2-Mercapto-5-methyl-l,3,4-thiadiazole

Tautomerism was reviewed quite extensively in CHEC(1984) <1984CHEC(6)545> and CHEC-II(1996) <1996CHEC-II(4)379>. The tautomeric ability of the 2-mercapto-5-methyl-l,3,4-thiadiazole 9 was studied by its reaction with the electrophilic Cl3 FnCSCl <2003JP01>. 2-Mercapto-5-methyl-l,3,4-thiadiazole 9 was considered to exist mainly as the thione tautomer however, electrophilic substitution occurred on the thiol (Scheme 1). 

High-vacuum pyrolysis of 2,5-dimercapto-l,3,4-thiadiazole 34 and 2-mercapto-5-methyl-l,3,4-thiadiazole 9 performed between ambient and 800 °C gave products that were trapped by matrix-isolation techniques and characterized by IR spectroscopy. Pyrolysis of the dimercaptothiadiazole 34 gave HNCS, CS2, and HCN (Equation 2), whereas the thiadiazolethione 9 showed a more complex fragmentation pattern forming HNCS, CH3NCS, HCN, and CS2 (Equation 3) <2002J(P2)1620>. 

Halogenation of 2-methyl-l,3,4-thiadiazole 9 can be achieved under free radical conditions. Trichloro- and tribromomcthyl-l, 3,4-thiadiazolcs have been obtained by this method <1980LA1216>. Rapid and selective free radical monochlorination of the 2-mercapto-5-methyl-l,3,4-thiadiazole 9 was achieved using sodium hypochlorite under microwave conditions (Equation 27) <1998JCM586>. 

The mechanism of the oxidation of 2-mercapto-5-methyl-l,3,4-thiadiazole (McMT) to its disulfide dimer and its subsequent reduction was examined with a combined approach employing experimental data and digital simulation. To elucidate the influence of proton transfers on these redox processes, special attention was paid to the influence of various bases and proton donors on both the oxidation and reduction reactions. In particular, McMT oxidation is facilitated by a rapid bimolecular proton transfer from McMT to weak bases such as pyridine that produces McMT , the thiol-ate form, which is then oxidized. There is no such facilitation in the presence of the sterically hindered base 2,6-di-r-butylpyridine, suggesting that the facilitation occurs through the formation of a discrete hydrogen-bonded complex/ ... 

Reaction of sodio 7-aminocephalosporanic acid with l-(lH)-tetrazoylacetic acid gave intermediate 27. Reaction of this last with 2-mercapto-5-methyl-1,3,4-thiadiazole led to the widely used parenteral cephalosporin, cefazolin (28). 

Methazolamide Methazolamide, N-(4-methyl-2-sulfamoyl-l,3,4-thiadiazol-5-yliden) acetamide (21.2.3), is made by an intermediate product of acetazolamide synthesis— 2-acetylamino-5-mercapto-l,3,4-thadiazol (9.7.3). This is benzylated with benzylchloride at the mercapto group, forming 2-acetylamino-5-benzylthio-l,3,4-thiadiazole (21.2.1). Further methylation of the product with methyl iodide leads to the formation of N-(4-methyl-2-benzylthio-l,3,4-thiadiazol-5-yliden)acetamide (21.2.2). Oxidation and simultaneous chlorination of the resulting product with chlorine in an aqueous solution of acetic acid, and reacting the resulting chlorosulfonic derivative with ammonia gives (21.2.3) [5-7]. 

Potential 2-hydroxy- and 2-mercapto-l,3,4-thiadiazoles have been examined both by infrared and by ultraviolet spectra in the solid state and in solution by Sheinker et They concluded that these compounds exist in the 2-oxo and 2-thione forms, respectively. To 2,5-dimercapto-l,3,4-thiadiazole the 2-mercapto-5-thione structure (155) was given. The structure of this compound has been the subject of some controversy. Stanovnik and TiSler have added some valuable arguments to the discussion. They measured the pKfl values of 155, its iV-methyl, iV -phenyl, and iV -phenyl-/S-methyl derivatives (156), and of the conjugate acids of these and the S-methyl derivative (pKn ) (Table III). In all compounds 156 with R = H, the infrared spectrum showed an absorption band near 2300 cm characteristic of the SH group. They also had pK i values near —1.5, Avhich in connection with the infrared evidence was taken as characteristic of an SH group in this situation. Since the 2,5-dithiol structure is excluded by ultraviolet spectral evidence, the 2-mercapto-5-thione structure (155) seems rather well established. It has previously been shown bj Thorn to predominate in chloroform solution, whereas he concluded that the dithione form (157) should predominate in ethanol solution. However, the pK i value for 155, — 1.36, makes it rather probable that Thorn used the monoanion of 155 instead of the acid itself for spectral comparison, and in that case his conclusions have a very weak foundation. 

Physical Properties of 1,3,4-Thiadiazoles. Ultraviolet spectra of some 2-benzylideneamino-5-phenyl-1,3,4-thiadiazoles have been reported. The n.m.r. spectral properties and conformational preferences of some open-chain and cyclic aromatic sulphides that contain 1,3,4-thiadiazole units, spectroscopic data of metal (Mn, Fe, Co, Ni, Cu, or Zn) chelates of iV-(5-phenyl-l,3,4-thiadiazol-2-yl)dithiocarbamic acids, conductometric and i.r. and Raman determinations on thirteen complexes of Zn, Cd, or Hg with 2-methyl-5-mercapto-1,3,4-thiadiazole, and thermogravimetry of some noble- and common-metal chelates of 5-amino-l,3,4-thiadiazole-2-thiol were also described, as well as the mass-spectral fragmentation of 2-phenyl-... 

Acetamido-5-mercapto-l, 3,4-thiadiazole is prepared as described under acetazolamide. This on treatment with/>-chlorobenzyl ehloride forms the corresponding />-chloro benzyl mercapto derivative, which when reacted with methyl bromide in the presenee of sodium methoxide yields the acetylamino thiadiazoline derivative. On oxidation with aqueous ehlorine it gives rise to the 2-sulphonyl chloride derivative which finally yields methazolamide on amidation with ammonia. 

The reaction of hydroxamoyl chlorides with hydrazine has also been investigated and hydrazide-oximes XXIX (. 69 obtained. However, the hydrazine derivative XXX yields N-substituted 2-amino-5-methyl-mercapto-l,3,4-thiadiazoles XXXI upon reaction with hydroxamoyl chlorides ( ). 

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 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). 

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,... 

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). 

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-... 

The interaction of sodium perthiocyanate (438) and suitable bifunctional dihalides readily produces polymers (444) which are claimed to be useful catalysts in the production of polyurethane foams. The use of l,4-di(chloro-methyl)benzene in ethanol, for example, gives 444 (R = p-CH2C6H4CH2, terminating in p-CH2C6H4CH2OEt, mol wt 2960) in 90% yield.354 5-Mercapto-3-methylthio-1,2,4-thiadiazole yields the tin-containing derivatives 445 (R = Bu, Ph, or cyclohexyl n = 1-3) on treatment with alkyltin halides in tetrahydrofuran.355... 

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