1.2- Benzisothiazole 4-chloro

Benzisothiazole, 4-chloro-nitration, 6, 154 nucleophilic reactions, 6, 154 synthesis, 6, 169... 

Isothiazolium salts (59) react with phenylhydrazine to give pyrazoles (60) (72AHC(14)l) (see Section 4.02.1.6). When treated with hydrazine hydrate, 3-chloro-l,2-benzisothiazole gives di-(o-cyanophenyl) disulfide (73SST(2)556), but 2,1-benzisothiazole gives o-aminobenz-aldehyde azine (72AHC( 14)43). 2-Substituted saccharins give the expected o-sulfamoyl-benzohydrazides. 

Chloro-l,2-benzisothiazole reacts with sodium cyanide to give a mixture containing mainly o-cyanophenyl thiocyanate with some di-(o-cyanophenyl) disulfide. An 80% yield of the latter was obtained using cuprous cyanide in DMF (73SST(2)556). 

Hydroxy and mercapto substituents at the 3- and 5-positions can also exist in tautomeric forms (see Section 4.01.5.2) and can be alkylated at either the substituent or the ring nitrogen atom. 3-Methoxy groups are not replaced by nucleophiles, but both 3- and 5-alkylthio groups react readily, as does 3-methoxy-l,2-benzisothiazole. Alkylthio compounds can be oxidized to sulfoxides and sulfones, and the latter readily undergo nucleophilic replacement. All the hydroxy compounds react with phosphorus pentachloride to give the chloro derivatives. 

Chloroisothiazoles and 3-chloro-l,2-benzisothiazoles are less reactive, and the more vigorous conditions necessary for replacement often cause ring cleavage. Halogens at all positions can be replaced by cyano groups (see Section 4.02.3.9). 

Bromination follows a similar course, except that 2,1-benzisothiazole produces the 4,5,7-tribromo derivative when excess of reagent is used (72AHC(14)43), and 3,5-disubstituted 1,2-benzisothiazoles are brominated at the 4-position (80JCR(S)197). 7-Amino-4-chloro-l,2-benzisothiazole is brominated at the 6-position (71JCS(C)3994). 

Benzisothiazoles can be prepared by the reaction of aromatic chloro compounds with sulfur and ammonia. Thus, 2,6-dichlorobenzylidene chloride gives 4-chloro-l,2-benzisothiazole (72AHC(14)43), and 2-chlorobenzophenone gives 3-phenyl-l,2-benziso-thiazole (79GEP27 34866). 

CN 5-[2-[4-(l,2-Benzisothiazol-3-yl)-l-piperazinyl]ethyl]-6-chloro-l,3-dihydro-2//-indol-2-one hydrochloride hydrate... 

The first synthesis of ziprasidone was disclosed by Lowe and Nagel in a patent issued to Pfizer in 1989. Initially, the left-hand fragment of ziprasidone, 3-benzisothiazolylpiperazine (40), was prepared according to the method of Yevich and coworkers (Scheme 12). The amide 38 was treated with phosphorous oxychloride to give 3-chloro-l,2-benzisothiazole (39). Compound 39 was then reacted with molten piperazine at 125 °C to provide piperazine 40 in 68% yield. 

Benzo[6]thiophene-2,3-quinones are reported to undergo several interesting transformations. Oxidation of 5-chIorobenzo[6]thiophene-2,3-quinone with H202 in the presence of ammonia gives 5-chloro-l,2-benzisothiazole-3-carboxamide (Scheme 157) (70AHC(11)177). 

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