Szimmavy N-Acetyl-u,L-penicillamine (1) was converted by HNO, into a thionitrite (3) which was stable as a solid and atypically so even in solution; X-ray structural parameters are given for (3), and both homolytic and heterolytic reactions are described.

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The progress of the rearrangement could be followed easily by the shift of the carbonyl absorption in the infrared spectrum from the thiol ester position (5.95 p in the case of the acetate esters) to the amide position a t about 6.15 p . I n most cases the amide was isolated by direct distillation, the polythioformaldehyde remaining undistilled, m.p. 185-190".L6 The infrared and n.m.r. spectra of the latter were identical with those of an authentic sample.In the presence of base, a typical thiolsulfonate reacts readily and completely with a thiol to form a disulfide and a sulfinic acid salt even a t -86". In the absence of base, fairly rapid reaction occurs, which proceeds only part way, but can be pushed toward completion by use of excess thiol or thiolsulfonate. Steric factors significantly affect reactivity of thiolsulfonates, more so than do electronic effects noted thus far. As ancillary points, gas-liquid chromatography was investigated for qualitative and quantitative analysis of thiols, and a tertiary alkyl thiolsulfonate was synthesized, apparently for the first time.(1) (a) This investigation was supported by the U. S.

Synthesis is reported of 2-amino-5-mercapto-5-methylhexanoic acid (2) as a bishomologue of penicillamine (1). In this synthesis, alkylation of diethyl acetamidomalonate gave ethyl 2-acetamido-2-carbethoxy-5-methyl-4-hexenoate (4). Addition of -toluenethiol to 4 using BF3-Et20 then gave ethyl 2-acetamido-2-carbethoxy-5-benzylthio-5-methylhex.anoate (6) in 63-74% yield; this reaction appears to be the first use of BFg-EtaO as a catalyst for effecting Markownikoff-type addition of a thiol to an alkene. The bishomologue 2 was obtained from 6 either by decarboxylation to the amide (5), debenzylation of 5 to 7, and hydrolysis, or (preferably) by decarboxylation and hydrolysis to the amino acid 8 in one step and debenzylation. The bishomologue 2 resisted hot strong acid. It reacts with formaldehyde, Fe(III), or Cu(II) much less readily than does 1 and therefore affords a promising means of probing biological properties of 1 where it is unclear whether these properties depend upon ring formation involving SH and NH2 or upon independent action of functional groups.

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2,5-Dimercaptoterephthalic acid was prepared by four routes to permit assessment of their relative merits for a bifunctional system and to permit confirmation of structures of useful intermediates through interconnections of the routes (Scheme I). The routes were: (I) conversion of the phenol to the , -bisthiocarbamate, rearrangement of this to the S,S-bisthiocarbamate, then saponification; (II) cleavage of 2,5-bisbenzyl thioether moieties of the terephthalate diester, then saponification; (III) reaction of potassium hydrosulfide with 2,5dibromoterephthalic acid; and (IV), route II but with the acid instead of the ester. 2-Mercaptoterephthalic acid was prepared by similar routes for the same reasons.Both the mono-and dimer capto acids reacted with aminoalkyl thiolsulfonates to give unsymmetrical aminoalkyl disulfides (Scheme II). Several products of Schemes I and II are of interest for further chemical studies and, particularly, for biological evaluation as antiradiation drugs, against histoplasmosis, or against schistosomiasis.

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For study of the chemistry of an amino acid derived hydrodisulfide (10, Me2C(SR)CH(NHAc)C02Me, R = SH), a synthetic route to a hydrodisulfide derivative of TV-acetyl-DL-penicillamine was developed. Conversion of IV-acetyl-DL-penicillamine (3) to the ester (4, R = H) was accomplished with diazomethane. With acetylsulfenyl chloride, 4 gave the acetyl sulfide (5, R = Ac) instead of the disulfide (7, R = SAc). With (methoxycarbonyl)sulfenyl chloride, 4 gave the corresponding unsymmetrical disulfide (8, R = SC02Me), which could not be converted to the hydrodisulfide. Conversion of 4 to the sulfenyl iodide (9, R = I) and treatment with thioacetic acid regenerated 4. With acetyl methoxycarbonyl disulfide, however, 4 gave the acetyl disulfide 7. Methanolysis of 7 then gave the hydrodisulfide 10. Solutions of 10 in chloroform were unchanged after 6 days at room temperature and 1 day at 55 °C and then consumed the expected amount of iodine. Washing with bicarbonate led to immediate decomposition; neat 10 completely decomposed during storage at -10 °C for 36 h, and the half-life of 10 in HCl-methanol was about 12 h. Treatment of 10 with cyanide ion gave thiocyanate ion, and treatment with 2,4-dinitrochlorobenzene gave a dinitrophenyl derivative [13, R = 2,4-(N02)2C6H3S] identical with 13 prepared from 4 by using 2,4-dinitrobenzenesulfenyl chloride.