Development and application of rhodium(III)-catalysed C-H activation methodologies

• Main Author: Webb, Nicola Jayne
• Other Authors: Marsden, Stephen P.
• Published: University of Leeds 2014
• Subjects: 540
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.638900

In recent years, rhodium(III)-catalysed C-H activation methodologies have come to the fore and proved to be an invaluable and powerful synthetic tool for the preparation of heterocycles. C-H activation using rhodium(III)-catalysed processes with internal oxidants has considerably improved the accessibility of these scaffolds. Furthermore, the alkynes and alkenes used to intercept the arylmetal species in the aforementioned systems have been either electronically neutral or electron-deficient. Chapter 1 outlines the investigation of electron-rich substrates, using vinyl esters as acetylene synthons and vinyl ethers as acetaldehyde enolate/acyl anion equivalents. From this study, a competing rhodium-catalysed Lossen rearrangement was identified and the regiochemical preference of vinyl ether substrates was determined. The preliminary screening identified the formation of a 3,4 unsubstituted isoquinolone from the reaction of vinyl acetate with the acyl hydroxamates. As a result, the synthesis of 3,4-unsubstituted isoquinolones, using vinyl acetate, a cheap bulk chemical, as an acetylene equivalent was explored. The procedure works well for a range of substituted N-(pivaloyloxy)benzamide derivatives; in total, 17 examplar 3,4-unsubstituted isoquinolones were prepared with an average yield of 75%. Heterocyclic pivaloyl hydroxamates were also tolerated in the reaction. These conditions offer distinct advantages over traditional methods. The utility of the procedure was demonstrated in the synthesis of two intermediates towards hepatitis C virus inhibitors. The ensuing chapter describes the optimization of this methodology using aryl ketoximes for the synthesis of 3,4-unsubstituted isoquinolines. To conclude, the final chapter describes the isolation and attempted optimisation of a highly fluorescent tetracyclic imide. Mechanistic studies used to determine the formation of the imide identified putative intermediates, however the synthetic procedure could not be optimised further. Using a novel strategy, via a key C-H activation/annulation reaction of a range of bespoke alkynes and N-(pivaloyloxy)benzamides, a library of nine imides was prepared.