Palladium Catalyst Recycling for Heck-Cassar-Sonogashira Cross-Coupling Reactions in Green Solvent/Base Blend

The identification of a green, versatile, user-friendly, and efficient methodology is necessary to facilitate the use of Heck-Cassar-Sonogashira (HCS) cross-coupling reaction in drug discovery and industrial production in the pharmaceutical segment. The Heck-Cassar and Sonogashira protocols, using N-hydroxyethylpyrrolidone (HEP)/water/N,N,N ',N '-tetramethyl guanidine (TMG) as green solvent/base mixture and sulfonated phosphine ligands, allowed to recycle the catalyst, always guaranteeing high yields and fast conversion under mild conditions, with aryl iodides, bromides, and triflates. No catalyst leakage or metal contamination of the final product were observed during the HCS recycling. To our knowledge, a turnover number (TON) up to 2375, a turnover frequency (TOF) of 158 h(-1), and a process mass intensity (PMI) around 7 that decreased around 3 after solvent, base, and palladium recovery, represent one of the best results to date using a sustainable protocol. The Heck-Cassar protocol using sSPhos was successfully applied to the telescoped synthesis of Erlotinib (TON: 1380; TOF: 46 h(-1)).

Automated summary

The use of N-hydroxyethylpyrrolidone (HEP)/water/N,N,N',N'-tetramethyl guanidine (TMG) as solvent/base mixture and sulfonated phosphine ligands in the Heck-Cassar and Sonogashira protocols allows for high yields and fast conversion under mild conditions, with the catalyst being recyclable without leakage or metal contamination.