#139 ORTHO-DOT SYNTHESIS: To 26.4 g veratrol that was being magnetically stirred without any solvent, there was added 50 g chlorosulfonic acid a bit at a time over the course of 20 min. The reaction was exothermic, and evolved considerable HCl. The deeply colored mixture that resulted was poured over 400 mL crushed ice and when all had thawed, it was extracted with 2×150 mL CH2Cl2. Removal of the solvent under vacuum gave a residue that set up as a crystalline mass. The weight of the crude 3,4-dimethoxybenzenesulfonyl chloride was 37.1 g and it had a mp of 63–66 °C. Recrystallization raised this to 72–73 °C. Reaction with ammonium hydroxide gave the sulfonamide as colorless needles from EtOH, with a mp of 132–133 °C.
The finely pulverized 3,4-dimethoxybenzenesulfonyl chloride (33 g) was added to 900 mL of crushed ice in a 2 L round-bottomed flask equipped with a heating mantle and reflux condenser. There was then added 55 mL concentrated H2SO4 and, with vigorous mechanical stirring, there was added 50 g of zinc dust in small portions. This mixture was heated until a vigorous reaction ensued and refluxing was continued for 1.5 h. After cooling to room temperature and decantation from unreacted metallic zinc, the aqueous phase was extracted with 3×150 mL Et2O. The pooled extracts were washed once with saturated brine and the solvent was removed under vacuum. The residue was distilled to give 20.8 g of 3,4-dimethoxythiophenol boiling at 86–88 °C at 0.4 mm/Hg.
A solution of 10 g 3,4-dimethoxythiophenol in 50 mL absolute EtOH was protected from the air by an atmosphere of N2. There was added a solution of 5 g 85% KOH in 80 mL EtOH. This was followed by the addition of 6 mL methyl iodide, and the mixture was held at reflux for 30 min. This was poured into 200 mL H2O and extracted with 3×50 mL Et2O. The pooled extracts were washed once with aqueous sodium hydrosulfite, then the organic solvent was removed under vacuum. The residue was distilled to give 10.3 g of 3,4-dimethoxythioanisole with a bp of 94–95 °C at 0.4 mm/Hg. The product was a colorless oil that crystallized on standing. Its mp was 31–32 °C.
To a mixture of 15 g POCl3 and 14 g N-methylformanilide that had been warmed briefly on the steam bath there was added 8.2 g of 3,4-dimethoxythioanisole, the exothermic reaction was heated on the steam bath for an additional 20 min, and then poured into 200 mL H2O. Stirring was continued until the insolubles had become completely loose and granular. These were removed by filtration, washed with H2O, sucked as dry as possible, and then recrystallized from 100 mL boiling EtOH. The product, 4,5-dimethoxy-2-(methylthio)benzaldehyde, was an off-white solid, weighing 8.05 g and having a mp of 112–113 °C. Anal. (C10H12O3S) C,H.
A solution of 2.0 g 4,5-dimethoxy-2-(methylthio)benzaldehyde in 8 mL nitroethane was treated with 0.45 g anhydrous ammonium acetate and heated on the steam bath for 4.5 h. Removal of the excess solvent under vacuum gave a red residue which was dissolved in 5 mL boiling MeOH. There was the spontaneous formation of a crystalline product which was recrystallized from 25 mL boiling MeOH to give, after cooling, filtering and air drying, 1.85 g of 1-(4,5-dimethoxy-2-methylthiophenyl)-2-nitropropene as bright orange crystals with a mp of 104–105 °C. Anal. (C12H15NO4S) C,H,N.
A suspension of 1.3 g LAH in 50 mL anhydrous THF was placed under an inert atmosphere and stirred magnetically. When this had been brought to reflux conditions, there was added, dropwise, 1.65 g of 1-(4,5-dimethoxy-2-methylthiophenyl)-2-nitropropene in 20 mL THF. The reaction mixture was maintained at reflux for 18 h. After being brought back to room temperature, the excess hydride was destroyed by the addition of 1.3 mL H2O in 10 mL THF. There was then added 1.3 mL of 3 N NaOH followed by an additional 3.9 mL H2O. The loose, inorganic salts were removed by filtration, and the filter cake washed with additional 20 mL THF. The combined filtrate and washes were stripped of solvent under vacuum yielding a light yellow oil as a residue. This was dissolved in 20 mL IPA, neutralized with 0.9 mL concentrated HCl, and diluted with 200 mL anhydrous Et2O. There was thus formed 1.20 g of 4,5-dimethoxy-2-methylthioamphetamine hydrochloride (ORTHO-DOT) as a pale yellow crystalline product. This melted at 218–219.5 °C, and recrystallization from EtOH yielded a white product and increased the mp to 222–223 °C with decomposition Anal. (C12H20ClNO2S) C,H,N.
DOSAGE: greater than 25 mg.
DURATION: unknown.
QUALITATIVE COMMENTS: (with 25 mg) “Vague awareness, with the feeling of an impending something. Light food sat uncomfortably. By the late afternoon there was absolutely nothing. Threshold at best.”
EXTENSIONS AND COMMENTARY: This material, ORTHO-DOT, can be looked at as the sulfur homologue of with the sulfur atom located in place of the oxygen at the 2-position of the molecule. At what level this compound might show activity is completely unknown, but wherever that might be, it is at a dosage greater than that for the isomer, ALEPH-1 (or ), which was fully active at 10 milligrams (ALEPH can be looked at as TMA-2 with the sulfur atom located in place of the oxygen at the 4-position of the molecule). A lot of variations are easily makable based on this structure, but why bother? ALEPH is the much more appealing candidate for structural manipulation.
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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