Novel C-C bond formation strategies for access to secondary and tertiary amides enabled by new synthetic technologies

Williams, Jason D.

Thesis

Novel C-C bond formation strategies for access to secondary and tertiary amides enabled by new synthetic technologies

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Creator

Williams, Jason D.

Rights statement

Strathclyde Thesis Copyright

Awarding institution

University of Strathclyde

Date of award

2018

Thesis identifier

T16142

Person Identifier (Local)

201451385

Qualification Level

Doctoral (Postgraduate)

Qualification Name

Doctor of Philosophy (PhD)

Department, School or Faculty

Department of Pure and Applied Chemistry

Abstract

Amidation reactions represent a commonly used reaction within multiple industries, yet robust methods for their sustainable synthesis remain a significant challenge. The majority of current research into amide-forming transformations focuses on condensation of an amine with a carboxylic acid, via activation of the acid. However, the advent of modern synthetic technologies has brought about opportunities to discover new methodologies in this area, with the aim of achieving amide formation through alternative and efficient approaches. This thesis describes the development of two complementary amidation methods, which use new synthetic technologies to enable a less common disconnection, giving access to secondary and tertiary amides via C-C bond formation. Chapter 2 describes the use of photoredox catalysis, to develop a decarboxylative umpolung formation of tertiary amides. This proceeds by oxidation of sodium oxamate salts, followed by reaction of the resulting carbamoyl radical with electron-poor olefins. A variety of substrates have been found to be amenable to this protocol, and steps have been made towards exploring alternative solvent and photocatalyst systems, to attain a more sustainable system. Furthermore, DFT calculations have been used to explain and corroborate experimental results, in order to bolster reaction understanding, and maximise potential utility. Chapter 3 describes the development of a flow chemistry methodology, which enables the synthesis of secondary amides, by the reaction of Grignard reagents with isocyanates. Initial investigations of this seemingly straightforward reaction revealed a major deleterious side reaction, which occurred in all but the most sterically hindered cases. It was found that this could be minimised through ensuring fast mixing of the two reagents, which then led towards the use of continuous flow chemistry. Further reaction investigation identified that inclusion of a catalytic quantity of CuBr2 reduced the extent of side product formation to an almost negligible level, to deliver an excellent yield of the desired product. After application to a wide range of substrates, kinetic data was obtained using quantum cascade laser infrared microscopy, which demonstrated a significant rate acceleration bestowed by the addition of the copper additive.

Advisor / supervisor