5-Phenylisothiazole

Sometimes compounds which exist predominantly in the hydroxyl form give products of N-methylation with diazomethane, for example 3-hydroxy-5-phenylisothiazole (63AHCi2)245) of course, the ambident anion (493) is an intermediate. 3-Hydroxypyrazoles, under rather severe conditions, can be converted into 3-chloropyrazoles with POCI3 <66AHQ6)347). 

Thiol-thione tautomers have not been extensively studied, but UV and IR evidence show that 5-phenylisothiazole-3-thiol exists in the SH form. Ring-chain tautomerism of 2,3-dihydro derivatives of 1,2-benzisothiazole can occur (26a 26b) and the position of equilibrium depends very much on the solvent, physical state and nature of the substituents (69JOC919, 81KGS1209). 

The only example of a 3-aminoisothiazole so far described is 3-amino-5-phenylisothiazole (31), which is formed by oxidative cyclizationofthiobenzoylacetamidine (30). Compound 31 brominates normally, but diazotization and coupling with jS-naphthol give a mixture of the azo compound and 3-hydroxy-5-phenylisothiazole. ... 

Amino-5-phenylisothiazole is slightly less basic (pA 2.27) than the isomeric 5-amino-3-phenylisothiazole pK 2.65). Both 3- and 5-aminoisothiazoles can theoretically exist in tautomeric forms, but the presence of bands in the infrared spectrum at 3490 and 3400 cm (in CCI4) indicates that, at least in the case of 3-amino-5-phenylisothiazole, the amino form predominates. See also reference 17b. 

Calculations allow one to justify the observed behavior (Fig. 19) (99MI233). In the case of 3- and 5-phenylisothiazole, the reaction should implicate a Dewar isomer, because the excited triplet isothiazole derivative cannot be converted into the corresponding biradical. 

Photochemical reactions of both 3- and 5-phenylisothiazoles were described in the literature giving in each case, low yields of a mixture of phenylthiazoles . 

Coupling comparable with that found in awft -oximes is also observed in cyclic systems such as pyridine, quinoline, 5-phenylisothiazole and isoxazole in which the nitrogen lone-pair lies E(cis) to the adjacent hydrogen. Confirmation of the importance of the lone-pair orientation is further derived from the fact that removal of the nitrogen lone-pair by protonation or quatenization results in the reduction of H) to the value found in... 

Goerdeler and Mittler18 employed the appropriate thiones to prepare 3 amino-, 3-hydroxy- and 3 methoxy-5-phenylisothiazoles [Eq. (1)]. 

Hydroxy- and alkoxyisothiazoles are readily available by direct ring synthesis12,18,28, 38,44,52 125 (see Section I) and, therefore, other methods have been little explored. However, 3-hydroxy-5-phenyl-isothiazole has been prepared from the corresponding diazonium compound,18,118 and 4-cyano-3-methoxy-5 phenylisothiazole from 3-chloro-4-cyano-5-phenylisothiazole and sodium methoxide.57 3-Iso-thiazolones have been obtained from penicillin sulfoxide128 and 1,4-thiazepines which are related to penicillins (Scheme 35).127... 

UV studies suggested that 3-hydroxyisothiazole exists as such in nonpolar solutions, whereas the NH form predominates in more polar solvents.129 3-Hydroxy-5-phenylisothiazole, however, appears to exist in the OH form even in methanolic solution.18... 

The action of diazomethane on 3-hydroxyisothiazole gave approximately equal proportions of 0- and iV-methyl products,129 whereas 3-hydroxy-5-phenylisothiazole gave exclusively an A-methyl derivative.18 Nucleophilic reagents lead to ring cleavage,132-134 which will be discussed in a later section (see Section IV). 

Dimercapto-4-cyanoisothiazole is alkylated primarily on the 3-mercapto group in agreement with molecular orbital calculations.143 A 5-methylmercapto group may be displaced by other nucleophiles such as hydrazine122 or alkoxide.51 3-Mercapto-5-phenylisothiazole has been oxidized to the 3-sulfonic acid and sulfonamide.66... 

In benzene solution 56 phototransposes (Scheme 38) only by the electrocyclic ring closure-heteroatom migration pathway to yield 51, 52 and 54 in 2%, 15%, and 5% yields respectively. In the presence of TEA, however, the major product (Scheme 39) of the photoreaction of 56 is 5-phenylthiazole (53) formed in 14% yields, with 52 and 54 formed in 4% and 5% yields respectively. 4-Deuterio-5-phenylisothiazole (56-4d) also phototransposed (Scheme 40) to 4-deuterio-5-phenylthiazole (53-4d), confirming that this product was formed by the N-2-C-3 interchange pathway, and 52-5d and 54-4d as expected for products formed by the electrocyclic ring closure-heteroatom migration mechanistic pathway. 

A related reaction is the oxidation of isothiazoles to the corresponding oxides. Treatment of 3-amino-5-phenylisothiazole 16 with persulfuric acid gave 17 in 60% yield.24 Nitric acid in acetic anhydride has also been used.25 In another example, oxidation of 18 gave 19 in 99% yield.26 Noteworthy is the fact that the other sulfur atoms are unaffected by this oxidation. 

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