Decarboxylative Transformations: Synthetic Applications and Mechanistic Investigations Submitted

Abstract

and biological sources. Recent advances in decarboxylative activation has allowed for the application of these reagents as building-blocks in organic synthesis; presenting viable, green alternatives to traditional organometallic or organohalide reagents. This thesis focuses on the development of novel transition metal catalysed decarboxylations, and investigation into the mechanisms of these, and related transformations. In the first part of the thesis, an extensive overview of the latest Carboxylic acids are cheap, shelf-stable reagents readily available from several commercial and biological sources. Recent advances in decarboxylative activation has allowed for the application of these reagents as building-blocks in organic synthesis; presenting viable, green alternatives to traditional organometallic or organohalide reagents. This thesis focuses on the development of novel transition metal catalysed decarboxylations, and investigation into the mechanisms of these, and related transformations. In the first part of the thesis, an extensive overview of the latest decarboxylative methodologies is presented, with discussion of the mechanistic aspects of different metal-catalysed decarboxylations. This is followed by a mechanistic investigation into the silver-catalysed decarboxylation of benzoic acids. In this system, an ortho substituent is required to facilitate decarboxylation. Using DFT, kinetic studies and the Fujita-Nishioka LFER we were able to show that the ortho-effect is a combination of electronic and steric effects, contrary to previous reports. In the second part of the thesis a practical, mild and highly selective protocol for the mono-deuteration of a variety of (hetero)arenes is described. Ag-catalysis was shown to facilitate the deuterodecarboxylation of (hetero)aromatic carboxylic acids in D2O/DMSO. The last two parts of this thesis focus on the formation and activation of carbon-fluorine bonds. Organofluorine compounds are of great importance to the agrochemical and pharmaceutical industries; however, there are limited examples of selective C-F bond formation that do not require stoichiometric metals, harsh conditions or toxic reagents. Using transition metal catalysis, we investigated a fluorodecarboxylation methodology. Initially this was explored in aromatic systems; though no synthetically useful yields were realised. However, aliphatic carboxylic acids were successfully transformed under aqueous conditions. The developed protocol was exploited to access benzylic fluorides. Subsequently, we established unprecedented metal-free conditions to activate their C-F bonds towards nucleophilic displacement; presenting a novel, decarboxylative methodology to furnish carbon-carbon and carbon-heteroatom bonds.