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

• Published in: ChemSusChem Vol. 14; no. 12; pp. 2591 - 2600
• Main Authors: Fantoni, Tommaso, Bernardoni, Sara, Mattellone, Alexia, Martelli, Giulia, Ferrazzano, Lucia, Cantelmi, Paolo, Corbisiero, Dario, Tolomelli, Alessandra, Cabri, Walter, Vacondio, Federica, Ferlenghi, Francesca, Mor, Marco, Ricci, Antonio
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 21.06.2021; John Wiley and Sons Inc
• Subjects: Bromides; Catalysts; Chemical reactions; Cross coupling; green chemistry; Heck-Cassar-Sonogashira; homogeneous catalysis; Iodides; Palladium; Phosphines; Recycling; Solvents; TPPTS; cross-coupling; homogeneous catalysis; green chemistry; TPPTS; Heck-Cassar-Sonogashira
• ISSN: 1864-5631; 1864-564X
• DOI: 10.1002/cssc.202100623

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). Recycle and reuse: Heck‐Cassar‐Sonogashira cross‐coupling using the green N‐hydroxyethylpyrrolidone (HEP)/H2O/N,N,N′,N′‐tetramethyl guanidine (TMG) blend, sulfonate phosphines, and aryl iodides, bromides, and triflates affords the corresponding products in high yield free from metal contamination. The catalyst/HEP/H2O solution can be recycled, increasing turnover number and frequency up to 2375 and 158 h−1, respectively, with a low process mass intensity close to 3 after solvent, base, and palladium recovery. Additionally, Erlotinib synthesis is described.