Directing Group-Free Regioselective meta-C-H Functionalization of Pyridines.

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.