2-Methylthiazole, bromination

Thiazole does not undergo bromination easily, though 2-methylthiazole brominates at C-5 when the... 

Thiazole does not undergo bromination easily, though 2-methylthiazole brominates at C-5 when the 5-position is not free no substitution occurs, thus 2,5-dimethylthiazole, despite its two activating substituents, is not attacked. Halogenation of simple oxazoles has not been reported. 

When unsubstituted, C-5 reacts with electrophilic reagents. Thus phosphorus pentachloride chlorinates the ring (36, 235). A hydroxy group in the 2-position activates the ring towards this reaction. 4-Methylthiazole does not react with bromine in chloroform (201, 236), whereas under the same conditions the 2-hydroxy analog reacts (55. 237-239. 557). Activation of C-5 works also for sulfonation (201. 236), nitration (201. 236. 237), Friede 1-Crafts reactions (201, 236, 237, 240-242), and acylation (243). However, iodination fails (201. 236). and the Gatterman or Reimer-Tieman reactions yield only small amounts of 4-methyl-5-carboxy-A-4-thiazoline-2-one. Recent kinetic investigations show that 2-thiazolones are nitrated via a free base mechanism. A 2-oxo substituent increases the rate of nitration at the 5-position by a factor of 9 log... 

Halogenation (e.g., bromination) takes place in chloroform for the 2,4-dialkylthiazoles, and the majority of studies have been of 2,4-dimethylthiazole (227, 228). In other cases and in acetic or stronger acids, substitution occurs at the 5-position and is promoted by electronreleasing groups in the 2-position. When the releasing group is in the 4-(or 5-)-position, steric hindrance may decrease the yield of substitution at the 5- (or 4-) position. Nevertheless, the thiazole nucleus is not very reactive since 4-methylthiazole and 2.5-dimethylthiazole are inert in dilute sulfuric acid with bromine (229-231). 

Simple thiazole cannot be directly halogenated under standard conditions, but 2-methylthiazole can be brominated at the 5-position. If there are two substituents on the thiazole ring, the last vacant position then may be readily halogenated [1,2],... 

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). 

Acetamido-4-methylthiazole when enzymatically brominated is converted to a mixture of 2-acetamido-4-methyl-5-bromothiazole (200) and dibromacetamido-4-methyl-5-bromothiazo]e (201) (Scheme 127) (138, 436). 

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. 

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