Isothiazole dioxides, synthesis

Isothiazole, 3,5-dichloro-4-cyano-synthesis, 6, 166 Isothiazole, dihydro-1,1-dioxide... 

Thieno[3,4-d]isothiazole, 2,3-dihydro-3-oxo-1,1-dioxide, 6, 989 biological activity, 6, 1024 Thieno[2,3-c]isothiazole-3-carboxylic acid synthesis, 6, 1023... 

Sulfur dioxide has long been used in an industrial synthesis of isothiazole from propene, sulfur dioxide, and ammonia over a catalyst at 200°C.51... 

Few examples of substitution reactions on intact heterocycles have been reported. Notable is the synthesis of 3-aminothieno[3,4-d]isothiazole 1,1-dioxides (51) by the fusion of thieno[3,4-d]iso-... 

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. 

Phenyl-l,3,4-oxathiazol-2-one (370), prepared from primary amides and tri-chloromethanesulfenyl chloride, undergoes a ready thermal elimination of carbon dioxide with the formation of the nitrile sulfide ylide (371). This can be trapped by a wide variety of unsaturated dipolarophiles, and with an alkyne provides a ready route to isothiazoles (372) (see Chapter 4.17). Applications to 1,2,4-thiadiazole synthesis are described in Chapter 4.25. Thermolysis of l,3,4-oxadiazolin-5-ones (500 C/10 mmHg) results in the loss of CO2 and generation of the corresponding nitrilimine (78JOC2037). 

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. 

Scheme 35 General synthesis of 3-amino-isothiazole S,S-dioxide derivatives Method H...

Sdieme 41 Synthesis of isothiazol-and dihydro-isothiazol-3-one S,S-dioxides Method I... 

Functionalisation of the isothiazol-3-one S,S-dioxide system at C-5 provided several interesting derivatives. An example regarding the synthesis of some protein tyrosine phosphatase inhibitors [56] is reported below in... 

There are parallels, but also methods unique to particular 1,2-azoles, in the principal methods available for the construction of pyrazoles, isothiazoles and isoxazoles neither the reaction of propene with sulfur dioxide and ammonia at 350 °C, which gives isothiazole itself in 65% yield, nor a synthesis from propargyl aldehyde and thiosulfate (shown below) have direct counterparts for the other 1,2-azoles. 

A direct synthesis of trisubstituted isothiazole 1,1-dioxides, which are difficult to prepare by other methods, has been achieved by treatment of a substituted meth-anesulfonamide with diethyl oxalate in ethanol. Thus, the disodium salt of 3,4-dihydroxy-5-(ethoxycarbonyl)isothiazole 1,1-dioxide (42) is obtained in high yield when 41 is treated with diethyl oxalate in the presence of sodium ethoxide at room temperature (equation 24)35. Regioselective nucleophilic substitution of 3,4-dichloro- and 4-chloro-3-ethoxy-5-(ethoxycarbonyl)isothiazole 1,1-dioxide, prepared from 42, oxalyl chloride and ethanol occurs at the C-3 and C-4 positions with alcohol, amines and iV-(trimethylsilyl) amines. 

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