Unveiled reactivity of masked diformylmethane with enamines forming resonance-assisted hydrogen bonding leads to di-meta-substituted pyridines

• DOI: 10.1038/s42004-024-01228-w
• Publication Date: 2024-06-28T05:02:25Z
• Authors: Sihyeong Yi; Ji Hyae Lee; Hana Cho; Kannan Vaithegi; Dawon Yi; Sijun Noh; Seung Bum Park
• Keywords: Reactivity

Abstract Pyridine, an essential structure in drug development, shows a wide array of bioactivities according to its substitution patterns. Among the bioactive pyridines, meta -substituted pyridines suffer from limited synthetic approaches despite their significance. In this study, we present condensation-based method enabling facile incorporation biologically relevant functional groups at position pyridine. This methodology unveiled concealed reactivity 3-formyl(aza)indoles as diformylmethane analogs for synthesizing dissymmetric di- without ortho and para substitutions. Furthermore, uncovered resonance-assisted hydrogen bonding (RAHB) requirement situ generation enamines, key intermediates transformation. Successful development designed linked applications—core remodeling natural products, drug–natural product conjugation, late-stage functionalization molecules, synthesis regioisomeric CZC24832. discovered anti-inflammatory agents through evaluation synthesized bi-heteroaryl analogs, signifying utility methodology.