# Mechanism-Inspired Ligand Design for Efficient Copper-Catalyzed C–N Coupling of Aryl and Heteroaryl Chlorides

## TL;DR

A new copper catalyst system efficiently forms C–N bonds from aryl and heteroaryl chlorides under mild conditions with low catalyst loadings.

## Contribution

A sterically hindered oxalamide ligand enables efficient copper-catalyzed C–N coupling of aryl chlorides at low loadings.

## Key findings

- The catalytic system achieves turnover numbers up to 2300 with catalyst loadings as low as 0.03–1 mol%.
- Monoligated Cu(I) species dominate reactions of aryl chlorides due to steric bulk of the ligand.
- Oxidative addition to the amine complex is the rate-limiting step in the reaction.

## Abstract

Cross-coupling reactions to form C–N bonds catalyzed
by
copper are becoming sustainable and cost-effective alternatives to
those catalyzed by palladium. An array of ligand classes has been
reported over the past two decades to create copper catalysts that
couple aryl iodides and bromides. However, these systems typically
require higher catalyst loadings than are required for palladium,
and the couplings of aryl chlorides catalyzed by copper complexes
require particularly high loadings, high temperatures, or both. We
report a catalytic system designed to destabilize the bis-ligated
copper­(II) oxalamide complexes that are the major species in reactions
of aryl bromides catalyzed by complexes of oxalamide ligands. A sterically
hindered oxalamide ligand in combination with Cu­(I) or Cu­(II) leads
to the coupling of aryl and heteroaryl chlorides with a set of primary
amines, as well as aqueous ammonia, under mild conditions at low catalyst
loadings (0.03–1 mol %) with turnover numbers up to 2300. Mechanistic
studies reveal that increased steric bulk on the amide causes a monoligated
copper species with a Cu­(I) oxidation state to be the major copper
complex in the reactions of aryl chlorides. Both Cu­(I) and Cu­(II)
amine complexes containing this oxalamide have been isolated, structurally
characterized, and observed in the catalytic systems by EPR and NMR
spectroscopy. Initial kinetic studies indicate that oxidative addition
to the amine complex is rate limiting, and the identity of the halide
on the aryl halide (Cl vs Br) changes the oxidation state of the major
copper species in solution.