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

Abstract

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.

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

“…Comparatively, traditional methods involve complex steps for introducing functional groups at the meta position of pyridines. Our innovative methodology offers a streamlined approach, enabling the robust synthesis of diverse di- meta- substituted pyridines in a single step from corresponding terminal acetylenes—eliminating the need for precious transition metal catalysts or corrosive reagents 38 . While conventional approaches rely on heteroarene cyclization 37 or palladium-mediated C–C bond formation 39 for introducing heteroaromatics at the meta position of pyridines, our methodology provides a more efficient and practical alternative.…”

Transition-Metal and Photocatalyst-Free, Redox-Neutral Heteroarylation of C(sp3)–H Bonds

“…Notably, coupling of the pyridine motif to the sp 3 C−H bond has several advantages. 25 Pyridines are versatile in various chemical domains, forming fundamental structures in numerous agrochemicals, 26 pharmaceuticals 27−29 and natural compounds, 30,31 but they also serve as essential building blocks for creating chiral ligands 32,33 and innovative materials 34 Chemists have consequently developed various methodologies for pyridine synthesis. 35 Among these methods, the use of abundant C−H precursors containing a pyridine fragment is particularly valuable due to its cost-effectiveness and simplicity, reducing the need for a multistep synthesis.…”