Applications of rhodium-catalysed hydroacylation in heterocycle synthesis

• Main Author: Majhail, Manjeet K.
• Other Authors: Willis, Michael C.
• Published: University of Oxford 2016
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.728953

The work compiled in this thesis documents the development of new methodologies towards the synthesis of a range of N-containing heterocycles. These methods utilise intermolecular Rh(I)-catalysed hydroacylation of chelating aldehydes with alkynes and alkenes to install carbonyl groups, which are exploited in subsequent heterocycle forming cascades. Chapter 1 presents a literature review of the development of both intramolecular and intermolecular rhodium-catalysed hydroacylation, with the focus of different methods to suppress decarbonylation and promote constructive catalysis. A brief description of some precedented examples of hydroacylation in heterocycle synthesis is also included. Chapter 2 describes the optimisation studies for the hydroacylation of S-/N-chelating aldehydes with terminal and internal propargylic amines. The studies are largely focussed on achieving high regioselectivity for the linear gamma-amino enone product. The cyclisation of these gamma-amino enone adducts to form pyrrole rings is also described. Chapter 3 presents the de novo one-pot cascade synthesis of mono-, di- and tri- substituted pyrroles via a highly regioselective hydroacylation pathway. The pyrroles are exploited in further modifications to access fully substituted heteroaromatic systems or in a three-component coupling of aldehydes, propargylic amines and boronic acids or alkynes to access 'traceless' pyrrole rings. The one-pot cascade methodology is extended to the synthesis of dihydropyrroles, through the hydroacylation of allylic amines, which grants access to pyrrolidine rings via diastereoselective reductions. Chapter 4 details the initial investigations towards the development of rhodium- catalysed hydroacylation of ynamides with chelating aldehydes. This provides access to beta-amino enones in a regioselective manner. These hydroacylation products, which are known to be versatile building blocks, are subsequently exploited in the synthesis of five- and six-membered heterocycles via bi-nucleophilic additions. Chapter 5 discusses the conclusions of the research and the potential for further work. Chapter 6 compiles the experimental procedures and data.