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Title: Sequential processes using catalytic C-O bond activation
Author: Harkness, Gavin J.
ISNI:       0000 0004 6500 8759
Awarding Body: University of St Andrews
Current Institution: University of St Andrews
Date of Award: 2018
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This thesis is centred around sequential C-C bond forming processes using oxygenated electrophiles. A major part of this research focuses on the constructive deoxygenation of 2-methoxyphenol (guaiacol), a major breakdown product of the renewable feedstock, lignin. 1,2-dielectrophiles are known to be challenging substrates for catalysis if both leaving groups are of similar reactivity, however high selectivity was observed in the palladium- catalysed Grignard cross-coupling of 2-methoxyphenyl-1H-imidazole-1-sulfonate. The previously untested Grignard cross-coupling catalyst, [PdCl₂(Xylyl-Phanephos)], was found to be highly active. A 2-benzoxazolyl functionality was shown to be an excellent directing group for the chelation-controlled nucleophilic aromatic substitution of aryl methyl ethers. However, this modified Meyers reaction is limited to aryl ethers containing an ortho-chelating group. To expand the ether scope, nickel-catalysed Grignard cross-coupling was studied. [NiCl₂(PⁿBu₃)2] showed increased activity in the Grignard cross-coupling of challenging ortho-substituted anisoles compared to the well-renowned [NiCl₂(PCy₃)2] and several Ni0 -NHC systems, with a ligand steric effect demonstrated. The success of [NiCl₂(PⁿBu₃)2] was extended to more activated methoxynaphthalene substrates, in which the lowest reported catalyst loadings (0.1-0.25 mol%) were reported. Induction periods at 0.1 mol% suggested the requirement of inorganic Lewis-acidic magnesium salts to be formed in situ before any considerable activity was observed. Further work is required to increase reaction and ether scope, but this work provides a basis for exploiting lignin- derived phenols as a framework in the synthesis of functionalised chemicals of higher value. The final results chapter concerns an alternative sequential C-C bond forming process using another oxygenated electrophile. [PdCl₂((S)-Xylyl-Phanephos)] was used to accomplish a Grignard cross-coupling of vinyl tosylate, with the product then subjected to a highly enantioselective methoxycarbonylation using the same catalyst. This lead to a concise synthesis of (S)-Flurbiprofen.
Supervisor: Clarke, Matt Sponsor: Engineering and Physical Sciences Research Council (EPSRC) ; University of St Andrews
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Catalysis ; Cross-coupling ; Constructive deoxygenation ; C-O bond activation ; Carbonylation ; Flurbiprofen ; Chemical bonds