New Strategies for Copper-Catalyzed Cross-Coupling of Alkyl Electrophiles

Project Summary/Abstract The overarching goal of the Liu group is to facilitate the discovery and synthesis of complex bioactive small molecules by developing novel copper-catalyzed reactions and to elucidate the reactive intermediates in copper-catalyzed bond-forming reactions. The selective construction of carbon–carbon (C–C) and carbon–heteroatom (C–X) bonds remains the most important synthetic tool in organic chemistry, with these reactions playing a vital role in the synthesis of natural products, pharmaceuticals, and agrochemicals. However, most such transformations rely on the least abundant elements in Earth's crust. Owing to their many attractive characteristics, copper catalysts represent an appealing alternative to precious-metal catalysts, although copper-catalyzed cross-coupling reactions still have various limitations. Recently, we and others recognized that copper catalysis provides a powerful strategy for the functionalization of sp3-hybridized carbon radicals to construct C–C and C–heteroatom bonds. To date, our group has developed a menu of copper-catalyzed coupling reactions for alkyl electrophiles via the activation of C–COOH, C–N, C–H, and C–O bonds, with an initial focus on the installation of fluoroalkyl groups into medicinally relevant moieties. These promising results led us to envision the emergence of copper-catalyzed, radical-activated cross-coupling reactions as a powerful tool for solving a range of long-standing synthetic problems. In this proposal, we will demonstrate that merging the copper-catalyzed functionalization of C(sp3) radicals with different radical generation pathways offers a viable approach for the cross- coupling of unactivated alkyl electrophiles. Specifically, we aim to develop reactions such as the deoxygenative cross-coupling of alcohols, the selective alkylation of C(sp3)–H bonds, and the cross-coupling of unactivated alkyl halides. These transformations are either unknown or have limited reaction scope. The development and mechanistic understanding of these transformations will make a significant contribution toward advancing the field of transition- metal catalysis.