Reactions of isothiazoles

Thermal extrusion of sufur dioxide from spirobenzosultam 243 has been utilized in the synthesis of 2-ary 1-dehydrothiopyrans 245 05T8848 . Tandem alkylation-sulfanylation of benzo- and pyridosultams 242 with 4-bromobutyl thiocyanate gives sultams 243 that yields 245 after extrusion of sufur dioxide and [1,5]-hydrogen shift. 

The regioselective cross-coupling reactions of multiple, including isothiazoles have been reviewed 05T2245 . 

A highly stereoselective synthesis of the (3-substituted P-amino sulfone 271 involves the addition of a sulfonyl anion, derived from A-PMB sultam 268 upon treatment with NaHMDS, to chiral A-sulfinyl imine (5)-269 06OL789 . Removal of the A-sulfinyl followed by basic workup affords amine 271. The stereochemical outcome of the adduct 270 was established via proton NMR analysis of the Mosher s amide derived from 271. 

The Diels-Alder reaction between isothiazole-dioxides and various dienes represents an attractive approach toward a range of bi- and tricyclic derivatives containing the fused 

3-dipolar cycloaddition of diazoalkanes 276 and nitrile oxides 279 to isothiazole dioxides 275 provides an easy entry into fused bicyclic isothiazole systems 277 and 280, respectively 06JHC1045 . The adducts from 4-bromoisothiazole (R1 = Br) are labile and undergo spontaneous debromination to form the aromatic bicyclic pyrazolo-isothiazoles 278 

The regioselective ozonation of alkylidene-sultams 282 followed by reaction with di azomethane leads to the formation of highly reactive bicyclic trioxo-isothiazolidine 284 

5-Dichloro- and 3,5-dibromoisothiazole-4-carbonitriles 285a/b undergo regioselective Stille, Negishi, Sonogashira coupling reactions at C-5 to provide 3-halo-5-substituted 

A convenient method for the synthesis of trioxo-benzothiazine 181 involves a ring expansion reaction of benzoisothiazole 180 07H1843 . Directed ort/ o-mctalation of benzenesulfonamide 176 coupled with carboxylation gives rise to 2-carboxybenzene-sulfonamide 178 which is then converted to benzoisothiazole 179 under the TMSCl-Nal deprotective-cyclization conditions. Bromination of 179 followed by ring expansion mediated by 20% KOH according to the Abramovitch procedures furnishes the benzo-thiazine 181. Optical resolution of 181 using (-)-menthoxyacetyl chloride yields its (+) and (-) enantiomers. 

Sulfonation of 183 with sodium sulfite yields sulfonic acid 185 via an in situ iodomethyl derivative. Ring opening of 185 by sodium methoxide generates methyl ester 186, which undergoes ring-closure, upon treatment with sodium hydride, to afford benzothiazinone dioxide 187. 

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Individual aspects of nitrile oxide cycloaddition reactions were the subjects of some reviews (161 — 164). These aspects are as follows preparation of 5-hetero-substituted 4-methylene-4,5-dihydroisoxazoles by nitrile oxide cycloadditions to properly chosen dipolarophiles and reactivity of these isoxazolines (161), 1,3-dipolar cycloaddition reactions of isothiazol-3(2//)-one 1,1-dioxides, 3-alkoxy- and 3-(dialkylamino)isothiazole 1,1-dioxides with nitrile oxides (162), preparation of 4,5-dihydroisoxazoles via cycloaddition reactions of nitrile oxides with alkenes and subsequent conversion to a, 3-unsaturated ketones (163), and [2 + 3] cycloaddition reactions of nitroalkenes with aromatic nitrile oxides (164). 

The standard means for preparing oxicams 285, initially developed by Lombardino, is through the base-promoted rearrangement reaction of isothiazole dioxides 286, which in turn are prepared from saccharin derivatives such as 287 (Scheme 40) <1981AHC(28)73>. The oxicam core can be further derivatized by N-alkylation of oxicam 285 and amidation of the C-3 ester functionality of 288 to form the common drug scaffold 289. 

Halogenation of pyrazole gives 4-monohalo-pyrazoles, for example 4-iodo-, or 4-bromopyrazole under controlled conditions. Poor yields are obtained on reaction of isothiazole and isoxazole " with bromine, again with attack at C-4, but with stabilising groups present, halogenation proceeds betteC and efficient... 

Isothiazole is aromatic. The NMR spectra confirm a largely undisturbed delocalization of the tt-electrons. In consequence, the aromaticity of isothiazole is greater than that of isoxazole, just as the aromaticity of thiophene is greater than that of furan. From the calculated r-electron densities, it follows by analogy to isoxazole (see p 138) that electrophilic substitution should occur at the 4-position, while nucleophiles should attack the 3-position. The most important reactions of isothiazoles can be summarized as follows ... 

Reactions of Isothiazoles.—Photolytic. Whilst photoisomerization of isothiazoles to thiazoles is well documented, examples of this reaction occurring with isothiazol-3(2H)-ones have not previously been reported. Irradiation of (10 R = alkyl or Ph) gave the corresponding thiazolone (11). The isomerization probably involves homolysis to a biradical, which cyclizes to an a-lactam and subsequently undergoes ring-expansion. Support for the homolytic step comes from the isolation of a small amount of (12) from the photolysis of (10 R = Ph). 

Even heterocyclic carbon-carbon double bonds undergo the [3+2] cycloaddition reaction with azides, as exemplified by the reaction of isothiazol-1,1-dioxides with aryl- and benzyl azides . 

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