Nitrogen-centred radicals (NCRs) are powerful reaction intermediates that allow key bonds to nitrogen to be formed. However, the generation of NCRs typically requires pre-functionalised precursors that can be difficult to access and harsh reaction conditions in the formation of the NCR itself which has limited synthetic application. In this thesis, the application of visible-light mediated photoredox catalysis towards the generation of iminyl and amidyl radicals is demonstrated and the advances to NCR chemistry this has facilitated. Initial work developed electron-poor O-aryl oximes as suitable precursors for hydroimination reactions, activated via single-electron reduction under photoredox conditions. These precursors are accessible by a simple condensation reaction with the commercially available hydroxylamine and can be purified by recrystallization. The realisation of a transition metal-free protocol was made possible by using the organic dye eosin Y as the photocatalyst. This activation mode was then extended to the generation of (carb)amidyl-radicals from easy-to-make O-aryl hydroxylamides. Similar transition metal-free photoredox reaction conditions could be applied in intramolecular hydroamidation reactions allowing the preparation of lactams and cyclic (thio)carbamates. For the first time N-Boc and N-Cbz protected amidyl-radicals were utilised despite the very high electrophilic nature of these species. Finally, one of the big challenges associated with NCR chemistry was addressed; the development of multicomponent reactions for the divergent synthesis of complex N-containing molecules. Previously developed O-aryl precursors proved unsuitable and instead a novel class of alpha-imino acid precursors were identified that can be activated via oxidation under photoredox conditions. This activation mode was also rendered transition metal-free by using the Fukuzumi photoredox catalyst. These new NCR precursors proved crucial in developing a divergent methodology that allows the synthesis of up to fifteen iminofunctionalised products from a single starting material. Moreover, this methodology could be applied to the modification of complex natural products such as immunosuppressant drug mycophenolic acid and alkaloid thebaine. One could envisage such an approach may be ideal for a drug discovery type situation where changes in functionality can greater alter drug activity.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:756865 |
| Date | January 2018 |
| Creators | Davies, Jacob |
| Contributors | Greaney, Michael |
| Publisher | University of Manchester |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | https://www.research.manchester.ac.uk/portal/en/theses/metalfree-visiblelight-promoted-generation-of-nitrogencentred-radicals-via-photoredox-catalysis(88120039-e096-4f79-8205-fd2f58b9319e).html |
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