5- Chlorinated isothiazoles

A series of five-membered heterocycles with two and three heteroatoms were synthesized. 4-Hydroxyisothiazoles 57 were prepared from a-amino ketones with sulfur monochloride (1968BCJ959). Polar solvents, especially N,Af-dimethylfor-mamide, were preferable (Scheme 28). In a similar reaction of 1-amino-l-phenyl-2-propanone with sulfur monochloride 5-chlorinated isothiazole 58 was obtained in high yield. 

Chioro-4-methylisothiazole is formed by chlorination of 4-methyl-isothiazole under the influence of irradiation, together with an equal quantity of 4-chloromethylisothiazole. Side-chain halogenation of 3-methylisothiazoles has also been carried out with iV-bromosuccin-imide to give bromomethyl and dibromomethyl derivatives. See also reference 17b. 

Usually, N-sulfinyl compounds (59) behave as thionyl transfer reagents, similar to, but milder than, thionyl chloride. For example, o-diamines with A-sulfinylbenzeneamine (59 R = Ph) afford fused 1,2,5-thiadiazoles, as in Scheme 8a.77 The advantage of using Af-sulfinyl compounds, rather than thionyl chloride itself, is that concomitant chlorinations and oxidations are avoided. This is of particular importance in the synthesis of 2,1-benzisothia-zoles (Section V,B,6). Singerman s reagent, N-sulfinylmethanesulfonamide (60) is especially valuable 78 it was used very successfully in the synthesis of a series of benzobis(isothiazoles).79... 

The syntheses by Naito and co-workers of 4-hydroxy, 4-cyano, and related isothiazoles from a-iminoketones or a-iminonitriles and sulfuryl or thionyl chloride29,30 may be envisaged as a variant of the general method if it is assumed that the reagents introduce a sulfur atom and also provide chlorine for oxidative cyclization (Scheme 10). 

A number of important isothiazole syntheses depend on oxidative cyclization of substituted jS-mercaptoacrylonitriles possibly by the following mechanism (Scheme 16), e.g., with chlorine as the oxidant. 

The use of chlorine as the oxidant has given 4-cyano-3,5-dichloro-isothiazole,51 and hydrogen peroxide forms a 3-hydroxy derivative in good yield (Scheme 18)44,52... 

Ozo-2-halo-2,3-dihydrobenz[d]isothiazole-l, 1 -dioxides Free halogen reacts with the saccharin anion (19). The standard procedure for preparing 3-oxo-2-chloro-2,3-dihydrobenz[d]isothiazole-1,1-dioxide (iV-chlorosaccharin) (40) is still passing of chlorine gas through a cold aqueous solution of 19a.173,174... 

Electrolysis of alkyl arenedithioates in MeCN with benzyltriethylammonium chloride as electrolyte yields 5-aryl-4-cyano-3-methylisothiazoles. It is suggested that the dithioester is chlorinated at the anode and reacts with 3-iminobutyronitrile, which is formed from MeCN by the cathodically generated base, to the isothiazole [144]. 

Benzo[d]isothiazoles 220 and 221 (Scheme 56) were synthesised as oxi-dosqualene cyclase inhibitors. By reaction of fluorobenzophenones 216 with potassium benzylthiolate followed by S-chlorination, cleavage of the benzyl group with SO2CI2 and reaction with NH3, compound 217 was formed. Methoxy deprotection and alkylation with 1,6-dibromohexane gave intermediate 218, which was converted to 220 with Af-allylmethylamine. Intermediate 218 was oxidised to the S,S-dioxide 219 and then functionalised at C-6 affording 221. Similarly, benzo[d]isothiazole 223 was prepared from benzophenone 222 [68]. 

The production of chlorinated by-products is largely avoided when A-sul-phinylmethanesulphonamide (MeSOaNSO) is used as the cyclization agent for o-toluidines or A-sulphinyl-o-toluidines, in boiling pyridine. The procedure has been successful in the production of numerous 2,1-benzisothiazoles (including naphth[l,2-c]isothiazole), but failed to yield the hydroxy- or amino-substituted heterocycles from the corresponding substituted o-toluidines. ... 

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