Novel Methodologies for the Catalytic Synthesis of Amides

Abstract

The amide bond is one of the most important functionalities in both industrial and medicinal chemistry. Traditional amidation methods involve the use of coupling reagents; however the production of stoichiometric by-products resulted in the ACS’s Green Chemistry Institute Pharmaceutical Roundtable highlighting the need for catalytic and waste free syntheses of amides in 2005.

This thesis details research concerning the development of novel catalytic protocols for the synthesis of amides from a variety of different starting materials. These methods have been fully optimised and the substrate scope for each approach has been explored. Mechanistic studies have also been performed to elucidate plausible reaction pathways.

In Chapter 1, following an introduction to amides, a discussion on their synthesis is detailed. This section covers the direct uncatalysed coupling of carboxylic acids and amines, the use of coupling reagents and catalytic methods. Metal/non-metal and homogeneous/ heterogeneous catalysts for the preparation of amides from a variety of different starting materials are presented.

The Results and Discussion section begins with a report detailing a cheap and simple method for the acylation of amines using catalytic acetic acid and esters as the acyl source. The Nacetylation of amines formed the initial focus of the investigations, however it was also shown the methodology could be successfully applied to synthesise higher amides as well.

Chapter 3 details work on a selective and relatively mild protocol for the hydration of organonitriles in water. Low loadings of a commercially available palladium catalyst and a cheap ligand afford primary amide products in high yields in the absence of hydration promoting additives such as oximes and hydroxylamines.

In Chapter 4, a low temperature method for the efficient rearrangement of aldoximes into primary amides is presented. The protocol successfully converts aldoximes into primary amides using cheap and simple reagents, namely a copper catalyst and sodium salt, without the need for nitriles to accelerate the process.

Chapter 5 builds on the work outlined in the previous chapter to enable the conversion of aldehydes into primary amides in a one-pot reaction at low temperature.

Date of Award	4 Sept 2019
Original language	English
Awarding Institution	University of Bath
Supervisor	Christopher Frost (Supervisor) & Steven Bull (Supervisor)