Chemoselective C–H functionalisation of aliphatic azacycles : utilisation of electrophilic iodine as a mild oxidant

Rights statement
Awarding institution
  • University of Strathclyde
Date of award
  • 2018
Thesis identifier
  • T15963
Person Identifier (Local)
  • 201490647
Qualification Level
Qualification Name
Department, School or Faculty
  • Over half of the small molecules approved for use in the U.S.A. by the FDA in 2012 contained at least one nitrogen heterocycle. Of these, 11% contained a piperidine motif, emphasising the importance of saturated nitrogen-containing heterocycles in drug discovery. As such, rapid, step-efficient and reliable diversification strategies of this functional group are highly desirable. Late-stage C–H functionalisation of high value scaffolds is a powerful tool that has potentially wide application in the pharmaceutical industry. The underlying principle is to use the subtle difference in reactivity of C–H bonds to carry out selective and efficient functionalisation of a complex late-stage intermediate or final compound. This strategy could be harnessed to expedite the exploration of the medicinal chemistry properties of biologically active small molecules. There are a wide array of methods at the disposal of synthetic chemists to carry out selective C–H functionalisation, which are discussed within this thesis, but a number of these are not applicable to the late-stage functionalisation of modern drug molecules. This can be due to functional groups being incompatible with the reaction conditions, the inconvenience of installing an appropriate directing group, or the functionalisation not being sufficiently selective. This body of work provides an introduction to the field of late-stage C–H functionalisation. Chapter two describes the development and consolidation of a C–H functionalisation protocol for the α-C–H oxidation of cyclic amines to lactams using molecular iodine as the oxidant. This transition metal-free process, carried out under ambient reaction conditions, was then applied to the late-stage oxidation of a selection of high value small molecules with relevance to the pharmaceutical and agrochemical sectors. The impact of this work within a medicinal chemistry application is also discussed. With an understanding of this process in hand, diversification of this oxidative platform is explored in chapter three, which describes the discovery of a β-C–H trifluoroacylation protocol. Chapter four describes how these findings were refined and consolidated into the development of a robust methodology to carry out oxidative C–H sulfonylation of saturated nitrogen heterocycles at the β-position. The functionality installed into resulting enaminyl sulfone scaffolds was then exploited to provide access to a wide array of highly functionalised azacyclic scaffolds. Iodine-mediated oxidation is demonstrated to provide access to either α or β-functionalised products, which have been showcased to have application for medicinal and synthetic chemistry.
Advisor / supervisor
  • Burley, Glenn
Resource Type
  • Previously held under moratorium in Chemistry department (GSK) from 24/05/2018 until 18/06/2021.
Embargo Note
  • This thesis is restricted to Strathclyde users only until 24th May 2023.