Ag-Catalyzed Remote Unactivated C(sp3)-H Heteroarylation of Free Alcohols in Water

Catalyzed by silver salt, the unactivated C(sp(3))-H heteroarylation of free alcohol at the delta position is realized under gentle thermal conditions in water through a radical procedure. Both protonic acids and Lewis acids are found to be efficient for activating pyridines for this Minisci-type reaction. The reaction enjoys a good functional group tolerance and substrate scope. Terminal secondary and tertiary alcohols are suitable substrates. With either electron-donating or -withdrawing groups, the electron-deficient heteroarene substrates generate the target products in moderate to good yields. A gram-scale experiment can be successfully operated. A radical blocking experiment and a radical clock experiment are studied to support the radical mechanism.

Automated summary

The unactivated C(sp(3))-H heteroarylation of free alcohol at the delta position was achieved through a radical procedure catalyzed by silver salt under gentle thermal conditions in water. Protonic acids and Lewis acids were found to efficiently activate pyridines for this Minisci-type reaction. The reaction showed good functional group tolerance and substrate scope, with terminal secondary and tertiary alcohols being suitable substrates. Both electron-donating and -withdrawing groups on the electron-deficient heteroarene substrates yielded the target products in moderate to good yields. The study also included a successful gram-scale experiment and radical blocking/experiment experiments to support the radical mechanism.