2- Bromo-5-chlorothiazole

The Hantzsch synthesis of thiazoles is an excellent method for the synthesis of simple thiazoles, however for some substituted examples low yields have been reported as a result of dehalogenation of the a-haloketone. An alternative method for the synthesis of highly substituted thiazoles has been reported, thus starting from the 2-bromo-5-chlorothiazole 76 it was possible to introduce substituents selectively at the 2-position by a palladium-catalysed cross coupling reaction to give 77 (74-92%). In order to introduce a substituent into the 5-position,... 

This method has been applied to the synthesis of 4-methyl (659), 4-aryl (416, 519, 659), 4,5-dimethyl (137, 220, 221), 4,5-dialkyl (229, 681), 4-methyl-5-O-acetoxyethyl) (229), 4-methyl-5-(j3-carbethoxyethyl) (229), 4-ary 1-5-bromo (579), and 2-chlorothiazoles from the corresponding a-thiocyanatoketones (Table 11-28). 

The 4- and 5-chloro isomers are best made by selective reductive de-halogenation of 2,4- and 2,5-dichlorothiazoles (62BSF1735). 5-Bromo-2-chlorothiazole was made from the 2-amino-5-bromo derivative (45HCA985). Under homolytic conditions (NCS in the presence of dibenzoyl peroxide) 4-methylthiazole gave a mixture of the 5-chloro,... 

The halogen dance reaction is also applied to the synthesis of the 5-substituted 4-bromo-2-chlorothiazole derivatives 89 <07SL3016>. Treatment of 5-bromo-2-chlorothiazole with 1.2 equiv. of LDA at -80 °C brings about full conversion to the halogen dance product 88, which is trapped with various electrophiles to give the 5-substituted thiazoles 89. For example, 4-bromo-5-trimethylsilyl-thiazole is obtained in 71% yield when 5-bromo-2-... 

An operationally simple halogenation of 4,5-dimethyl-2-arylthiazoles provides a regioselective approach to bromo- or chloro-methyl substituted thiazoles <04TL69>. Thus, treatment of 117 and its hydrochloride salt with NBS and NCS affords 4-bromothiazole 118 and 4-chlorothiazole 119, respectively, with >99% regioselectivity. The remarkable regioselectivity observed may arise from a Pummerer-type rearrangement mechanism via 120. 

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