess hydride and 10% NaOH to bring the reaction to a basic pH with the conversion of aluminum oxide to a loose, white, filterable consistency. This was removed by filtration, and washed first with THF followed by IPA. The filtrate and washes were stripped of solvent under vacuum, the residue added to 1 L dilute H2SO4. This was washed with 2×75 mL CH2Cl2, made basic with 25% NaOH, and extracted with 3×100 mL CH2Cl2. After combining, the solvent was removed under vacuum providing an orange oil. This was distilled at 135–160 °C at 0.4 mm/Hg to give a light yellow oil. This was dissolved in 20 mL of IPA, and neutralized with 32 drops of concentrated HCl producing white crystals spontaneously. These were dissolved by bringing the IPA suspension to a boil on the steam bath and, with stirring, diluted with 80 mL of warm anhydrous Et2O. There was the immediate formation of crystals which were removed by filtration, washed with an IPA/Et2O mixture, and then with Et2O. After air drying there was obtained 1.5 g of 3,5-diethoxy-4-methylthiophenethylamine hydrochloride (4-TSB) as white crystals. The mp was 194.5–196 °C. Anal. (C13H22ClNO2S) C,H.

DOSAGE: greater than 240 mg.

DURATION: unknown.

QUALITATIVE COMMENTS: (with 80 mg) “There was a real effect about three hours into this experiment—a little bit spacey while I was talking to Mr. X. But the talk went well, and we were all really friendly. There was no hint that he suspected anything. A couple of hours later, nothing.”

(with 160 mg) “Twinges at a couple of hours, but the rest of the day disappointing as to any effect from the drug.”

(with 240 mg) “No effects at all.”

EXTENSIONS AND COMMENTARY: Here is an excellent presentation of a report that shows false positives or maybe false negatives. Something at low levels. Nothing at higher levels. Always tend to trust the absence of an effect in preference to the presence of an effect, if one of the two observations is presumed to be in error.

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.

Ordering Information

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.

PiHKAL (ISBN 0-9630096-0-5) is available for US$24.50 (plus $10 domestic first-class shipping) from Transform Press.

Transform Press,
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Berkeley, CA 94701

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