Issue 30, 2021

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

Abstract

C(sp3)–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(sp3)–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.

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

Supplementary files

Article information

Article type
Edge Article
Submitted
12 4 2021
Accepted
28 6 2021
First published
02 7 2021
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY-NC license

Chem. Sci., 2021,12, 10380-10387

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

S. Suh, L. E. Nkulu, S. Lin, S. W. Krska and S. S. Stahl, Chem. Sci., 2021, 12, 10380 DOI: 10.1039/D1SC02049H

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