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Decarboxylative C-N Final ChemRxiv.pdf (701.86 kB)
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Decarboxylative sp3 C–N Coupling via Dual Copper/Photoredox Catalysis

preprint
submitted on 12.02.2018 and posted on 12.02.2018 by David W. C. MacMillan, Yufan Liang, Xiaheng Zhang

Over the last three decades, significant progress has been made in the development of methods to construct sp2 C–N bonds using palladium, copper, or nickel catalysis. However, the incorporation of alkyl substrates to form sp3 C–N bonds remains one of the major challenges in the field of cross-coupling chemistry. Here, we demonstrate that the synergistic combination of copper catalysis and photoredox catalysis can provide a general platform to address this long-standing challenge. This novel cross-coupling system employs naturally abundant alkyl carboxylic acids and commercially available N-nucleophiles as coupling partners, and is applicable to a wide variety of primary, secondary, and tertiary alkyl carboxylic acids (via in situ iodonium activation). At the same time, a vast array of N-nucleophiles, including N-heterocycles, amides, sulfonamides, and anilines, can undergo C–N coupling to provide N-alkyl products in good to excellent efficiency at room temperature and in short order (5 minutes to 1 hour). We have also demonstrated that this C–N coupling protocol can be applied to substrates bearing multiple amines with high regioselectivity, as well as complex drug molecules, enabling the rapid construction of molecular complexity and the late stage functionalization of bioactive pharmaceuticals.

Funding

NIH R01 GM103558-03

History

Email Address of Submitting Author

yufanl@princeton.edu

Email Address(es) for Other Author(s)

dmacmill@princeton.edu

Institution

Princeton University

Country

USA

ORCID For Submitting Author

0000-0002-0533-2982

Declaration of Conflict of Interest

No conflict of interest to declare

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