Andrew Boggiano

Pyridine is one of the most abundant motifs in pharmaceuticals and agrochemicals. However, chemists were constrained in their ability to append substituents at the meta-position of pyridines. Two complementary one-pot approaches developed independently have helped to overcome this challenge. While one involves breaking the pyridine ring to form linear imines, the other relies on 1,4-dipolar cycloadditions to disrupt the aromaticity of pyridine.

Abstract

The pyridine core is among the most common motifs found in pharmaceuticals and agrochemicals. Consequently, the C−H functionalization of pyridine is a prized reaction, as it can help access a broad spectrum of valuable chemicals. However, the intrinsic electronic properties of pyridines hinder their meta-C−H functionalization, requiring drastic conditions affecting functional group compatibility. A synthetic manoeuvre to overcome this challenge involves the temporary conversion of pyridines into electron-rich intermediates and subsequent regioselective electrophilic functionalization. This was recently accomplished by a ring-opening ring-closing sequence via Zincke imine intermediates by McNally and co-workers, and a dearomatization-rearomatization sequence via oxazino-pyridine intermediates by the Studer group. The mildness and simplicity of these protocols enable them to work with complex molecular setups for synthesizing natural products and bioactive molecules.

Nature Communications, Published online: 12 July 2022; doi:10.1038/s41467-022-31397-y