Iron-catalysed regioselective functionalisation of activated arenes

Waddell, Lachlan James Noble (2024) Iron-catalysed regioselective functionalisation of activated arenes. PhD thesis, University of Glasgow.

Abstract

The primary aim of this PhD was the development of new iron(III)-catalysed methodology for the regioselective functionalisation of activated arenes. The first section describes the optimisation and application of an iron(III) chloride-catalysed thiocyanation protocol using a saccharin-based electrophilic reagent. This was shown to be an efficient and rapid procedure with a wide substrate scope. The utility of the methodology was demonstrated with the synthesis and functionalisation of various biologically active compounds. The parathiocyanation process was also combined with a subsequent tandem ortho-bromination for the one-pot dual functionalisation of anisole. This dual functionalised arene was then used as a key building block for the bi directional, late-stage synthesis of a diverse library of arenes.

Analogous saccharin-based reagents were then used to develop procedures for the trifluoromethylthiolation and thioarylation of activated arenes. For the trifluoromethylthiolation process, diphenyl selenide was utilised as Lewis base in a dual catalytic Lewis acid/Lewis base process. The iron(III) triflimide catalysed thioarylation process was faster and was performed under milder conditions than the previously developed methodology in the group, which used succinimide-based reagents.

The final methodology project focused on the extension of a previously developed one-pot, two-step amidation process for the rapid synthesis of diaryl sulfonamides. This consisted of an iron(III) triflimide-catalysed iodination of activated arenes using NIS, followed by a copper-catalysed Ullmann-type coupling with primary sulfonamides. This was found to give good to excellent yields and allowed the preparation of a wide range of diaryl sulfonamides. The utility of the one-pot process was demonstrated by the synthesis of three BET bromodomain inhibitors.

The second aim of this PhD was the development of novel PET imaging agents for two biological targets, the translocator protein (TSPO) and the sphingosine-1-phosphate-5 receptor (S1P5). Ten potential TSPO ligands were synthesised based on the structure of the quinoline-2-carboxamide, [¹⁸F]LW223, a promising TSPO radiotracer previously developed in the group. The physicochemical properties of these compounds were evaluated and future work will determine their binding affinities with TSPO in human tissue. In the S1P5 project, synthetic routes to organotin and organoboron precursors of lead candidate TEFM78 were developed for radiofluorination and preparation of PET imaging agent [¹⁸F]TEFM78. Both precursors are currently being assessed for automated radiofluorination and the preparation of high activity [¹⁸F]TEFM78 for subsequent animal studies.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Subjects: Q Science > QD Chemistry
• Colleges/Schools: College of Science and Engineering > School of Chemistry
• Supervisor's Name: Sutherland, Professor Andrew and France, Dr. David
• Date of Award: 2024
• Depositing User: Theses Team
• Unique ID: glathesis:2024-84486
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 12 Aug 2024 09:53
• Last Modified: 12 Aug 2024 09:57
• Thesis DOI: 10.5525/gla.thesis.84486
• URI: https://theses.gla.ac.uk/id/eprint/84486

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