Palladium-catalysed synthesis of diaryl ethers promoted by a soluble organic base Martyna I. Ostrowska 1 , Dr James Morris 2 *, Dr Liam T. Ball 1 * 1 School of Chemistry, University of Nottingham, UK, 2 Syngenta, Jealott’s Hill International Research Centre, UK Metal-catalysed cross-couplings are powerful tools for the synthesis of a diverse range of pharmaceuticals and agrochemicals. Despite significant advances achieved in this area, most of these reactions are carried in a presence of insoluble inorganic bases or metal alkoxides, which leads to heterogeneous reaction mixtures and ‘clumping’ of the base during reactions. 1,2 This in turn leads to reproducibility issues, problematic sampling and poor isolated yields. Additionally, overheating of inorganic deposits during microwave synthesis could raise the risk of explosion. Furthermore, reaction heterogeneity results in poor scalability, an issue that is especially acute when High-Throughput-Experimentation (HTE) screens are translated to the synthetic laboratory. Recently, these issues have been addressed in C-N and C-S couplings 3,4 by using a milder, soluble organic base. However, the equivalent procedure for Pd-catalysed C-O cross-couplings is currently unknown. 5,6 To address the above-mentioned problems, we have developed the first Pd-catalysed O -arylation of phenols with aryl triflates that uses a soluble organic base. The methodology tolerates a broad range of sterically and electronically diverse coupling partners and is compatible with both microwave heating and HTE formats. We anticipate that this methodology will prove to be a useful tool in both academic and industrial discovery programmes.
References 1. Engle, K.; Wethman, R.; Derosa, J.; Tran, V. T.; et al. An Under-Appreciated Source of Reproducibility Issues in Cross- Coupling: Solid-State Decomposition of Primary Sodium Alkoxides in Air. ACS Catal. 2021 , 11 , 502–508. 2. Dommisse, R. A.; Meyers, C.; Maes, B. U. W.; Loones, K. T. J.; et. al. Study of a New Rate Increasing “Base Effect” in the Palladium-Catalyzed Amination of Aryl Iodides. Org. Chem. 2004 , 69 , 6010–6017. 3. Buchwald, S. L.; Dennis, J. M.; White, N. A.; Liu, R. Y. Breaking the Base Barrier: An Electron-Deficient Palladium Catalyst Enables the Use of a Common Soluble Base in C-N Coupling. Am. Chem. Soc. 2018 , 140 , 4721–4725. 4. Buchwald, S. L.; Yeung, C. S.; Xu, J.; Liu, R. Y. Monophosphine Ligands Promote Pd-Catalyzed C−S Cross-Coupling Reactions at Room Temperature with Soluble Bases. ACS Catal. 2019 , 9 , 6461–6466. 5. Buchwald, S. L.; Burgos, C. H.; Huang, X.; Barder, T. E. Significantly Improved Method for the Pd-Catalyzed Coupling of Phenols with Aryl Halides: Understanding Ligand Effects. Chem. Int. Ed. 2006 , 45 , 4321–4326. 6. Buchwald, S. L.; Zhang, H.; Ruiz-Castillo, P.; Schuppe, A. W. Improved Process for the Palladium-Catalyzed C–O Cross- Coupling of Secondary Alcohols. Lett. 2020 , 22 , 5369–5374.
P27
© The Author(s), 2023
Made with FlippingBook Learn more on our blog