Push button, automated flow synthesis of biaryls and stilbenes using palladium-catalysed cross-coupling reactions

A ligand-free, palladium-based heterogeneous nanocatalyst supported on TiO₂ was synthesized using a wet impregnation method and was incorporated into an automated continuous flow system for the synthesis of pharmaceutically relevant biaryls and stilbenes via Suzuki–Miyaura and Mizoroki–Heck cross-coupling reactions. The catalyst was prepared using 21.2 mg of palladium acetate on 1 g of TiO₂ and was characterized by BET, FTIR, XRD, SEM, TEM, and EDX analyses, through which a high dispersion and notable stability of the palladium nanoparticles were confirmed. Reactions were carried out using 1.0 mmol of substrate, 1.2 mmol of coupling partner, 2.0 mmol of base, and 200 mg of catalyst, with a residence time of 35 minutes. In the Mizoroki–Heck reaction, DMF was employed as the solvent, and an optimized temperature of 130 °C was found to yield up to 90 % conversion. Through studies on base and solvent effects, triethylamine and potassium carbonate were identified as providing superior performance. Catalyst loading experiments showed that an optimal loading of 3.0 mol% Pd/TiO₂ was required, as both lower and higher amounts led to reduced conversions. Remarkably, selective formation of Z-stilbene was observed, in contrast to the more commonly produced trans isomer in related processes. A greener, faster, and more reproducible approach to on-demand pharmaceutical synthesis has thus been demonstrated through this methodology.

• Onisuru, O
• Alimi, O
• Fapojuwo, D
• Oseghale, C
• Meijboom, R

• Department of Chemical Sciences, University of Johannesburg, P.O. Box 524, Auckland Park, Johannesburg 2006, South Africa

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