Acetoxy Group-Directed Regioselective C2 Alkenylation of Indoles via Pd–Ag Bimetallic Catalysis

Regioselective C–H functionalizations of indoles reported to date with directing groups at C3 mainly rely on functional groups that are linked to the indole via C–C bonds. However, groups that are linked to the indole core by C–X linkages are also attractive due to the possibility of further modifications of the C–X bond. Herein, we report a 3-acetoxy directing group for the regioselective C2 alkenylation of indoles via a C–H activation-based, cross-dehydrogenative, oxidative Heck-type reaction. The reaction is catalyzed by Pd(II) and Ag(I) with stoichiometric Cu(II) as the oxidant and provides the 2-alkenylated indoles in yields of 52–84%. The reaction conditions are compatible with several functional groups at different positions as well as different N-protecting groups or free NH groups on the indole core. With respect to the alkene coupling partners, the reactions are successful with acrylates, vinyl sulfates, and phosphates. Specifically designed experiments, as well as density functional theory (DFT) computational studies, reveal that a heterodinuclear [Pd(μ-OAc)3Ag] bimetallic species is the actual catalyst responsible for the C–H alkenylation. A mechanistic path involving this catalytic species was also found to be favorable over other possible pathways for explaining the observed regioselectivity through DFT studies.