Isothiazole halogenation

In azole chemistry the total effect of the several heteroatoms in one ring approximates the superposition of their separate effects. It is found that pyrazole, imidazole and isoxazole undergo nitration and sulfonation about as readily as nitrobenzene thiazole and isothiazole react less readily ica. equal to m-dinitrobenzene), and oxadiazoles, thiadiazoles, triazoles, etc. with great difficulty. In each case, halogenation is easier than the corresponding nitration or sulfonation. Strong electron-donor substituents help the reaction. 

Claisen condensation, 6, 156 reactions, S, 92 IsothiazoIe-3-carboxyIic acids decarboxylation, 6, 156 Isothiazole-4-carboxylic acids decarboxylation, 6, 156 Isothiazole-5-carboxylic acids decarboxylation, S, 92 6, 156 IR spectroscopy, 6, 142 Isothiazole-3-diazonium borofluoride decomposition, 6, 158 IsothiazoIe-4-diazonium chloride, 3-methyl-reactions with thiourea, 6, 158 Isothiazole-5-diazonium chloride, 4-bromo-3-methyl-halogen exchange, 6, 163 Isothiazole-5-diazonium chloride, 3-methyl-reactions... 

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. 

Formyl- and 4-bromo-3-formyl-isothiazole have been prepared in good yield from the dibromomethyl compounds obtained by side-chain halogenation of the appropriate 3-methylisothiazole with N-bromosuccinimide. 3-Acetyl- and 3-acetyl-4-bromo-isothiazole have been prepared from the 3-cyanoisothiazoles and methyl magnesium iodide. ... 

Halogen-metal exchange has also been used to give a 5-lithioisothiazole derivative (73JMC978), but this route appears to offer no advantage over direct metalation. However, direct metalation of 3,5-disubstituted isothiazoles at the 4-position has not been reported, and in this case halo-... 

The nitration of 3-alkylisothiazoles [190, 193, 194], 5-alkylisothiazoles [190, 193], and other derivatives of isothiazole containing halogen atoms or electron-donating substituents at positions 3 and 5 [183, 193-197] takes place similarly. 

Examples of the ipso-nitration of halogen-substituted isothiazoles [387] and thiazoles [388-390] are known. 2,4-Disubstituted 5-bromo- and 5-iodooxazoles react with nitrogen tetroxide to form the 5-nitro derivatives [391],... 

Of the substituted pyridines, the halogenated derivatives have been the most intensively studied.144,145 Treatment of 3,5-dichloropyridine A-oxide at 74° with 0.1 A NaOD led to exchange in three positions of the molecule, whereas with 3-chloropyridine iV-oxide relative rates of exchange were position 2>6>4>5. In l-methyl-4-pyridone, 1,3,5-trimethyl-4-pyridone, and 3,5-dibromo-l-methyl-4-pyridone, deuteration in basic D20 at 100° gives 2- and 6-substitution.146 With the poly-azaindenes (45) -(47) already discussed in the acid exchange section,141 base-catalyzed deuteration occurs in the positions indicated 45 3 and 5 46 2, 3, 5, and 6 and 47 2, 5, 6, and 7. In other isolated heterocycles some selectivity is observed in base-catalyzed exchange, e.g., certain imidazoles,147 thiazole,148 isothiazole,148 benzothiazole,149 and benzoxazole.149... 

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... 

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