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 K3PO4 in ethanol at 40 °C. The protocol features broad substrate scope (34 examples), good functional group compatibility, high yields, and gram-scale applicability.