3- Mercapto-l,2,4-thiadiazoles

Oxidative cyclization of dithiobiuret under basic conditions provides bis(5-amino-l,2,4-thiadiazolyl)-3,3 -disulfide 92 via oxidative dimerization of the intermediate 5-amino-3-mercapto-l,2,4-thiadiazole 91. However, alkylation of disulfide 91 under basic conditions gives the thioalkyl-l,2,4-thiadiazole 93 (Scheme 9) <2003H(60)1401>. 

The unstable sodium salt of 5-chloro-3-mercapto-l,2,4-thiadiazole (336)151 reacts also with cyanogen bromide forming 5-chloro-3-thio-cyanato-l,2,4-thiadiazole (337).202 The sparingly soluble neutral sodium salt of 5-hydroxy-3-thiocyanato-l,2,4-thiadiazole (339) is similarly obtained (336->338->339) its free acid, like other 5-hydroxy-l,2,4-thiadiazoles, is fairly strong, but unstable.202... 

PhCH2), obtained in their turn by treatment of 3-alkyl(or aralkyl) thio-5-chloro-l,2,4-thiadiazoles (344 R = Me or PhCH2) with ammonium sulfide.91 Additional support in favor of structure 340 for perthiocyanic acid is the alternative production of its disodium salt (343) from 5-chloro-3-mercapto-l,2,4-thiadiazole (344 R = Na) and sodium sulfide.151... 

The mercury salt of 3-mercapto-l,2,4-thiadiazole (mercuric 1,2,4-thiadia-zole 3-thiolate) is obtainable by cleaving the corresponding disulfide with mercury, and is convertible to the unstable sodium 3-thiolate by the action of sodium sulfide.315... 

The direct exploitation of known reactions has provided 1,2,4-thiadiazole-5-thiones, substituted 5-amino-3-mercapto-l,2,4-thiadiazoles, and 5-(substituted)amino-3-trichloromethy 1-1,2,4-thiadiazoles."... 

Amino and 5-amino-l,2,4-thiadiazoles both exist predominantly in the amino forms. The IR spectrum of 5-mercapto-l,2,4-thiadiazole does not show a clear SH absorption as would be expected for structure 6 and therefore the thione tautomers 7 and 8 have been suggested (Scheme 2). Similarly, IR evidence suggests that perthiocyanic acid exists as the dithione 9 as opposed to stmcture 10 <1984CHEC(6)463>. 

The enhanced reactivity of 5-halogeno-l,2,4-thiadiazoles over 3-halogeno-l,2,4-thiadiazoles has been mentioned before (see Section 5.08.7.1). Nucleophilic substitution at this center is a common route to other 1,2,4-thiadiazoles, including 5-hydroxy, alkoxy, mercapto, alkylthio, amino, sulfonamido, hydrazino, hydroxylamino, and azido derivatives. Halogens in the 3-position of 1,2,4-thiadiazoles are inert toward most nucleophilic reagents, but displacement of the 3-halogen atom can be achieved by reaction with sodium alkoxide in the appropriate alcohol <1996CHEC-II(4)307>. 

Amidines and amidoximes react with carbon disulfide and a mixture of carbon disulfide and sulfur to afford 5-mercapto-l,2,4-thiadiazole derivatives (see Section 5.08.9.3). 

Mercapto-l,2,4-thiadiazoles are distinctly acidic. The pK of 5-thio-3-methyl-l,2,4-thiadiazole at 25°C is 5.18 <65AHC(5)119>. The position of equilibrium in the tautomers of 5-thio-l,2,4-thiadiazoles (10) (R = H) appears to be on the thione side (11) or (12). The solid state IR spectrum of (10) (R = Ph) shows no sign of SH absorption <92PS(66)32i>. However, treatment of (10) (R = Ph, / -Tol) with diazomethane does not produce any A-methylated products, but only the 5-methyl derivatives (137) (R = Ph, /)-Tol). Methylation of (10) (R = Ph) with methyl sulfate and with methyl iodide in sodium hydroxide gives only the S-methyl derivatives (137) (Scheme 31) <92PS(66)321>. In 1989 Yousef et al. reported that (10) (R = Ph) reacted with aromatic sulfenyl chlorides and with formaldehyde to give the A-substituted products (26) and (27) (Scheme 31). At the same time, alkylation... 

