C2/C4 Regioselective Heteroarylation of Indoles by Tuning C–H Metalation Modes

The development of a rational strategy to achieve the complete regioselectivity and the capability to switch regioselectivity is an appealing, yet challenging, puzzle in transition-metal-catalyzed oxidative Ar–H/Ar–H cross-coupling. Disclosed herein is an iridium-catalyzed C2/C4 regioselective C–H heteroarylation of indoles with the help of a pivaloyl group at the C3 position. The judicious choice of the catalytic systems allows the C2-heteroarylation of indole via a concerted metalation–deprotonation (CMD) process and the C4-heteroarylation via a trimolecular electrophilic substitution (SE3) pathway. The oxidants Cu­(OAc)2·H2O and Ag2O are demonstrated to play a vital role in the C2/C4 regioselectivity. In this Article, a heteroaryl–Ir­(III)–heteroaryl complex prior to reductive elimination is successfully isolated and characterized, which represents the first example of capturing the bis­(hetero)­aryl metallic intermediate in oxidative Ar–H/Ar–H cross-coupling. The regiodivergent heteroarylation of indoles developed herein provides an opportunity to rapidly assemble diverse C4- and C2-heteroarylated indoles.