Catalytic approaches towards amidation of unactivated ester derivatives

  • Nicola Caldwell

Student thesis: Doctoral Thesis

Abstract

Amide bond forming reactions are commonly encountered within a synthetic chemistry environment. Traditionally, a stoichiometric coupling reagent is employed to facilitate the condensation of a carboxylic acid and an amine. However, a number of disadvantages are inherent in this process, including by-product formation, poor atom economy, elevated cost, and variable yields. An organocatalytic approach using N-heterocyclic carbenes (NHCs) would provide a more atom-economical route towards the synthesis of amides, addressing some of the issues outlined above. However, upon investigating anhydrous reaction conditions required for handling NHCs, a novel base-catalysed amidation manifold was identified. Catalytic amounts of base were found to mediate amidation of unactivated esters using amino alcohols in the absence of carbene catalyst. Based on this initial observation, full optimisation of the base-catalysed amidation process was carried out using a combination of linear screening and Design of Experiments (DoE) techniques. Optimised conditions (Scheme 1a) were used to examine substrate scope, demonstrating that a wide range of products could be prepared using this methodology (53 examples, 40 - 100%), including oxazolidinone derivatives and medicinally-relevant compounds. Mechanistic investigations indicated formation of a transesterification intermediate, followed by intramolecular rearrangement to the more stable amide product. Subsequently, optimisation of a more sustainable base-catalysed amidation process (Scheme 1b) was carried out in order to address the green credentials of this reaction (16 examples, 42 - 100%). Additionally, by employing an alcohol additive to facilitate in situ formation of the activated ester species, the base-catalysed amidation methodology could be adapted to the direct synthesis of amide products (25 examples, 32 - 95%).Finally, several novel NHC systems were designed and evaluated for their ability to catalyse a direct amidation reaction.
Date of Award1 Apr 2015
LanguageEnglish
Awarding Institution
  • University Of Strathclyde
SponsorsEPSRC (Engineering and Physical Sciences Research Council)
SupervisorCraig Jamieson (Supervisor) & Christopher Tuttle (Supervisor)

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