Novel synthetic methodology employing transition metal catalysed reactions of α-diazo-β-keto sulfonamides and α-cyano-α-diazoacetates; the impact of substituents on the reaction pathway

The central focus of this thesis is the reactivity of α-diazo-β-keto sulfonamides, α-cyano-α-diazoacetates and α-arylsulfonyl-α-diazoacetates employing rhodium and copper catalysts. While the α-diazo-β-keto sulfonamides were specifically designed to investigate rhodium- and copper-catalysed intramolecular C–H insertion, the α-cyano-α-diazoacetates and α-arylsulfonyl-α-diazoacetates probed intramolecular aromatic addition. The precise impact of the substituents of an α-diazocarbonyl compound, on the ensuing rhodium- and copper-catalysed reaction pathway(s), is also examined in this work through comparison to analogous transformations reported previously in the group and in the literature. Chapter 1 contains a review of the impact of the variation of substituents on the reactivity of the metal-carbenes derived from α-diazocarbonyl compounds and provides important context for some of the key findings in this work. Chapter 2 explores the copper- and rhodium-mediated transformations of α-diazo-β-keto sulfonamides. The copper-mediated reactions of α-diazo-β-keto sulfonamides led to a range of products, including alkynesulfonamides, enamines, and α-halosulfonamides, with no evidence for intramolecular C–H insertion in any of the reactions, in contrast to the reactivity of the comparable α-diazo-β-oxo sulfones and α-diazosulfonates. Use of copper(II) triflate (5 mol%) led to the isolation of a series of alkynesulfonamides (up to 12% yield) and enamines (up to 64% yield). Use of copper(II) chloride (5 mol%) led to the formation, in addition, of α-halosulfonamides; use of stoichiometric amounts of copper(II) chloride/bromide enabled facile halogenation of the α-diazo-β-keto sulfonamide to form α-halosulfonamides (up to 63% yield). Notably, copper is essential for the successful halogenation of the α-diazo-β-keto sulfonamides. Chapter 3 describes the investigation of rhodium- and copper-catalysed reactions of α-cyano-α-diazoacetates. The rhodium-mediated transformations were found to lead to a number of different products including oxa-azulenones (up to 53% ee) arising from intramolecular aromatic addition, overcyclopropanation products (as single diastereomers) from the unanticipated cyclopropanation of oxa-azulenones and cyanohydrins from reaction with adventitious water. Critically, the extent of formation of the overcyclopropanation product and cyanohydrin could be controlled by changing the reaction concentration and rigorously pre-drying the rhodium catalyst and α-cyano-α-diazoacetate solutions. Furthermore, the enantiopurity of the recovered oxa-azulenones was sensitive to a number of factors including the nature of the rhodium catalyst, the reactant concentration, presence of water and the cyanohydrin. The impact of the bridgehead and C(4) substituent on the position of the norcaradiene–cycloheptatriene (NCD–CHT) equilibrium was also explored in detail, principally through 1H and 13C NMR spectroscopy and IR spectroscopy. Variable temperature 1H NMR studies of two oxa-azulenones were conducted providing valuable insight into the position of the NCD–CHT equilibrium and its temperature sensitivity. Additionally, trapping the NCD of one of the oxa-azulenone as the PTAD cycloadduct substantiates the existence of the NCD–CHT equilibrium. Interestingly, while rhodium-catalysed intramolecular aromatic addition is feasible with α-cyano-α-diazoacetates, under the same conditions α-arylsulfonyl-α-diazoacetates give a completely different outcome. Chapter 4 contains the full experimental details and spectroscopic characterisation of the compounds synthesised in this work.

Grantor dc:publisher

University College Cork

Year dc:date.issued

2025

Author dc:creator

• Judge, Evan

Advisors dc:contributor.advisor

• Maguire, Anita
• Collins, Stuart

• C–H insertion
• Aromatic addition
• Diazo compounds
• Copper catalysis
• Rhodium catalysis
• α-Halosulfonamides
• Enamines
• Alkynesulfonamides
• Cyanohydrins
• Oxa-azulenones

Statement dc:rights

• © 2025, Evan Judge.

Licence dc:rights.uri

• https://creativecommons.org/licenses/by-nc-nd/4.0/

Language dc:language.iso

en

Handle dc:identifier.uri

https://hdl.handle.net/10468/18932

OAI identifier oai:identifier

oai:cora.ucc.ie:10468/18932