Iridium-catalyzed reductive γ-lactonization of ortho-acylbenzoic acids in water: sustainable access to phthalides

Abstract

We demonstrate that the iridium-catalyzed reductive γ-lactonization of ortho-acylbenzoic acids serves as a synthetically practical and efficient route to phthalides. This protocol features the use of water as the solvent and formic acid as the reducing agent. It has advantages of high yields and selectivity, good functionality compatibility, high catalyst efficiency (S/C up to 5000), environmental- and practitioner-friendliness, easy product purification (by filtration or extraction), and high level of scalability. The hydrogen bond between the carboxyl and carbonyl groups of substrates activates the carbonyl toward hydride reduction. The KIE study reveals that the formation of iridium hydride serves as the rate-determining step of the whole process. Derivatization of products delivers more densely functionalized phthalides that may display potential bioactivities and other applications. Our protocol is also implemented as a key step in the one pot decagram-scale synthesis of the drug molecule (±)-3-n-butylphthalide.