Transformation of Pyridines into 2D and 3D Fused Bicyclic Heterocycles

Abstract

Skeletal editing of heteroarenes in complex molecules represents a transformative synthetic strategy that transcends the limitations of conventional peripheral functionalization, enabling the profound structural diversification of molecular frameworks. Here, we demonstrate a powerful metal-free approach for converting pyridines into planar (2D) and three-dimensional (3D) fused bicyclic heterocycles through a precisely orchestrated process of nucleophilic addition, 6π-electrocyclic ring opening/ring closure, and fused ring formation. This methodology exploits the unique reactivity of N-pyridinium salts with hydrazine nucleophiles, accommodating diverse functional groups in a sequential one-pot protocol. In addition, a modified procedure enabled the synthesis of C3-brominated heterocyclic scaffolds. The synthetic utility is further demonstrated by successful late-stage modifications of structurally complex bioactive molecules. Comprehensive mechanistic investigations, including the isolation of key intermediates and computational studies, offer critical insights into the reaction pathway. Our findings establish a versatile platform for the strategic reconstruction of pyridine cores, significantly expanding the accessible chemical space. Notably, the newly synthesized pyrazolopyridazine scaffolds exhibit low-micromolar inhibitory activity over JNK1, positioning them as promising candidates with a substantial medicinal chemistry value for further optimization. This bioactivity validation underscores how our findings establish a versatile platform for the strategic reconstruction of pyridine cores, considerably expanding the accessible chemical space for drug discovery.