1.2- Benzisothiazoles substitution

X-Ray diffraction studies have been carried out on other 1,2-benzisothiazoles (72JCS(P2)2125, 74CSC535, 76G769) and complexes of substituted 1,2-benzisothiazoles with... 

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... 

Isothiazolium salts (59) react with phenylhydrazine to give pyrazoles (60) (72AHC(14)l) (see Section 4.02.1.6). When treated with hydrazine hydrate, 3-chloro-l,2-benzisothiazole gives di-(o-cyanophenyl) disulfide (73SST(2)556), but 2,1-benzisothiazole gives o-aminobenz-aldehyde azine (72AHC( 14)43). 2-Substituted saccharins give the expected o-sulfamoyl-benzohydrazides. 

Benzisothiazole is lithiated at the 3-position, which corresponds to the 5-position in the mononuclear series (75JHC877). 4-Methylisothiazole forms the 5-lithio derivative, but the presence of by-products produced in subsequent reactions suggests the possibility of lithi-ation at the 3-position also (72AHC(14)l). 3-Substituted 1,2-benzisothiazoles suffer attack at sulfur and cleavage of the N—S bond (72AHC(14)43, 73SST(2)556). 

Substituted 1,2-benzisothiazole 1,1-dioxides form benzo-1,2-thiazepines (86) with 1-diethylaminoprop-l-yne (76H(5)95). 2,1-Benzisothiazole does not react with maleic... 

Both 1,2- and 2,1-benzisothiazoles react with electrophiles to give 5- and 7-substituted products (see Section 4.02.3.2). The isothiazole ring has little effect on the normal characteristics of the benzene ring. C-Linked substituents react almost wholly normally, the isothiazole ring having little effect except that phenyl substituents are deactivated (see Section 4.17.2.1). There are, however, considerable differences in the ease of decarboxylation of the carboxylic acids, the 4-isomer being the most stable (see Section 4.02.3.3). 

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). 

When saccharin is treated with diethyl phosphorothiolothionate, the 3-ethylmercapto compound is obtained, rather than the expected organophosphorus compound (77 ACS(B)460). Treatment of saccharin with phosphorus pentoxide and amines gives 3-(substituted-amino)-1,2-benzisothiazole 1,1-dioxides, via an intermediate phosphate (81ZN(B)1640). Reduction of saccharin with zinc and hydrochloric acid gives 2,3-dihydro-l,2-benzisothiazole 1,1-dioxide, the method being used to estimate saccharin in foodstuffs (75MI41701). 

Benzisothiazoles are best prepared by oxidative cyclization of o-aminothiobenz-amides (see Section 4.17.9.1.1), reaction of o-toluidines with thionyl chloride (see Section 4.17.9.2.1) or by sulfuration of 2,1-benzisoxazoles (see Section 4.17.10.2). 1,2-Benzisothiazoles can also be prepared from o-disubstituted benzene compounds, cyclodehydration of o-mercaptobenzaldoximes or oxidative cyclization of p-mercaptobenzylamines (see Section 4.17.9.1.1) being the most convenient. Both series of benzo compounds are readily substituted at the 5- and 7-positions by electrophilic reagents. 

Benzisothiazole 1,1-dioxides and saccharin derivatives are best prepared by cyclization of o-substituted benzenesulfonamides (see Section 4.17.9.1.2). 

The succinimide derivative (234) can be used in peptide synthesis for conversion of amino acids into their succinimide esters (235 Scheme 41) (79CL1265). 3-Substituted mercapto-1,2-benzisothiazole 1,1-dioxides (236) have been recommended as an odourless means of storage of thiols. The latter are readily regenerated by the action of piperidine (81CL1457). 

Oxidation of the substituted isothiazolium-2-imines 7 with H2O2 in AcOH gave stable 3-hydroperoxy-2-benzoylaminohexahydro-l,2-benzisothiazole 1-sulfoxide rac cis 8 and the sultam 9. The sultam 9 could then be converted into novel hydroxysultams 10 by reduction with Na2S03 / H2O in excellent yields. If necessary, 10 could be reoxidised to 9 with H2O2 <00JPR291>. 

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). 

Cycloaddition of benzyne intermediates with aminothiazadienes provide access to substituted 2,4-diamino-4//-l,3-benzothiazines 196 in high yields. The benzynes are prepared by the treatment of (phenyl)[o-(trimethylsilyl)aryl]-iodonium triflates with 1.5 equiv of tetrabutylammonium fluoride (Scheme 20). Interestingly, 3-substituted-l,2-benzisothiazoles 197 are obtained when 4 equiv of tetrabutylammonium fluoride is used <2005H(65)1615>. 

Other heterocycles which have received attention include the aminoisothiazoles and the 3-amino-2,l-benzisothiazoles. The former compounds give rise to bluish-red dyes or reddish-blue dyes if substituted by a nitro group but they have been of little commercial interest. However, dyes derived from 3-amino-6-nitro-2,l-benzisothiazole (69MI11200), such as structure (50), are blue to greenish-blue and have achieved commercial status. Dyes... 

Fluoro benzisothiazoles (6) were synthesized via carbonyl directed nucleophilic aromatic substitution. Displacement of the ortho fluoro substituent in 2,4-difluorobenzaldehyde, 2 4 -difluoroacetophenone and 2,4-difluorobenzophenone with benzyl mercaptan and potassium... 

A reaction of rather less general application, but one which produces valuable intermediates, is the treatment of dithiosalicylamide and its A-substituted derivatives with phosphorus pentachloride. Thus, A.A-diethyldithiosalicylamide (20) yields 3-chloro-2-ethyl-l,2-benz-isothiazolium chloride (21).14-16 This salt (21) is a versatile compound for example, heating it with diethylamine gives 3-diethylamino-l,2-benzisothiazole (22)16, treatment with base yields 2-ethyl-l,2-benzisothiazolinone (23), and reaction with ammonia, followed by hydrochloric acid, affords 3-ethylamino-l,2-benzisothiazole (24).14 This final reaction involves an interesting rearrangement which will be discussed in more detail in Sections II, C, 2 and II, C, 3. 

These compounds and their reactions will be dealt with in Section II, E, but it may be mentioned here that treatment of 1,2-benziso-thiazolinone (25) with phosphorus pentachloride,17 phosphoryl chloride,18,19 phosgene, or oxalyl chloride20,21 affords 3-chloro-l,2-benzisothiazole (26). If the 1,2-benzisothiazoline is substituted at the nitrogen atom, then a salt similar to 21 is the product. 

Substituted 1,2-benzisothiazoles are, generally, solids of higher melting point most compounds reported in the literature in the last 20 years are listed in the tables at the end of this chapter. 

Some ultraviolet absorption data are available for certain substituted 1,2-benzisothiazoles,13 21,27 as are limited NMR data.26,27... 

The parent compound in this series is formally tautomeric with l,2-benzisothiazole-3-thiol [Eq. (5)]. All the known compounds of this type are substituted at the nitrogen atom. 

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