Phenylisothiazoles

Vernin et al. independently observed that during the irradiation in benzene of 2-iodothiazole to generate 2-thiazolyl radicals, the resulting 2-phenylthiazole (216) isomerized into a mixture of 4-phenylthiazole (214) and 3-phenylisothiazole (213) (Scheme 103) (489). Marking the 4- and... 

C3NS S N — — — Methyl 3-hydroxy-4-phenylisothiazole-5-sulfonate dehydromethionine... 

Phenylisothiazole is nitrated predominantly in the meta position of the phenyl group, whereas 4-phenylisothiazole is nitrated ortho and para in the phenyl group <72AHC(14)1). Nitration of 3-phenyl-l,2,4-oxadiazole gives a mixture of m- and p-nitrophenyl derivatives <6301196). 

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). 

Amino-3-phenylisothiazole cyclizes on reaction with 2-azido-3-ethylbenzothiazolylium borofluoride to give compound (110) (78HCA108). 4-Aminoisothiazole reacts with 1,4-dibromobutane to give 4-pyrrolidinylisothiazole (80MI41700). 

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. 

However, such an explanation was not convincing for other authors. Maeda and Kojima found that the irradiation of 2-phenylthiazole in ethanol at 80°C led to the same products described before but in a different ratio. Under the same reaction conditions, 5-phenylthiazole gave 4-phenylisothiazole, while 4-phenyl-thiazole was converted into 3-phenylisothiazole. The most important observation those authors made was that deuterium incorporation occurred when the reaction was carried out in benzene at 80°C in the presence of deuterium oxide. In fact, 2-phenylthiazole furnished deuterated 3-phenyl-4-deuteroisothiazole and... 

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. 

Recently, the photochemical behavior of 4-phenylisothiazole has been reanalyzed (98JOC5592). This compound, on irradiation in ether, gave ring-opening products and 4-phenylthiazole (3% yield) (Scheme 40). The irradiation in methanol... 

Fig. 19. Relative energy of the excited states of 3-phenylisothiazole and of some reactive intermediates.

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... 

Photolysis (4045-4078 A) of anhydro-5-hydroxy-l,3,2-oxa-thiazolium hydroxide (169, R = Ph) gives benzonitrile (77%), sulfur (> 90%), and carbon dioxide. This reaction has been interpreted as involving the bicyclic intermediate 172, which then transforms via the thiazirin 173 into the thiobenzonitrile oxide 174. The postulated intermediates 172 and 173 are analogous to those proposed (139 and 140) for another photoreaction. The possible involvement of the thionitrile oxide 174 is indicated by its trapping with dimethyl acetylene dicarboxy-late this yields 4,5-dimethoxycarbonyl-3-phenylisothiazole (175). ... 

The anhydro-5-hydroxy-l,3,2-oxathiazolylium hydroxide system (83) and DMAD thermally yielded an intermediate 1 1 cycloadduct (84) which lost C02 forming dimethyl 2-phenylisothiazole-3,4-dicarboxylate (85) (72CB196). Irradiation of (83) in neat DMAD formed the valence tautomer (82) which lost C02 to give the nitrile sulfide dipole (81) captured by DMAD to form dimethyl 3-phenylisothiazole-4,5-dicarboxylate (80) (75JA6197) (see also CHEC 4.17). 

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