Chloro-thiadiazoles

The use of isothioureas (67 R = S-alkyl) similarly affords 3-alkyl-thio-5-chloro-l, 2,4-thiadiazoles (69 R = S-alkyl) in 35-65% yields.89,91 The method is widely applicable and has provided a variety of 5-chloro -1,2,4-thiadiazoles.9 2 9 4... 

The ingenious general synthesis of 1,2,4-thiadiazoles from amidino compounds and tri-, di-, and monochloromethanesulfenyl chlorides has been employed repeatedly since its original development by Goerdeler and his co-workers.3,119 By far the greatest number of these applications has involved the use of the fully chlorinated methyl mercaptan, resulting in 5-chloro-1,2,4-thiadiazoles. 

The replacement of 5-chloro substituents by oxygen functions has been effected by the use of ethylene glycol and its homologs,125 126 glyddol (2-hydroxymethyloxiran),308 and sodium phenoxide.309 Prolonged treatment of 3-substituted 5-chloro-1,2,4-thiadiazoles with boiling acetic add yields the corresponding A2-l,2,4-thiadiazolin-5-ones.310... 

Nucleophilic replacement of a 5-bromo by an isothiourea group and careful alkaline hydrolysis of the resulting 5-alkylthiouronium salt is a method of preparing l,2,4-thiadiazole-5-thione unsubstituted in its 3-position. An alternative procedure314 is the successive treatment of 5-chloro-1,2,4-thiadiazoles with trisodium thiophosphate, and add-catalyzed decomposition of the intermediate salt [HetSPO(ONa)2] in situ 15 5-Chloro-l,2,4-thiadiazoles are also a useful source of 5-alkyl and -aryl sulfones and 5-alkyl and -aryl thiols these are readily obtainable by the action of the appropriate sodium sulfinates or thiols.316-318 The action of... 

The cyclocondensation of amidines with trichloromethylsulfenyl chloride furnishes 5-chloro-1,2,4-thiadiazoles 4 ... 

Reactivity towards nucleophilic reagents is not very high. 1,2,5-Oxadiazoles, and 1,2,3- and 1,2,4-thiadiazoles are subject to ring cleavage. Halogenated compounds such as 5-chloro-1,2,4-thiadiazole, 3(5)-chloro-1,2,4-triazole and 5-chlorotetrazole undergo nucleophilic substitution reactions. 

The chlorine in 5-chloro-l,2,3-thiadiazole is displaced by methoxide ion <1974JHC343>. 

Chloro-l,2,3-thiadiazole-4-carboxamides 38 react with the sodium salt of diethyl malonate to give the corresponding malonic acid derivatives 39. The yield in these reactions falls as the electron-releasing properties of the 4-substituents in the aromatic ring increase (Equation 8) <1997JCM396>. 

The c-fused chloro benzimidazo[l,2-c][l,2,3]thiadiazole 9 can undergo nucleophilic displacements with secondary amines heating compound 9 with morpholine affords the adduct 42 (Equation 10) <2003TL6635>. 

A novel series of a-substituted phenoxy-A-methyl-l,2,3-thiadiazole acetamides 51 is obtained through nucleophilic substitution of the chloro compound 50 with several phenols, and the resultant phenoxy derivatives were evaluated against heptatitis B vims (HBV) (see Section 5.07.12) (Equation 13) <2003JHC925>. 

Chloro-3-methylthio-l,2,4-thiadiazol-2-ium salts 51 have undergone nucleophilic displacement with a variety of nitrogen and carbon nucleophiles to give bicyclic compounds such as 52. The substitution reaction and cyclization... 

The use of the dehydrating agent 2-chloro-l,3-dimethylimidazolinium chloride (DMC) in combination with DMSO for the preparation of 1,2,4-thiadiazoles via a type A synthesis has been published. Excellent yields >90% are reported along with a mechanism for the transformation <1999JOC6989>. 

The preparation of 5-chloro-l,2,4-thiadiazol-2-ium chlorides 95 by treatment of formimidoyl isothiocyanates 94 with a twofold excess of methanesulfenyl chloride has been reported in an unusual variation of a type C synthesis. These salts show interesting chemical behavior toward several nitrogen and carbon nucleophiles. The nature of the N-substituent determines the stability of the salt 95. When the substitutent on nitrogen is /-butyl, the salt 95 decomposes readily in solution to give the 5-chloro-l,2,4-thiadiazole 96 (Scheme 10) <2003HAC95>. 

A useful method for the synthesis of 5-chloro-l,2,4-thiadiazoles 125 is the reaction of amidines with trichloromethyl-sulfenyl chloride (Equation 34). 

Unsymmetrical 3,4-dihalo-l,2,5-thiadiazoles 118 and 119 were prepared from 3-amino-4-chloro-l,2,5-thiadiazole 117 via a Sandmeyer-like reaction involving successively tert-butyl nitrite and either copper bromide or copper iodide in anhydrous acetonitrile (Scheme 17) <2003H(60)29>. The bromo and iodo thiadiazoles 118 and 119 undergo selective Stille and Suzuki C-C coupling chemistry (see Section 5.09.7.6). 

Chlorophenyl)-4-phenyl-l,2,5-thiadiazole 128 was prepared from 3-trifluoromethylsulfonyloxy-4-phenyl-1,2,5-thiadiazole 127 by palladium-catalyzed cross-coupling reaction with the tributyl(4-chlorophenyl)stannane (Equation 20) <1996H(43)2435>. The addition of lithium chloride improves the yield. The 3-chloro- and 3-bromo-l,2,5-thiadiazole derivatives were also reactive, but only the bromo compound gave the product in comparable yield (see Section 5.09.7.6). 

O-Alkylation of 4-hydroxy-3-morpholino-l,2,5-thiadiazole 132 has been achieved with the chiral cyclic chloro-methyl sulfite 133 which subsequently suffers ring opening on treatment with simple alcohols <2001RCB436> or alkylamines <2002RJ0213> to afford the timolol analogues 134 with very little racemization (Scheme 20). This indicated an almost exclusive attack of the oxy anion on the exocyclic carbon atom and is a significant improvement on the previous oxirane method, which suffers from racemization. An alternative biocatalytic asymmetric synthesis of (A)- and (R)-timolol has also appeared <2004S1625>. 

The only example of this kind is the thermal isomerization of 1-cyanocyclopentyl-iminosulfur dichloride into 3-chloro-4-(4-chlorobutyl)-l,2,5-thiadiazole. The reaction has been previously reviewed in CHEC(1984) <1984CHEC(6)513, 1973JOU2522>. 

The reaction between 2-oximino acetonitriles 183 and disulfur dichloride was used to prepare several 3-chloro-4-alkyl-l,2,5-thiadiazoles for muscarinic agonist studies <1995USP5418240, 1998H(48)2111, 1996EJM221,... 

JME538, 1997CH739>. The main thiadiazole product 185, however, suffered chlorination in the a-position. The isolation of 2-amino acrylonitrile 184 from the reaction mixture supported decomposition of the 2-oximino acetonitrile 183 furthermore, treatment of the pure acrylonitrile under typical reaction conditions gave exclusively ot-chloro-3-chloro-l,2,5-thiadiazole 185 (Scheme 27 Table 11). Mechanisms explaining the formation of both thiadiazoles were proposed <1998H(48)2111>. 

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