Ligand controlled orthogonal selectivity between distal positions of fully unbiased aliphatic amines

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