Isothiazoles bromination

Isothiazoles with electron-releasing substituents such as amino, hydroxy, or alkoxy in the 3- or 5-position are brominated in high yield in the 4-position. Alkylisothiazoles give lower yields, but 3-methylisothiazole-5-carboxylic acid has been brominated in 76% yield (72AHC(14)1). Again, thiazoles with an electron-releasing substituent in the 2- or 4-position are brominated at the 5-position (79HC(34-1)5). 

Beckmann rearrangement, 6, 156 Isothiazole, 3-alkoxy-tautomerism, 6, 145 Isothiazole, alkyl-bromination, 5, 58 Isothiazole, 3-alkyl-5-amino-synthesis, 6, 166 Isothiazole, alkylthio-mass spectra, 6, 142 Isothiazole, amino-azo dyes from, 1, 330 tautomerism, 6, 157 Isothiazole, 3-amino-synthesis, 5, 135 tautomerism, 6, 146 Isothiazole, 4-amino-azo dyes from, 6, 175 diazotization, 6, 158 methylation, 5, 95 quaternization, 6, 158 reactions... 

Isothiazole-4,5-dicarboxylic acid, 3-phenyl-dimethyl ester synthesis, S, 150 Isothiazole-5-glyoxylic acid ethyl ester reduction, 6, 156 Isothiazole-4-mercurioacetate reactions, 6, 164 Isothiazole-5-mercurioacetate reactions, 6, 164 Isothiazoles, 6, I3I-I75 acidity, 6, 141 alkylation, 6, 148 aromaticity, S, 32 6, 144-145 basicity, 6, I4I biological activity, 6, 175 boiling points, 6, I43-I44, 144 bond fixation, 6, 145 bond orders, 6, I32-I34 calculated, 6, 133 bromination, S, 58 6, 147 charge densities, 6, 132-134 cycloaddition reactions, 6, 152 desulfurization, S, 75 6, 152 deuteration, S, 70... 

The 4-position of isothiazole is attacked by electrophilic reagents, and many simple derivatives are thus readily available by direct substitution followed, if necessary, by suitable transformation of the group introduced. For example, bromination of 3-methylisothiazole... 

Isothiazole-5-carboxylic acid, 3-methyl-bromination, 5, 58 Isothiazolecarboxylic acid chlorides Amdt-Eistert reaction, 6, 157 Reissert reactions, 6, 157 Isothiazolecarboxylic acids esters... 

Isothiazole and alkylisothiazoles may be brominated under various conditions,18,70,92 but yields are often poor possibly because of the formation of perbromo compounds. Isothiazoles with electronreleasing substituents, however, undergo facile bromination and high yields have been reported for isothiazoles with amino,3, 7 9-93-95 hydroxy,18 or alkoxy93,96 substituents in the 3- or 5-position. An isothiazole with an electron-withdrawing substituent, 3-methyl-isothiazole-5-carboxylic acid, has been brominated in 76% yield.70... 

On treatment with mercuric acetate in aqueous acetic acid at 100°, isothiazole gives a 48% yield of a dimercuriacetate, which with bromine affords 4,5-dibromoisothiazole. Unlike lithiation, a nitro group does not interfere, and mercuriation provides a convenient route to 5-bromo-4-nitroisothiazole (Scheme 30).106... 

As pointed out, the 3-position in fused isothiazoles is activated for nucleophilic substitution. Amino groups in activated azine positions after diazotization are frequently displaced by the anion of the acid used in the diazotization reaction. Similarly, this type of reaction can be used to substitute the 3-amino group in (118) with a bromine substituent (73CJC1741). 

Azine approach. Cyclization by oxidative formation of the S—N bond is frequently the final step in isothiazole syntheses. This approach can be used in the synthesis of the parent cation from the thioformyl precursor (129). 2-Substituted derivatives would require thioketone precursors and such compounds are more readily available as vinyl thioethers, e.g. (130). Bromine is used for the oxidative cyclization in this instance giving (13lj (73CC150). 

The reaction of ethyl / -aminocrotonate (158) with isothiocyanates RNCS (R = p-02NC6H4, / -02NC6H4C0, EtOCO or Et02CCH2) yields the thiocarbamates 159, which cyclize to isothiazoles on treatment with bromine (equation 70)9°. 

Only one synthesis leads to 2 alkyl-4-nitroisothiazolium salts (68) from open-chain precursors. Condensation of nitroketeneaminals with isothiocyanates followed by N—S bond formation using bromine leads to the isothiazoles 68 (20-25%) (Scheme 14).60... 

Perhaloisothiazoles containing both bromine and iodine atoms can be prepared from the readily available 3-hydroxy-isothiazole <1997RCB1792>. The addition of bromine, followed by spontaneous HBr elimination, occurs with a different regiochemistry on isothiazole d, d -dioxide 69 (R = H) and 70 (R = R = H, R = Bn, n = Z), and the corresponding 5-bromo derivative 69 (R = Br) <1997T15859> and the 4-bromo compound 70 (R = Br) <2003T9399> are obtained, respectively. For the synthesis of 4-chloro and 4,5-dichloro derivatives 70, see Section 4.05.9.1.1. 

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