Chemistry - Doctoral Theses

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https://hdl.handle.net/10468/179

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Studies in palladium and rhodium catalysis: synthetic strategies for C–C bond formation
(University College Cork, 2024) Power, Mark; Mcglacken, Gerard P.; Irish Research Council; Higher Education Authority
This thesis concerns studies in palladium and rhodium catalysis for carbon-carbon bond formation. Chapter 1 involves the synergistic use of tetrabutylammonium acetate (NBu4OAc) with palladium catalysis to expand on the synthesis of dibenzofurans via C-H activation. Dibenzofuran and its derivatives are ubiquitous and important medicinal and natural products. Many contain electron-rich aryl rings. Previously, we found that the wellestablished conditions, which promote C−H functionalisation through Concerted MetalationDeprotonation (CMD), proved unsatisfactory for electron-rich diarylether precursors. Herein, we report a Pd-catalysed C−H functionalisation protocol that works with electron-rich arenes. We suspect that tetrabutylammonium acetate can act as base, ligand and solvent, rendering this protocol a simple and efficient route to electron-rich dibenzofurans. A variety of functionalised dibenzofurans are successfully accessed through this protocol. The methodology can be applied to benzochromenes, with varying degrees of success. However, this protocol can be expanded to enable a robust, one-pot Buchwald-Hartwig, C–H activation sequence to access biologically relevant indoloquinoline scaffolds from simple building blocks. In Chapter 2, rhodium-catalysed asymmetric conjugate additions are performed with indolyl boronic acids. The indole ring system represents one of the most abundant and important heterocycles in natural products, Active Pharmaceutical Ingredients (APIs), drugs and other materials. The prominence of indole compounds makes efficient protocols to derivatise the heterocycle highly desirable. A particular importance is placed on asymmetric protocols and utilising unprotected (NH) variants. Herein, we report a Hayashi-Miyaura-type Rh-catalysed asymmetric conjugate addition using free NH indole boronic acids and enones. Each position on the carbocyclic backbone of indole can be accessed, with a variety of enones. Yield of up to 94%, and e.r. values up to 99:1 can be achieved using mild reaction conditions. Furthermore, a 1,2-addition to benzil can be performed in excellent yield and e.r. Finally, a one-pot conjugate addition and intramolecular cyclisation of 7-indolyl boronic acid allows for the synthesis of a novel tetracyclic indole, similar to that found in natural products.
Studies in iridium and manganese catalysis in C-H activation and reductive transformations
(University College Cork, 2024) Courtney, Eimear; Mcglacken, Gerard P.; Irish Research Council; Higher Education Authority
Heteroaromatic compounds are fundamental building blocks in pharmaceutical, agrochemical and material chemistry. The efficient and selective derivatisation of heteroarenes is a critical tool for organic synthesis. C−H activation has emerged as an effective means to access diversified heteroaromatic motifs. In particular, iridium-catalysed C−H borylation has proven a useful means of heteroarene functionalisation, due to its ability to produce highly versatile aryl organoboronate intermediates. The quinoline nucleus is a ubiquitous, strategic target, given its role as a key scaffold in a plethora of synthetic and naturally occurring pharmacologically active compounds. Chapter 1 showcases a robust one-pot protocol which enables rapid late-stage functionalisation of this important class of pharmacophores. Chapter 1, Part I describes the direct borylation and transformation of the C-7 position of 6-fluoroquinolones in excellent yields. This protocol is further expanded upon in Chapter 1, Part II to include the borylation of the biologically significant N-ethyl 3-carboxylate-6-fluoroquinolone in good yields. Furthermore, we have identified a tuneable reactivity applicable to the N-substituted 3-carboxylate-6-fluoroquinolone motif, which can be controlled through judicious choice, and equivalents, of borylating agent employed. In recent years, earth-abundant 3d transition metal catalysts, such as manganese, have gained popularity as alternatives to expensive precious metals. This trend stems from the urgent need to develop new, efficient, and sustainable green methodologies. The use of readily available metals, instead of rare noble metals, is a key focus in green chemistry. Chapter 2 of this thesis explores the synthesis of various carbonyl manganese phosphine complexes and their applications in C–H activation. Chapter 2, Part I details the synthesis and characterisation of three carbonyl manganese phosphine complexes through spectroscopic methods and investigates their role in C–H activation reactions. Additionally, the formation of corresponding manganacycle complexes was studied to understand the fate of the ligand during the catalytic cycle. Chapter 2, Part II describes the preparation of a polymer-bound phosphine manganese complex from commercially available sources via a straightforward one-step process. This catalyst has shown broad applicability and promising results in protocols such as C–H activation, (de)hydrogenation, and hydrofunctionalisation, yielding valuable products ranging from chemical feedstocks to complex heteroaromatic motifs in moderate to good yields.
Synthesis of novel IMPDH inhibitors
(University College Cork, 2024) Upadhyay, Amit; O'Sullivan, Tim; Irish Research Council; Higher Education Authority
