Merging Directed C−H Activations with High-Throughput Experimentation: Development of Predictable Iridium-Catalyzed C−H Aminations Applicable to Late-Stage Functionalization

Abstract

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 accessible directing group chemical space for the reaction, in combination with functional group tolerance screening and substrate scope investigations, allowed for the generation of an empirical predictive model to guide 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 nano molar range highlights the opportunities for more sustainable screening with decreased material consumption.

Recent advances in metal directed C–H amidation/amination using sulfonyl azides and phosphoryl azides

“…Remarkable progress has been achieved in the field of C-H bond activation chemistry over the past two decades. 36,41 Two significant terms commonly encountered in metaldirected C-H amidation/amination are C-H activation and C-H functionalization. C-H functionalization refers to a chemical process that involves the conversion of a C-H bond into another element or functional group (often represented as a functional group R), irrespective of the underlying mechanism.…”

“…39,40 C-H activation refers to the transformation of a previously unreactive C-H bond into a reactive species through the action of a transition metal catalyst, leading to the formation of a C-bound metal complex. [39][40][41][42][43][44] This intermediate species can then undergo further functionalization. Therefore, C-H acti-vation reactions can be considered a specific subset within the broader category of C-H functionalization reactions.…”

“…Therefore, C-H acti-vation reactions can be considered a specific subset within the broader category of C-H functionalization reactions. A multitude of articles [37][38][39][40][41][42][43][44] have delved deeply into the complex inner workings and the myriad ways in which this reaction can manifest. In some recent forward-looking pieces by T. Dalton and his team 42 in 2021, and E. Weis 41 in 2022, a fascinating array of research areas were explored, all with the common goal of addressing the sustainability hurdles linked to the activation of C-H bonds.…”