Overcoming the Limitations of γ- and δ-C-H Arylation of Amines through Ligand Development

Abstract

L,X-Type transient directing groups (TDGs) based on a reversible imine linkage have emerged as broadly useful tools for C-H activation of ketones and free amines. However, competitive binding interactions among multiple reaction components (TDG itself, substrate, and substrate-TDG adduct) with the palladium catalyst often lead to the formation of multiple unreactive complexes, rendering ligand development extremely challenging. Herein, we report the finding of versatile 2-pyridone ligands that addresses these problems and significantly improves the γ-methylene arylation of alkyl amines, extending the coupling partners to a wide range of medicinally important heteroaryl iodides and even previously unreactive heteroaryl bromides. The combination of an appropriate transient directing group and pyridone ligand has also enabled the δ-arylation of alkyl amines. Notably, our transient directing group design reveals the importance of matching the size of the Pd-chelation with different transient directing groups and the size of palladacycles generated from γ- and δ-C-H bonds: TDGs that coordinate with Pd(II) to form a six-membered chelate are selective toward γ-C-H bonds, whereas TDGs that coordinate with Pd(II) via a five-membered chelate tend to activate δ-C-H bonds. These findings provide an avenue for developing protecting group free and selective C-H functionalization using the transient directing group strategy.

Figure 1.

Amine based bioactive molecules bearing N-containing heterocycles at the γ position.

Figure 2.

Amine based pharmaceuticals bearing aromatic groups at the δ position.

Scheme 1.

Early TDG Designs Involving a L,L-Type Binding Mode

Scheme 2.

L,X-Type TDG Enabled Arylation of Aldehydes, Ketones, and Amines

Scheme 3.

This Work: 2-Pyridone Enabled Methylene γ-C(sp³)-H Heteroarylation and δ-C(sp³)-H Arylation of Free Amines

Scheme 4.

Catalyst Loading and Synthetic Applications