Benzylic C-H isocyanation/amine coupling sequence enabling high-throughput synthesis of pharmaceutically relevant ureas

C(sp(3))-H functionalization methods provide an ideal synthetic platform for medicinal chemistry; however, such methods are often constrained by practical limitations. The present study outlines a C(sp(3))-H isocyanation protocol that enables the synthesis of diverse, pharmaceutically relevant benzylic ureas in high-throughput format. The operationally simple C-H isocyanation method shows high site selectivity and good functional group tolerance, and uses commercially available catalyst components and reagents [CuOAc, 2,2 '-bis(oxazoline) ligand, (trimethylsilyl)isocyanate, and N-fluorobenzenesulfonimide]. The isocyanate products may be used without isolation or purification in a subsequent coupling step with primary and secondary amines to afford hundreds of diverse ureas. These results provide a template for implementation of C-H functionalization/cross-coupling in drug discovery.

Automated summary

This study presents a straightforward C(sp(3))-H isocyanation method for the efficient synthesis of pharmaceutically relevant benzylic ureas, demonstrating high site selectivity and functional group tolerance. The approach utilizes commercially available catalyst components and reagents, allowing for the direct use of isocyanate products in subsequent coupling steps to generate diverse ureas, thus serving as a template for drug discovery through C-H functionalization/cross-coupling.