Sequential processes using catalytic C-O bond activation
Abstract
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.
Type
Thesis, PhD Doctor of Philosophy
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