Enantioselective synthesis of atropisomeric indoles via iron-catalysed oxidative cross-coupling

Heterobiaryl compounds that exhibit axial chirality are of increasing value and interest across several fields, but direct oxidative methods for their enantioselective synthesis remain elusive. Here we disclose that an iron catalyst in the presence of a chiral PyBOX ligand and an oxidant enables direct coupling between naphthols and indoles to yield atropisomeric heterobiaryl compounds with high levels of enantioselectivity. The reaction exhibits remarkable chemoselectivity and exclusively yields cross-coupled products without competing homocoupling. Mechanistic investigations enable us to postulate that an indole radical is generated in the reaction but that this is probably an off-cycle event, and that the reaction proceeds through formation of a chiral Fe-bound naphthoxy radical that is trapped by a nucleophilic indole. We envision that this simple, cheap and sustainable catalytic manifold will facilitate access to a range of heterobiaryl compounds and enable their application across the fields of materials science, medicinal chemistry and catalysis.

Automated summary

We report a new iron-catalyzed system that enables the direct coupling of naphthols and indoles to obtain atropisomeric heterobiaryl compounds with high enantioselectivity. The reaction exhibits remarkable chemoselectivity and exclusively produces cross-coupled products without competing homocoupling. Mechanistic investigations suggest the generation of an indole radical as an off-cycle event, with the reaction proceeding through the formation of a chiral Fe-bound naphthoxy radical that is trapped by a nucleophilic indole. This catalytic system is expected to provide access to a range of heterobiaryl compounds and facilitate their application in materials science, medicinal chemistry, and catalysis.