The powerful combination of novel organosulfur methodology and continuous flow technology

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Kearney, Aoife M.
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University College Cork
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The work described in this thesis focuses on the use of novel methodologies in the form of continuous flow technology, FlowNMR, and FlowIR, as well as traditional batch techniques, to deliver powerful transformations based on organosulfur chemistry. The main objective of this work was the synthesis of key building-blocks for biologically relevant compounds coupled with the use of Process Analytical Technologies (PAT), to gain critical mechanistic insight and understanding, not previously accessible, to further add to the knowledge in the field, and deliver more efficient processes. Chapter 1 is a literature overview of the use of Process Analytical Technologies in continuous flow systems, with specific attention on the positive impacts of PAT in enabling the telescoping of multi-step sequences, both in industry and academia. Chapter 2 describes the synthesis of α-sulfenyl-β-chloroenones through a NCS chlorination transformation, and their subsequent use in a Stille cross-coupling reaction to form chalcone derivatives. Key mechanistic insight into the formation of the α-sulfenyl-β-chloroenones was provided through use of reaction monitoring via a combined FlowNMR and FlowIR study. This technology expanded our understanding of the mechanistic pathway to these substrates, showing for the first time the formation of the E-isomer as the kinetically favoured product, with isomerisation leading to the thermodynamically more favoured Z-isomer. Significantly, while exploring the reactivity of these compounds, through alteration of the synthetic steps in the sequence, complimentary routes to either the Z- or E-sulfoxide chalcone derivatives were designed; this provided access to the Z-sulfoxide chalcones for the first time. Chapter 3 details the successful extension of the NCS-mediated chlorination reaction to include lactam derivatives, synthesising a number of novel α-sulfenyl-β-chloro-enelactams. Once again, the mechanistic route to these derivatives was confirmed through use of FlowNMR as a reaction monitoring tool. Continuous flow technology was incorporated into the synthesis of the α-sulfenyl lactam core, leading to a three-step telescoped reaction sequence involving in situ sulfonyl azide formation, followed by diazo transfer and a rhodium-catalysed S– H insertion, with real-time monitoring provided by FlowIR spectroscopy. The effect of ring size and substituents on the NCS-mediated transformation was investigated with 5-membered, 6-membered, and a fused ring derivative prepared during this work. Notably, this work demonstrated for the first time that the NCS chlorination sequence is effective in lactams, in addition to the acyclic systems, despite the increased conformational constraints in a cyclic system. A number of five-membered β-chloroenelactams exhibited cytotoxic properties against specific cancer cell lines when screened for biological activity in The National Cancer Institute, Maryland, US. Chapter 5 outlines the successful optimisation of a three-step synthesis towards E-α-sulfenyl-β-hydroxyacrylamides in batch, without handling or isolation of any reaction intermediates, and the development, for the first time, of a three-step telescoped continuous flow reaction sequence. The use of continuous flow technology improved the synthetic route, providing the product in a high degree of purity in a fraction of the time required for the same process in batch, with clear potential for scale-up. An investigation into the feasibility of conducting the three-step sequence using an advanced CSTR was undertaken, for comparison with batch and continuous flow processing. Insight into the transformation was gained by both a high-field (600 MHz) and low-field (80 MHz) FlowNMR study, revealing for the first time, the appearance of the Z-isomer of β-hydroxyacrylamide in the aqueous acetonitrile reaction medium, in contrast to the E-isomer typically isolated from batch reactions. Chapter 6 describes the synthesis of a series of amino-tetralin and amino-indane derivatives for use in a transaminase-mediated kinetic resolution biotransformation. Full experimental details and spectroscopic characterisation of the compounds synthesised in the work are provided in Chapters 4, 5, and 6. Lastly, Chapter 7 contains the overall conclusions of the thesis.
Organosulfur chemistry , Diazo chemistry , Continuous flow technology , Process analytical technology
Kearney, A. M. 2023. The powerful combination of novel organosulfur methodology and continuous flow technology. PhD Thesis, University College Cork.
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