The Chemical Properties of Isothiazoles

The isothiazoles possess the typical properties of a heterocyclic aromatic system without the ring lability so characteristic of the analogous isoxazoles.87 The chemistry reflects the relative inertness of the 3-position, the susceptibility of the 4-position to electrophilic attack, and the susceptibility of the 5-position to nucleophilic attack. The ring nitrogen is only weakly basic, but can be induced to form quaternary derivatives, and the N-S bond may be cleaved under certain circumstances. 

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 

Nakagawa, and K. Takahashi, Ghent. Pharm. Bull. 16, 160 (1968). 

Isothiazoles are sulfonated readily with oleum97 or sulfur trioxide,98 but formylation with dimethylformamide and phosphorus oxychloride, and acylation under Friedel-Crafts conditions, failed.70 On the basis of spectroscopic studies Anderson76 suggested that a 

4- methyl substituent would supply electrons more efficiently to the 

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Meso-ionic Isothiazoles.— The synthesis and chemical properties of novel meso-ionic compounds of the dehydrodithizone (2,3-diphenyltetrazolium 5-sulphide) family derived from pyrazole, isothiazole, and isoxazole have been described. The member (28) of the isothiazole series is accessible from 3-methylisothiazole... 

The intensified activity in the study of the chemistry of isothiazole, noted in the previous Report, has been sustained, possibly with an emphasized interest in condensed ring-systems. Now that numerous syntheses of isothiazoles are available, the careful and detailed investigation of both the physical and chemical properties of this ring-system, and its correlation with related structures, are particularly timely. The possible involvement of isothiazole derivatives in the biosynthetic pathway to penicillins and cephalosporins is a suggestion of exceptional interest (see ref. 43, below) that will no doubt stimulate further significant work. 

Chemical Properties. - WQuatemization of Isothiazoles. 3-Chloroisothiazole is quaternized by FSOsMe the salt is then treated with MeNH2 and passed through an ion-exchanger (Cl ) to give (19 R = R = Me Z = Cl). Other... 

The n.m.r. spectra of the isothiazolo[5,l-e]isothiazoles (82) show magnetic equivalence of ring protons or substituents at the pairs of sites N-l/N-6, C-2/C-5, and C-3/C-4, thus demonstrating that, in solution, the compounds possess real or time-averaged symmetry. Their chemical properties resemble those of enamines and pyrroles. Their electron-rich nature, suggested by n.m.r. chemical... 

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