Multivariate Screening-Guided Development of a Sustainable Copper- and Amine-Free Heck–Cassar–Sonogashira Cross-Coupling Reaction in Ethanol

Transition-metal-catalyzed cross-coupling reactions have significantly advanced carbon–carbon bond formation. The Heck–Cassar–Sonogashira reaction, traditionally using Pd catalysts, copper cocatalysts, and amines in polar solvents, has drawbacks, including oxidative homocoupling and harmful solvents. Recent innovations address these issues with copper-free conditions, greener solvents, and alternative metals, but none offer a perfect solution. Starting from a recently characterized cationic palladium precatalyst, [Pd(π-allyl)( t -BuXPhos)]Cl, formed in situ in alcoholic solvents, we used a multivariate screening strategy to identify conditions allowing a copper- and amine-free Heck–Cassar–Sonogashira reaction using 0.25 mol % [Pd] loading with K 3 PO 4 in ethanol at 40 °C. The protocol features broad substrate scope (34 examples), good functional group compatibility, high yields, and gram-scale applicability.