Green Approach for Pd-Catalyzed C–N Bond Formation with Weak Nitrogen Nucleophiles Using Saponin-Based Micellar Catalysis: Arylation of Anilines, Amides, Carbamates, Ureas, and Sulfonamides

A general, convenient, and versatile protocol for the Pd-catalyzed C(sp²)–N cross-coupling has been developed that enabled coupling of several types of amine nucleophiles with aryl/heteroaryl halides in water at ambient temperature under micellar catalysis conditions. The commercially available plant-based natural saponin, a known surfactant, served as micellar catalysis promoting the C(sp²)–N cross-coupling reaction effectively with a wide range of amine derivatives such as aliphatic amines, aromatic amines, amides, carbamates, sulfonamides, and ureas, each of which previously required a different catalyst system to achieve optimal results. Also, the saponin-mediated micellar catalysis system effectively promoted cross-coupling of an array of heteroarene substrates, which are otherwise challenging substrates, as the heteroatom in a N-heteroarene has the ability to displace phosphine ligands from the metal center and can deactivate the catalyst system. The attractive features of this protocol are the use of water as a green solvent, the in situ generation of a micellar-catalysis system from natural saponin, promoting the reaction at room temperature in a short period, and notably the ability to recycle aqueous reaction medium containing still an active micellar-catalysis. The FE-SEM, EDS, and DLS analysis revealed that the saponin formed an aggregate in the shape of a sphere, incorporating the Pd-catalyst, and resulting in significantly increasing the reactivity. We also demonstrated that this operationally simple procedure can be successfully applied to a broad range of substrates including some API intermediates, and is amenable to scale-up.