Inosine-5’-monophosphate dehydrogenase (IMPDH) is an important enzyme involved in the biosynthesis of guanine nucleotides. The use of IMPDH as a target for developing novel antimicrobial agents forms the basis of this research. Chapter 1 provides an overview of recently developed antimicrobial IMPDH inhibitors from the literature. The background to this project and the main aims and objectives are also outlined. Chapter 2 describes the development of synthetic routes to two related compound libraries. The first series comprises benzyl-containing urea analogues, while the second series all contain a common 3-nitro-4-chlorophenyl ring. The introduction of several heteroaryl/aryl rings via Suzuki- Miyaura coupling is also described. The synthesis of a third group of compounds incorporating a squaramide bioisostere in place of the urea group is discussed in Chapter 3. In silico analysis of all compounds is described in Chapter 4. Important ADME properties (e.g. LogP, TPSA, pKa) are calculated to determine the suitability of these compounds for future development. This chapter also details the screening of several compounds for activity against P. aeruginosa IMPDH, with a number of molecules displaying sub-micromolar activity. Additionally, biological evaluation of three potent candidates against S. aureus IMPDH and E. coli IMPDH is included in this chapter. A docking study of both synthesised and virtual inhibitors using the CpIMPDH enzyme as the target is contained in Chapter 5. Chapter 6 details the main conclusions of this work and proposes several avenues for future investigation. Chapter 7 contains all relevant experimental procedures, including spectroscopic and analytical data.
Aromatic addition reactions of α-diazo-β-ketonitriles
(University College Cork, 2024) Tyner, Ciara; Maguire, Anita; Collins, Stuart; Irish Research Council; Higher Education Authority
The central focus of this thesis is the intramolecular aromatic addition reaction of α-diazo-β-ketonitriles using rhodium and copper catalysts, and examination of the structural properties and reactivity of the resulting azulenones. In depth comparison of the reactivity and properties of the α-diazo-β-ketonitriles and the resulting azulenones to the analogous α-diazoketones and azulenones bearing a bridgehead methyl group in place of the nitrile is a key element of the work. The power of benchtop NMR spectroscopy to monitor labile intermediates is demonstrated in this work. Chapter One provides an overview of the literature related to this work with a particular focus on recent developments in aromatic addition reactions of α-diazocarbonyl compounds. Chapter Two describes the successful synthesis and characterisation of a series of α-diazo-β-ketonitriles (13 novel compounds) and their precursors. A number of synthetic routes were explored to lead to these compounds, each of which involved multiple reaction steps and required considerable optimisation. Conjugation with the nitrile unit contributed to the increased stability of the α-diazo-β-ketonitriles which could be readily stored for long periods without deterioration, while the precursor β-ketonitriles were labile and had to be used shortly after preparation. Chapter Three describes the investigation of the aromatic addition reactions of the novel α-diazo-β-ketonitriles using a range of rhodium and copper catalysts and, on one occasion, a ruthenium catalyst. The impact of the nitrile substituent on the reactivity of the α-diazocarbonyl is explored in detail resulting in cleaner reactions than with the corresponding α-diazoketones due to fewer side reactions, presumably due to the more stable carbenoid. Enantioselection in the aromatic addition process was successful using a copper bis(oxazoline) catalyst providing the corresponding azulenone with up to 75% ee. Interestingly, the presence of the nitrile on the carbene had little impact on the enantiofacial discrimination. The impact of the nitrile substituent on the stability and reactivity of the azulenones is very significant, increasing their lability towards rearrangement to form tetralones and, indeed in many cases, the azulenones could not be isolated or recovered from the reaction mixtures. The tetralones exist predominantly as the enol tautomers due to conjugation with the nitrile. One of the key advances in this study was successful trapping of the novel labile azulenones as cycloadducts through addition of PTAD to the aromatic addition reactions. Interestingly, the presence of PTAD did not impact negatively on the transition metal catalysed process. The impact of the nitrile substituent on the position of the norcaradiene-cycloheptatriene equilibrium is also explored in detail, principally through 1H and 13C NMR spectroscopy and IR spectroscopy at room temperature and in variable temperature NMR studies. The presence of the nitrile substituent has a very significant impact in shifting the equilibrium towards the norcaradiene relative to the position of the equilibrium in the corresponding azulenones with a bridgehead methyl substituent. Chapter Four describes the use of a benchtop NMR spectrometer to monitor the aromatic addition reactions of the α-diazo-β-ketonitriles to form labile azulenones followed by rearrangement to the tetralones, demonstrating the power of this technique for monitoring and detecting labile intermediates at relatively low field (80 MHz). The reactivity profiles of α-cyano-α-diazoacetamides were also monitored by benchtop NMR spectroscopy in both static and flow mode. Chapter Five contains the full experimental details and spectroscopic characterisation of the compounds synthesised in this work.
Photochemical transformations of α-diazocarbonyl compounds in flow
(University College Cork, 2024) O'Callaghan, Katie S.; Maguire, Anita; Collins, Stuart; Synthesis and Solid State Pharmaceutical Centre
This thesis describes a detailed investigation of the synthetic and mechanistic aspects of the reactivity of a series of α-diazocarbonyl compounds including aryldiazoacetates, α-diazo-β-ketoesters and an α-diazo-β-ketosulfone, under continuous flow photolysis. These photochemical transformations yielded 2,3-dihydrobenzofurans, γ- and β-lactones, oxazoles and Wolff rearrangement products indicating the synthetic versatility of these metal-free processes. Continuous flow technology was also applied to telescope sulfonyl azide generation, diazo transfer and subsequent photochemical reactions, enabling three steps to be carried out without the need to isolate or handle any hazardous materials. The use of Process Analytical Technologies (FlowNMR and FlowIR™) throughout this work provided key insights into reaction progress and offered improved process safety through reaction monitoring.

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