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 photoredox catalysis and copper catalysis can provide a general platform to address this long-standing challenge. This novel cross-coupling system employs naturally abundant alkyl carboxylic acids and readily available N-nucleophiles as coupling partners, and is applicable to a wide variety of primary, secondary, and tertiary alkyl carboxylic acids. 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 excellent efficiency at room temperature and in short order (5 minutes to 1 hour). A total of more than 140 successful decarboxylative N-alkylation examples including more than 15 classes of nucleophiles are demonstrated. We have also showcased that this C–N coupling protocol can be applied to substrates bearing multiple nucleophilic sites with high regioselectivity, as well as complex drug molecules, enabling the rapid construction of molecular complexity and the late stage functionalization of bioactive pharmaceuticals.

Decarboxylative sp3 C–N coupling via dual copper/photoredox catalysis

2019 Spring National Meeting

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