Benzisothiazole formation

Isothiazole behaves as a typical stable aromatic molecule. Thermolysis of substituted isothiazoles at 590 °C leads to the formation of thioketenes (80MI41700) and phenyl-isothiazoles undergo photoisomerism (Section 4.17.6.2) (73BSF1743, 81T3627). 1,2-Benzisothiazole boils at 220 °C without appreciable decomposition, and the 2,1-isomer... 

A few isothiazoles, 2,1-benzisothiazoles and monocyclic sultams have been prepared by methods involving formation of the 4,5-bond. Thus, condensation of a-cyanooximes (179) with ethyl mercaptoacetate or related compounds gives a compound (180) which cyclizes... 

The photolysis of 10.3a in pentane or the reaction of 10.3a with PPhs generate the corresponding sulfur diimide ArN=S=NAr (Ar = 2,4- Bu2-6-MeC6H2) as the major product, presumably via the intermediate formation of the thionitrosoarene." By contrast, thermolysis in arene solvents results in ring closure to give the 2,1-benzisothiazole 10.4 and the corresponding aniline."... 

Treatment of the sulpholene (19) with hydroxylamine in refluxing ethanol has led to the formation of isothiazol-3-sulpholenes (21) which presumably progressed via the oxime intermediate (20). Subsequent heating of (21) in toluene at 185°C in a sealed tube led to the generation of the diene (22) which could be trapped with 1 -phenylmaleimide and with DMAD, thus providing a new route to 1,2-benzisothiazole derivatives <96TL4189>. 

Phosphorus pentasulfide is used to replace oxygen atoms with sulfur atoms the reaction is commonly carried out in a solvent heated under reflux. Solvents employed include carbon disulfide, aromatic hydrocarbons, and pyridine. If an oxygen atom is part of a heterocycle, then the reagent may replace it with sulfur, as in the formation of 2,1-benzisothiazoles from 2,1-benzisoxazoles.119 Such replacements are, however, not general some prior ring opening appears to be necessary before the reagent can act. For example, under normal conditions furan is not attacked. 

A series of benzisothiazolone derivatives 238 has been prepared from methylthiosalicylate 235 O60L4811>. The key cyclization step features the formation of a TV-acylnitrenium ion 237, generated by the hypervalent iodine reagent, phenyliodine(III)bis(trifluoroacetate) (PIFA). This ion cyclizes to benzisothiazol-3-one 238 upon intramolecular trapping of the thiol moiety. 

Products isolated from the thermal fragmentation of A-arylbenzamide oximes and A-arylbenzamide O-phenylsulfonyl oximes have been accounted for by invoking a free-radical mechanism which is initiated by the preferential homolysis of the N-O bond." Time-resolved IR spectroscopy has revealed that photolysis of A, A -diphenyl-l,5-dihydroxy-9,10-anthraquinone diimine affords acridine-condensed aromatic products via excited-state intramolecular proton transfer." The absolute and relative rates of thermal rearrangements of substituted benzyl isocyanides have been measured,and it has been found that the relative rates are independent of temperature and exhibit excellent Hammett correlations. Thionitrosoarene (25), thought to be generated by desulfurization of the stable A-thiosulfinylaniline (24), has been established" " as an intermediate in the formation of 3,3a-dihydro-2,l-benzisothiazole (26) from o-alkylthionitrosoarene (24). 

Although 1,2,5-thiadiazoles have been shown to undergo cycloaddition with benzyne <82CC299>, the predominant mode of attack is at sulfur. The result is extrusion of a nitrile and formation of a 1,2-benzisothiazole (22) (Scheme 4) <88JCS(Pl)2l4l>. 

Few other reactions of simple 1,2-benzisothiazoles have been described in the literature. There is, for example, no report of the formation of a quaternary salt directly from the parent compound. The isothiazole ring is generally quite stable to oxidation or reduction ... 

Adducts are formed from bis(trifluoromethyl)thioketene and aryl azides (78JOC2500). The yellow, crystalline products are believed to be the so far unknown A3-l,2,3,4-thiatriazo-lines (23 equation 50), as indicated by 19F and IR spectra and the formation of 2,1-benzisothiazole on thermolysis (Section 4.28.2.3.l(i)). 

