2-Chlorooxazole-4-carboxylate

Substituted oxazolo[4,5-Z ]pyridines 138 (and quinolines) were synthesised in high yields from zwitterion or hydroxyamidine derivatives 137, obtained by treatment of non-enolisable amides 136 with the complex base NaNH2-/-BuONa, via hetaryne intermediates. Intramolecular cyclization and NH3 elimination to give 138 were performed in dimethylacetamide by heating or microwave irradiation <03S2033>. Different approaches to oxazolo[4,5-c]quinoline-4(5/f)-ones from ethyl 2-chlorooxazole-4-carboxylate have also been described <03OL2911>. 

The readily available ethyl 2-chlorooxazole-4-carboxylate proved to be a versatile scaffold for the synthesis of 2,4-disubstituted oxazoles and 2,4,5-trisubstituted oxazoles. 

By using a sequence of regiocontrolled halogenation and palladium-catalyzed coupling reactions, the synthesis of variously substituted oxazoles from 2-chlorooxazole-4-carboxylate was accomplished. The methodology was applied to the synthesis of a series of 2,4-disubstituted, 2,5-disubstituted, and 2,4,5-trisubstituted oxazoles (Equation 37) [37]. 

Disubstituted oxazole 26 was prepared from 2-chlorooxazole-4-ethylcarboxylate via the Suzuki coupling with phenylboronic acid [26]. The carboxylic functionality at C(4) of 26 could then be exploited by a variety of synthetic transformations. 

It has been reported2-61 that 2-substituted 5-ethoxyoxazole-4-carboxylic acids on treatment with phosphorus pentachloride give the corresponding acid chlorides (252), which rearrange spontaneously or on heating to the 5-chlorooxazole-4-carboxylates (253). 

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