Late-Stage Functionalization of Pharmaceuticals by C-C Cross-Coupling Enabled by Wingtip Flexible N-Heterocyclic Carbenes

The synthesis of complex molecules by palladium-catalyzed cross-coupling has been pivotal in all stages of drug discovery research. However, this approach has been generally restricted to classical aryl halide electrophiles, requiring the use of a limited pool of precursors. Herein, we report the first highly chemoselective approach to the cross-coupling of bench-stable C-O electrophiles in which abundant phenols can be systematically used as electrophilic cross-coupling partners. By using this approach, we have achieved late-stage functionalization of >20 pharmaceuticals covering various architectures and drug targets. Wingtip flexible N-heterocyclic carbenes as ancillary ligands enable to address major challenges of this mode of catalysis, such as fast oxidative addition to prevent hydrolysis of C-O electrophiles and facile reductive elimination to establish the C-C bond forming step in complex settings. This reactivity can be applied to sequential cross-coupling using the same class of bench-stable Pd(II) precursors. The design of wingtip flexible N-heterocyclic carbene ligands will enable the cross-coupling of a broad range of electrophiles for the development of important medicines.