Oxidation of sulfur-containing azoles quite often leads to the formation of sulfones and sulfoxides. Thus, 3-alkyl-1,2-benzisothiazoles 142 with MCPBA give the oxaziridines 143, and the use of a chiral 3-alkyl substituent leads to pure diastereomers. Reaction of 1,2,3-benzothiadiazole with 30% hydrogen peroxide in a mixture of acetic acid and methanol for 45 days affords 144 in 60% yield. 

The mixed-crystal system formed by indomethacin and saccharin (l,2-benzisothiazol-3(2H)-one-l,1-dioxide) has been used to evaluate the feasibility of using supercritical fluids as media for the design and preparation of new cocrystals [44]. In this work, the relative merits of supercritical fluid processes (i.e., cocrystallization with a supercritical solvent, supercritical fluid as anti-solvent, and the atomization and anti-solvent technique) were evaluated, as well as the influence of processing parameters on product formation and particle properties of the yields. It was reported that while the anti-solvent and atomization procedures yielded pure cocrystal products, only partial to no cocrystal formation took place when using the crystallization process. 

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. 

Analogously, the reaction of 2-bromophenyl-A-methylsulfoximine 432 with terminal alkynes in the presence of a palladium catalyst results in the formation of both 1,2-benzothiazine 433 and 1,2-benzisothiazoles 434. A preference for the former is seen with alkylalkynes while the latter are preferentially formed with alkynylarenes <20050L143>. 

Isothiazoles and benzisothiazoles were described in the first edition of Comprehensive Heterocyclic Chemistry (CHEC-I) <84CHEC-i(6)i3i>. The present work summarizes and augments, where appropriate, information from the first edition, but concentrates very much on literature published since 1982. Wherever possible, information is arranged in a similar format to that used in the first edition to facilitate comparisons. The chemistry of isothiazoles is regularly reviewed in Progress in Heterocyclic Chemistry, and specific subjects are discussed occasionally in Advances in Heterocyclic Chemistry, for example benzisothiazoles <85AHC(38)105> and aromaticity <93AHC(56)303>. 

An example of the formation of the sulfur-carbon bond is the cyclization of the iV-thiolinylaniline to the 2,1-benzisothiazole (Scheme 15) <87CL2293>. There are more cases of nitrogen-carbon bond... 

X = S) to DMAD to yield dimethyl 5-phenylisothiazole-3,4-dicarboxylate is much slower than the corresponding oxathiazolone (282) (X = O) <89JCS(Pl)2489>. The thermal decomposition of ethyl 2-azido-3-(3-azido-2-thienyl)propenoate (283) results in the formation of ethyl 5-cyano-isothiazole-3-carboxylate (284) together with the thienopyridazine (285) <84JCS(P1)915>. The addition of benzyne to 3,4-dimethyl-1,2,5-thiadiazole (286) gives 3-methyl-1,2-benzisothiazole <82CC299>. 

Lawson7 discussed the factors influencing the yields of 1,2-benzisothiazoles from 2-(alkylthio)phenyl-substituted oximes. This reaction, one of the standard synthetic methods, has been used extensively by a group at the University of Hull in their syntheses of substituted 1,2-benzisothiazoles.8 A variation involves the formation of a seven-membered heterocyclic ring (1) which is then pyrolyzed to the 1,2-benzisothiazole (2).9... 

A completely new synthesis of 1,2-benzisothiazoles, developed by a group in Japan, involves the use of o-mesitylenesulfonylhydroxylamine in the presence of base, as in the formation of the 1,2-benzisothiazole 10 from the thiochromanone 11. The benzo [b] thiophen-3(2//)one 12 is an equally good precursor.18... 

Nucleophilic displacement of the chlorine atom of 3-chloro-1,2-benzisothiazole has proved to be a popular procedure. Boeshagen and Geiger34 have continued their earlier work on nitrogen nucleophiles, and now include carbon, oxygen, and sulfur nucleophiles.35 In some cases, rearrangements occur, as in the formation of 3-amino-2-acylbenzo[6]thiophenes (20) from reaction of 21 with methyl ketones. Similar results are obtained from the reaction of other carbon nucleophiles, and it has been suggested that attack may be either at the 3-carbon or the sulfur atom.36 The reaction of 3-chloro-1,2-benzisothiazole (8) with the anion of ethyl cyanoacetate, for example,... 

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