6-(2-Aminopropyl)-5-methoxy-1,3-benzoxathiol · 2-Methoxy-4,5-methylenethiooxyamphetamine
#167 4T-MMDA-2 SYNTHESIS: To a well-stirred solution of 120 g thiourea in 800 mL2 NHCl, there was added a solution of 100 g benzoquinone in 500 mL acetic acid over the course of 15 min. Stirring was continued for an additional 0.5 h at room temperature, and then the reaction mixture was heated on the steam bath for 1 h. With cooling in ice water, a heavy crop of crystals separated. These were removed by filtration and air dried to provide 90.1 g of 5-hydroxy-1,3-benzoxathiol-2-one (2-mercaptohydroquinone cyclic carbonate ester) with a melting point of 170.5–172.5 °C.
To a suspension of 100 g finely powdered anhydrous K2CO3 in 400 mL acetone containing 50 g methyl iodide there was added 41 g 5-hydroxy-1,3-benzoxathiol-2-one, and the mixture stirred overnight at room temperature. The solids were removed by filtration, and the solvent removed under vacuum. The residue was distilled to give a fraction subliming over as a solid at an oven temperature of 110 °C at 0.1 mm/Hg. This was a yellowish solid, weighing 27.4 g and having a mp of 66–72 °C. Recrystallization from MeOH gave 5-methoxy-1,3-benzoxathiol-2-one as a white solid with a mp of 75.5–76.5 °C.
To a solution of 30 g 85% KOH in 75 mL warm H2O, there was added an equal volume of warm MeOH followed by 16 g 5-methoxy-1,3-benzoxathiol-2-one, and the mixture was held under reflux conditions for 2 h. After cooling to room temperature, the mix was acidified with HCl and extracted with 2×100 mL CH2Cl2. Removal of the solvent from the pooled extracts gave a yellow oil that crystallized on standing. The product, 2-mercapto-4-methoxyphenol, weighed 14 g and had a mp of 56–57 °C.
A solution of 10 g 2-mercapto-4-methoxyphenol in 100 mL MEK was added over the course of 1 h to a vigorously stirred suspension of 25 g finely powdered anhydrous K2CO3 in 200 mL MEK that contained 14 g methylene bromide. The reflux was maintained for 48 h. After cooling, the mixture was freed of solids by filtration and the filter cake washed with 50 mL additional MEK. The combined washes and filtrate were stripped of solvent under vacuum, and the product distilled to give 3.3 g of 5-methoxy-1,3-benzoxathiol as a yellowing oil that had a bp of 110–120 °C at 1.7 mm/Hg. There was considerable residue in the pot, which was discarded. The NMR spectrum was excellent, with the methylene protons a two-hydrogen singlet at 5.6 ppm.
To a mixture of 3.2 g POCl3 and 2.8 g N-methylformanilide that had been heated briefly on the steam bath (to the formation of a deep claret color) there was added 2.3 g 5-methoxy-1,3-benzoxathiol, and steam bath heating was continued for an additional 5 min. The reaction mixture was poured into 100 mL H2O, and after a few minutes stirring, the insolubles changed to a loose solid. This was collected by filtration, H2O washed and, after sucking as dry as possible, recrystallized from 30 mL boiling MeOH. This provided 1.9 g of 6-formyl-5-methoxy-1,3-benzoxathiol as brownish needles that melted at 119–120 °C.
A solution of 1.5 g 6-formyl-5-methoxy-1,3-benzoxathiol in 50 mL nitroethane was treated with 0.3 g anhydrous ammonium acetate and heated on the steam bath for 5 h. Removal of the solvent under vacuum gave a residue that crystallized. This was recrystallized from 110 mL boiling EtOH providing, after filtering and air drying, 1.3 g 5-methoxy-6-(2-nitro-1-propenyl)-1,3-benzoxathiol as San Francisco Giants-orange-colored crystals.
A solution of AH was prepared by the treatment of a solution of 1.3 g LAH in 10 mL THF, at 0 °C and under He, with 0.8 mL 100% H2SO4. A solution of 1.1 g of 5-methoxy-6-(2-nitro-1-propenyl)-1,3-benzoxathiol in 25 mL THF was added dropwise, and the stirring was continued for 1 h. After a brief period at reflux, the reaction mixture was returned to room temperature, and the excess hydride destroyed by the addition of IPA. The salts were converted to a filterable mass by the addition of 5% NaOH and, after filtering and washing with IPA, the combined filtrate and washings were stripped of solvent under vacuum. The residue was dissolved in dilute H2SO4 which was washed with 3×75 mL CH2Cl2 and then, after being made basic with 25% NaOH, the product was extracted with 2×75 mL CH2Cl2. The extracts were pooled, and the solvent removed under vacuum. Distillation of the residue gave a fraction that boiled at 140–155 °C at 0.3 mm/Hg which weighed 0.7 g. This was dissolved in 4 mL IPA, neutralized with 14 drops of concentrated HCl, heated to effect complete solution, then diluted with 10 mL of anhydrous Et2O. The white crystals that formed were removed, Et2O washed, and air dried to give 0.6 g 6-(2-aminopropyl)-5-methoxy-1,3-benzoxathiol hydrochloride (4T-MMDA-2).
DOSAGE: greater than 25 mg.
DURATION: unknown.
QUALITATIVE COMMENTS: (with 25 mg) “At three hours after having taken the material, I felt that there might have been a little exhilaration. And maybe a hint of tremor and of teeth clench. Perhaps this is a threshold dose.”
EXTENSIONS AND COMMENTARY: There is no logical way to try to guess where the active level of this might be. In a comparison of 4-oxy with 4-thio- and with 4-alkyl (as, for example, , and ) the analogue with the sulfur atom lies intermediate in potency between the oxygen atom and the carbon atom. Then, perhaps, 4T-MMDA-2 should be somewhat more potent than . Which is where the trials have gone to, and the absence of effects therefore declares that line of reasoning invalid. What else could be used for clues? The whole benzofuran project, which had the same cyclic nature, was without activity. They had a carbon where the sulfur was of 4T-MMDA- 2, so, by that reckoning, this compound should be even less active. Maybe that is the formula to follow. The bottom line is inescapable. None of these extrapolations can hold a candle to the only experiment that can give believable findings, the actual trial of a new compound in man.
The positional isomer of the heterocyclic carbonate used here is also known. Instead of using benzoquinone as a starting material with thiourea as the sulfur source (giving the 1,4- oxygen orientation), one can start with resorcinol in reaction with ammonium thiocyanate as the sulfur source (in the presence of copper sulfate) and get the positional isomer with a 1,3- oxygen orientation. This material (also known as thioxolone, or tioxolone, or 6-hydroxy-1,3-benzoxathiol-2-one, and which is commercially available) should follow the same chemistry shown here for the 5-hydroxy analogue, and give 5T-MMDA-2 (5-(2-aminopropyl)-6-methoxy-1,3-benzoxathiole or 2-methoxy-5,4-methylenethiooxyamphetamine) as a final product. I would guess, based on the findings that compare with , that this would be a relatively low-potency compound. At least it should be an easy one to make!
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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