Merck Center for Catalysis at Princeton University, Princeton, NJ, USA.
Nature. 2018 Jul;559(7712):83-88. doi: 10.1038/s41586-018-0234-8. Epub 2018 Jun 20.
Over the past three decades, considerable progress has been made in the development of methods to construct sp carbon-nitrogen (C-N) bonds using palladium, copper or nickel catalysis. However, the incorporation of alkyl substrates to form sp 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 from which to address this challenge. This cross-coupling system uses naturally abundant alkyl carboxylic acids and commercially available nitrogen nucleophiles as coupling partners. It is applicable to a wide variety of primary, secondary and tertiary alkyl carboxylic acids (through iodonium activation), as well as a vast array of nitrogen nucleophiles: nitrogen heterocycles, amides, sulfonamides and anilines can undergo C-N coupling to provide N-alkyl products in good to excellent efficiency, at room temperature and on short timescales (five minutes to one hour). We demonstrate that this C-N coupling protocol proceeds with high regioselectivity using substrates that contain several amine groups, and can also be applied to complex drug molecules, enabling the rapid construction of molecular complexity and the late-stage functionalization of bioactive pharmaceuticals.
在过去的三十年中，使用钯、铜或镍催化发展构建 sp 碳-氮 (C-N) 键的方法取得了相当大的进展。然而，将烷基底物并入形成 sp C-N 键仍然是交叉偶联化学领域的主要挑战之一。在这里，我们证明铜催化和光氧化还原催化的协同组合可以提供一个通用的平台来解决这一挑战。该交叉偶联体系使用天然丰富的烷基羧酸和市售的氮亲核试剂作为偶联伙伴。它适用于多种伯、仲和叔烷基羧酸（通过碘鎓活化），以及大量的氮亲核试剂：氮杂环、酰胺、磺酰胺和苯胺可以进行 C-N 偶联，在室温下和短时间内（五分钟至一小时）以良好至优异的效率提供 N-烷基产物。我们证明，该 C-N 偶联方案在含有多个胺基的底物中具有高区域选择性，并且还可以应用于复杂的药物分子，从而能够快速构建分子复杂性并对生物活性药物进行后期功能化。
