Enabling the synthesis and reactivity of α-diazocarbonyl compounds using continuous flow chemistry

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O'Mahony, Rosella M.
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University College Cork
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Use of diazo compounds for large scale synthesis has been limited due to the challenges associated with these hazardous reagents; this thesis explores how continuous flow processing can be employed to enable safe generation, handling and use of diazo compounds and their precursors, specifically sulfonyl azides, to overcome these challenges and thereby enable the consideration of the use of diazo chemistry in future synthetic processes. The first chapter is a literature review of recent advances in the available approaches for the generation of diazo compounds with a particular emphasis on telescoping in situ generation with subsequent transformations; use of batch and/or continuous flow processing conditions are discussed. The second chapter shows for the first time that tosyl azide can be efficiently generated and used for diazo transfer, to a range of substrates, under continuous flow conditions, obviating the requirement to prepare, store or handle this hazardous reagent. Successful application to a broad of substrates was demonstrated including β-ketoesters, diethyl malonate, a β-ketoamide and β-oxo-sulfones. Extensive studies were carried out to find the optimum conditions for in situ sulfonyl azide formation and diazo transfer. A novel quench was designed and successfully implemented, to safely address unreacted or excess tosyl azide. The third chapter describes the extension of the continuous flow diazo transfer methodology to synthesis and use of mesyl azide as the diazo transfer reagent, with the advantage of facile removal of the water soluble byproducts by phase separation in continuous flow. While the hazards associated with use of mesyl azide are greater than those of tosyl azide, under traditional batch conditions, use of flow technology overcomes these barriers. Use of the “salt assisted liquid-liquid extraction” (SALLE) separation technique in conjunction with a designed in-line liquid–liquid separator, provided a clean outflow of α-diazo-β-keto ester in acetonitrile of sufficient quality to enable telescoping of the sulfonyl azide formation and the diazo transfer step with a subsequent thermal Wolff rearrangement. An interesting application of FlowNMR is described which enabled investigation of the mechanism of mesyl azide formation. Use of an alternative water soluble diazo transfer reagent, m-carboxybenzenesulfonyl azide, in both organic and aqueous media was explored. The fourth chapter builds on the diazo transfer in flow methodology successfully developed in Chapters 2 and 3, and specifically explores its incorporation in the synthesis of the key API intermediate, methyl 2-hydroxyl-2-chlorophenylacetate, used in the synthesis of the anti-platelet drug, Plavix®. As the original diazo transfer process, in aqueous acetonitrile, was not compatible for the formation of aryl diazo acetates, an alternative flow protocol for generation of tosyl azide was developed in an aqueous-free medium. Telescoping the formation of tosyl azide, diazo transfer and subsequent transition metal catalysed OH insertion of the α-aryl-α-diazoacetate product in flow was achieved; notably the rhodium catalysed OH insertion was cleaner in flow than under batch conditions. Full experimental details, including spectroscopic and analytical data for all compounds prepared, are reported at the end of each chapter.
Diazo , Tosyl azide , Mesyl azide , Flow chemistry , Continuous flow
O'Mahony, R. M. 2020. Enabling the synthesis and reactivity of α-diazocarbonyl compounds using continuous flow chemistry. PhD Thesis, University College Cork.