TY - JOUR
T1 - HARC as an open-shell strategy to bypass oxidative addition in Ullmann-Goldberg couplings
AU - Lavagnino, Marissa N.
AU - Liang, Tao
AU - MacMillan, David W.C.
N1 - Funding Information:
The authors are grateful for financial support provided by the National Institute of General Medical Sciences (NIGMS), the NIH (under Award R35GM134897-01), the Princeton Catalysis Initiative, and kind gifts from Merck, Janssen, BMS, Genentech, Celgene, and Pfizer. M.N.L. acknowledges Princeton University for a first-year fellowship and also acknowledges Princeton University, E. Taylor, and the Taylor family for an Edward C. Taylor Fellowship. The content is solely the responsibility of the authors and does not necessarily represent the official views of NIGMS.
Publisher Copyright:
© 2020 National Academy of Sciences. All rights reserved.
PY - 2020/9/1
Y1 - 2020/9/1
N2 - 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we present an alternative aryl halide activation strategy, in which the critical oxidative addition (OA) mechanism has been replaced by a halogen abstraction-radical capture (HARC) sequence that allows the generation of the same Cu(III)-aryl intermediate albeit via a photoredox pathway.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.
AB - 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.
KW - C-N coupling
KW - Halogen atom abstraction
KW - Photoredox catalysis
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U2 - 10.1073/pnas.2011831117
DO - 10.1073/pnas.2011831117
M3 - Article
C2 - 32817531
AN - SCOPUS:85090511312
SN - 0027-8424
VL - 117
SP - 21058
EP - 21064
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 35
ER -