Sonication-Enhanced Suzuki-Miyaura Cross-Coupling for Efficient Diflunisal Production: A Combined Experimental and Theoretical Investigation.

The palladium-catalyzed Suzuki-Miyaura cross-coupling reaction is a pivotal method for synthesizing industrially important compounds, such as Diflunisal. In this study, we report the use of a ligand-free PdCl catalyst under ultrasonic irradiation to enhance the synthesis of Diflunisal. A systematic investigation is conducted to elucidate the impact of key operating parameters on the reaction efficiency. Our findings demonstrate that ultrasound-assisted, ligand-free PdCl-catalyzed Suzuki-Miyaura cross-coupling reactions can significantly intensify the synthesis process, providing a more efficient and sustainable route for Diflunisal production. Furthermore, this work delves into the reaction mechanism of the Suzuki-Miyaura process within a ,-dimethylformamide (DMF) solvent system, leveraging density functional theory (DFT) calculations. The results indicate that the oxidative addition of 5-bromosalicylic acid to PdCl, involving cleavage of the Br-C bond, is the rate-determining step of the reaction. Additionally, we analyze the role of the inorganic base, revealing its critical function in reducing the activation barriers of the transmetalation step, thereby facilitating the overall reaction progress.