Ligand-Controlled Orthogonal Selectivity between δ and γ Positions of Long-Chain Picolinamides

Aliphatic C(sp3)–H bonds are inherently difficult to activate, owing to their inertness and chemical indistinguishability. This challenge has been overcome mostly by a directing group approach; however, the regioselectivity in distal aliphatic positions has mostly been substrate-dependent, with substrate bias being a prerequisite for distal C(sp3)–H activation, a direct consequence of the Thorpe–Ingold effect. Extending the methodology to straight-chain aliphatic substrates, in which all the available positions are compatible toward functionalization, has been a long-standing problem. To this aim, we attempted to develop a ligand-enabled orthogonal selectivity between the distal δ and γ positions of long-chain picolinamides in a regioselective fashion. These alkyl amines, with the assistance of a picolinic acid directing group, can be orthogonally functionalized between their γ and δ positions just by changing the ligand, with all other reaction parameters remaining constant, signifying the immense importance of the ligand in controlling the selectivity between the aforementioned positions of such inert C(sp3)–H bonds. Experimental as well as DFT studies have been carried out to generalize the nature of the ligand that would be successful in promoting orthogonal selectivity between these positions, with electron-rich pyridone ligands favoring selective distal δ functionalization while electron-deficient pyridone ligands tuning the selectivity favorably toward the γ position. This regioselective orthogonal selectivity tuned from γ to δ positions has also been mechanistically established through control reactions, kinetic studies, and theoretical calculations.