Ligand-Controlled Selectivity in the Pd-Catalyzed C-H/C-H Cross-Coupling of Indoles with Molecular Oxygen

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.

Automated summary

Two indoles linked by a C-C bond have emerged as promising scaffolds in medicinal chemistry. In this study, selective C-H/C-H cross-coupling of N-substituted indoles without directing groups was achieved under mild conditions, driven by molecular oxygen. The ligand-controlled selectivity can be exploited to achieve selective cross-coupling between two indoles with different substitution patterns.