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#172 5-TOM


[3D .mol structure]
SYNTHESIS: To a solution of 6.6 g KOH pellets in 100 mL hot EtOH there was added a solution of 15.4 g methylthio-m-cresol (3-methyl-4-(methylthio)phenol, Crown-Zellerbach Corporation) in 25 mL EtOH. This was followed by the addition of 17 g methyl iodide, and the mixture was held at reflux on the steam bath for 16 h. The reaction mixture was poured into 400 mL H2O, acidified with HCl, and extracted with 4x50 mL CH2Cl2. These were pooled, washed with 3x50 mL 5% NaOH, once with dilute HCl, and then the solvent was removed under vacuum. The residue was 3-methyl-4-(methylthio)anisole, a clear pale yellow oil, weighing 12.7 g. Distillation at 150-160 °C at 1.7 mm/Hg, or at 80-90 °C at 0.25 mm/Hg, did not remove the color, and gave a product with no improvement in purity.

To a mixture of 82 g POCl3 and 72 g N-methylformanilide that had been heated on the steam bath for 10 min, there was added 33.6 g 3-methyl-4-(methylthio)phenol, and heating was continued for an additional 2 h. This was poured into 1.2 L H2O, producing a brown gummy crystalline mass that slowly loosened on continued stirring. This was filtered off, washed with additional H2O, and sucked as dry as possible. This was finely ground under 60 mL of cold MeOH, refiltered, and air dried to give 17.8 g of a nearly white crystalline solid with a mp of 94-96 °C. Recrystallization from 50 mL boiling MeOH gave a product of higher purity, but at some cost in yield. With this step there was obtained 13.4 g of 2-methoxy-4-methyl-5-(methylthio)benzaldehyde with a mp of 98-99 °C. An additional recrystallization from IPA increased this mp by another degree. From this final recrystallization, a small amount of material was left as an insoluble residue. It was also insoluble in acetone, but dissolved readily in CH2Cl2. It melted broadly at about 200 °C and was not identified. Proof of the structure of 2-methoxy-4-methyl-5-(methylthio)benzaldehyde was obtained by its successful reduction (with amalgamated Zn in HCl) to 2,5-dimethyl-4-(methylthio)anisole. This reference convergence compound was prepared separately from 2,5-dimethylanisole which reacted with chlorosulfonic acid to give the 4-sulfonyl chloride derivative, which was in turn reduced to the 4-mercapto derivative (white crystals from MeOH, with a mp of 38 °C sharp). This, upon methylation with methyl iodide and KOH in MeOH, gave 2,5-dimethoxy-4-(methylthio)anisole (white crystals from MeOH, with a mp of 67-68 °C). The two samples (one from the aldehyde reduction, and the other from this independent synthesis), were identical in all respects.

A solution of 1.9 g 2-methoxy-4-methyl-5-(methylthio)benzaldehyde in 40 mL nitroethane was treated with 0.5 g anhydrous ammonium acetate and heated under reflux, with stirring, with a heating mantle for 3.5 h, at which time TLC analysis showed no unreacted aldehyde and only a trace of slow moving materials. Removal of the excess nitroethane under vacuum gave a yellow plastic film (the wrapping of the magnetic stirrer had dissolved off) which was extracted first with 35 mL boiling MeOH, then with 2x35 mL boiling IPA. Separately, the MeOH extract and the combined IPA extracts, on cooling, deposited 0.6 g each of fluffy needles. The mother liquors were combined and allowed to evaporate to about 15 mL final volume, providing another 0.4 g crude product. All three samples melted at 101-102 °C. These were combined, and recrystallized from 50 mL boiling MeOH to provide, after filtering and air drying, 1.4 g of 1-(2-methoxy-4-methyl-5-methyl-thiophenyl)-2-nitropropene as bright yellow crystals with a mp of 102-102.5 °C. Anal. (C12H15NO3S) C,H.

