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

01 April 2024, Version 1
This content is a preprint and has not undergone peer review at the time of posting.


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.


boryl radical
[3π + 2σ] cycloaddition
pyridine bioisostere
vinyl azide

Supplementary materials

supporting information
Materials and methods, experimental procedures, mechanistic studies, 1H NMR spectra, 13C NMR spectra and mass spectrometry


Comments are not moderated before they are posted, but they can be removed by the site moderators if they are found to be in contravention of our Commenting Policy [opens in a new tab] - please read this policy before you post. Comments should be used for scholarly discussion of the content in question. You can find more information about how to use the commenting feature here [opens in a new tab] .
This site is protected by reCAPTCHA and the Google Privacy Policy [opens in a new tab] and Terms of Service [opens in a new tab] apply.