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

Abstract

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.

Recent Development on Cp*Ir(III)‐Catalyzed C−H Bond Functionalization

“…In 2019, by utilizing Cu(OAc) 2 ⋅ H 2 O or Ag 2 O as the terminal oxidant, You developed a regio‐divergent C−H/C−H oxidative cross‐coupling of C3‐pivaloyl indoles with various heterocycles. (Scheme ).…”

“…Mechanistic investigations including DFT calculations indicated that this process might involve the generation of bis(hetero)aryl intermediates followed by reductive elimination to give the desired bisheterocyclic products. A CMD (concerted metalation deprotonation) might be operational for C2‐arylation of indoles, while a trimolecular electrophilic substitution (S E 3) process might be involved in C4‐heteroarylation (Scheme ).…”

Recent Advances in Metal‐catalyzed Alkylation, Alkenylation and Alkynylation of Indole/indoline Benzenoid Nucleus

“…The DG installation causes enhancement of the electron density at the C4 position and promotes the electrophilic metalation, which is supported by DFT studies in terms of preferential formation of a six‐membered metallacycle (Scheme 1). [3f] …”

Bulky iminophosphine‐based nickel and palladium catalysts bearing 2,6‐dibenzhydryl groups for ethylene oligo‐/polymerization

“…These catalysts were generally ligated by α‐ diimine, iminopyridyl, iminepyridazine, iminopyrrolyl, salicylaldimine, and many others. However, linear crystalline PEs with high melting temperatures were usually produced by phosphine‐containing Ni and Pd catalysts with variable ligands that include that include SHOP (Shell higher olefin process) type ligands, phosphine‐sulfonates, phosphino‐phenolate, phosphine phosphonic amides, bisphosphine monoxide, and many others. Recently, a series of phosphine based Pd catalysts have emerged as alternatives for copolymerizations of ethylene with polar monomers.…”