Abstract
This thesis details the synthesis and functionalisation of pyrroles, an important class of heterocycle prevalent in a wide range of drugs, natural products, and materials. Due to pyrrole’s highly electron rich nature, attempted functionalisation of pyrrole can sometimes lead to degradation and polymerisation. Efficient methods for the synthesis of pyrroles are therefore highly valuable. Sulfonium salts offer a unique handle for functionalisation and have gained wide interest in literature. Pyrrolyl sulfonium salts, before this work, had limited applications but have been central to the methodology developed herein. The work described in this thesis, focuses on the applications of pyrrolyl sulfonium salts in cross-couplings and oxidations.The introductory chapter covers pyrroles molecular properties and it’s resulting electron rich nature, reactivity and regioselectivity. Pyrrole halides and previous work on pyrrolyl sulfonium salts are then discussed, followed by recent developments in sulfonium salt chemistry with a focus on cross-coupling applications, and heteroaromatic sulfonium salts.
The first results chapter describes the synthesis of pyrrolyl sulfonium salts, with a range of sulfonium handles in both the C2 and C3 position. These salts were then subjected to Suzuki-Miyaura cross-coupling conditions. The outcome of these reactions led to the synthesis of different pyrrolyl sulfonium salts in attempts to optimise the cross-coupling reaction. The salts tested were found to be incompatible with the basic Suzuki-Miyaura reaction conditions, which led to the work detailed in chapter 2.
Chapter 2 discusses the optimisation of pyrrolyl sulfonium salts under Stille cross-coupling conditions. A range of C2 and C3 substituted pyrroles were then synthesised in good yields, including di and tri heteroaromatic species.
Chapter 3 describes the development of a regioselective oxidation of pyrrole to form the more hindered isomer of the corresponding ∆3-pyrrol-2-one. This regioselectivity is enabled by formation of a pyrrolyl thianthrenium salt ‘in situ’; the mechanism for this oxidation was studied. A wide range of ∆3-pyrrol-2-ones were synthesised, including the synthesis of an anti-HIV agent.
This methodology was also applied to the oxidation of indoles, and indolin-3-ones. For the oxidation of indole, indolin-3-ones are selectively formed over the more commonly obtained 2-oxindole oxidation products. The indole-3-ones can then be resubjected to the reaction conditions to form 2-hydroxyindolin-3-ones.
Finally, chapter 4 details the synthesis of a range of N-carboxy pyrroles via a Clauson-Kaas reaction with O-substituted carbamates. The carboxy protecting group on pyrrole has been underutilised but displayed synthetically useful application in an acylation reaction under acidic conditions. The N-carboxy pyrroles also demonstrated different regioselectivity in acylation reactions with triflic anhydride compared to N-sulfonyl pyrroles.
| Date of Award | 2 Oct 2024 |
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| Original language | English |
| Awarding Institution |
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| Supervisor | Catherine Lyall (Supervisor) & Simon Lewis (Supervisor) |