#125 META-DOT SYNTHESIS: To 27 g 1,3-dimethoxybenzene that was being well stirred, there was added, dropwise, 29 g concentrated H2SO4 over a period of 15 min. Stirring was continued for 1 hour, and then the mixture was poured slowly into 250 mL of saturated aqueous K2CO3. The precipitate that formed was removed by filtration, and dried at 125 °C to give 59.6 g crude potassium 2,4-dimethoxybenzenesulfonate. This was finely ground, and 30 g of it was treated with 35 g of POCl3 and the mixture heated on the steam bath for 2 h. This was cooled to room temperature, and then poured over 300 mL crushed ice. When all had thawed, this was extracted with 2×150 mL Et2O. The extracts were pooled, washed with saturated brine, and the solvent removed under vacuum to give a residue which solidified. There was thus obtained 14.2 g 2,4-dimethoxybenzenesulfonyl chloride as white solids with a mp of 69–72 °C. Heating of a small portion with concentrated ammonium hydroxide gave the corresponding sulfonamide which, on recrystallization from EtOH, produced white needles with a mp of 165.5–166.5 °C.
To a stirred and gently refluxing suspension of 11 g LAH in 750 mL anhydrous Et2O, there was added 13.2 g 2,4-dimethoxybenzenesulfonyl chloride in an Et2O solution. The refluxing was maintained for 48 h then, after cooling externally with ice water, the excess hydride was destroyed by the slow addition of 600 mL of 10% H2SO4. The phases were separated, and the aqueous phase extracted with 2×200 mL Et2O. The organics were pooled, washed once with 200 mL H2O, and the solvent removed under vacuum. The residue was dried azeotropically through the addition and subsequent removal of CH2Cl2. Distillation of the residue provided 8.0 g 2,4-dimethoxythiophenol as a colorless oil, boiling at 89–92 °C at 0.5 mm/Hg.
To a solution of 7.8 g 2,4-dimethoxythiophenol in 40 mL absolute EtOH there was added a solution of 4 g 85% KOH in 65 mL EtOH. This was followed by the addition of 5 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 8.0 g of 2,4-dimethoxythioanisole as a colorless oil with a bp of 100–103 °C at 0.6 mm/Hg.
To a mixture of 15 g POCl3 and 14 g N-methylformanilide that had been warmed briefly on the steam bath there was added 7.8 g of 2,4-dimethoxythioanisole. The 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 boiling MeOH. The product, 2,4-dimethoxy-5-(methylthio)benzaldehyde, was an off-white solid weighing 8.6 g. It could be obtained in either of two polymorphic forms, depending on the concentration of aldehyde in MeOH at the time of crystal appearance. One melted at 109–110 °C and had a fingerprint IR spectrum including peaks at 691, 734, 819 and 994 cm-1. The other melted at 124.5–125.5 °C and had major fingerprint peaks at 694, 731, 839 and 897 cm-1. Anal. (C10H12O3S) C,H.
A solution of 8.2 g 2,4-dimethoxy-5-(methylthio)benzaldehyde in 30 mL nitroethane was treated with 1.8 g anhydrous ammonium acetate and heated on the steam bath for 4 h. Removal of the excess nitroethane under vacuum gave a colored residue which crystallized when diluted with MeOH. Recrystallization of the crude product from boiling EtOH gave, after filtration, washing and air drying to constant weight, 8.3 g 1-(2,4-dimethoxy-5-methylthiophenyl)-2-nitropropene with a mp of 112–113 °C. Anal. (C12H15NO4S) C,H,N.
A suspension of 6.5 g LAH in 250 mL anhydrous THF was placed under a N2 atmosphere and stirred magnetically and brought to reflux. There was added, dropwise, 8.0 g of 1-(2,4-dimethoxy-5-methylthiophenyl)-2-nitropropene in 50 mL THF. The reaction mixture was maintained at reflux for 18 h. After being brought to room temperature, the excess hydride was destroyed by the addition of 6.5 mL H2O in 30 mL THF. There was then added 6.5 mL of 3 N NaOH, followed by an additional 20 mL H2O. The loose, white, inorganic salts were removed by filtration, and the filter cake washed with an additional 50 mL THF. The combined filtrate and washes were stripped of solvent under vacuum yielding a residue that was distilled. The free base boiled at 125–128 °C at 0.1 mm/Hg and was a white oil which solidified on standing. It weighed 5.1 g and had a mp of 47–48.5 °C. This was dissolved in 50 mL IPA, neutralized with concentrated HCl (until dampened universal pH paper showed a deep red color) and diluted with anhydrous Et2O to the point of turbidity. There was a spontaneous crystallization providing, after filtering, washing with Et2O, and air drying, 2,4-dimethoxy-5-methylthioamphetamine hydrochloride (META-DOT) with a mp of 140.5–142 °C. Anal. (C12H20ClNO2S) C,H,N.
DOSAGE: greater than 35 mg.
DURATION: unknown.
QUALITATIVE COMMENTS: (with 35 mg) “There was a vague awareness of something all afternoon, something that might be called a thinness. Possibly some brief cardiovascular stimulation, but nothing completely believable. This is a threshold level at the very most.”
EXTENSIONS AND COMMENTARY: Again, as with the studies with , it is apparent that the activity of META-DOT is going to be way down from the most interesting of these isomers, (ALEPH-1, or just ). In the rectal hyperthermia assay (which calculates the psychedelic potential of compounds by seeing how they influence the body temperature of experimental animals in comparison to known psychedelics) the three DOT’s were compared with . And the results fell into line in keeping with the activities (or loss of activities) found in man. was about half as active as DOM, but both ORTHO-DOT and the compound described here, META-DOT, were down by factors of 50× and 30× respectively. These animal studies certainly seem to give results that are reasonable with a view to other known psychedelic drugs, in that was down from DOM by a factor of more than 1000×, and was some 33× more potent than DOM.
I have a somewhat jaundiced view of this rabbit rectal hyperthermia business. One is presumably able to tell whether a compound is a stimulant or a psychedelic drug by the profile of the temperature rise, and how potent it will be by the extent of the temperature rise. But the concept of pushing thermocouples into the rear ends of restrained rabbits somehow does not appeal to me. I would rather determine both of these parameters from human studies.
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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