L,X-type transient directing groups (TDG) 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 novel ligand development 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 ligand has also enabled the σ-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 σ-C–H bonds: TDGs that coordinate with Pd(II) to form a 6-membered chelate are selective toward γ-C–H bonds, whereas TDGs that coordinate with Pd(II) via a 5-membered chelate tend to activate σ-C–H bonds. These findings provide an avenue for developing protecting group free and selective C–H functionalization using the transient directing group strategy.

Overcoming the limitations of γ, and σ-C–H arylation of amines through ligand development

2019 Spring National Meeting

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.