Site-Selective N-1 and C-3 Heteroarylation of Indole with Heteroarylnitriles by Organocatalysis under Visible Light

Site-selective N-1 and C-3 arylation of indole has been sought after because of the prevalent application of arylindoles and the intricate reactivities associated with the multiple sites of the N-unsubstituted indole. Represented herein is the first regioselective heteroarylation of indole via a radical-radical cross-coupling by visible-light irradiation. Steady and time-resolved spectroscopic and computational studies revealed that the hydrogen-bonding interaction of organic base and its conjugated acid, namely with indole and heteroarylnitrile, determined the reaction pathway, which underwent either proton-coupled electron-transfer or energy-transfer for the subsequent radical-radical cross-coupling, leading to the regioselective formation of C-3 and N-1 heteroarylation of indoles, respectively. The parallel methodologies for regioisomeric N-1 and C-3 heteroaryl indoles with good functional group compatibility could be applied to large-scale synthesis and late-stage derivatization of bioactive compounds under extremely mild reaction conditions.

Automated summary

This study reports the first regioselective heteroarylation of indole through a radical-radical cross-coupling using visible-light irradiation. Spectroscopic and computational studies show that the hydrogen-bonding interaction between an organic base and its conjugated acid plays a crucial role in determining the reaction pathway, resulting in regioselective formation of C-3 and N-1 heteroarylation of indoles. This methodology has great potential in large-scale synthesis and late-stage derivatization of bioactive compounds.