Telescoping the synthesis and heterogeneous transition metal catalysed asymmetric transformations of α-diazoketones and α-diazoacetamides in continuous flow

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Date
2020-09-17
Authors
Crowley, Daniel C.
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University College Cork
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Abstract
This project aims to expand the extensive work carried out by the Maguire group on the synthesis and reactivity of α-diazocarbonyl compounds over the last 25 years, with primary focus on the intramolecular aromatic addition of α-diazoketones. This transformation is studied in depth with particular focus on exploiting contemporary techniques and methodologies, such as immobilised catalysis and continuous flow processing, to enhance the practical synthetic potential of this powerful transformation. Chapter 1 provides a literature review as background to this research project focussing, in particular, on methodologies for the synthesis of α-diazocarbonyl compounds and selectivity patterns in intramolecular aromatic addition processes. Chapter 2 focuses on the synthesis of α-diazocarbonyl compounds including α-diazoketones, α-diazo-β-ketonitriles, α-cyano-α-diazoamides and α-diazo-β-diketones. Traditional methods, such as acylation of diazoalkanes, are compared to newer, safer methods proceeding via diazo transfer on continuous flow, developed during this work. Specifically, continuous flow processing is utilised to harness the powerful synthetic utility of hazardous triflyl azide for α-diazocarbonyl compound synthesis, while offsetting the potential hazards inherent in its use. Chapter 3 describes the transition metal catalysed transformations of the α-diazocarbonyl compounds synthesised in Chapter 2. Results achieved with homogeneous copper–bis(oxazoline) catalyst systems are compared with those achieved with novel immobilised copper catalysts in both batch and continuous flow; the synthesis of the immobilised copper catalysts is also discussed. This is the first report of enantioselective, copper mediated aromatic addition using an immobilised catalyst in either batch or continuous flow with enantiopurities of up to 85% ee achieved. Furthermore, novel rhodium(II) mandelate catalysts, designed by the Maguire group, are applied across the array of α-diazocarbonyl compounds studied in the project, investigating their chemo- and stereoselectivity for intramolecular aromatic addition. Excellent control of both the chemo- and enantioselection (up to 89% ee) was achieved with the novel rhodium(II) mandelate catalysts. Finally, Chapter 4 combines the sulfonyl azide synthesis and α-diazocarbonyl compound synthesis explored in Chapter 2 with the transition metal catalysed transformation studied in Chapter 3. This furnishes a three-step telescoped sequence, whereby hazardous sulfonyl azides and α-diazocarbonyl compounds are synthesised in situ from readily handled starting iv materials, and, without being isolated or stored, are subjected directly to transition metal catalysis downstream, furnishing enantioenriched products. This chapter describes the steps taken in the process to ensure removal of by-products from upstream transformations, which would be detrimental to the transition metal catalysts, as well discussing the studies undertaken to ensure the safety of the transformation. This telescoped process realises the synthetic potential of these hazardous reagents in a manner safer than traditional batch processes, and the scale-up of the three-step telescoped process is successfully explored. Chapter 5 contains the full experimental details and spectroscopic characterisation of the compounds synthesised in this work.
Description
Crowley, Daniel
Keywords
Diazo carbonyl , Flow chemistry , Rhodium copper catalysis , Asymmetric catalysis
Citation
Crowley, D. C. 2020. Telescoping the synthesis and heterogeneous transition metal catalysed asymmetric transformations of α-diazoketones and α-diazoacetamides in continuous flow. PhD Thesis, University College Cork.