Water-soluble alkylphosphines as ligands in palladium-catalyzed aqueous-phase cross-coupling reactions: Mechanistic advances and catalytic activity

Application of green chemistry practices to organic synthesis has been achieved through aqueous-phase, homogeneous catalysis. Aqueous phase catalysis offers an alternative to the use of environmentally harmful organic solvents. Specifically, sterically demanding, water-soluble ligands have been synthesized and applied to aqueous-phase palladium catalyzed cross-coupling reactions. The ligands t-Bu-Pip-phos and t-Bu-Amphos produce catalysts with the highest activity known for aqueous phase Suzuki-Miyaura cross-coupling. A variety of functionalized aryl bromides and phenylboronic acids were coupled in aqueous acetonitrile in excellent yield. Turnover numbers up to 734 000 mmol/mmol palladium have been achieved under mild conditions.; Spectroscopic investigation of solution phase palladium complexes with t-Bu-Pip-phos, t-Bu-Amphos and Cy-Pip-phos have been explored. The catalyst derived from Cy-Pip-phos gave lowered activity in room temperature coupling reactions despite the similarities in electron donating ability and steric demand of ligands that produce highly active catalysts. Nuclear magnetic resonance spectroscopy studies of palladium complexation with Cy-Pip-phos correlate with lowered activity.; Catalysts derived from t-Bu-Amphos efficiently couple aryl bromides in both neat water and a 1:1 toluene:water biphasic system. Coupling of aryl bromides and phenylboronic acids in a toluene:water system produced three recycled yields of greater than 80% at low catalyst loading (2 mol %). Couplings in neat water provide an environmentally friendly synthesis for carboxylic acid derivatives such as the FDA approved NSAID drug diflunisal.