A solution of 2.0 g LAH in 100 mL anhydrous THF was cooled, under He, to 0 °C with an external ice bath. With good stirring there was added 1.28 mL 100% H2SO4 dropwise, to minimize charring. This was followed by the addition of 1.35 g 1-(2-methoxy-4-methyl-5-methylthiophenyl)-2-nitropropene in 50 mL anhydrous THF over the course of 5 min. After a few min further stirring, the temperature was brought up to a gentle reflux on the steam bath, and then all was cooled again to 0 °C. The excess hydride was destroyed by the cautious addition of 5 mL IPA followed by sufficient 5% NaOH to give a white granular character to the oxides, and to assure that the reaction mixture was basic (about 5 mL was used). The reaction mixture was filtered, and the filter cake washed first with THF and then with IPA. The combined filtrate and washings were stripped of solvent under vacuum and the residue dissolved in 150 mL dilute H2SO4. This was washed with 3x50 mL CH2Cl2 (the color stayed in the organic layer), made basic with aqueous NaOH, and extracted with 2x50 mL CH2Cl2. After the solvent was removed under vacuum, the residue was distilled at 110-125 °C at 0.4 mm/Hg to give 0.9 g of a colorless oil. This was dissolved in 4 mL IPA, neutralized with about 11 drops of concentrated HCl, and then diluted with 20 mL anhydrous Et2O. After about a ten second delay, white crystals formed. These were removed by filtration and air dried, to give 0.6 g of 2-methoxy-4-methyl-5-methylthioamphetamine hydrochloride (5-TOM) as white crystals with a mp of 156-157 °C. A second crop obtained from the mother liquors on standing weighed 0.3 g and melted at 150-156 °C. Anal. (C12H20ClNOS) C,H.

DOSAGE: 30 - 50 mg.

DURATION: 6 - 10 h.

QUALITATIVE COMMENTS: (with 35 mg) There was an awful lot of visual activity, and in general I found the day quite good, once I got past the early discomfort.

(with 40 mg) I knew that I was sinking into a deep reverie after an hour into it. I was not totally unconscious since I seemed to respond to external stimuli (at least most of the time). But I certainly wasn't all that much there. The exper-ience dominated completely. At one point (perhaps the peak?) I remember seeing a very quiet sea with a horizontal shoreline and a clear sky. This image seemed to come back rather frequently. At other times I would see a set of disjointed horizontal lines on this beach. These lines reminded me of spectral lines. For a short period of time I thought they were some kind of expression of my energy levels that I didn't understand. In retrospect, I suspect the horizontal lines were only expressions of how my mind was reacting to the material. I don't remember talking to anyone until I had started to come down from the experience. I eventually could see real images, but they were greatly distorted. It was as if I was looking at Cubism paintings by Picasso, having intense and strange colorations. As I came back into the real world, I realized that I had had an extraordinary trip. I had not been afraid at any time. The experience seemed unique, but quite benign. The experience for my fellow travelers was probably much more anxious. I wasn't particularly interested in food when I came down. I slept well. I was quite lethargic the next day. It really took me another day to integrate back into normal life. Would I repeat it? Possibly, but at a way smaller dose.

(with 50 mg) The body was complete whacked, and the mental simply didn't keep up with it. There was some early nausea going into it, and my sinuses never cleared, and I somehow became irritable and angry. In fact, the impatience and grimness lasted for a couple of days. There were some visual events that might have been interesting to explore, but too much other stuff got in the way.

(with 50 mg) There was much eyes-closed fantasy, and quite a bit of it with erotic undertones. In efforts to direct my actions, I found it difficult to find the point of initiation of a task. Reading and writing both impossible. I am somehow de-focused. But art work became quite rewarding. The experience was heavy going in, but rich coming out. Good dosage.

EXTENSIONS AND COMMENTARY: The bottom line is that 5-TOM is a pretty heavy-duty experience, with more negative reports than positive ones. I have received no mentions of a completely ecstatic time, and not even very many neutral experiences. The consensus is that it wasn't worth the struggle. Some cramping, some nausea, and a generalized discomfort. And that one case of a catatonic response. An approach to possible individual variation in the metabolic handling of the sulfur atom is the rationale for the preparation of the compound TOMSO, and it is discussed there.

The two-carbon homologue of 5-TOM has been prepared. It uses, of course, the same aldehyde, but the condensation was with nitromethane which yielded the nitrostyrene as an orange powder with a melting point of 118-119 °C from methanol. This was reduced with LAH in ether containing anhydrous AlCl3, giving 2-methoxy-4-methyl-5-methylthiophenethylamine hydrochloride as white crystals with a melting point of 257-258 °C. It has been named 2C-5-TOM, but it has not yet been entered into the screening program so it is pharmacologically still a mystery.

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