1.2.3- Thiadiazole metallation

Bond angles and lengths obtained from ab initio calculations on 1,2,3-thiadiazole 1 are presented in Table 1 <1991JOM309> and can be compared to values for 4-phenyl-l,2,3-thiadiazole 10 obtained by X-ray diffraction (Section 5.07.3.1). kb initio calculations were also carried out for the ring protonated at N-2 and N-3. These calculations reveal that N-2 is the preferred site of protonation by almost 9kcalmol 1. This parallels the preferred site of metal coordination to 1,2,3-thiadiazoles found in several studies <1996CHEC-II(4)289>. 

One study found that metalation of 5-phenyl-l,2,3-thiadiazole 43 with methyllithium gives 4-lithio-5-phenyl-l,2,3-thiadiazole, which is stable and reacts with aldehydes and ketones in high yields (Equation 11) <1985S945>. 

Electrophilic reactions of 1,2,4-thiadiazoles are very limited. The parent base forms salts with mineral acids, forms a methiodide, and also gives addition compounds with heavy metal salts. 

Thiadiazoles are weak bases. They form salts with mineral acids and addition compounds with heavy-metal salts. Methylation of 5-amino-l,2,4-thiadiazoles 17 leads to the product of methylation at the 4-position 18 (Equation 2) <1996CHEC-II(4)307>. More recently, the reaction of the 3-methylthio derivative 19 with methyl iodide led to methylation at N-4 to afford product 20 (Equation 3) <2001CHE1005>. 

Reactions of 1,2,4-thiadiazoles with radicals and carbenes are virtually unknown. Catalytic hydrogenations and dissolving metal reductions usually cleave the N-S bond in a reversal of the oxidative cyclization procedures used in synthesis of 1,2,4-thiadiazoles (see Section 5.08.9.4). 

Metal derivatives of 1,2,4-thiadiazoles have not been reported, presumably, because of their instability toward bases. 

There are few examples of metal complexes reacting with 1,2,3-thiadiazoles to form stable products one case involves the formation of the 2-substituted derivative (23) with tungsten penta-carbonyl (Equation (9)) <83CB230>. Reaction of simple 1,2,3-thiadiazoles with peracid occurs preferentially at N3 to give an A-oxide <84CHEC-I(6)447>. 

Ring protons of 1,2,3-thiadiazoles are known to undergo rapid deuterium exchange under basic conditions, yet to date there have been no published estimates or experiments to determine the pA of these protons. Few attempts have even been made to metalate and alkylate this heterocycle. One study <85S945> found that metalation of 5-phenyl-1,2,3-thiadiazole (25) with methyllithium gives 4-lithio-5-phenyl-l,2,3-thiadiazole, which is stable and reacts with aldehydes and ketones in high yields (Equation (11)). Also, treatment of 4-phenyl-1,2,3-thiadiazole with lithium diisopropylamide, in the presence of TMS-Cl, affords 4-phenyl-5-trimethylsilyl-1,2,3-thiadiazole. 

Metallation of the 1,2,4-thiadiazole ring is not known to date, presumably because of its instability to base. 

Metallation of 3,4-dimethyl-l,2,5-thiadiazole (55) to the anion (56) was accomplished with the use of a nonnucleophilic base, lithium diisopropylamide <82JHC1247>. Nucleophilic attack at sulfur resulted in an alkyllithium reagent <70CJC2006>. The lithiomethyl derivative (56) was carboxylated to (57) with carbon dioxide and converted to the vinyl derivative (58) via an esterification, reduction, mesylation, and base elimination sequence (Scheme 12). 

Thiadiazoles having one or two thio groups in the 2- and/or 5-positions react with metals to form bidentate ligands they are widely used as antioxidants. An interesting reaction of mesoionic (95) with acetylene dicarboxylate is the formation of thiophene (97) via the intermediate (96) (Scheme 15) <84CHEC-I(4)545>. 

A greatly improved experimental procedure for the synthesis of thieno[2,3-d]-1,2,3-thiadiazole caiboxylates 68 was reported by Stanetty et al. and involved diazotisation of aminothiophene derivatives 67 <99JHC761>. In these systems, substituents could be introduced into the 5-position by nucleophilic displacement of a chlorine atom or by metallation of the unsubstituted compound (68 R = H) and subsequent electrophilic quenching <99JPR391>. 

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