Synthesis of substituted pyridines with diverse functional groups via the remodeling of (Aza)indole/Benzofuran skeletons

Substituted pyridines with diverse functional groups are important structural motifs found in numerous bioactive molecules. Several methodologies for the introduction of various bio-relevant functional groups to pyridine have been reported, but there is still a need for a single robust method allowing the selective introduction of multiple functional groups. This study reports a ring cleavage methodology reaction for the synthesis of 2-alkyl/aryl 3-electron-withdrawing groups (esters, sulfones, and phosphonates) 5-aminoaryl/phenol pyridines via the remodeling of 3-formyl (aza)indoles/benzofurans. Totally ninety-three 5-aminoaryl pyridines and thirty-three 5-phenol pyridines were synthesized showing the robustness of the developed methodology. The application of this methodology further provided a privileged pyridine scaffold containing biologically relevant molecules and direct drug/natural product conjugation with ethyl 2-methyl nicotinate. Substituted pyridines are important structural motifs present in various bioactive molecules, however their multi-functionalization remains challenging. Here, the authors report a facile approach for introducing various functional groups on the pyridine scaffold by remodeling of 3-formyl (aza)indoles/benzofurans via a ring cleavage reaction.

Automated summary

Substituted pyridines with diverse functional groups are important in bioactive molecules. This study reports a method for introducing multiple functional groups to pyridine via ring cleavage reaction. The robustness of the methodology was demonstrated by synthesizing a variety of 5-aminoaryl and 5-phenol pyridines, and the application of the methodology provided a privileged pyridine scaffold for drug conjugation.