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.
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