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

Aliphatic\nC(sp<sup>3</sup>)–H bonds are inherently difficult\nto activate, owing to their inertness and chemical indistinguishability.\nThis challenge has been overcome mostly by a directing group approach;\nhowever, the regioselectivity in distal aliphatic positions has mostly\nbeen substrate-dependent, with substrate bias being a prerequisite\nfor distal C(sp<sup>3</sup>)–H activation, a direct consequence\nof the Thorpe–Ingold effect. Extending the methodology to straight-chain\naliphatic substrates, in which all the available positions are compatible\ntoward functionalization, has been a long-standing problem. To this\naim, we attempted to develop a ligand-enabled orthogonal selectivity\nbetween the distal δ and γ positions of long-chain picolinamides\nin a regioselective fashion. These alkyl amines, with the assistance\nof a picolinic acid directing group, can be orthogonally functionalized\nbetween their γ and δ positions just by changing the ligand,\nwith all other reaction parameters remaining constant, signifying\nthe immense importance of the ligand in controlling the selectivity\nbetween the aforementioned positions of such inert C(sp<sup>3</sup>)–H bonds. Experimental as well as DFT studies have been carried\nout to generalize the nature of the ligand that would be successful\nin promoting orthogonal selectivity between these positions, with\nelectron-rich pyridone ligands favoring selective distal δ functionalization\nwhile electron-deficient pyridone ligands tuning the selectivity favorably\ntoward the γ position. This regioselective orthogonal selectivity\ntuned from γ to δ positions has also been mechanistically\nestablished through control reactions, kinetic studies, and theoretical\ncalculations.