Regiospecific cross-coupling of haloaryls and pyridine to 2-phenylpyridine using water, zinc, and catalytic palladium on carbon

A novel and simple protocol for the reductive cross-coupling of halobenzenes (PhX; X=Cl, Br, I) with pyridine is presented, using catalytic (0.5 mol%) palladium on carbon. Catalyst regeneration is effected using molecular hydrogen generated in situ from the palladium-catalysed reduction of water with zinc powder. Notably, this transformation does not require the presence of reactive B(OH)(2) or SnBu3 groups. Three separate processes are observed: cross-coupling (PhX + pyridine), homocoupling (PhX + PhX), and hydro-dehalogenation (reduction of PhX to PhH). The cross-coupling is regiospecific, forming only the 2-phenylpyridine isomer (ca. 50% isolated yield). The influence of various reaction parameters (temperature, reagent concentrations, and additives such as NaOH or a phase-transfer agent) on substrate conversion and product distribution is examined. Kinetic studies show the reaction rate is a function of zinc loading, catalyst loading, substrate concentration, and, above all, of the amount of water present. Possible mechanisms for the three processes in this system are discussed. It is proposed that the cross-coupling occurs via the formation of phenyl free-radicals, which subsequently react with pyridine molecules adsorbed on the catalyst surface.