Generating the Pd-catalyzed δ C-H chalcogenation of aliphatic picolinamides: systematically decreasing the bias

Reaching out to the distal sp³ C-H bonds remains a daunting challenge to synthetic organic chemists, primarily due to the relative inertness of the C-H bonds 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 for site-selective δ-C-H functionalization. The successful employment of the Thorpe-Ingold effect explains the reactive intermediates involved. The present protocol also provides direct access to the introduction of structural modifications on 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 provided evidence for the reaction pathway and the plausible mechanistic cycle involved.