Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 117, Issue 35, Pages 21058-21064Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2011831117
Keywords
photoredox catalysis; C-N coupling; halogen atom abstraction
Categories
Funding
- National Institute of General Medical Sciences (NIGMS)
- NIH [R35GM134897-01]
- Princeton Catalysis Initiative
- Princeton University
- Taylor family
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The copper-catalyzed arylation of unsaturated nitrogen heterocycles, known as the Ullmann-Goldberg coupling, is a valuable transformation for medicinal chemists, providing a modular disconnection for the rapid diversification of heteroaromatic cores. The utility of the coupling, however, has established limitations arising from a highbarrier copper oxidative addition step, which often necessitates the use of electron-rich ligands, elevated temperatures, and/or activated aryl electrophiles. Herein, we present an alternative aryl halide activation strategy, in which the critical oxidative addition (OA) mechanism has been replaced by a halogen abstraction-radical capture (HARC) sequence that allows the generation of the same Cu(III)-aryl intermediate albeit via a photoredox pathway. This alternative mechanistic paradigm decouples the bond-breaking and bond-forming steps of the catalytic cycle to enable the use of many previously inert aryl bromides. Overall, this mechanism allows access to both traditional C-N adducts at room temperature as well as a large range of previously inaccessible Ullmann-Goldberg coupling products including sterically demanding ortho-substituted heteroarenes.
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