Thesis
Mechanistic and computational investigations into the copper(I)-catalysed sulfonylative cross couplings of sulfur dioxide and related sulfinate intermediates
- Creator
- Rights statement
- Awarding institution
- University of Strathclyde
- Date of award
- 2022
- Thesis identifier
- T17144
- Person Identifier (Local)
- 201869606
- Qualification Level
- Qualification Name
- Department, School or Faculty
- Abstract
- Sulfur(VI)-containing molecules, such as sulfones and sulfonamides, are widely observed in medicinally-relevant compounds, and have been shown to be effective in the treatment of diseases such as leprosy, cancer, and arthritis.1 As a result, the desire for novel methods for the preparation of such molecules, especially more environmentally sustainable methods, is extremely high. In a 2017 publication by Willis and Chen,2 a three-component copper(I)-catalysed sulfonylative Suzuki-Miyaura reaction of arylboronic acids, a sulfur dioxide surrogate termed “DABSO”, and (hetero)aryl iodides was described as providing a facile and more environmentally sustainable route to access such sulfur-containing molecules than previously reported. The work described herein, is a result of attempts to investigate the utility of this transformation within an industrial pharmaceutical setting, and with a view to optimising these processes for the use of sulfur dioxide gas, alongside the technology available within our laboratories, specifically the high pressure reactive gas equipment, the CAT96. Initial optimisation studies resulted in the discovery of a number of previously undisclosed issues associated with the pertinent sulfonylative transformations, such as side-reactions and unclean reaction profiles, which in turn led to a full spectroscopic and computational investigation into the mechanism of the reaction, including a detailed exploration of the side reactions. As a result, a highly detailed profile of the overarching and interconnected processes at play was constructed. Moreover, the established knowledge of copper(I)-catalysed sulfonylative cross-couplings and the associated computational infrastructure subsequently provided an in silico screening platform to address a challenging cross-coupling with electron-deficient fluorinated sulfinate reaction partners, which had not been reported using copper chemistry. This latter in silico investigation, building on literature reports of effective ligands for copper(I)-catalysed sulfinate coupling,3-5 and exploring ligand design to aid a challenging reductive elimination step, led to the synthesis and screening of a selection of novel, highly fluorinated, L-Proline-based ligands within the catalytic system under investigation.
- Advisor / supervisor
- Sneddon, Helen F. (Helen Fiona)
- Resource Type
- DOI
- Funder
- Embargo Note
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