Late-Stage Amination of Drug-Like Benzoic Acids: Access to Anilines and Drug Conjugates through Directed Iridium-Catalyzed C−H Activation

Abstract

The functionalization of C−H bonds, ubiquitous in drugs and drug-like molecules, represents an important synthetic strategy with the potential to streamline the drug-discovery process. Late-stage aromatic C−N bond–forming reactions are highly desirable, but despite their significance, accessing aminated analogues through direct and selective amination of C−H bonds remains a challenging goal. The method presented herein enables the amination of a wide array of benzoic acids with high selectivity. The robustness of the system is manifested by the large number of functional groups tolerated, which allowed the amination of a diverse array of marketed drugs and drug-like molecules. Furthermore, the introduction of a synthetic handle enabled expeditious access to targeted drug-delivery conjugates, PROTACs, and probes for chemical biology. This rapid access to valuable analogues, combined with operational simplicity and applicability to high-throughput experimentation has the potential to aid and considerably accelerate drug discovery.