Mechanochemical Generation of Active Pd/BippyPhos Catalyst for Efficient C-N Cross-Coupling in Air.

Carbon-nitrogen (C-N) bond-forming cross-coupling reactions catalyzed by palladium-based systems, known as Buchwald-Hartwig aminations, are widely used in natural product synthesis, pharmaceuticals, agrochemicals, and materials science. However, these reactions typically require organic solvents and inert atmospheres, such as argon, increasing environmental, health, and safety (EHS) concerns. Using electron-rich bulky phosphine ligands in combination with [Pd(π-cinnamyl)Cl]₂, we generate a highly active palladium catalyst capable of achieving efficient C-N bond formation in the solid state. Remarkably, while previous studies showed that the formation of this palladium-phosphine complex occurs only in protic solvents such as water or alcohols, but not in classical organic solvents, we demonstrate its generation in the absence of any solvent, as confirmed by solid-state ³¹P NMR, supporting its role as the active catalytic species.. This process enables the coupling of a broad range of aryl bromides and chlorides with amines, anilines, amides, carbamates, or ureas, delivering good to excellent yields. This mechanochemical method operates with minimal palladium loading and proceeds efficiently in air, offering a practical and sustainable alternative to traditional solution-phase reactions.