A novel strategy for alkylation <i>via</i> amide activation: synthesis of <i>N</i>-substituted 2-pyridones and tetrahydropyridines

This study introduces a novel strategy for utilizing amides as direct alkylating agents. The activation of amides with Tf₂O and 2-F-Py induces the migration of the alkyl group from the nitrogen of the amide to the nitrogen of 2-F-Py. Following a one-pot hydrolysis or reduction step, <i>N</i>-substituted 2-pyridones or tetrahydropyridines are generated <i>in situ</i>. A total of 34 related compounds were synthesized with high yields across various substrates. This methodology was further applied to the synthesis of key intermediates for C3a receptor inhibitors. Mechanistic studies indicate the formation of a pyridinium salt as a reactive intermediate in the process. Overall, this work presents a novel approach to the application of amides in synthetic chemistry.