The design and investigation of sulfur-based reagents for cross-coupling processes

Thesis

Described in this thesis are new methodologies for the synthesis of important biaryl structures, with a focus on 2-arylpyridines and heteroaryls. This is achieved through the development and application of two novel sulfur-based reagents in palladium-catalysed cross-coupling reactions: firstly, heteroaromatic base-activated latent sulfinates, and secondly, primary aryl sulfinamides.

Chapter 1 is a literature review detailing the challenges and the recent strategies developed to access industrially important 2-(hetero)arylpyridine compounds. The use of (hetero)aryl sulfinates in palladium-catalysed desulfinative cross-coupling reactions is also discussed, as this forms the groundwork for the research described in this thesis.

Chapter 2 describes the development and use of base-activated latent sulfinate reagents, notably heteroaromatic β-nitrile and β-ester sulfones, in palladium-catalysed desulfinative (- SO₂) cross-coupling arylation reactions. In this approach, neutral, masked reagents are activated under the basic cross-coupling conditions to give the heteroaryl sulfinate in situ, which then reacts with readily available aryl bromides to access a broad range of pyridine biaryls. The robustness of these latent sulfinate reagents is demonstrated and exploited through multi-step transformations to give complex pyridine structures.

Chapter 3 discusses the extension of the latent sulfinate approach from Chapter 2, towards the development of a palladium-catalysed cross-electrophilic coupling of two (hetero)aryl halides, via the in situ formation of masked sulfinate nucleophilic partner. Initial investigation has demonstrated the feasibility of this process and highlighted strategies for further optimisation.

Chapter 4 details the investigation of primary aryl sulfinamide reagents as nucleophiles in a novel desulfinamidative C(sp²)-C(sp²) cross-coupling reaction (-SONH). The use of sulfinamide reagents allows cross-coupling to proceed at a lower temperature than the aryl sulfinate reactions. The viability of carbocyclic aryl sulfinamides in these processes have been established, with the potential for extension to heteroaryl nucleophiles in the future.

Chapter 5 summaries the research in this thesis and suggests potential areas for future work.

Chapter 6 presents the experimental data and procedures for this research.

Authors: Cook, XAF

• DOI: 10.5287/ora-d5ayrq8b9
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: 2-pyridyl; sulfinamides; arylation reactions; reaction optimisation; cross-coupling reactions; 2-arylpyridines; Desulfinamidative; biaryl; Desulfinative reactions; Masked sulfinates; palladium catalysis
• Subjects: Chemistry, Organic; Methodology; Synthesis; Chemistry