2-Bromo-4-methylthiazole, reaction with

Bromothiazole (1) reacts with thiourea in alcohol to yield a mixture of dithiazolyl monosulfide (2) and A-4-thiazoline-2-thione (3) (Scheme 1) (4-6). Treatment of 2-bromo-4-methvlthiazole with potassium hydrogen sulfide in alcohol is reported to result in the formation of bis(4-methyl-2-thiazolylisulfide (7). which probably results from the reaction between the initially formed 2-mercaptothiazole and the initial 2-bromo-4-methylthiazole. 

As in the case of oxazoles, the pyridine-like N-atom makes electrophilic substitution reactions more difficult. Thus thiazole does not react with halogens. Donor substituents enhance the reactivity, e.g. 2-methylthiazole reacts with bromine to give 5-bromo-2-methylthiazole. Thiazole cannot be nitrated. 4-Methylthiazole reacts slowly to yield the 5-nitro compound, 5-methylthiazole even more slowly to give the 4-nitro compound, but 2,4-dimethylthiazole reacts fastest producing 2,4-dimethyl-5-nitrothiazole. Sulfonation of thiazole demands the action of oleum at 250°C in the presence of mercury(II) acetate, and occurs at the 5-position. Acetoxymercuration of thiazole with mercury(II) acetate in acetic acid/water proceeds stepwise by way of the 5-acetoxymercury compound and the 4,5-disubstituted product to 2,4,5-tris(acetoxymercury)thiazole. 

In 1987, Yamanaka s group described a Pd-catalyzed reaction of halothiazoles with terminal acetylenes [51]. While the yield for the Sonogashira reaction of 2-bromo-4-phenylthiazole (89) with phenylacetylene to afford 90 was moderate (36% after desilylation), the coupling of 4-bromothiazole and 5-bromo-4-methylthiazole with phenylacetylene gave the desired internal acetylenes 91 and 92 in 71% and 65% yield, respectively. 

Hence bromine in dichloromethane converted 2-methylthiazole into 5-bromo-2-methylthiazole in 48% yield (76JAP76/48655). In this reaction HBr was present as a base acceptor. In its absence the yield was halved, and with an equimolar proportion of aluminium chloride the yield fell to 10%. It is evident that although 2-methylthiazole can be brominated under mild conditions, its activity is sharply reduced by protic or aprotic acids capable of complexing with the annular nitrogen (86CHE663). 

In case of reaction of ethyl 2-bromo-4-methylthiazole-5-carboxylates with potassium fluoride the substitution was facilitated by crown ether [84],... 

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