Novel Methodology for the Synthesis of Isoindole Derived Heterocycles

  • Lucy Peacock

Student thesis: Doctoral ThesisPhD


This thesis presents research into the development of a novel conjugate-addition/cyclisation methodology for the synthesis of isoindole derived nitrones. To begin, a review of the principle methods for synthesising nitrones is reported, followed by a discussion of the current uses of nitrones and the requirement for straightforward syntheses of nitrones contained within an isoindole scaffold.The synthesis of an aryl cyclisation substrate possessing the key ortho- relationship between an alpha,beta-unsaturated ester and formyl group is then described. The planned conjugate-addition/cyclisation reaction using hydroxylamine was carried to afford a different nitrone structure to that expected, which was later confirmed by X-ray crystallography. A full discussion of the work undertaken to elucidate the compound structure and to probe the reaction mechanism is reported.A monocyclic nitrone reported in the literature was thought to have been synthesised according to a 1,3-azaprotio cyclotransfer mechanism. Application of the newly discovered conjugate-addition/cyclisation protocol to a linear substrate successfully afforded this monocyclic nitrone, leading us to propose our mechanism as a plausible alternative.Exploration of the scope and limitation of the nitrone forming reaction afforded total of fourteen isoindole derived nitrones. Applying the protocol to modified cyclisation substrates afforded five dihydroisoquinoline derived nitrones and a bicyclic hydroxamic acid also.Research into the reactivity of isoindole derived nitrones is then presented. Varying degrees of success were obtained, largely due to the fact that the substrate does not react as a nitrone, but as its isoindole tautomer. An attempted 1,3-dipolar cycloaddition reaction with tert-butyl acrylate instead afforded a bridged hydroxylamine product, synthesised by a [4+2] Diels-Alder cycloaddition reaction.The final part of this thesis reports the application of the [4+2] cycloaddition reaction between nitrone and an alkyne as a novel route for the synthesis of substituted naphthalenes.
Date of Award6 Jun 2014
Original languageEnglish
Awarding Institution
  • University of Bath
SupervisorSteven Bull (Supervisor)

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