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

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.

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.

Nature-inspired remodeling of (aza)indoles to meta-aminoaryl nicotinates for late-stage conjugation of vitamin B3 to (hetero)arylamines.

Despite the availability of numerous routes to substituted nicotinates based on the Bohlmann-Rahtz pyridine synthesis, the existing methods have several limitations, such as the inevitable ortho-substitutions and the inability to conjugate vitamin B3 to other pharmaceutical agents. Inspired by the biosynthesis of nicotinic acid (a form of vitamin B3) from tryptophan, we herein report the development of a strategy for the synthesis of meta-aminoaryl nicotinates from 3-formyl(aza)indoles. Our strategy is mechanistically different from the reported routes and involves the transformation of (aza)indole scaffolds into substituted meta-aminobiaryl scaffolds via Aldol-type addition and intramolecular cyclization followed by C-N bond cleavage and re-aromatization. Unlike previous synthetic routes, this biomimetic method utilizes propiolates as enamine precursors and thus allows access to ortho-unsubstituted nicotinates. In addition, the synthetic feasibility toward the halo-/boronic ester-substituted aminobiaryls clearly differentiates the present strategy from other cross-coupling strategies. Most importantly, our method enables the late-stage conjugation of bioactive (hetero)arylamines with nicotinates and nicotinamides and allows access to the previously unexplored chemical space for biomedical research.