Development of Novel Methods for CO2 Utilisation, Amination and Amidation

This thesis is split into two parts based on three distinct areas of research. Part 1 focuses on CO2 utilisation for the construction of α,β-unsaturated carboxylic acids, and is divided into three chapters. In Chapter 1, a review is done of the research conducted in this area. Chapter 2 discusses developments made to a novel methodology in which the C–C bond and C=C bond of α,β-unsaturated carboxylic acids is formed in a one-pot process. The reaction involves phosphonium ylide-mediated CO2 utilisation in conjunction with a novel Wittig type reaction (hence referred to as the Wittig CO2 utilisation methodology). The experimental work for this project is outlined in Chapter 3. The greenhouse gas CO2 is perhaps the most significant waste product of the industrialised world. Developing a method for the conversion of a harmful environmental waste product into carboxyl-containing organic products can allow CO2 to be used as a one-carbon (C1) chemical building block. The synthetic targets of this project were α,β-unsaturated carboxylic acids – a structural motif that is ubiquitous in nature and pharmaceutical targets. The Wittig CO2 utilisation methodology involves the activation of CO2 followed by a novel Wittig-type reaction, in a one-pot process. In this project, the carbonyl sources for the Wittig reaction were expanded to include aromatic, heterocyclic, and aliphatic aldehydes as well as ketones. α,β-Unsaturated carboxylic acids containing trisubstituted C=C double bonds were synthesised from two complementary routes, depending on the desired substitution of the alkene bond. This telescoped process demonstrated a high degree of selectivity for the E-alkene. Included among the substrates synthesised were pharmaceutical intermediates, underscoring the synthetic value of the process. Isotopic labelling was also possible with this methodology. Part 2 details the development of two novel protocols, mediated by the same organophosphorus protomer, and is split into six chapters. The first methodology discussed is an amination protocol. The second methodology is based on an amidation reaction. Chapter 4 discusses the advancements made in amination and amidation strategies reported in the literature, with a particular focus on the sustainability of the methodologies. Chapter 5 outlines the development of the amination protocol, and the corresponding experimental work is detailed in Chapter 8. The amination reaction involved the use of alcohols as starting materials for the the N-alkylation of amines. A range of π-activated alcohols were used in the synthesis of amines in moderate to high yields (19 examples in yields of 45 – 99%). In chapter 6, the same promoter used in the amination protocol is utilised in the development of a novel amidation methodology. Chapter 9 contains the experimental work for the amidation methodology developed in this project. The amidation reaction required sub-stoichiometric quantities of the phosphorus promoter in an operationally simple protocol. Excellent scope and functional group tolerance was shown (31 examples, in yields of 54 – 90%). Chapter 7 details the green chemistry metric analysis carried out using the two novel methodologies developed in these projects. A green chemistry metric analysis determined that the amination and amidation processes developed in this project had competitive metric values.