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

• Published in: Communications chemistry 2024-06, Vol.7 (1), p.146-10, Article 146
• Main Authors: Yi, Sihyeong, Lee, Ji Hyae, Cho, Hana, Vaithegi, Kannan, Yi, Dawon, Noh, Sijun, Park, Seung Bum
• Format: Article
• Language: English
• Subjects: 14; 14/63; 639/638/309/2132; 639/638/403/933; 639/638/549/933; 82; Analogs; Biological activity; Chemical synthesis; Chemistry; Chemistry and Materials Science; Chemistry/Food Science; Condensates; Conjugation; Functional groups; Hydrogen bonding; Indoles; Methodology; Natural products; Pharmaceutical sciences; Pyridines; Resonance; Substitutes
• ISSN: 2399-3669; 2399-3669
• DOI: 10.1038/s42004-024-01228-w

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 a condensation-based synthetic method enabling the facile incorporation of biologically relevant functional groups at the meta position of pyridine. This methodology unveiled the concealed reactivity of 3-formyl(aza)indoles as diformylmethane analogs for synthesizing dissymmetric di- meta -substituted pyridines without ortho and para substitutions. Furthermore, we uncovered resonance-assisted hydrogen bonding (RAHB) as the requirement for the in situ generation of enamines, the key intermediates of this transformation. Successful development of the designed methodology linked to wide applications—core remodeling of natural products, drug–natural product conjugation, late-stage functionalization of drug molecules, and synthesis of the regioisomeric CZC24832. Furthermore, we discovered anti-inflammatory agents through the functional evaluation of synthesized bi-heteroaryl analogs, signifying the utility of this methodology. Pyridine is an essential structural motif in medicinal chemistry and shows a wide range of bioactivities based on its substitution patterns, however, the meta-substitution of pyridine remains challenging. Here, the authors develop the synthesis of dissymmetric di-meta-substituted pyridines from 3-formyl(aza)indoles through the in situ generation of enamines via resonance-assisted hydrogen bonding, showcasing various synthetic applications in medicinal chemistry.