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

Abstract

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. Direct oxidative methods for the enantioselective synthesis of heterobiaryl compounds that exhibit axial chirality remain elusive. Now, the use of an iron catalyst in the presence of a chiral PyBOX ligand and an oxidant enables the direct coupling of naphthols and indoles with high levels of enantio- and cross-selectivity.