Oxazole with diverse 2-substitutents

Simple triazoles are thermally stable to ca. 300°C. However, triazole carboxamides, when heated to 150°C in sulfolane, rearrange with the elimination of nitrogen to give 2-substituted oxazoles. The reaction is general and it is useful for the synthesis of oxazoles with diverse 2-substitutents in excellent yields even for bulky substituents (Scheme 1). This reaction does not occur photochemically... 

The Diels-Alder reaction of oxazoles with alkenes, alkynes, and heterodieno-philes has become a valuable tool for the construction of highly substituted pyridines, furans, and other heterocycles and has now been exploited for the synthesis of diverse compounds from pharmaceuticals to complex natural products. These reactions have been extensively reviewed. The purpose of this chapter is to provide an introduction to the use of oxazoles in Diels-Alder cycloadditions and an update on these reactions since 1985. 

The Diels-Alder reaction of oxazoles with alkynes has become a preferred method for the synthesis of substituted furans with diverse applications. A large number of early examples of this reaction have been tabulated. Activated dienophiles such as acetylenic ketones and esters can be used, although unactivated alkyl, aryl, and silyl alkynes have been used as well. In particular, the reaction of 4-phenyloxazole with substituted acetylenes is frequently used for preparing 3,4-disubstimted furans. Cycloadducts derived from 4-phenyloxazole typically decompose under milder conditions than 4-alkyloxazoles, allowing the synthesis of a wider range of functionalized furans. Several examples are shown below. 

Oxazoles and benzoxazoles are viable participants in the heteroaryl Heck reaction, whereby the alkyl halide or aryl halide is coupled to the unfunctionalized oxazole. First developed by Ohta and colleagues, it was demonstrated that a diverse array of aromatic heterocycles can be substrates in the reaction with chloropyrazines. While substitution was expected to occur at the 2-position, the reaction with chloropyrazine as the aryl halide resulted in substitution at the 5-position. When benzoxazole is used as the coupling partner, substitution is effected at the 2-position. More recently, a systematic study by Strotman and co-workers has demonstrated that slight modifications of the reaction conditions can allow completely regioselective coupling at either the 2- or 5-position. ... 

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