Reductive Functionalization of Pyridine-Fused N-Heteroarenes

ConspectusThe selective functionalization/transformation of ubiquitous pyridine-fused N-heteroarenes is a practical method to synthesize structurally novel N-heterocycles, which is important for the development of medicines, bioactive agents, agrochemicals, materials, ligands, sensors, pigments, dyes, etc. However, owing to thermodynamic stability, kinetic inertness, and lone electron pair–induced catalyst deactivation of the pyridine-fused N-heteroarenes, limited strategies (e.g., C–H activation/functionalization, electrophilic substitution, and the Minisci reaction) are available to realize the synthetic purpose and maintain the aromaticity of the final products. Moreover, the relevant transformations have limitations such as needing harsh reaction conditions, requiring the preinstallation of specific coupling agents containing transformable functionalities or directing groups, using less environmentally benign oxidants and/or acidic activators, and poor selectivity. Herein, considering that imines, enamines, radicals, and cyclic amines are generated during the reduction of pyridine-fused N-heteroarenes, the precise transformation of these reductive intermediates offers a fundamental basis for developing novel tandem reactions. Our group revealed that a slow reduction rate, synergistic catalysis, and controlled electroreduction are effective strategies for fulfilling the selective reductive functionalization of pyridine-fused N-heteroarenes. Thus, we established a series of new synthetic methods that provide diverse construction modalities for functionalized N-heterocycles. The striking features of these synthetic methods include high efficiency, atom economy, and the use of readily accessible N-heteroarenes as transformable feedstocks in the absence of flammable and pressurized H2 gas, alongside a promising potential of the obtained N-heterocyclic products. The present study would be appealing to the fields of synthetic organic chemistry, catalysis, biomedical chemistry, and functional materials. This Account describes the application of reductive dearomatization as substrate-activating and tandem reaction-initiating modes and summarizes the reductive functionalization of pyridine-fused N-heteroarenes via selective alkylation, arylation, and annulation at nitrogen, α, β, and other remote carbon sites achieved over the past 8 years. Details regarding the development of new reactions and their plausible mechanisms and perspectives are discussed. We hope our contributions to this field will aid in the further development of novel strategies for the functionalization/transformation of pyridine-fused N-heteroarenes and tackle the intractable challenges in this area.