Palladium-Catalyzed C–H Amination of C(sp2) and C(sp3)–H Bonds: Mechanism and Scope for N‑Based Molecule Synthesis

Nitrogen-containing compounds are the most common structural architectures in drug candidates, natural and biological products, and small-molecule therapeutics. Within the body of work of transition-metal-catalyzed direct C–H amination reactions, palladium remains in the forefront and has been established as one of the most useful transition metals for C–N bond formation. The fundamental organometallic reactivity of palladium in its 0, I, II, III, and IV oxidation states make it special and useful in challenging carbon–heteroatom bond-formation reactions. Palladium undergoes facile formation of chelation-assisted palladacycle and palladium-nitrenoid intermediates that open an avenue for new bond formation. It has been utilized in various new synthetic approaches toward both intermolecular and intramolecular C–N bond formation reactions that employ nitrogen sources ranging from free, unprotected amines to electrophilic nitrogen sources. Palladium’s compatibility with various functional groups and oxidants as well as the mild reaction conditions (temperature and air atmosphere) used with this metal have attracted many scientists to the area and will continue to advance new mechanistic insights and opportunities to explore palladium catalysis for C–N bond synthesis. Here, we summarize the progress of Pd-catalyzed C–N bond advances involving both the reaction development and mechanisms in numerous synthetically useful intra- and intermolecular C–H catalytic aminations.