Preparation of Isothiazoles

There are two series of benzisothiazoles, derived from benz[c]iso-thiazole (2) and benz[d]isothiazole (3), and both, if the benzene ring were suitable weakened, could doubtless be oxidized to isothiazole-dicarboxylic acids. In their first synthesis Adams and Slack 

Adams and Slack s second isothiazole synthesis involved the preparation of j3-iminothiobutyramide (9) from the nitrile 8 and cycliza- 

Hiibenett and his colleagues have shown that propylene reacts with sulfur dioxide and ammonia in the presence of a catalyst such as activated alumina to give a high yield of isothiazole [Eq. (1)]- This reaction is applicable to certain substituted propenes thus, isobutylene 

Hiibenett, F. H. Flock, and H. Hofmann, Angew. Chem. Intern. Ed. Engl. 

An elegant synthesis of both isothiazole and 3-methylisothiazole has been reported by Wille and his co-workers.This depends on the cyclization with liquid ammonia of the cis form of the addition product 14 which is obtained from the appropriate acetylenic carbonyl 

2-Alkylisothiazol-3-ones have been prepared by a similar re-action.  

---

B. Preparation of Isothiazoles Involving Oxidative Formation of a Nitrogen-Sulfur Bond. 3... 

Probably the most convenient laboratory preparation of isothiazole was devised by Wille and his collaborators34 (Scheme 11) and depends on the cyclization with liquid ammonia of the cis-addition product from propargyl aldehyde and sodium thiosulfate or thiocyanate.34, 35... 

E. Preparation of Isothiazoles from j8-Mercaptoacrylonitriles and Related Compounds... 

Sulfur-nitrogen bonds are readily formed by oxidation of imino-thiols such as 8, and this method is a useful one in the preparation of isothiazoles generally. A further example is given below. 

A different synthetic pathway, which is useful for the preparation of 4-cyano-isothiazoles 28-31 substituted at C-3 with different heteroatoms (Hal, S, 0), is exploited by Methods E (Scheme 8). These procedures start from dicyanomalonate 26 and different electrophiles giving the key intermediates 27a-d, subsequently cyclised to the isothiazole-4-carbonitriles 28-31. A number of modifications of these procedures are known and are very useful for obtaining different starting materials for the preparation of isothiazole derivatives of biological interest [1,2,4]. 

---