Department of Chemistry, University of Wisconsin-Madison, 1101 University Avenue, Madison, Wisconsin 53706, United States.
High-Throughput Experimentation and Lead Discovery Capabilities, Merck & Co., Inc., Kenilworth, New Jersey 07033, United States.
J Am Chem Soc. 2021 Sep 15;143(36):14438-14444. doi: 10.1021/jacs.1c07117. Epub 2021 Aug 31.
Azoles are important motifs in medicinal chemistry, and elaboration of their structures via direct N-H/C-H coupling could have broad utility in drug discovery. The ambident reactivity of many azoles, however, presents significant selectivity challenges. Here, we report a copper-catalyzed method that achieves site-selective cross-coupling of pyrazoles and other N-H heterocycles with substrates bearing (hetero)benzylic C-H bonds. Excellent -site selectivity is achieved, with the preferred site controlled by the identity of co-catalytic additives. This cross-coupling strategy features broad scope for both the N-H heterocycle and benzylic C-H coupling partners, enabling application of this method to complex molecule synthesis and medicinal chemistry.
唑类是药物化学中的重要结构单元，通过直接的 N-H/C-H 偶联来构建其结构在药物发现中具有广泛的应用。然而，许多唑类化合物的双反应性带来了显著的选择性挑战。在这里，我们报道了一种铜催化的方法，该方法实现了吡唑和其他 N-H 杂环与具有（杂）苄基 C-H 键的底物的位点选择性交叉偶联。通过共催化添加剂的身份来控制，实现了优异的 - 位选择性。该交叉偶联策略在 N-H 杂环和苄基 C-H 偶联伙伴方面具有广泛的适用性，使得该方法能够应用于复杂分子的合成和药物化学。
