Sonogashira breathes easy: a practical room-temperature homogeneous coupling in continuous flow under air

Abstract

The Sonogashira cross-coupling reaction is a cornerstone of modern organic synthesis, yet its implementation under mild, scalable, and operationally simple conditions remains a challenge. To address this, we developed a homogeneous, room-temperature Sonogashira coupling protocol in continuous flow that operates efficiently at room temperature under air. Using an E-FLOW-10 flow platform, we optimized a catalytic system based on Pd(OAc)₂, CuI, and PPh₃ in a mixed Et₃N/MeOH solvent system. Crucially, separating the palladium and copper catalysts into two distinct feed streams prevented rapid Pd-black formation and significantly enhanced reaction efficiency. This work demonstrates a practical Sonogashira coupling in flow, overcoming previous limitations associated with heterogeneous systems and elevated temperatures.