Skeletal Editing of Pyridines to Thiophene-2-carbaldehydes

Skeletal editing, especially for nitrogen-containing aromatic heterocycles, has become an increasingly important strategy for drug modification and development, enabling rapid compound diversification without de novo synthesis. Despite their pervasiveness, established methods fall notably short in selective atomic swap due to the high stability of aromatic compounds. In this study, we report a CN-to-S atom swap approach for direct skeletal editing of pyridines into thiophenes via addition of nucleophiles, ring-opening, and ring-closing (ANRORC) processes. Elemental sulfur, acting as amphiphilic reagent, mediates this process through successive electrophilic and nucleophilic addition of central sulfur atom at predictable sites. The power of this skeletal editing strategy has been highlighted through the modification of the skeletal of natural products and drug molecules in a precise and controllable manner