Reaching out to the distal sp3 C‒H bonds remain a daunting challenge to synthetic organic chemists primarily due to the relative inertness of C‒H bond in alkanes. As such, most reports have envisaged the employment of sterically biased substrates, which render the other possible positions inaccessible for functionalization. Herein, we report a palladium-catalyzed highly selective δ-chalcogenation of aliphatic picolinamides, whereby both sterically biased and relatively unbiased substrates are made feasible towards site-selective δ-C−H functionalization. Successful employment of Thorpe-Ingold effect explains the reactive intermediates involved. The present protocol also provides direct access to the introduction of structural modifications on the α-amino acid structural motifs such as leucine with high regioselectivity. Sequential hetero-di-functionalization has been carried out at δ-sp3 C−H bonds, resulting in the desymmetrization of quaternary centers. A thorough mechanistic investigation has been carried out, which gave impetus to the reaction pathway and the plausible mechanistic cycle involved.
