Fullbrook, Jeremy Jon
(2003).
Generating structural diversity in \(\alpha\)[alpha],\(\alpha\)[alpha]-difluoromethyl ketones.
University of Birmingham.
Ph.D.
Abstract
This thesis describes attempts to use palladium-catalysed cross-coupling methodology in the synthesis of \(\alpha\),\(\alpha\)-difluoroketones contained within a diverse array of molecular motifs. 1-(\(N\),\(N\)-Diethylcarbamoyloxy)-2,2-difluoro-1-(tributylstannyl)ethene undergoes Stille cross coupling with a variety of aryl, heteroaryl, vinyl and allyl organic electrophiles. Conditions, which promote in situ transmetallation to a more reactive copper intermediate, were essential for obtaining significant quantities of product. 1-(\(N\),\(N\)-Diethylcarbamoyloxy)-2,2-difluoro-1-iodoethene also underwent coupling with a range of aryl, heteroaryl and vinyl stannanes. Due to the difficulties with cleavage of this protecting group, the synthesis and potential application of an \(N\)-ethyl-\(N\)-(2-methylallyl)carbamate has been studied. A 2-methoxyethoxymethyl (MEM) protecting group strategy proved very successful for the synthesis of a range of difluoromethyl aryl ketones. Two consecutive coupling reactions were possible from a difluoroenol stannane, in which coupling of initial styrene products bearing a triflate group afforded a range of biarylethenes. Cleavage occurred under mild electrophilic conditions with protic, halogen, sulfur and carbon electrophiles. Diene products have been tested for reactivity in Sharpless Asymmetric Dihydroxylation. A 1,4-diene has been converted through to a fluorinated analogue of a dideoxyxylulose. A 1,3-diene has been successfully converted through to a difluorodeoxyxylulose of current interest. Key points involve regioselective and highly enantioselective dihydroxylation of the non-fluorinated olefin. Application of a special protecting group for the allylic alcohol was essential, as was control of the pH of the reaction medium.
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