The last decades have seen major developments in two, so far mostly unconnected fields, which if combined, have the potential to transform modern drug discovery. On the chemistry side, C-H activation methodologies applied to late-stage functionalization (LSF) of drug-like molecules allow for rapid, controlled synthesis of new analogues. On the technology side, the high-throughput experimentation (HTE) process has allowed for expeditious synthesis of compound libraries and reaction optimization. Herein we present the development of a methodology directed C-H activation specifically designed with LSF and HTE in mind. By relying solely on a soluble Cp*Ir(III) precatalyst and azides as the nitrogen source, we were able to bypass the use of low-solubility oxidants and additives, allowing for the use of stock solutions and sub-microliter reaction volumes. The reaction was successfully applied to the amination of building blocks bearing 21 distinct directing groups. LSF applications allowed for the functionalization of a series of complex drugs and natural products with excellent regioselectivity and functional group tolerance. The utility of the method is further aided by the generation of informer libraries and functional group tolerance studies, giving the potential user a good understanding of the limitations and opportunities for applications on complex substrates. We believe that the utility for LSF and HTE, combined with functional group tolerance within complex molecules and predictable reaction outcome, will render the presented methodology valuable for the synthetic, medicinal chemistry and broader organic chemistry communities.

C-H activations meet high-throughput experimentation: Development of general Ir-catalyzed directed C-H aminations

ACS Spring 2022

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