Functionalized 5‐Amino‐4‐cyanoxazoles, their Hetero‐ and Macrocyclic Derivatives: Preparation and Synthetic Applications

An approach to a series of new 5‐amino‐4‐cyanoxazoles is described. Synthesis of the title compounds relied on a two‐step sequence including heterocyclization of 2‐amido‐3,3‐dichloroacrylonitriles with aliphatic secondary amines (dimethylamine, morpholine), primary aliphatic amines with active functional groups (2‐aminoethanol and glycine ethyl ester), and aniline. An efficient and straightforward protocol introduces a carboxylate group at the C‐2 position of 5‐amino‐4‐cyanoxazoles, connected to the heterocycle directly or through an aliphatic linker. This carboxylic group is an attractive motif that can be found in a variety of drug‐relevant compounds and also used for further modifications. Furthermore, efficient transformations of selected trisubstituted compounds were used to demonstrate their rich synthetic potential – e. g., as precursors to 2‐(4‐cyano‐5‐(dimethylamino)oxazol‐2‐yl)acetamides, oxazole‐containing macrocyclic structures, 2‐(oxazol‐2‐yl)acetamides, amino pyrazoles, 3‐(4‐cyano‐5‐aminoxazol‐2‐yl)coumarins, and oxazole amino acids. An approach for the synthesis of new 5‐amino‐4‐cyanoxazoles with carboxylate group at the C‐2 position, connected to the heterocycle directly or through an aliphatic linker, was developed. This process features readily available starting materials, simple operations, and good to high yields. Wide synthetic applicability of the obtained compounds was also successfully demonstrated by further modifications.