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Ostrowska, Martyna (2025) Palladium-catalysed synthesis of diaryl ethers promoted by a soluble organic base. PhD thesis, University of Nottingham.

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Abstract

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 the presence of insoluble inorganic bases or metal alkoxides, which leads to heterogeneous reaction mixtures and ‘clumping’ of the base during reactions. This in turn leads to reproducibility issues, problematic sampling and poor isolated yields. Furthermore, reaction heterogeneity limits applications of the cross-coupling reactions in enabling technologies, such as high-throughput experimentation (HTE) and flow chemistry. Recently, these issues have been addressed in C-N and C-S couplings by using milder, soluble organic base. However, the equivalent procedure for Pd-catalysed C-O cross-couplings is currently unknown.

This Thesis describes the development of the first Pd-catalysed O-arylation of phenols with aryl triflates promoted by an organic base, aiming to overcome the many practical difficulties associated with using the inorganic / insoluble reagents.

Firstly, Chapter 2 details the optimisation of the reaction conditions for the new C-O cross-coupling. The investigated variables included the type of Pd precursor, the choice of ligand and the nature of the organic base. The combination of a milder and sterically hindered amine-type base with monophosphine AdBippyPhos ligand was found to be the most efficient for this coupling system.

Following this, the substrate scope of both aryl triflates and phenols is evaluated in Chapter 3. In agreement with the literature, the reaction tolerates a broad range of electrophiles and works well with bulky and electron-rich nucleophiles. Pleasingly, limitations associated with the electronic nature of phenols were overcome by the conversion of electron-deficient phenols into the corresponding triflates and successful coupling with electron-rich nucleophiles. The methodology is compatible with enabling industrial technologies and could be translated directly from batch reactions in a microwave to synthesis in flow. A gram-scale flow synthesis of Fluazifop-methyl herbicide was carried out to demonstrate the robustness of this novel cross-coupling.

Details of mechanistic studies are discussed in Chapter 4. Pseudo-zero order kinetic profile, a first-order dependence of the Pd as well as catalysts resting state were revealed during a thorough kinetic analysis. The reductive elimination was confirmed to be rate-determining, and the electronic dependency of the substrate scope in the investigated cross-coupling was analysed by Hammett studies. Finally, two possible pathways for the phenol transmetallation were proposed.

Item Type:	Thesis (University of Nottingham only) (PhD)
Supervisors:	Ball, Liam
Keywords:	diaryl ethers, palladium-catalysts
Subjects:	Q Science > QD Chemistry > QD241 Organic chemistry
Faculties/Schools:	UK Campuses > Faculty of Science > School of Chemistry
Item ID:	81707
Depositing User:	Ostrowska, Martyna
Date Deposited:	31 Dec 2025 04:40
Last Modified:	31 Dec 2025 04:40
URI:	https://eprints.nottingham.ac.uk/id/eprint/81707

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