This thesis is concerned with exploring novel applications of N-oxides as organocatalysts. Specifically, aromatic N-oxides have been successfully implemented as catalysts within the Baeyer-Villiger oxidation of α,β-unsaturated ketones and electrophilic aromatic bromination reactions. Chapter 1 provides a review of the current applications of N-oxides, highlighting their use as organic oxidants, neutral ligands and in particular organocatalysts. These roles exploit several key features of the N-oxide, including the intrinsic weakness and polarity of the N→O bond, their Lewis basicity and ability to function as hydrogen bond acceptors. As organocatalysts, these species have predominantly been utilised as nucleophilic catalysts, however their potential to act as hydrogen bond catalysts represents an emerging area of interest. Chapter 2 describes the development of an organocatalysed Baeyer-Villiger oxidation, for which N-oxides and carboxylates have been identified as suitable catalysts. The optimised protocol, which employs DMAP as the pre-catalyst, was applied to a wide range of saturated and more specifically α,β-unsaturated ketones, with enhanced reaction rates and/or chemoselectivities achieved in the majority of cases. From extensive mechanistic studies, it is proposed that the N-oxide functions as a hydrogen bond acceptor; facilitating concerted proton transfer within the addition step. The unique role of the catalyst allowed for predictions to be made about the rate determining step of the oxidations performed. A series of by-products obtained from the over oxidation of (E)-4-phenyl-3-buten-2-one were characterised and the mechanistic pathway for their formation has been fully elucidated. Development of the reaction conditions for the selective formation of many of these species is also provided. Additionally, the novel reactions of 3-(4-methoxyphenyl)but-3-en-2-one are examined. Chapter 3 details investigations into the applicability of the novel, relatively bench stable formate ester, (formyloxy)(phenyl)methyl acetate, as a formylating reagent. A high yielding and operationally simple procedure for the synthesis of this formate ester from commercially available, inexpensive (E)-4-phenyl-3-buten-2-one is described in Chapter 2. A solvent and catalyst free protocol has been developed for the N-formylation of various amino species including primary and secondary (aliphatic and aromatic) amines and an amino acid ester as well as the O-formylation of alcohols. Demonstrating its synthetic utility, the developed methodology was applied to the one-pot synthesis of an isocyanide from the corresponding amine as well as the N-formylation of an unprotected amino acid under aqueous conditions. Chapter 4 outlines preliminary studies into the application of N-oxides as nucleophilic catalysts for electrophilic aromatic bromination reactions with elemental bromine. The development of novel methodology for the 4-picoline N-oxide catalysed regioselective monobromination of tert-butylbenzene is discussed, for which a reactive N-oxide bromine complex is thought to be generated in situ. Conditions have also been established for a KI promoted system, with IBr proposed as the catalytic species. Both methodologies allow for selective electrophilic aromatic bromination of toluene in the light without competitive benzylic bromination. Chapter 5 contains experimental procedures and compound characterisation data for Chapters 2-4 inclusive.
|Date of Award||27 Jun 2017|
|Supervisor||Steven Bull (Supervisor) & Jonathan Williams (Supervisor)|