Application of hindered ether solvents for palladium catalyzed coupling reaction of Suzuki-Miyaura, Sonogashira and cascade Sonogashira reactions Suwiwat Sangon 1 , Andrew Hunt 2 , Nontipa Supanchaiyamat 1 , James Sherwood 2 , Duncan MacQuarrie 2 , Pakin Noppawan 3 , 1 Khon Kaen University, Thailand, 2 University of York, UK, 3 Mahasarakham University, Thailand Cross-coupling and cascade reactions typically employ unsustainable and toxic volatile organic solvents. 2,2,5,5-tetramethyloxolane (TMO) and 2,5-diethyl-2,5-dimethyloxolane (DEDMO) with inherently non-peroxide forming ethers have been used as effective, sustainable, and potentially bio-based alternative solvents for Suzuki-Miyaura (SM) and Sonogashira reactions. Cascade Sonogashira reactions utilizing a simple methodology in these sustainable solvents demonstrated significant potential. Suzuki-Miyaura reactions demonstrated good yields for a range of substrates, 71-89% in TMO and 63-92% in DEDMO. In addition, Sonogashira reaction exhibited the excellent yields of 85-99% performed in TMO, which was significantly higher than traditional volatile organic solvents, THF and toluene, and higher than reported non-peroxide forming ether of eucalyptol. The cascade reactions are important in the development of active pharmaceutic ingredients and the investigation of such methods revealed that TMO demonstrated better performance, than the conventional problematic solvents. Furthermore, green metric assessment including process mass intensity (PMI), reaction mass efficiency (RME), atom economy (AE) and optimum efficiency (OE) confirmed that the methodology employing TMO was more sustainable and greener than the traditional solvents, THF and toluene, thereby demonstrating promise of TMO as alternative solvents for Pd-catalyzed cross-coupling reactions. References 1. J. Sherwood, J. H. Clark, I. J. S. Fairlamb and J. M. Slattery, Green Chem., 2019, 21, 2164–2213. 2. F. Byrne, B. Forier, G. Bossaert, C. Hoebers, T. J. Farmer, J. H. Clark and A. J. Hunt, Green Chem., 2017, 19, 3671–3678. 3. P. Noppawan, S. Sangon, N. Supancaiyamat, J. Sherwood and A. J. Hunt, ACS Sustain. Chem. Eng., 2022, 10, 4486–4493. 4. J. F. Campos, M.-C. Scherrmann and S. Berteina-Raboin, Green Chem., 2019, 21, 1531–1539.
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