Hydrogenation and other palladium mediated transformations for the construction of important molecular frameworks

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dc.contributor.advisorMcglacken, Gerard P.
dc.contributor.authorKehoe, Roberta A.en
dc.contributor.funderScience Foundation Ireland
dc.contributor.funderSynthesis and Solid State Pharmaceutical Centre
dc.contributor.funderHigher Education Authority
dc.date.accessioned2024-09-17T13:57:45Z
dc.date.available2024-09-17T13:57:45Z
dc.date.issued2024
dc.date.submitted2024
dc.description.abstractThis thesis is presented as a thesis by publication and includes two peer-reviewed published chapters and a third chapter to be submitted, pending external nanoparticle analysis. The numbering of the compounds, schemes and figures are unchanged and are as per the published manuscripts. Therefore, compound, figure and scheme numbering etc. is independent for each chapter. This work mostly describes the use of palladium catalysts in hydrogenation reactions to form molecular structures of interest in pharmaceuticals and medicine. Chapter 2 Building molecular complexity usually requires numerous synthetic steps, isolations, and purifications. In addition, many reagents/solvents can be required, and the processes can take a lot of time. Designing one-pot tandem reaction methods is an environmentally friendly approach to building complexity which negates the need for intermediate isolation/purification and saves on time and costs. In this chapter, a one-pot Mizoroki-Heck/direct arylation/hydrogenation sequence was developed to access biologically significant alkylated benzofuroquinolines, benzofuropyridines and dibenzofurans. This one-pot method combines three mechanistically distinct palladium-catalysed reactions from a single pre-catalyst without the need for exogeneous ligands and inorganic base. A library of novel compounds was synthesised, including a deuterated derivative, and some green metric calculations were carried out. Chapter 3 Extended aromatic systems exhibit an associated 2D character which is often not conducive to clinical success. Compounds with more 3D (sp3) character often progress further in clinical studies. Introducing this ‘3-dimentionality’ at a late-stage allows for initial access to the unparalleled scope and broad applicability of sp2-sp2 cross-coupling which is then followed by hydrogenation to add a third dimension. This work describes the use of simple hydrogenation reagents and conditions to selectively reduce tetracyclic benzofuroquinolines, incorporating more sp3 character into the target compounds at ‘late stage’. Deuterium was also incorporated to form deuterated derivatives. Additionally, the deuteration provided some interesting insights into the source of the deuterium/hydrogen in this reaction. The role of the oxygen atom in benzofuroquinoline was also explored. Chapter 4 The Z-alkene motif is ubiquitous in chemistry and is found across pharmaceutical, agricultural and materials industries. The selective formation of Z-alkenes by hydrogenation methods remains a challenge, as isomerisation to the E-alkene can occur in addition to over-reduction to the respective alkane. The widely used Lindlar’s catalyst facilitates the selective hydrogenation of alkynes to Z-alkenes. However, there are many problems associated with the use of this catalyst. The use of ligand stabilised nanoparticles can facilitate the formation of Z-alkenes with low catalytic loadings and increased reproducibility. This chapter describes the development and use of ligand stabilised palladium-dodecanethiolate nanoparticles for the semi-hydrogenation of alkynes to form Z-selective alkenes. These nanoparticles also facilitate the introduction of deuterium into the alkene bond while maintaining selectivity and excellent deuterium incorporation.en
dc.description.statusNot peer revieweden
dc.description.versionAccepted Versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.citationKehoe, R. A. 2024. Hydrogenation and other palladium mediated transformations for the construction of important molecular frameworks. PhD Thesis, University College Cork.
dc.identifier.endpage400
dc.identifier.urihttps://hdl.handle.net/10468/16384
dc.language.isoen
dc.publisherUniversity College Corken
dc.relation.projectinfo:eu-repo/grantAgreement/SFI/SFI Investigator Programme/12/IP/1315/IE/The Direct Arylation of Pyrones, Coumarins, Pyridones and Quinolones/
dc.relation.projectinfo:eu-repo/grantAgreement/SFI/SFI Research Centres/12/RC/2275/IE/Synthesis and Solid State Pharmaceutical Centre (SSPC)/
dc.relation.projectinfo:eu-repo/grantAgreement/SFI/SFI Frontiers for the Future::Award/21/FFP-A/8784/IE/SOSEarth: Sustainable Organic Synthesis using Earth Abundant Metals for Critical Pharmaceutical Transformations/
dc.rights© 2024, Roberta A. Kehoe.
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subjectSynthesisen
dc.subjectCatalysisen
dc.subjectDeuterationen
dc.subjectHydrogenationen
dc.subjectPalladiumen
dc.titleHydrogenation and other palladium mediated transformations for the construction of important molecular frameworks
dc.typeDoctoral thesisen
dc.type.qualificationlevelDoctoral
dc.type.qualificationnamePhD - Doctor of Philosophyen
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