5- Hydroxythiazole

Thiazole-N-oxides are prepared by the action at low temperature (-10°C) of hydrogen peroxide in acetic acid (474). 4-MethyIthiazole and 2,4-dimethylthiazole afforded the corresponding N-oxides with yields of 27 and 58%, respectively (Scheme 88). Thiazole-N-oxides without a methyl group in the 2-position are so unstable that they have a tendency to form 2-hydroxythiazoles and are decomposed by oxidation, whereas a 2-methyl group would prevent such rearrangement (474). 

Reaction wifli Salts and Esters of Thiocarbamic Acid 2-Hydroxythiazoles and Derivatives... 

Thus the condensation of dichloroether or chloroacetone fails to give the parent compound, 2-hydroxythiazole (158a), Rj = R2 = R3 = H (221). However, 2-hydroxythiazole can be obtained in 12% yield from chloro-acetaldehyde (386). The condensation of ammonium thiocarbamate with cf-chloroketones gives the corresponding 2-hydroxy derivatives in 25 to 70% yields (76, 221, 304, 412) (Table 11-24). These compounds condensed with ClP(S)(OEt)2 give the corresponding 2-thiazolyl-thiophosphates (791). 

TABLE 11-24 2-HYDROXYTHIAZOLE DERIVATIVES CARBONYL COMPOUNDS AND SALTS THIOCARBAMFC ACID (158a)... 

Hydroxythiazoles give 2-chIorothiazole derivatives almost quantitatively upon treatment with phosphorus oxychloride (221, 229, 428). This constitutes a convenient synthesis method for these compounds when the conversion of 2-aminothiazoles to 2-chlorothiazole derivatives fails. Esters of thiocarbamic acid or thiourethanes also react with a-halocarbonyl compounds to give the corresponding 2-alkoxythiazoles (50, 68, 209, 272). 

The cyclization of a-thiocyanatoketones (183) in aqueous acid, concentrated sulfuric acid in acetic acid and water, or alkaline solution leads to 2-hydroxythiazoles after dilution in water. 

TABLE 11-27. 2-HYDROXYTHIAZOLE DERIVATIVES BY CYCIJZATION OFa-THlOCYANATO KETONES IN ACIDIC MEDIA... 

With cr-thiocyanatoacetophenones, 4-aryl-2-hydroxythiazoles can be obtained in 80 to 90% yields in an acetic acid solution with the addition of dilute sulfuric acid (87, 392, 416, 428, 484, 519). 

These compounds can also be obtained from the corresponding 2-hydroxythiazoles and phosphorylchloride (68, 109, 137, 221, 229, 428, 519), but the method is restricted by the availability of the hydroxy compounds, which are discussed in another section (Chapter VII),... 

The nucleophiles used are OH (32) [the 2-hydroxythiazole can also be obtained by acidic hydrolysis with strong mineral acids (33)], OR" (5, 8, 30, 34), SR" (8, 9, 12), ArSH (35), and amines (4, 7, 14, 33). Benzamide also reacts with 2-bromothiazole, yielding 2-benzamidothiazole (36). Sulfonamide also reacts with 2-halogenothiazoles in presence of a base and copper powder, yielding 2-sulfonamidothiazoles (37, 38). 

A novel application of the Ritter reaction to the synthesis of 2-hydroxythiazoles was reported recently by Yura,19 using acetylenic thiocyanates. 

Both 2-hydroxythiazole and 2-mercaptothiazole have been studied to determine the position of the protomeric equilibrium (8a 8b 8c). Most studies indicate that (8b) is largely predominant in neutral solution for X = O or S. The equilibrium constant KT of the protomeric system (12a) (12b) for 4,5-dimethyl-A4-thiazoline-2-thione in water (Scheme 5) has been evaluated as KT= 106 (69ACS2879). These compounds are strongly... 

Hydroxythiazole and benzothiazole exist mainly in the A4-thiazolin-2-one form (185b). They are quite stable and react mostly in addition-elimination reactions rather than undergoing ring opening reactions. 

The cyclization of a-thiocyano ketones (250) in aqueous acid or alkaline solution leads to 2-hydroxythiazoles (251) after dilution with water (Scheme 184). The yields are moderate. With a-thiocyanoacetophenones (252), 4-aryl-2-hydroxythiazoles (254) can be obtained in high yields (Scheme 185). Very early, Arapides (1888LA(249)27> was able to demonstrate the formation of the acyclic compound (253) in the course of this reaction. 

By condensing carbon oxysulfide with a-aminonitriles, the corresponding 5-amino-2-hydroxythiazoles can be obtained (Scheme 194). In the presence of benzaldehyde the reaction leads to 5-benzylideneaminothiazole derivatives in good yields. 

Hydroxy derivatives are expected to show the same tautomeric preferences for the oxo form in ortho and para positions to the nitrogen as in the parent monocycle. Thus, for the 2-hydroxythiazole (395) comparison of the spectroscopic data with the data for its AT-methyl and O-methyl derivatives is consistent with the oxo form the same preference has been shown for its [5,4-c] isomer (68CJC691). 

Hydroxythiazole, from chloroacetaldehyde and ammonium thiocaibamate, 258 4-Hydroxy-2-thiazolecarboxylic acid ethyl ester, self condensation of, 294 synthesis of, from ethylcyanoacetate and ethylthioglycolate, 294 from thioamides and a-haloacids or esters, 294... 

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