Wang Peng, Verma Pritha, Xia Guoqin, Shi Jun, Qiao Jennifer X, Tao Shiwei, Cheng Peter T W, Poss Michael A, Farmer Marcus E, Yeung Kap-Sun, Yu Jin-Quan
Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
Discovery Chemistry, Bristol-Myers Squibb Company, 350 Carter Road, Princeton, New Jersey 08540, USA.
Nature. 2017 Nov 22;551(7681):489-493. doi: 10.1038/nature24632.
The directed activation of carbon-hydrogen bonds (C-H) is important in the development of synthetically useful reactions, owing to the proximity-induced reactivity and selectivity that is enabled by coordinating functional groups. Palladium-catalysed non-directed C-H activation could potentially enable further useful reactions, because it can reach more distant sites and be applied to substrates that do not contain appropriate directing groups; however, its development has faced substantial challenges associated with the lack of sufficiently active palladium catalysts. Currently used palladium catalysts are reactive only with electron-rich arenes, unless an excess of arene is used, which limits synthetic applications. Here we report a 2-pyridone ligand that binds to palladium and accelerates non-directed C-H functionalization with arene as the limiting reagent. This protocol is compatible with a broad range of aromatic substrates and we demonstrate direct functionalization of advanced synthetic intermediates, drug molecules and natural products that cannot be used in excessive quantities. We also developed C-H olefination and carboxylation protocols, demonstrating the applicability of our methodology to other transformations. The site selectivity in these transformations is governed by a combination of steric and electronic effects, with the pyridone ligand enhancing the influence of sterics on the selectivity, thus providing complementary selectivity to directed C-H functionalization.
碳氢键（C-H）的定向活化在开发具有合成用途的反应中至关重要，这归因于配位官能团所赋予的邻近诱导反应性和选择性。钯催化的非定向C-H活化有可能实现更多有用的反应，因为它可以作用于更远的位点，并应用于不含合适导向基团的底物；然而，其发展面临着与缺乏足够活性的钯催化剂相关的重大挑战。目前使用的钯催化剂仅与富电子芳烃反应，除非使用过量的芳烃，这限制了其合成应用。在此，我们报道了一种与钯结合的2-吡啶酮配体，它能以芳烃作为限量试剂加速非定向C-H官能化反应。该方法与多种芳香族底物兼容，并且我们展示了对无法大量使用的高级合成中间体、药物分子和天然产物的直接官能化。我们还开发了C-H烯基化和羧基化方法，证明了我们的方法在其他转化反应中的适用性。这些转化反应中的位点选择性受空间和电子效应的共同控制，吡啶酮配体增强了空间效应在选择性上的影响，从而为定向C-H官能化提供了互补的选择性。
