4-Thiotrescaline · 4-Thiotrisescaline · 3,5-Diethoxy-4-ethylthiophenethylamine
#179 4-T-TRIS 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 He 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 12.8 g of diethyl disulfide which seemed to produce an exothermic reaction. After being held for a few min at reflux temperature, the reaction mixture was added to 600 mL dilute H2SO4 which produced two clear phases. The petroleum ether phase was separated, and the aqueous phase extracted with 2×75 mL Et2O. The organics were combined, and the solvents removed under vacuum. There was obtained as residue 24 g of a viscous oil. This was distilled at 93–110 °C at 0.3 mm/Hg yielding 21.5 g 1,3-diethoxy-2-ethylthiobenzene which spontaneously crystallized. Grinding under a small amount of hexane, filtering, and hexane washing provided 18.5 g of white crystals with a mp of 26–27 °C. Anal. (C12H18O2S) C,H.
To a stirred solution of 17.3 g of 1,3-diethoxy-2-ethylthiobenzene in 175 mL CH2Cl2 there was added 11.8 g elemental bromine dissolved in 100 mL CH2Cl2. There was an immediate loss of color, and the obvious evolution of HBr gas. After stirring at ambient temperature for 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 75 mL CH2Cl2, the pooled extracts washed first with H2O, and then with saturated brine. Removal of the solvent under vacuum provided 34.2 g of a pale yellow oil with several globs of H2O that were mechanically removed. This wet product was distilled at 105–125 °C at 0.35 mm/Hg to yield 4-bromo-1,3-diethoxy-2-ethylthiobenzene as an off-white oil weighing 21.6 g. It could not be crystallized. Anal. (C12H17BrO2S) C,H.
To a solution of 20.2 g diisopropylamine in 200 mL anhydrous THF that had been cooled to -10 °C under a He atmosphere with an external ice/MeOH bath, there was added 125 mL of a 1.6 M solution of butyllithium in hexane. There was then added, in sequence, 5.1 mL of dry CH3CN followed by the dropwise addition of 15.3 g 4-bromo-1,3-diethoxy-2-ethylthiobenzene diluted with a little anhydrous THF. There was only a modest color development. Analysis by thin-layer chromatography showed that the reaction components were largely starting bromide and only a little product nitrile. An additional 2.5 mL dry CH3CN was added, followed immediately by a solution of lithium diisopropylamide prepared separately from 14 mL isopropylamine in 50 mL hexane treated with 60 mL butyllithium solution. There was an immediate darkening of color. After 15 min stirring, the bromo starting material was gone, by TLC analysis. The reaction mixture was then poured into 1 L dilute H2SO4. The organic phase was separated and the aqueous fraction extracted with 2×100 mL CH2Cl2. These extracts were 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 124–145 °C and gave an amber liquid weighing 2.4 g. It was largely starting bromo compound with a little nitrile, and was not processed further. The second fraction distilled at 140–190 °C and weighed 6.2 g. Although this was largely product nitrile, it was quite complex by chromatographic analysis. It was redistilled at 0.3 mm/Hg and several fractions taken. The material collected at 145–165 °C weighed 3.2 g and was approximately 80% 3,5-diethoxy-4-ethylthiophenylacetonitrile by TLC assay. This was used in the subsequent reduction. The earlier fraction in this second distillation (130–145 °C) weighed 2.1 g but contained only 50% product nitrile by TLC analysis, and was discarded.
A solution of LAH in anhydrous THF under N2 (20 mL of a 1.0 M solution) was cooled to 0 °C and vigorously stirred. There was added, dropwise, 0.53 mL 100% H2SO4, followed by 3.0 g 3,5-diethoxy-4-ethylthiophenylacetonitrile diluted with a little anhydrous THF. The reaction mixture was stirred at room temperature for 1 h, and then at reflux on the steam bath for an additional 0.5 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 and convert the aluminum oxide to a loose, white, filterable consistency. This was removed by filtration, and washed first with THF followed by IPA. The combined 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 a residue that was distilled. A fraction boiling at 135–150 °C at 0.3 mm/Hg weighed 1.2 g and was a light yellow oil. This was dissolved in 20 mL of IPA, and neutralized with 17 drops of concentrated HCl which produces white crystals spontaneously. These were dissolved by bringing the IPA suspension to a boil on the steam bath and, with stirring, there was added 40 mL of hot anhydrous Et2O. There was the immediate formation of crystals which were removed by filtration, washed with an IPA/Et2O mixture, followed by Et2O. After air drying there was obtained 1.0 g of 3,5-diethoxy-4-ethylthiophenethylamine hydrochloride (4-T-TRIS) as sparkling white crystals. The mp was 177–178 °C. Anal. (C14H24ClNO2S) C,H.
DOSAGE: greater than 200 mg.
DURATION: unknown.
QUALITATIVE COMMENTS: (with 120 mg) “Maybe there is some physical effect? There is a slight tingling or numbing of my hands and fingers, and a certain amount of gas. It is certainly negative on the mental side, but go up slowly due to the physical.”
(with 200 mg) “There was a passing awareness at the third hour. Otherwise, no effects, either mental or physical.”
EXTENSIONS AND COMMENTARY: As with the sulfur-free counterpart, the phenethylamine with three ethyl groups hanging out from it is not active in man. It doesn’t matter where the sulfur is, since the isomer is also without action. The labor of making the amphetamine analogues of these triethylated things seems hardly worth the effort.
13 May 2016 · Creative Commons BY-NC-SA ·

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.

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.
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.
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