A general protocol for the synthesis of N-substituted 4-pyridones from skipped diynones is presented via a base or Ag(I)-catalyzed hydroamination pathway.

Abstract

Cs₂CO₃ or CF₃COOAg catalyze the intramolecular 6-endo hydroamination of the Z-enaminones derived from the Michael-type addition of primary amines to skipped diynones, yielding N-substituted 4-pyridones in good to excellent yields. The transformation occurs in one-pot operation, with the first step being noncatalyzed. While the Cs₂CO₃-catalyzed protocol is much faster, it fails to provide significant yields in the case of enaminones derived from aryl-substituted diynones. On the other hand, the Ag(I)-catalyzed one is a slower process but more widely applicable. Several N-substituted 4-pyridones inhibit SecA ATPase at micromolar concentrations.