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#12 BIS-TOM

4-METHYL-2,5-bis-(METHYLTHIO)AMPHETAMINE

SYNTHESIS: A solution of 9.0 g 2,5-dibromotoluene in 50 mL petroleum ether was magnetically stirred under a He atmosphere. To this there was added 50 mL of a 1.6 M hexane solution of butyllithium, and the exothermic reaction, which produced a granular precipitate, was allowed to stir for 12 h. The mixture was cooled to 0 °C and there was then added 7.5 g dimethyldisulfide. There was a heavy precipitate formed, which tended to become lighter as the addition of the disulfide neared completion. After 20 min additional stirring, the reaction mixture was poured into H2O that contained some HCl. The phases were separated and the aqueous phase extracted with 50 mL Et2O. The organic phase and extract were combined, washed with dilute NaOH, and then with H2O. After drying over anhydrous K2CO3, the solvent was removed under vacuum and the residue distilled to give a fraction that boiled at 75-85 °C at 0.3 mm/Hg and weighed 5.3 g. This was about 80% pure 2,5-bis-(methylthio)toluene, with the remainder appearing to be the monothiomethyl analogues. A completely pure product was best obtained by a different, but considerably longer, procedure. This is given here only in outline. The phenolic OH group of 3-methyl-4-(methylthio)phenol was converted to an SH group by the thermal rearrangement of the N,N-dimethylthioncarbamate. The impure thiophenol was liberated from the product N,N-dimethylthiolcarbamate with NaOH treatment. The separation of the phenol/thiophenol mixture was achieved by a H2O2 oxidation to produce the intermediate 3-methyl-4-methylthiophenyldisulfide. This was isolated as a white crystalline solid from MeOH, with a mp of 78-79 °C. Anal. (C16H18S4) C,H. It was reduced with zinc in acetic acid, and the resulting thiophenol (a water-white liquid which was both spectroscopically and microanalytically correct) was methylated with methyl iodide and KOH in MeOH to give the desired product, 2,5-bis-(methylthio)toluene, free of any contaminating mono-sulfur analogues.

A solution of 3.9 g of 2,5-bis-(methylthio)toluene in 20 mL acetic acid was treated with a crystal of iodine followed by the addition of 3.5 g elemental bromine. This mixture was heated on the steam bath for 1 h, which largely discharged the color and produced a copious evolution of HBr. Cooling in an ice bath produced solids that were removed by filtration. Recrystallization from IPA gave 1.9 g of 2,5-bis-(methylthio)-4-bromotoluene as a white crystalline solid with a mp of 133-134 °C. Anal. (C9H11BrS2) C,H. An alternate synthesis of this intermediate was achieved from 1,4-dibromobenzene which was converted to the 1,4-bis-(methylthio)benzene (white crystals with a mp of 83.5-84.5 °C) with sodium methylmercaptide in hexamethylphosphoramide. This was dibrominated to 2,5-dibromo-1,4-bis-(methylthio)benzene in acetic acid (white platelets from hexane melting at 195-199 °C). This, in Et2O solution, reacted with BuLi to replace one of the bromine atoms with lithium, and subsequent treatment with methyl iodide gave 2,5-bis-(methylthio)-4-bromotoluene as an off-white solid identical to the above material (by TLC and IR) but with a broader mp range.

A solution of 2.4 g 2,5-bis-(methylthio)-4-bromotoluene in 100 mL anhydrous Et2O, stirred magnetically and under a He atmosphere, was treated with 10 mL of a 1.6 M solution of butyllithium in hexane. After stirring for 10 min there was added 2.5 mL N-methylformanilide which led to an exothermic reaction. After another 10 min stirring, the reaction mixture was added to 100 mL dilute HCl, the phases were separated, and the aqueous phase extracted with 2x50 mL Et2O. The combined organic phase and extracts were dried over anhydrous K2CO3, and the solvent removed under vacuum. The partially solid residue was distilled at 140-150 °C at 0.2 mm/Hg to give a crystalline fraction that, after recrystallization from 15 mL boiling IPA gave 2,5-bis-(methylthio)-4-methylbenzaldehyde as a yellow-brown solid which weighed 1.1 g and had a mp of 107-109 °C. An analytical sample from MeOH melted at 110-111 °C with an excellent IR and NMR. Anal. (C10H12OS2) C,H. An alternate synthesis of this aldehyde employs the 2,5-bis-(methylthio)toluene described above. A CH2Cl2 solution of this substituted toluene containing dichloromethyl methyl ether was treated with anhydrous AlCl3, and the usual workup gave a distilled fraction that spontaneously crystallized to the desired aldehyde but in an overall yield of only 11% of theory.

