C−H Bond Arylation of Pyrazoles at the β‐Position: General Conditions and Computational Elucidation for a High Regioselectivity

Abstract

Direct arylation of most five‐membered ring heterocycles are generally easily accessible and strongly favored at the α‐position using classical palladium‐catalysis. Conversely, regioselective functionalization of such heterocycles at the concurrent β‐position remains currently very challenging. Herein, we report general conditions for regioselective direct arylation at the β‐position of pyrazoles, while C−H α‐position is free. By using aryl bromides as the aryl source and a judicious choice of solvent, the arylation reaction of variously N‐substituted pyrazoles simply proceeds via β‐C−H bond functionalization. The β‐regioselectivity is promoted by a ligand‐free palladium catalyst and a simple base without oxidant or further additive, and tolerates a variety of substituents on the bromoarene. DFT calculations revealed that a protic solvent such as 2‐ethoxyethan‐1‐ol significantly enhances the acidity of the proton at β‐position of the pyrazoles and thus favors this direct β‐C−H bond arylation. This selective pyrazoles β‐C−H bond arylation was successfully applied for the straightforward building of π‐extended poly(hetero)aromatic structures via further Pd‐catalyzed combined α‐C−H intermolecular and intramolecular C−H bond arylation in an overall highly atom‐economical process.