O-Protected N-Hydroxyazoles as Privileged Dienes for the Synthesis of Substituted Aromatics

Abstract

This thesis describes investigations into the application of N-oxyazoles as reactive dienes in [4+2] cycloaddition reactions, followed by elimination of nitroxyl (HNO), for the synthesis of aromatic scaffolds. First an overview of the current state of the art in the use of [4+2] cycloaddition/elimination methodology for the synthesis of aromatics is provided. The review is broken down by the class of heteroaromatic diene used in the Diels-Alder reaction and highlights the advantages and drawbacks of each class in detail, providing exemplar published examples as evidence. Limited by unique drawbacks associated with each substrate, there is currently no class of heterodiene that is used as a ‘go to’ coupling partner for this type of Diels-Alder/elimination methodology, and so there is still significant demand for new classes of synthetically tractable heterodienes with good reactivity profiles towards a broad range of dienophiles that can be used to produce diverse libraries of aromatic products.

Chapter 2 describes investigations into the use of N-oxypyrroles 366 as reactive dienes in Diels-Alder reactions, followed by cheletropic elimination of their [4+2] cycloadduct products 368 to produce polysubstituted aromatics 375 (Figure 1a). O-TBS protected N-hydroxypyrroles 366 are identified as optimal substrates for the cycloaddition reaction, producing stable cycloadducts 368 which can separately be aromatised using typical fluoridic conditions for the deprotection of silyl ethers. A range of N-hydroxypyrroles 366 are synthesised using literature and novel syntheses and subjected to the optimised conditions with highly electron deficient dienophiles to produce their corresponding aromatic products 375 in good yields.

Chapter 3 details the use of Lewis acid catalysis to overcome reactivity limitations in the [4+2] cycloaddition reaction of N-silyloxypyrroles 366 with alkynes 388 (Figure 1a). Stoichiometric diethylaluminium chloride is found to dramatically enhance the rate of reaction of O-TBS-N-oxypyrroles 366 with mildly electron deficient alkynes 388, with kinetic studies carried out at the University of Bath Dynamic Reaction Monitoring (DReaM) facility to elucidate the origins of the requirement for stoichiometric catalyst to achieve good yields.

Chapter 4 describes investigations into the reaction of N-oxyazoles 435 with arynes for the synthesis of polyaromatic scaffolds 438 (Figure 1b). Having identified that less reactive N-oxypyrroles are required for reaction with highly reactive arynes, O-pivaloyl-N-oxypyrroles 435 were reacted with Kobayashi aryne precursors 453, followed by cheletropic elimination of the cycloadducts to produce polyaromatic compounds 438. Finally, an example of an N-oxyimidazole was reacted with benzyne to produce a polysubstituted isoquinoline.

Chapter 5 discusses the application of aza-norbornadienes as Nitroxyl Releasing Molecules (NORMs) (Figure 1c). The production of nitroxyl from the cheletropic elimination of aza-norbornadiene 499 is first detected utilising diaminonaphthalene (DAN) as an exogenous fluorescent sensor and subsequently the aromatic product of the cheletropic elimination of aza-norbornadiene TBS-NORM is configured to be a fluorophore DiPhen, which is used as a turn on sensor for detection of fluoride in solution. Finally, the potential of NORMs for the site selective release of HNO for the treatment of disease is discussed (Figure 1d).

Date of Award	22 Jun 2022
Original language	English
Awarding Institution	University of Bath
Supervisor	Steven Bull (Supervisor) & Alex Cresswell (Supervisor)