Thioproscaline · 3,5-Dimethoxy-4-n-propylthiophenethylamine
#174 TP SYNTHESIS: A solution was made of 12.1 g N,N,N′,N′-tetramethylethylenediamine and 13.8 g of 1,3-dimethoxybenzene 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 which produced a white granular precipitate. The reaction mixture was brought up to room temperature for a few minutes, and then cooled again to 0 °C. There was then added 15.8 g of di-n-propyl disulfide which changed the granular precipitate to a creamy appearance. Stirring was continued while the reaction mixture was brought up to room temperature and finally up to reflux. The reaction mixture was then added to 600 mL of dilute H2SO4. The two phases were separated, and the aqueous phase extracted with 2×75 mL Et2O. The organic phases were combined, and the solvent removed under vacuum. The residue was 24.2 g of a pale amber liquid which was distilled at 0.35 mm/Hg to give two fractions. The first boiled at 85–90 °C, weighed 0.5 g and appeared to be recovered dipropyl disulfide. The product 2-n-propylthio-1,3-dimethoxybenzene boiled at at 105–125 °C, and weighed 20.8 g. A small sample recrystallized from hexane had a mp of 27–28 °C. Anal. (C11H16O2S) C,H.
To a stirred solution of 19.8 g of 2-n-propylthio-1,3-dimethoxybenzene in 200 mL CH2Cl2 there was added 15.4 g elemental bromine dissolved in 100 mL CH2Cl2. The reaction was not exothermic, and it was allowed to stir for 1 h. The reaction mixture was washed with H2O containing sodium hydrosulfite (which rendered it nearly colorless) and finally washed with saturated brine. The solvent was removed under vacuum leaving 33.5 g of a pale yellow liquid. This was distilled at 112–120 °C at 0.3 mm/Hg to yield 4-bromo-2-n-propylthio-1,3-dimethoxybenzene as a pale yellow oil. Anal. (C11H15BrO2S) C,H.
To a solution of 16.8 g diisopropylamine in 100 mL anhydrous THF that was stirred under a N2 atmosphere and cooled to -10 °C with an external ice/MeOH bath, there was added in sequence 75 mL of 1.6 M butyllithium in hexane, 3.0 mL of dry CH3CN, and 8.7 g of 4-bromo-2-n-propylthio-1,3-dimethoxybenzene which had been dissolved in 20 mL THF. The bromo compound was added dropwise over the course of 5 min. The color became deep red-brown. Stirring was maintained for a total of 30 min while the reaction came to room temperature. It was then poured into 750 mL dilute H2SO4, the organic layer separated, and the aqueous phase extracted with 2×100 mL CH2Cl2. These extracts were pooled, washed with dilute H2SO4, and the solvent was removed under vacuum yielding a residue that was distilled. Two distillation cuts were taken at 0.3 mm/Hg. The first fraction boiled at 110–138 °C and weighed 0.7 g and was discarded. The second fraction came over at 148–178 °C and weighed 3.0 g. By thin layer chromatography this fraction was about 80% pure, and was used as such in the following reduction. A small sample was ground under methyl cyclopentane yielding white crystals of 3,5-dimethoxy-4-n-propylthiophenylacetonitrile with a mp of 35.5–37.5 °C.
A solution of LAH in THF (15 mL of a 1 M solution) under N2 was cooled to 0 °C and vigorously stirred. There was added, dropwise, 0.4 mL 100% H2SO4, followed by 2.7 g 3,5-dimethoxy-4-n-propylthiophenylacetonitrile dissolved in 10 mL anhydrous THF. The reaction mixture was stirred at 0 °C for a few min, then brought to a reflux for 30 min on the steam bath. 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 converted the aluminum oxide to a loose, white, filterable consistency. This was removed by filtration and washed with both THF and 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 aqueous NaOH, extracted with 3×75 mL CH2Cl2, the extracts pooled, and the solvent removed under vacuum. The residue was distilled at 137–157 °C at 0.3 mm/Hg to give 1.3 g of a colorless oil. This was dissolved in 10 mL of IPA, neutralized with 20 drops of concentrated HCl and, with continuous stirring, diluted with 50 mL anhydrous Et2O. The product was removed by filtration, washed with Et2O, and air dried to give 1.4 g of 3,5-dimethoxy-4-n-propylthiophenethylamine hydrochloride (TP) as bright white crystals with a mp of 164–165 °C. Anal. (C13H22ClNO2S) C,H.
DOSAGE: 20–25 mg.
DURATION: 10–15 h.
QUALITATIVE COMMENTS: (with 18 mg) “There was very little effect until more than two hours, when I came inside out of the cold and jumped to an immediate +1. It is hard to define, and I am quite willing to have it develop more, and if not, quite willing to go higher next time. I got into several quite technical conversations, but through it all I was aware of a continuous alteration. There was a drop at the seventh hour, and nothing at all was left at twelve hours.”
(with 27 mg) “My body feels heavy. This is not a negative thing, but it is there. I feel a heavy pressure at the back of the neck, which is probably unresolved energy. The nervous system seems to be somehow vunerable. Towards the end of the experience I considered a Miltown, but settled on an aspirin, and I still couldn’t sleep for about 24 hours. The imagery is extremely rich and there is quite a bit of eyes-open visual, but mostly eyes closed. I think the rewards are not worth the body price. Sometime again, maybe lower?”
EXTENSIONS AND COMMENTARY: There is a high potency here, but clearly there are signs of increased toxicity as well even over the ethyl homologue, . The butyl compound (see ) was the last of this series of phenethylamines and as is noted there, the physical problems lessen, but so do the psychedelic properties. The three-carbon amphetamine homologues are completely unexplored. The most reasonable starting material for these would be 4-thiosyringaldehyde, with S-alkylation and then the conventional nitroethane coupling followed with LAH reduction. The most appealing target as a potential psychedelic would be the methylthio homologue (3,5-dimethoxy-4-methylthioamphetamine, 3C-TM) or, as a potential euphoriant, the butylthio homologue (3,5-dimethoxy-4-n-butylthioamphetamine, 3C-TB). I am not sure that these alkylthio analogues would justify the labor needed to make them.
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.
Transform Press,
Box 13675
Berkeley, CA 94701

510 · 934 · 4930 (voice)
510 · 934 · 5999 (fax)