Palladium (II)‐Catalyzed C−H Activation with Bifunctional Ligands: From Curiosity to Industrialization

Author:

Wu Kevin1,Lam Nelson2,Strassfeld Daniel A.1,Fan Zhoulong1,Qiao Jennifer X.3,Liu Tao4,Stamos Dean5,Yu Jin‐Quan1ORCID

Affiliation:

1. Department of Chemistry Scripps Research Institute 10550 North Torrey Pines Road La Jolla CA 92037 USA

2. Department of Chemistry Cambridge University Cambridge CB2 1EW UK

3. Small Molecule Drug Discovery Bristol-Myers Squibb Research and Development 250 Water Street Cambridge MA 02141 USA

4. Discovery Chemistry Research & Technology Eli Lilly and Company Lilly Biotechnology Center 10290 Campus Point Dr San Diego CA 92121 USA

5. Research & Development Flagship Pioneering 55 Cambridge Parkway Suite 800E Cambridge MA 02142 USA

Abstract

AbstractIn 2001, our curiosity to understand the stereochemistry of C−H metalation with Pd prompted our first studies in Pd(II)‐catalyzed asymmetric C−H activation (RSC Research appointment: 020 7451 2545, Grant: RG 36873, Dec. 2002). We identified four central challenges: 1. poor reactivity of simple Pd salts with native substrates; 2. few strategies to control site selectivity for remote C−H bonds; 3. the lack of chiral catalysts to achieve enantioselectivity via asymmetric C−H metalation, and 4. low practicality due to limited coupling partner scope and the use of specialized oxidants. These challenges necessitated new strategies in catalyst and reaction development. For reactivity, we developed approaches to enhance substrate–catalyst affinity together with novel bifunctional ligands which participate in and accelerate the C−H cleavage step. For site‐selectivity, we introduced the concept of systematically modulating the distance and geometry between a directing template, catalyst, and substrate to selectively access remote C−H bonds. For enantioselectivity, we devised predictable stereomodels for catalyst‐controlled enantioselective C−H activation based on the participation of bifunctional ligands. Finally, for practicality, we have developed varied catalytic manifolds for Pd(II) to accommodate diverse coupling partners while employing practical oxidants such as simple peroxides. These advances have culminated in numerous C−H activation reactions, setting the stage for broad industrial applications.

Funder

National Institutes of Health

Scripps Research Institute

Publisher

Wiley

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