Pd-catalyzed, oxidant-promoted, regioselective C(sp2)-H/C(sp3)-H cross-dehydrogenative coupling for direct ortho-alkoxylation of 1-aryl-1H-indazoles via C-H bond activation.

A highly efficient palladium-catalyzed, PIDA-promoted, regioselective direct C(sp2)-H ortho-alkoxylation of 1-aryl-1H-indazoles with various primary/secondary aliphatic cyclic/acyclic alcohols has been developed utilizing a cross-dehydrogenative coupling (CDC) strategy. In this study, the developed protocol synthesized various substituted 1-phenyl-1H-indazole derivatives 2a-r/4a-g and substituted C-2'-alkoxylated-1-phenyl-1H-indazoles 5a-e in up to 80% yield. This method accommodates a wide range of alkoxy groups, demonstrates excellent functional group tolerance, and shows broad substrate applicability. A Pd-catalyzed, operationally simplified methodology was employed in the presence of PhI(OAc)2 as an oxidant and various primary/secondary aliphatic cyclic/acyclic alcohols as solvents at 90 °C for 24 hours, yielding a diverse array of substituted ortho-alkoxyl-1-aryl-1H-indazoles 2a-r/4a-g/5a-e. The mechanistic investigations were performed through several control experiments, which indicated a free-radical-mediated pathway. Furthermore, the protocol demonstrates strong synthetic utility through gram-scale C2'-alkoxylation of 1-aryl-1H-indazoles, including methoxy-to-alcohol conversion, delivering good to excellent yields in a one-pot, scalable process.