Isothiazole sulfonation

Isothiazole-carbo dic acids, 112,118 Isothiazole-sulfonic acid, 112... 

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 contrast to thiazoles, certain isothiazoles and benzisothiazoles have been directly oxidized to sulfoxides and sulfones. 4,5-Diphenyl-l,2,3-thiadiazole is converted by peracid into the trioxide (146). Although 1,2,5-thiadiazole 1,1-dioxides are known, they cannot be prepared in good yield by direct oxidation, which usually gives sulfate ion analogous to the results obtained with 1,2,4- and 1,3,4-thiadiazoles (68AHC 9)107). 

The exoeyelie earbonyl group of isothiazol-3-ones absorbs in the region 1610-1660 em <7lJHC59l). 2-Methylisothiazol-3-one itself has the C=0 and C=C bands at 1660 and 1629 em respeetively, in CCI4 solution <64TL1477). The low earbonyl frequeney is due in part to eontributions from the resonanee form (20b). The earbonyl frequeney inereases in sulfoxides (1660-1730 em ) and 1,1-dioxides (1690-1740 em ) where sueh forms are not favourable. Sulfoxides (1060-1190 em ) and sulfones (1330-1360 and 1150-1190 em ) absorb in the regions expeeted (e.g. saeeharin, 1353 and 1162 em ), but resonanee forms related to (13) eause a reduetion of the frequeney of the asymmetrie SO2 vibration to near 1280 em (70CB3166). A similar situation arises in 3-amino-1,2-benzisothiazole 1-oxides. 

Alkyl-5-acetamidoisothiazoles are nitrosated at the 4-position by nitrosylsulfuric acid (78JOC4154). Isothiazoles are sulfonated at the 4-position using either oleum or sulfur trioxide <72AHQ14)1). 

Aromatic pyrrolo[ 1,2-A isothiazoles are not known and only a sulfone analog of tetrahydro and one perhydro derivative have been prepared. 

The tetrahydro- and perhydropyrrolo[l,2- ]isothiazoles 367 and 368 were synthesized as sulfone derivatives from an olefin metathesis of the diene 366 with the first-generation Grubbs catalyst followed by hydrogenation under palladium on charcoal (Scheme 54) <2003T7047>. 

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). 

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... 

Isothiazoles have also been incorporated into a wide range of established drugs including phenothiazines,123 sulfones,121 sulfonamides,3,66,156 thiosemicarbazones,140,157 amidines,158 nitrohetero-cycles,159 and benzimidazoles,160 but this approach does not appear to have resulted in any major improvements. However, many isothiazoles not directly related to known drugs have biological activity, and representatives are listed in Table I, No attempt has been made to include the numerous patents which mention isothiazole derivatives as part of a series, but for which no special claims are made. 

Isothiazoles.1 These heterocycles can be prepared by reaction of a-acetylenic aldehydes or ketones with hydroxylamine-O-sulfonic acid and then with sodium hydrosulfide in a buffered aqueous solution. 

The synthesis of isothiazole-fused sulfone 265 is based on the same approach and was obtained from sulfolene 520 (see Section 4.05.7.3) <1996TL4189>. Treatment of different heterocyclic n-azidocarbaldehydes with hexamethyl-disilathiane (HMDST) in the presence of HCl as catalyst offers a novel and practicable route to fused isothiazoles 521-523 <1997PS(120)165, 2005SL1965, 2000EJ02171>. 

Thiete structures have been suggested as fragmentation products in the mass spectra of a thietane fused to a 3-lactam, an ortho disulfide of a thiolbenzoate ester, -propanethiol, thiirane carboxylic acid esters, isothiazoles, thiazoles, 1,3-dithiole 2-thiones, 1,3-dithiolene-2-ones, S-ethyl thio-benzoate, and thianaphthene sulfones. Tetramethylthiete may have been formed on thermolysis of the p-toluenesulfonyl-hydrazone of 2,2,4,4-tetramethyl-3-thietanone. " Thiete 2-thione may be an intermediate in the decomposition of 1,2-ditholium salts by the action of bases. " 2,2-Diphenyl-2H-thiete is suggested as an intermediate in the reaction of diphenyldiazomethane with 1,2,3-benzo-thiadiazole which yields 9-phenylthioxanthene and three other products. ... 

A higher yield (90%) may be obtained by ring closure with potassium thiohydroxylamino-/S-sulfonate (Scheme 12). The same reagent may be condensed with propargyl aldehyde to give an intermediate which forms isothiazole on treatment with alkali, possibly via a transient thiooxime derivative.36... 

Isothiazoles form S-oxides and dioxides (sulfoxides and sulfones) these are referred to as 1-oxides or 1,1-dioxides in this chapter. There are several possible forms of isothiazole having an exocyclic carbonyl group, but the ones which will be considered in most detail in this chapter will be isothiazolin-3-one derivatives (5). Fully saturated isothiazoles (6) are referred to as isothiazolidines. One of the most well-known isothiazolidines is the zwitterion dehydromethionine (7). Saturated... 

---