To a solution of 0.5 g 2,5-bis-(methylthio)-4-methylbenzaldehyde in 15 mL nitroethane there was added 0.15 g anhydrous ammonium acetate and the mixture was heated on the steam bath for 1 h. The excess solvent was removed under vacuum and the residue was dissolved in 10 mL boiling MeOH. This solution was decanted from a little insoluble residue, and allowed to cool to ice bath temperature yielding, after filtering and drying to constant weight, 0.55 g of 1-[2,5-bis-(thiomethyl)-4-methylphenyl]-2-nitropropene as pumpkin-colored crystals with a mp of 90-91 °C. This was not improved by recrystallization from EtOH. Anal. (C12H15NO2S2) C,H.

A cooled, stirred solution of 0.5 g LAH in 40 mL THF was put under an inert atmosphere, cooled to 0 °C with an external ice bath, and treated with 0.42 mL 100% H2SO4, added dropwise. A solution of 0.5 g 1-[2,5-bis-(thiomethyl)-4-methylphenyl]-2-nitropropene in 20 mL anhydrous THF was added over the course of 5 min, and the reaction mixture held at reflux for 30 min on the steam bath. After cooling again to ice temperature, the excess hydride was destroyed by the addition of IPA and the inorganics were converted to a loose, white filterable form by the addition of 1.5 mL 5% NaOH. These solids were removed by filtration and the filter cake was washed with 2x50 mL IPA. The combined filtrate and washings were stripped of solvent under vacuum to give a residue that was a flocculant solid. This was suspended in dilute H2SO4 and extracted with 2x50 mL CH2Cl2, and the combined organics extracted with 2x50 mL dilute H3PO4. The aqueous extracts were made basic, and the product removed by extraction with 2x75 mL CH2Cl2. After removal of the solvent under vacuum, the residue was distilled at 126-142 °C at 0.2 mm/Hg to give 0.2 g of product which crystallized in the receiver. This was dissolved in 1.5 mL hot IPA, neutralized with 4 drops of concentrated HCl, and diluted with 3 mL anhydrous Et2O to give, after filtering and air drying, 0.2 g. of 2,5-bis-(methylthio)-4-methylamphetamine hydrochloride (BIS-TOM) as white crystals with a mp of 228-229 °C. Anal. (C12H20ClNS2) C,H.

DOSAGE: greater than 160 mg.

DURATION: unknown.

QUALITATIVE COMMENTS: (with 160 mg) I was vaguely aware of something in the latter part of the afternoon. A suggestion of darting, physically (when going to sleep), but nothing at the mental level. This is as high as I will go.

EXTENSIONS AND COMMENTARY: It is reasonable, in retrospect, to accept that BIS-TOM is not an active compound. The replacement of the 2-position oxygen of DOM with a sulfur atom (to give 2-TOM) dropped the potency by a factor of 15x, and the replacement of the 5-position oxygen with a sulfur atom (to give 5-TOM) dropped the potency by a factor of about 10x. It would be a logical calculation that the replacement of both oxygen atoms with sulfur might drop the potency by a factor of 150x. So, with DOM being active at maybe 5 milligrams, a logical prediction of the active level of BIS-TOM would be 750 milligrams. And maybe this would be the right level, but with the hints of neurological disturbance that seemed to be there at 160 mg, there was no desire to go up by a factor of five again. The rewards would simply not be worth the risks.

The 2-carbon analogue, 2C-BIS-TOM, was prepared from the intermediate aldehyde above, first by reaction with nitromethane to give the nitrostyrene as tomato-colored crystals from EtOAc, mp 145-146 °C. Anal. (C11H13NO2S2) C,H. This was reduced with AH to give 2,5-bis-(methylthio)-4-methylphenethylamine hydrochloride as ivory-colored crystals with a mp of 273-277 °C.

Although there are many interesting psychedelic drugs with sulfur atoms in them (the TOM's, the TOET's, the ALEPH's and all of the 2C-T's), there just aren't many that contain two sulfur atoms. BIS-TOM bombed out, and 2C-BIS-TOM remains untried, but will probably also fail, as the phenethylamines are rarely more potent than the corresponding amphetamines. This leaves 2C-T-14 as the remaining hope, and its synthesis is still underway.

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