New Catalytic Methods for Amine and Azacycle Synthesis

  • Tom Mules

Student thesis: Masters ThesisMPhil


Azetidines are a valuable but under-represented N-heterocycle in medicinal chemistry. This is due to a lack of generalised methodology to synthesise the strained 4-membered ring, despite their favourable physicochemical properties and metabolic stability. This work provides a practical and scalable route towards azetidines from unprotected primary amines, via a formal [2+2] cycloaddition, a transformation that until now has required an oxime, azide or protected amine substrate. The strategy commences with a photocatalytic α-C–H alkylation of amines with vinyl boronic acid pinacol ester, using an organic photocatalyst in combination with azide ion as a hydrogen atom transfer (HAT) catalyst, providing a novel and direct synthesis of unmasked 1,3-amino boronic esters. This transformation has been optimised using a state-of-the-art flow system to give a 94% NMR conversion to the 1,3-amino boronic ester from the unprotected primary amine. Azetidines can be accessed via the N-chlorination of the 1,3-amino boronic ester, followed by N-deprotonation, cyclisation and a 1,2-metalate rearrangement. This route represents a novel strategy towards azetidines through the 1,2-metalate rearrangement of a boronate-complex. Alternatively, azetidines can then be accessed through an adaption of the Wenker synthesis, where oxidation of the 1,3-amino boronic ester to the corresponding 1,3-amino alcohol is followed by treatment with chlorosulfonic acid to form an ammonium sulphate salt, which undergoes a base-mediated cyclisation to yield azetidines.
Date of Award24 May 2023
Original languageEnglish
Awarding Institution
  • University of Bath
SupervisorAlex Cresswell (Supervisor) & James Taylor (Supervisor)

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