Ligand-Controlled Selectivity in the Pd-Catalyzed C–H/C–H Cross-Coupling of Indoles with Molecular Oxygen
Igor Beckers, Besir Krasniqi, Prashant Kumar, Daniel Escudero, Dirk De Vos
Abstract
Two indoles linked by a C–C bond have recently emerged as promising scaffolds in medicinal chemistry. Their synthesis, however, involves a multitude of reaction steps. So far, the direct C–H/C–H cross-coupling of two similar heteroaromatics lacking directing groups remains particularly challenging. Transition metals are often added as wasteful sacrificial oxidants to influence the selectivity in Pd-catalyzed C–H/C–H couplings. In this work, we report on the selective C–H/C–H cross-coupling of N-substituted indoles without directing groups, driven by molecular oxygen under mild conditions. The selectivity of the C–H activations was studied via kinetic experiments and computational investigations. A quantitative Hammett study of the aromatic carboxylate ligands shows that regioselectivity can be directed by rationally tuning their electronic properties. This ligand-controlled selectivity can be exploited to obtain selective cross-coupling between two indoles with different substitution patterns, as demonstrated in the synthesis of a potent insulin-like growth factor inhibitor.