Synthesis of isothiazoles by ring-formation

Nitrile sulfides are well suited for the synthesis of isothiazoles incorporating the C=N-S unit via their 1,3-dipolar cycloaddition reactions with double or triple-bonded dipolarophiles. Benzonitrile sulfide 210 is readily prepared from decarboxylation of oxathiazolone 209 using microwave irradiation 05SC807 . Subsequent cycloadditions to dimethyl acetylene-dicarboxylate (DMAD) and dimethyl fumarate afford 211 and 212, respectively. In the case of ethyl propiolate, a 1 1 regioisomeric mixture of phenylisothiazoles 213 and 214 is obtained. 

A tetrabutylammonium fluoride (4 equiv of Bu4NF)-promoted reaction between ortho-trimethylsilyl-phenyliodonium triflates 215 and dialkyl-aminothiazadienes 216 provides a novel approach to 3-substituted benzisothiazoles 219 05H(65)1615 . Interestingly, when 

5 equiv of TBAF is used, the same reaction furnishes only benzothiazines 222. Formation of isothiazoles 219 presumably involves the trapping of a benzyne intermediate by a nitrile sulfide 218 generated in situ at high concentration of fluoride ion. 

The more frequently used methods for construction of isothiazoles (and its partially or completely saturated analogs) consist of cyclization of compounds containing preformed N-C-C-C-S fragments with a S-N bond coimection. For example, 4,6-dinitrobenzisothiazole 225 is prepared from sulfenyl chloride 224 upon treatment with ammonia 05MC200 . Further functionalization at 4-position is achieved by nucleophilic replacement at the 4-nitro group. 

Af-Aroylisothiazolium imines 230 are prepared by cyclocondensation of thiocyano-butenals 227 with aryl hydrazides 228 05H(65)2705 . These imines are oxidized, and the resulting hydroperoxy sultams are reduced to give hydroxysultams 231. Under thermal conditions, these sultams undergo dehydration followed by 1,5-electrocyclization to give a novel series of heteropentalenes, the oxadiazolo-sultams 233. 

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