Late-Stage C-H Functionalization of Azines

Azines, such as pyridines, quinolines, pyrimidines, and pyridazines, are widespread components of pharmaceuticals. Their occurrence derives from a suite of physiochemical properties that match key criteria in drug design and is tunable by varying their substituents. Developments in synthetic chemistry, therefore, directly impact these efforts, and methods that can install various groups from azine C-H bonds are particularly valuable. Furthermore, there is a growing interest in late-stage functionalization (LSF) reactions that focus on advanced candidate compounds that are often complex structures with multiple heterocycles, functional groups, and reactive sites. Because of factors such as their electron-deficient nature and the effects of the Lewis basic N atom, azine C-H functionalization reactions are often distinct from their arene counterparts, and the application of these reactions in LSF contexts is difficult. However, there have been many significant advances in azine LSF reactions, and this review will describe this progress, much of which has occurred over the past decade. It is possible to categorize these reactions as radical addition processes, metal-catalyzed C-H activation reactions, and transformations occurring via dearomatized intermediates. Substantial variation in reaction design within each category indicates both the rich reactivity of these heterocycles and the creativity of the approaches involved.