The Use of High-Throughput Experimentation to Accelerate the Development of Methods for Complex Amine Synthesis
Technological innovations are crucial to advancing the chemical communities’ ability to develop new synthetic methodologies. To continue developing new reactions for the construction of important but increasingly complex molecules, modern chemists need to create faster and more environmentally sustainable methods for reaction discovery. The field of high-throughput experimentation (HTE) is vital to achieving these goals. HTE platforms exploit improvements in reaction dosing technology, parallelised reactors and analytical techniques to explore large numbers of reactions simultaneously in a materially conservative format. While HTE workflows have proven effective in developing new reactions and optimising production routes to drug molecules, the uptake of these techniques is slow across the chemical community. The slow uptake can be partially attributed to the prohibitive infrastructure costs associated with HTE. However, the lack of cohesive information of which reactions are compatible with HTE makes chemists hesitant to make infrastructure investments. One important molecular scaffold that still requires new general synthetic methods to access is ⍺-branched amines. The ability of the α-branched amine motifs to modulate key biological interactions and regulate the physicochemical properties of molecules has led them to become ubiquitous structural features in pharmaceutical agents. Despite many effective reactions being developed to synthesise this important motif, the assembly of α-branched amines commonly relies on a small number of reactions, such as reductive aminations. One of the most effective ways of assembling an α-branched amine motif is the 1,2-addition of a nucleophile to an in-situ formed iminium ion. However, most current reactions that exploit this approach are limited in the scaffolds they can produce. This thesis details the contributions to the development of a new carbonyl alkylative amination reaction for the synthesis of α-branched amine scaffolds utilising a novel HTE workflow. The introduction of this thesis seeks to provide a comprehensive overview of the reaction types compatible with HTE techniques. Analysis of the literature shows that a large majority of reaction types have been used in HTE workflows, although there are significant gaps for many common reactions. Chapter 2 describes the discovery and development of the next-generation zinc-mediated carbonyl alkylative amination reaction (Zn-CAA). The use of a metal reductant-mediated mechanism allows this reaction to overcome challenges associated with the light-mediated carbonyl alkylative amination reaction previously established in the Gaunt group. The scope of the Zn-CAA reaction demonstrates its ability to access a broad array of amine scaffolds, including some that were previously inaccessible under the light-mediated carbonyl alkylative amination platform. However, issues with the utilisation of primary and tertiary alkyl halide feedstocks in the Zn-CAA reaction prompted the development of a HTE workflow for the optimisation of reactions involving these substrates. Chapter 3 details the development of a HTE workflow utilising an economical and flexible reaction setup procedure, a novel chemical reactor, a parallel solid-phase workup methodology and quantitative 1H NMR high-throughput analysis. Finally, chapter 4 describes the use of the HTE platform for the successful optimisation of primary halides for the Zn-CAA reaction utilising a critical copper (I) iodide additive. The scope of the new copper-mediated Zn-CAA reaction was then investigated, revealing that the new reaction conditions enabled the use of several additional feedstocks. Further investigation into the scope of the reaction, utilising the HTE platform, evaluated a multitude of reagent combinations with an alternative analytical workflow. Chapter 4 concludes with the initial investigation into the mechanism of the Zn-CAA reaction. The experiments performed reveal the Zn-CAA reaction exists as a highly complicated radical and polar mechanistic equilibrium. Additionally, the equilibrium was found to shift depending on the type of scaffolds used for each reaction component.
high throughput experimentation, organic synthesis, organometallics, synthetic methodology
Networked Digital Library of Theses and Dissertations