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.