Isothiazol-3 2// -ones, 2-substituted

Few examples of functionalization on the benzene ring of benzisothiazole have been reported (see Section 4.05.7.2). Studies on the reactivity of unsaturated chains in cycloaddition reactions have been reported (see Section 4.05.7.3). The high reactivity of 4-vinylisothiazolin-3-one A-oxides in Diels-Alder cycloadditions, both as diene and dienophile, is illustrated by their tendency to dimerize. 5-Vinylisothiazole A,A-dioxides react at the vinyl function with different 1,3-dipoles. Isothiazolo-3-sulfolenes 265 give an o-quinodimethane which can be trapped with a dienophile. Different isothiazole derivatives substituted with a carbon chain functionalized with heteroatoms have been prepared as ligands for the formation of complexes. 3-Oxocamphorsulfonimide reacts with the anion of alkynes and several studies on the reactivity of the products with electrophiles are reported. 

A multiply bonded nitrogen atom deactivates carbon atoms a or y to it toward electrophilic attack thus initial substitution in 1,2- and 1,3-dihetero compounds should be as shown in structures (110) and (111). Pyrazoles (110 Z = NH), isoxazoles (110 Z = 0), isothiazoles (110 Z = S), imidazoles (111 Z = NH, tautomerism can make the 4- and 5-positions equivalent) and thiazoles (111 Z = S) do indeed undergo electrophilic substitution as expected. Little is known of the electrophilic substitution reactions of oxazoles (111 Z = O) and compounds containing three or more heteroatoms in one ring. Deactivation of the 4-position in 1,3-dihetero compounds (111) is less effective because of considerable double bond fixation (cf. Sections 4.01.3.2.1 and 4.02.3.1.7), and if the 5-position of imidazoles or thiazoles is blocked, substitution can occur in the 4-position (112). 

Friedel-Crafts acylation usually fails (72AHC(14)43), but 3-substituted l-methyl-2,1-benzisothiazole 2,2-dioxides can be acetylated at the 5-position (73JHC249). l-Methyl-2,1-benzisothiazol-3-one can be chlorsulfonated at the 5-position (78JHC529). Vilsmeier-Haack formylation causes cleavage of the isothiazole ring (80JCR(S)197). 

Double cyclizations can occur one interesting example is the formation of the thieno[2,3-c]isothiazole (97) from the cyano-substituted ketoester... 

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). 

Thiophene-1-oxide and 1 -substituted thiophenium salts present reduced aromaticity.144 A variety of aromaticity criteria were used in order to assess which of the 1,1-dioxide isomers of thiophene, thiazole, isothiazole, and thiadiazole was the most delocalized (Scheme 46).145 The relative aromaticity of those molecules is determined by the proximity of the nitrogen atoms to the sulfur, which actually accounts for its ability to participate in a push-pull system with the oxygen atoms of the sulfone moiety. The relative aromaticity decreases in the series isothiazole-1,1-dioxide (97) > thiazole-1,1 -dioxide (98) > thiophene-1-dioxide (99) then, one has the series 1,2,5 -thiadiazole-1,1 -dioxide (100) > 1, 2,4-thiadiaz-ole-1,1-dioxide (101) > 1,2,3-thiadiazole-1,1 -dioxide (102) > 1,3,4-thiadiazole-l,1-dioxide (103) in the order of decreasing aromaticity. As 1,2,5-thiadiazole-1,1-dioxide (100) was not synthesized, the approximations used extrapolations of data obtained for its 3,4-dimethyl-substituted analogue 104 (Scheme 46). 

The reaction of 2-substituted-5-aroyl-isothiazol-3-ones (214) with hy-droxylamine or arylhydrazines gives the 1,2,5-oxathiazoles 216 (Z = O) or 1,2,3-thiadiazoles 216 (Z = NAr ), as a result of a spontaneous rearrangement of unisolated oximes 215 (Z = O) or arylhydrazones 215... 

Volume 14 of this serial publication comprises six chapters of which four deal with general accounts of ring systems benzisothiazoles (M. Davis), 1,2-dihydroisoquinolines (S. F. Dyke), benzo[c]thiophenes (B. Iddon), and pyrazines (G. W. H. Cheeseman and E. S. G. Werstiuk). One chapter updates a previous review in this series and is concerned with the rapidly expanding chemistry of mononuclear isothiazoles (K. R. H. Wooldridge). The remaining chapter (O. Meth-Cohn and H. Suschitzky) deals with the cyclizations of ortho-substituted f-anilines. 

The treatment of a variety of 2-aryl substituted isothiazolo[5,4-6]pyridin-3-ones (210) with sodium hydroxide in refluxing ethanol for 15 min cleaved the isothiazole ring and gave the pyridines (211) in yields ranging from 60-70% <88JHC23>. 

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 (approximately equal to -dinitrobenzene), and oxadiazoles, thiadiazoles, triazoles, etc. with great difficulty. In each case, halogenation is easier than nitration or sulfonation. Strong electron-donor substituents assist the substitution. 

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. 

Hauser s approach was extended to cover 1 and 3-oxo-2,3-dihydrobenz-[d]isothiazole-1,1-dioxides with suitable substituents in the phenyl ring by employing iV-<-butylarylsulfonamides.57 The substituted 2-(N-t-butylsulfamoyl)benzoic acids are cyclized and dealkylated in one step by polyphosphoric acid.57... 

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