Medium Ring Nitrogen Heterocycles by Migratory Ring Expansion of Metallated Ureas

  • Jessica Hill

Student thesis: Doctoral ThesisDoctor of Philosophy (PhD)


Medium ring (8-12 members) and benzannulated medium heterocycles represent a class of synthetically challenging targets. Although natural products containing medium ring N- and O- heterocycles offer beneficial biological properties, there is a stark absence of medium rings in active pharmaceutical
ingredients, potentially highlighting the difficulties associated with their synthesis. Typical methods of synthesis include transition metal-catalysed processes, such as ring closing metathesis and ring expansion techniques, which require pre-organisation of the precursors to ensure a thermodynamic
driving force.
Research by the Clayden group has shown that the poor reactivity between carbanions and unactivated Csp2 ‘electrophiles’ can be overcome by tethering the two through a urea linkage. The principles of this unique protocol have been applied to the research within this thesis. Firstly, the N→C rearrangement
chemistry has been applied to cyclic systems where the urea nitrogen is tethered as part of a ring, ultimately resulting in ring expansion after aryl migration. This ring expansion methodology has been optimised and applied to a wide range of urea precursors, allowing access to complex structural architectures in few steps from simple starting materials. Secondly, when benzylic indole precursors were investigated, rather than obtaining the expected ring expansion products from the N→C aryl migration route, lithiation instead resulted in dearomative cyclisation, generating a range of polycyclic indoline structures. Finally, an n to n-2 ring contraction protocol has been developed to access privileged tetrahydroisoquinoline and tetrahydrobenzazepine structures from medium ring nitrogen heterocycles. Furthermore, this ring contraction methodology has been developed for applications in flow, for the efficient multigram synthesis of 1-aryl tetrahydrobenzazepine. The different synthetic methods disclosed within this thesis enables rapid access to a wide range of biologically and medicinally relevant scaffolds, from which further diversification is possible for
potential library design.
Date of Award23 Jan 2019
Original languageEnglish
Awarding Institution
  • The University of Bristol
SupervisorJonathan P Clayden (Supervisor)

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