Applications of rhodium-catalysed hydroacylation in heterocycle synthesis

Thesis

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.

Authors: Majhail, M

• DOI: 10.5287/ora-xke9jkp5v
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: Heterocycle synthesis; Hydroacylation; Rhodium catalysis; Organic synthesis
• Subjects: Chemistry, Organic