Pyridine-Boryl Radical-Catalyzed [3π + 2σ] Cycloaddition for the Synthesis of Pyridine Bioisosteres

Abstract

The exploration of C(sp3)-rich three-dimensional (3D) scaffolds as bioisosteres for planar aromatics has garnered increasing attention. While the bioisosterism of benzenes has been extensively studied, the bioisosterism of pyridines, the second most prevalent aromatic compounds in pharmaceuticals, faces additional challenges and has encountered surprisingly limited success. In this study, we propose unprecedented 2-azabicyclo[3.1.1]heptenes as effective bioisosteres of 1,3,5-trisubstituted pyridines in terms of not only 3D conformation but also basicity. We develop a pyridine-boryl radical-catalyzed [3π + 2σ] cycloaddition reaction of vinyl azides with bicyclo[1.1.0]butanes (BCBs) as an efficient synthetic approach. Synthetic manipulation of the products reveals valuable synthetic handles, allowing for the modular synthesis of various pyridine bioisosteres.