Isothiazol-3 -one 1,1-dioxides

Isothiazolo[5,4-c]pyridines have been prepared by a Diels-Alder reaction (Scheme 68) (90HCA69). The regioselective [4 + 2] addition of the dienophile 2-(t-butyl)isothiazol-3-one 1,1-dioxide (538) with 5-ethoxy-4-methyloxazole (537) in benzene at room temperature gave a 5 3 mixture of the exo to endo adducts (539) and (540) in an overall 85% yield. The two adducts (539) and (540) were surprisingly stable and separable by fractional crystallization from a methylene chloride/hexane mixture. Bubbling a stream of anhydrous hydrochloric acid into an ethanolic solution of these adducts (539) and (540) gave the isothiazolo[5,4-c]pyridine (541) as its hydrochloride in 63% yield. 

Another application of the well-known cyclization of ortV o-substituted benzenesulfonamides consists in the treatment of 415 (R =NR2, R = Me) with Et30Bp4 followed by aqueous H2SO4 affording good yields of benz-isothiazol-3-one 1,1-dioxides 416. Their alkaline hydrolysis afforded 415 (R = OH, R = R = H), which is stable at neutral pH but recyclizes to 416 under even mild acidic conditions (pH <4) <1999T237>. 

Few isothiazoles undergo simple cycloaddition reactions. 4-Nitroisothiazoles add to alkynes (see Section 4.17.7.4). With 5-thiones (84) and dimethyl acetylenedicarboxylate, addition to both sulfur atoms leads to 1,3-dithioles (85) (77SST(4)339, 80H(14)785, 81H(16)156, 81H(16)595). Isothiazol-3-one 1-oxide and the corresponding 1,1-dioxide give normal adducts with cyclopentadiene and anthracene (80MI41700), and saccharin forms simple 1 1 or 1 2 adducts with dimethyl acetylenedicarboxylate (72IJC(B)881). 

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. 

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). 

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... 

Acids or salts are utilized directly in Stephen s method 166 (iii) reaction with 3-chlorobenz[d]isothiazole-1,1-dioxide (6) (pseudosaccharin chloride3,166). The initial step is presumably formation of 29, followed by Mumm rearrangement. Frequently one obtains pseudosaccharin anhydride (32)25,162 as a by-product. From the reactions with silver acetate and below 3° only A-acetylsaccharin (33) besides 32 was isolated.167 In this context reexamination of the reported 3-O-benzene-sulfonylbenz[d] isothiazole-1,1-dioxide42 and the supposed 3-O-benzoyl... 

N-Acyl saccharins (13) in part resemble iV-alkyl saccharins in their reactions. From the hydrolysis of 3-oxo-2-acetyl-6-chloro-2,3-dihydro-benz[d]isothiazole-1,1-dioxide (64) with a base/alcohol mixture one obtains iV-acetyl-4-chloro-2-sulfamoylbenzoic acid (65). On heating with base the acetyl group is hydrolyzed off.180... 

The isothiazol-3(2//)-one 1,1-dioxides 254-257 with stabilizing aryl substituents in the 2-, 4- and/or 5-position are potential inhibitors toward human leukocyte elastase (HLE) (03ZN(B)111, 05JEIMC341). HLE is a serine protease implicated in several inflammatory diseases and represents a major target for the development of low-molecular weight inhibitors. 

Furthermore, oxidation of 402 and 403 with hydrogen peroxide furnished isothiazol-3(2//)-one 1,1-dioxides 404 and 405 (method B) as ring contraction products, which can be obtained directly by oxidation of imines 71 and 130 or perchlorates 73 and 132 (method A), respectively. The structures 402e (R = 4-Br), 404c (R = 3-N02) and 407b (R = 3-N02) were confirmed by X-ray diffraction (99JHC1081, Scheme 136). 

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