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.

Transient Ligand‐Enabled Transition Metal‐Catalyzed C−H Functionalization

“…Very recently, the δ‐arylation of alkyl amines enabled by the combination of 2‐(2methoxyphenyl)‐2‐oxoacetic acid (L36) and pyridine derivatives has been reported by Yu and co‐workers. In this process, 5‐substituted trifluoromethyl‐ and nitro‐2‐pyridone were identified as the optimal X‐type ligands by acting as an internal base to accelerate the C−H bond cleavage step, which can significantly improve the efficiency of the δ‐arylation of alkyl amines (Scheme b) . In 2016, the use of a stoichiometric amount of 3,5‐di‐ tert ‐butylsalicylaldehyde ( L37 ) as a precursor to form the removable and recoverable directing group for the γ‐arylation of free primary amines has also been reported by Murakami and co‐workers (Scheme c) …”

Multifunctional Tubular Organic Cage‐Supported Ultrafine Palladium Nanoparticles for Sequential Catalysis

“…As ac onsequence of Pd 2+ complexation with MTC1, the binding energies of 399.3 and 398.4 eV for nitrogen atoms from imine and BTD units,respectively,in MTC1 shift to higher binding energies at 399.6 and 398.6 eV in the N1sX PS spectrum of Pd II &MTC1 (Supporting Information, Figure S16), confirming the interactions between Pd 2+ and imine/BTD nitrogen atoms of MTC1. [10] To gain more insight into the sensing mechanism, aJ ob plot was obtained, showing amaximum emission intensity at about 0.3 and 1:2b inding stoichiometry between MTC1 and Pd 2+ (Figure 1d). Even when six equivalents of Pd 2+ were added to the solution of MTC1, we only observed the complex peaks with 1:1a nd 1:2m olar ratio of MTC1 and Pd 2+ ions in the mass spectrum of the sample (Supporting Information, Figure S17), further supporting the preferred binding of only two Pd 2+ ions inside MTC1.…”

Multifunctional Tubular Organic Cage‐Supported Ultrafine Palladium Nanoparticles for Sequential Catalysis

“…According to the titration results,the detection limit of Pd 2+ was determined to be 38 ppb (based on 3s/k; Supporting Information, Figure S13). [10] To gain more insight into the sensing mechanism, aJ ob plot was obtained, showing amaximum emission intensity at about 0.3 and 1:2b inding stoichiometry between MTC1 and Pd 2+ (Figure 1d). There was av ery slight disturbance in the fluorescence quenching of Pd 2+ in the presence of all metal ions except Pt 2+ .Addition of Pt 2+ as interfering metal ion led to more significant fluorescence quenching.…”