Isothiazoles nitration

The isothiazole ring causes deactivation of phenyl substituents, particularly in 3-phenyl-isothiazoles. Nitration of arylisothiazoles, however, occurs only in the benzene ring, the pattern of substitution varying greatly with the position of the aryl group on the isothiazole... 

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. 

In general, the carbonyl derivatives of isothiazole behave normally and condense readily with carbonyl reagents. The aldehydes reduce ammoniacal silver nitrate and undergo the Cannizzaro reaction. ... 

In the case of 3-phenylisothiazoles, the parent compound is nitrated to give a mixture of 3-(4-nitrophenyl) and 3-(3-nitrophenyl)isothiazole, but a series of substituted compounds gave exclusively the 3-nitrophenyl products in each case (68CPB160). 

Scheme 7.7. Rates of nitration relative to a single position of benzene (= I) for alkylthiazoles and -isothiazoles.

Scheme 7.10. Standard log nitration rates for isothiazoles [75JCS(P2)1620].

Abstract Synthesis methods of various C- and /V-nitroderivativcs of five-membered azoles - pyrazoles, imidazoles, 1,2,3-triazoles, 1,2,4-triazoles, oxazoles, oxadiazoles, isoxazoles, thiazoles, thiadiazoles, isothiazoles, selenazoles and tetrazoles - are summarized and critically discussed. The special attention focuses on the nitration reaction of azoles with nitric acid or sulfuric-nitric acid mixture, one of the main synthetic routes to nitroazoles. The nitration reactions with such nitrating agents as acetylnitrate, nitric acid/trifluoroacetic anhydride, nitrogen dioxide, nitrogen tetrox-ide, nitronium tetrafluoroborate, V-nitropicolinium tetrafluoroborate are reported. General information on the theory of electrophilic nitration of aromatic compounds is included in the chapter covering synthetic methods. The kinetics and mechanisms of nitration of five-membered azoles are considered. The nitroazole preparation from different cyclic systems or from aminoazoles or based on heterocyclization is the subject of wide speculation. The particular section is devoted to the chemistry of extraordinary class of nitroazoles - polynitroazoles. Vicarious nucleophilic substitution (VNS) reaction in nitroazoles is reviewed in detail. 

The nitration of the isothiazole (1,2-thiazole) ring takes place exclusively at position 4. The 4-substituted isothiazoles are either not nitrated at all [189, 190] or, as in the case of 4-phenylisothiazole, are nitrated in the benzene ring [191]. 

Table 1 The relative nitration rates (F) of thiazoles and isothiazoles...

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. 

Table 1 gives the relative rate constants for the nitration of thiazoles and isothiazoles. They demonstrate the higher reactivity of the thiazoles during nitration [190, 200], Such high regioselectivity is not observed during the nitration of thiazoles, as during the nitration of isothiazoles. 

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],... 

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