Isothiazolium

Isothiazoles and isothiazolium cations are attacked by carbanions at sulfur and on recyclization can give thiophenes, illustrated by (147) -> (148). 2-Alkyl-3-isothiazolinones e.g. 149) are also vulnerable to nucleophilic attack at sulfur (72AHC 14)1). 

Benzisothiazole is also stable to hot alkali (72Ahc(14)43), in marked contrast to 2,1-benzisoxazole, but isothiazolium salts are dequaternized (77IJC(B)886). 1,2-Benzisothiazole... 

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. 

Alkyl-3-chloroisothiazolium chlorides (131) react with ammonia to give 3-alkyl-aminoisothiazoles (132) (80MI41700), but with amines give mixtures of isomeric isothiazolium salts (133 and 134 Scheme 20) (79JOC1118), compound (134) presumably being formed by a similar mechanism to compound (132). 2-Alkyl-3-chloro-l,2-benzisothiazolium salts... 

The first synthesis of stable 3-hydroperoxy-sultams (24) which are a new class of sultam with oxidising properties, was reported. The synthesis involved oxidation of the isothiazolium salts (23) with hydrogen peroxide in acetic acid. Reduction of (24) with aqueous sodium bisulphite afforded the corresponding novel 3-hydroxysultams whereas thermolysis in ethanol resulted in the elimination of water to give 3-ketone derivatives, which are versatile as dieneophiles <96T783>. 

Base-induced dimerization of isothiazolium salts containing an active methyl group in the 5-position provides a flexible approach for the synthesis of novel substituted 6aA4-thia-l,6-diazapentalenes. For example, salts 198 and 199 upon treatment with dicyclohexylamine in DMSO yielded the thiadiazapentalenes 200 as shown in Equation (51) and Table 27 <1996MOL142>. 

Table 27 Base-induced dimerization of isothiazolium salts 198 and 199 (Equation 51)...

Accordingly, iV-phenyl-substituted isothiazolium salts bearing a benzo crown ether substituent were employed in this synthetic protocol and led to the synthesis of various crown ether-substituted 6aA4-thia-l,6-diazapentalenes 201... 

The synthesis of novel substituted 6aA4-thia-l,6-diazapentalenes 33 was achieved by a base-induced dimerization of two isothiazolium salts <2001PS(170)29>. It was shown that A -phenyl-substituted isothiazolium salts having active 5-methyl or 5-methylene groups can easily be obtained by reaction of (l-thiocyanatovinylaldehydes and substituted anilines <1995CZ175>. 

The conversion of functionalized arenes as represented by the general formula 97, into isothiazolium compounds (99) has been achieved by the sequence shown in Scheme 117.180 From a synthetic viewpoint, transformation of cyclopalladated products into thiocyanate derivatives is more efficiently achieved using monomeric dithiocarbamato complexes (98) rather than dimeric compounds. The generation of analogous dithiolylium perchlorates by a related procedure is described later (see Section IV,H). 

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>. 

For the 1,2-dithiolium system (35, R = CeHs, R = H) exchange was fotmd in the 3-position when carried out in CFSCOOD-D2O at 74°. The rate decreases as the concentration of acid increases, suggesting base-catalyzed exchange, the mechanism probably being analogous to isothiazolium exchange (Scheme 6). 

Replacement of a carbon in the thiazolium or isothiazolium cation by nitrogen to yield the thiadiazolium salts (36) and (37) increases the deprotonation rate by between 10 and 10. These compounds as well as 1,3,4-thiadiazole (38) and 1,2,3-thiadiazole (39) have been studied by Olofson et as part of a series of five-membered heterocyclic... 

With isothiocyanates, 57 generally yields the isothiazolium betaines 66 (Scheme 18). However, when R is bulky an equilibrium exists with the carbodiimide 67, which gives the imidazolium betaine 68 on heating for R = /Pr or spontaneously for R = Ph. Alternative mechanisms have been discussed. 

Hartung and co-workers have reported that oxidation of isothiazolium salts such as 13 with H2O2 in AcOH led to stable 3-hydroperoxy-2-phenylhexahydro-l,2-benzisothiazole 1-oxides 14 which could be isolated in fair-to-good yields (38-70%). 3-Hydroperoxy and 3-hydroxy sultams were observed as over oxidation products in some cases and was dependent on the substituent present in the 2-aryl ring <99HCA685>. 

Dihydro-1,3-thiazine derivatives (208) and (210) are prepared by the addition of alkyl propiolates to thioureas and dithiocarbamic acids respectively. In the latter case it is necessary to cyclize the initial products (209) with acetic anhydride (Scheme 96) (70AJC51). Ring expansion of isothiazolium chlorides (211) by the action of potassium cyanide provides a route to imine derivatives (212 Scheme 97) (79TL1281). 

From Isothiazolium Salts and Other Reactions. An interesting synthesis of benzo-TA is based on recyclization of chlorothiazolium salts 93 by the action of formamides. The quantitative yield of products depends on the formamide used and the reaction conditions. If R is a sterically encumbered group (Me2CH, Me3C, or Ph), benzo-TAs 94 are formed, while other formamides give isomers 95. With 1,2-dichlorobenzene, only the isomers 94 were obtained. The regioselectivity of this reaction was explained by the position of nucleophilic attack of the formamide (71CB3757) (Scheme 30). 

Isothiazolium salts have been reconverted to isothiazoles by dry distillation27 and by treatment with ammonia.145 The latter reaction incidentally confirms that isothiazoles are alkylated on the nitrogen and not the sulfur. Isothiazolium salts with a vacant 3-position have given 3-thiones on treatment with sulfur in pyridine [Eq. (16)].63,64... 

Finally some compounds related to the thiathiophthene no-bond resonance system may be regarded as containing contributions from isothiazolium forms (8 <-> 9).146... 

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. 

Bicyclic 5-5 Systems Three Heteroatoms 1 2 Table 12 Thieno[3,2-c]isothiazolium salts. 

Table 13 Thieno[3,2-rf]isothiazolium, furo[3,2-rf]isothiazolium, and pyrrolo[3,2-t/]isothiazolium...

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