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. 

An iridium‐catalyzed selective ortho‐monoiodination of benzoic acids with two equivalent C−H bonds is presented. A wide range of electron‐rich and electron‐poor substrates undergo the reaction under mild conditions, with >20:1 mono/di selectivity. Importantly, the C−H iodination occurs selectively ortho to the carboxylic acid moiety in substrates bearing competing coordinating directing groups. The reaction is performed at room temperature and no inert atmosphere or exclusion of moisture is required. Mechanistic investigations revealed a substrate‐dependent reversible C−H activation/protodemetalation step, a substrate‐dependent turnover‐limiting step, and the crucial role of the Ag^I additive in the deactivation of the iodination product towards further reaction.

Late-stage functionalization (LSF) has over the past years emerged as a powerful approach in the drug discovery process. At its best, it allows for rapid access to new analogues from a single drug-like molecule, bypassing the need for de novo synthesis. To be successful, methods able to tolerate the diverse functional groups present in drug-like molecules that perform under mild conditions are required. C−H methylation is of particular interest due to the magic methyl effect in medicinal chemistry. Herein we report an iridium-catalyzed carboxylate-directed ortho C−H methylation and d3-methylation of benzoic acids. The method uses commercially available reagents and precatalyst and requires no inert atmosphere or exclusion of moisture. Substrates bearing electron-rich and electron-poor groups were successfully methylated, including compounds with competing directing/coordinating groups. The method was also applied to the LSF of several marketed drugs, forming analogues with increased metabolic stability compared with the parent drug.

Herein, we report an iridium-catalyzed directed C–H amination methodology developed using a high-throughput experimentation (HTE)-based strategy, applicable for the needs of automated modern drug discovery. The informer library approach for investigating the accessible directing group chemical space, in combination with functional group tolerance screening and substrate scope investigations, allowed for the generation of reaction application guidelines to aid future users. Applicability to late-stage functionalization of complex drugs and natural products, in combination with multiple deprotection protocols leading to the desirable aniline matched pairs, serve to demonstrate the utility of the method for drug discovery. Finally, reaction miniaturization to a nanomolar range highlights the opportunities for more sustainable screening with decreased material consumption.