Mastering palladium-catalyzed cross-coupling reactions: the critical role of in situ pre-catalyst reduction design†

Palladium-catalyzed cross-coupling reactions are among the most used methods for carbon–carbon bond formation in the agrochemical and pharmaceutical segments. The key step common to all methodologies based on Pd(0) catalysis is the in situ generation of the active catalyst. This paper describes how to control pre-catalyst reduction in order to generate the target complex species while avoiding phosphine oxidation or, as in the case of the Heck–Cassar–Sonogashira and the Suzuki–Miyaura reactions, reactant consumption via dimerization. For PPh₃, DPPF, DPPP, Xantphos, SPhos, RuPhos, XPhos and sSPhos, we identified protocols that are able to maximize reduction via alcohols while preserving ligands and reagents. The correct combination of counterion, ligand, and base allowed the perfect control of the Pd(ii) reduction to Pd(0) in the presence of primary alcohols.