Merging Directed C–H Activations with High-Throughput Experimentation: Development of 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 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.

A Brief Introduction to Chemical Reaction Optimization

“…Examples include SPT Labtech’s Mosquito positive displacement multichannel pipetting system, which can dispense and aspirate volumes in the range of 25 nL to 1.2 μL, or Beckman’s Echo liquid handler, which can dispense volumes in the range of 2.5 nL to 5 μL using Echo Acoustic Technology. These platforms are increasingly used for nanoscale (or even picoscale) synthesis of pharmaceutically relevant compounds with examples of also incorporating nanoscale biological screening in a “direct-to-biology” approach. − …”

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…”

“…Notably, iridium catalysts have demonstrated effectiveness in the direct C-H amination of unactivated arenes using phosphoryl azides as nitrogen sources. [32][33][34][35][36] In summary, the choice of a metal catalyst for directed C-H amination depends on various factors, including the substrate, the desired product, and the reaction conditions. To gain a better understanding of metal-mediated C-H activation chemistry, it is essential to establish precise definitions for key terms commonly encountered in this field before delving deeper into the discussion.…”

“…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.…”

Multidimensional Screening Accelerates the Discovery of Rhodium Catalyst Systems for Selective Intra- and Intermolecular C–H Amidations

“…Recent advances in high-throughput experimentation (HTE) enabled the fast examination of multiple reactions with minimum resources in a relatively short period of time. − Thus, the HTE approach has been successfully applied to pharmaceutical synthesis − and catalyst design. − Benefitting from the HTE logic and known accessibility to both Cp X - and LX-type compounds, we envisaged generating a wide array of Cp X M­(LX) complexes in situ by simple premixing of [Cp X MCl 2 ] 2 and LX co-ligands. Moreover, we also envisioned additionally screening the metal centers and nitrenoid precursors (Scheme b, right).…”