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

Abstract

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.