Amidines are converted into 1,2,4-thiadiazoles by reaction with isothiocyanates, iminosulfenyl chlorides, di- and trichloromethyl sulfenyl chlorides, and carbon disulfide in the presence of sulfur <82AHC(32)285> for example, 5-mercapto-3-methyl-l,2,4-thiadiazole (205) is obtained by the treatment of acetamidine with carbon disulfide and sulfur under basic conditions (Equation (29)) <85JAP85255783>. A useful method for the synthesis of 5-chloro-l, 2,4-thiadiazole (206) (R = 6-methyl-2-pyridyl) involves the reaction of amidines with trichloromethylsulfenyl chloride (Equation (30)) <91JAP9183590>. 

The conversion of 5-amino-3,5-diphenyl-1,2,4-oxadiazoline (48) into 5-mercapto-3-phenyl-l,2,4-thiadiazole (47)78 under the influence... 

The action of methylthiol in ammoniacal methanol yields 5-methyl-thio derivatives91 the symmetrical bis(3-methylthio-l,2,4-thiadiazol-5-yl)sulfide (165) is thus accessible from the appropriate 5-mercapto and 5-chloroheterocycles91 (see also ref. 168). 

Mercapto-3-phenyl-l,2,4-thiadiazole is stable, but is completely degraded by hydrochloric acid at 150°.71 It forms characteristic salts with metals, e.g. the crystalline mercury salt.71,72,190... 

The action of aniline on 3-phenyl-5-mercapto-l,2,4-thiadiazole under restrained conditions is reported to remove the mercapto group as hydrogen sulfide, with formation of the corresponding 5-anilino compound.75,200 This replacement, normally difficult in aromatic systems, may be due to the unusual reactivity of the thiol grouping in this particular structural environment. 

Alkylation of mercapto groups in 1,2,4-thiadiazoles proceeds normally.71, 72 The reaction has provided authentic specimens of 3,5-di-methyl(or dibenzyl)mercapto-l,2,4-thiadiazoles, the identity of which with the /S-alkylation products of perthiocyanic acid provided evidence concerning the structure of the latter compound90 (see Section III,... 

Mono- and di-thiocyanato-1,2,4-thiadiazoles, obtained by the stepwise action of cyanogen bromide on barium 3,5-dimercapto-l,2,4-thiadiazole, and on 5-chloro- and 5-hydroxy-3-mercapto-1,2,4-thiadiazole, are somewhat labile. The structures of certain of their transformation products (e.g. mono- and di-sulfides), which may have one of several isomeric forms, are not fully elucidated. The reactivity of their cyano group, resembling that in cyanogen halides, is noteworthy it is easily removed by the action of alkalis, the parent thiol being regenerated.202... 

Amidines (282 R = H) also condense with carbon disulfide in the presence of sulfur to produce 5-mercapto-l,2,4-thiadiazoles (17) in reasonable yields, as indicated in Scheme 101 (68BRP1116198). A general method for the synthesis of 5-chloro-l,2,4-thiadiazoles (289 X = Cl) involves the reaction of amidines with trichloromethylsulfenyl chloride (288 X = Cl) in the presence of a base under mild conditions (Scheme 102) (65AHC(5)119). A variety of 3-substituted thiadiazoles (118) are obtained when dichloromethylsulfenyl chloride (288 X = H) is used in this reaction. 

The properties of mercapto-l,2,4-thiadiazoles, particularly those of the interesting 3,5-dimercapto compound (perthiocyanic add) have been established in fair detail for some time3 recent work has in the main been supplementary in nature. Attention is drawn to the extensive use of 5-mercapto-l,2,4-thiadiazoles in the production of cephalosporin derivatives this is briefly reviewed separately at the end of this Section. 

The action of trifluorobutenyl bromide (CF2=CFCH2CH2Br) on 3-phenyl-5-mercapto-l,2,4-thiadiazole and numerous analogs produces 5-(3,4,4-trifluoro-3-butenyl)thio derivatives (435), which are useful nema-tocides.344 The 5-alkylthio compound (436) is the product of the S-alkylation using l-(/ -chloro-2,4-dichlorophenetyl)imidazole.345 The formation of the monosulfide (437) from 3-isopropyl-5-mercapto-1,2,4-thiadiazole occurs under standard conditions.346... 

Methyl(and phenyl)-5-mercapto-l,2,4-thiadiazoles are converted by chloromethyl thiocyanate to the thiomethyl thiocyanates (RSCH2SCN) and are thence oxidized to the corresponding sulfinyl and sulfonyl thiocyanates with 3-chloroperoxybenzoic acid or hydrogen peroxide.347 3-Alkyl-... 

Chlorolysis. The action of chlorine on mercapto-l,2,4-thiadiazoles yields sulfenyl chlorides, sulfonyl chlorides, or chloro compounds, depending on the nature of the starting materials and the experimental conditions.147 Thus treatment of 3-tert-butylthio-l,2,4-thiadiazole with one mole of chlorine yields bis(l,2,4-thiadiazol-3-yl) disulfide (446) as a stable colorless solid. An excess of chlorine converts this to the 3-sulfonyl chloride (447), and further, with loss of sulfur dioxide, to the 3-chloro compound (448). Under appropriate conditions, the chlorolysis (to 448) may be performed in one operation (45%). The 3-sulfonyl chloride (447) yields sulfonamides nearly quantitatively the 3-chloro substituent in 448 is relatively inert (see Section IV.B).147... 

In rubber technology, the use of mercapto-l,2,4-thiadiazoles for several purposes507-510 has been described. Both monomeric511 and polysulfide structures512 are suitable rubber cross-linking agents. Polyethylene sheet is stabilized and protected by the addition (0.5%) of 2,4-dimethyl-l,2,4-thia-diazolidine-3,5-dithione.513 Poly(thiadiazolyl tetrasulfide) similarly stabilizes poly(vinylpyridines).514... 

Scheme 44 also shows two further synthetic routes to [l,3,4]thiadiazolo[2,3-c][l,2,4]triazinones. Reaction of the 3-mercapto- or 3-methylsulfanyltriazinone 221 (R1 = H or R1 = Me) with a set of isothiocyanates was reported to give the 2-amino-substituted fused ring system 222 in medium to good yield (36-84%) <1997JHC1351>. Derivative 223 was described to undergo cyclization to a fused thiadiazole 224 by treatment with carbon disulfide in the presence of potassium hydroxide in ethanol <2001PHA376>. 

The IR spectrum in Nujol of l,2,4-thiadiazolidine-3,5-dithione indicates that the dithione structure (18a) predominates. However, the dithione can be readily dialkylated on sulfur. Thus, treatment with 2,3-dichloropropene in aqueous sodium hydroxide forms (208 Scheme 73) (65AHC(5)119). The disulfenamide (209) condenses with aldehydes and ketones to give the corresponding imines (210) and (211 Scheme 74) (74ZOB2553). 5-Mercapto-3-methyl-thio-l,2,4-thiadiazole (212) reacts with di- -butyltin chloride in THF to give di-n-butyltin derivative (213 Scheme 75) (72USP3634442). 

In 1821 Wohler discovered that a solid deposited from concentrated aqueous solutions of thiocyanic acid. The solid, which was called isoperthiocyanic acid (3-imino-5-mercapto-1,2,4-dithiazole) (361), formed a new product perthiocyanic acid (3,5-dimercapto-l,2,4-thiadiazole) (18) when treated with alkali and then acid. On storage perthiocyanic acid (18) readily reverted to isoperthiocyanic acid (361) (65AHC(5)119). The mechanisms of these interconversions are still not known with certainty but the transformations outlined in Scheme 130 are suggested. Wohler proposed the initial formation of a dimer of thiocyanic acid for which structure (359) appears resonable. Addition of the imine function of (359) to the nitrile function of HSCN would produce the trimer (360) which could readily eliminate hydrogen cyanide to produce isoperthiocyanic acid (361). 

The reaction of oxalyl hydrazide with aryl isothiocyanate gives the bis(thiosemicarbazide) (162) which under acidic conditions cyclizes to the bis(l,3,4-thiadiazole) (163). Under alkaline conditions the 5-mercapto-l,2,4-triazole (164) is obtained (77BSB399). 

Atnino-5-thiot l,2,4 thiadiazole. See 5-Amino,2-mercapto-l, 3,4-lfa iadiazo le... 

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