Thesis
Investigations into the establishment of practically-accessible n-trifluoromethylation methods, and studies into a high-throughput experimentation methodology, for use in organic synthesis and medicinal chemistry
- Creator
- Rights statement
- Awarding institution
- University of Strathclyde
- Date of award
- 2024
- Thesis identifier
- T18092
- Person Identifier (Local)
- 202065725
- Qualification Level
- Qualification Name
- Department, School or Faculty
- Abstract
- Investigations have been conducted into new synthetic methods for the trifluoromethylation of nitrogen centres. In the opening Section, the medicinal chemistry properties of and current methods for the synthesis of relevant C-CF3 and N-CF3 motifs are reviewed, highlighting the key limitations associated with each. The details of this Section thus prompted the investigations outlined in this study. Chapter 2 begins with a discussion and disclosure of a novel synthetic method for the N-trifluoromethylation of amines, using a combination of Cu-CF3 and O-benzoyl hydroxylamines. Further work in this area has uncovered a catalytic version of the reaction where optimisation studies have revealed CuBr, TMSCF3, and SrF2 as effective reagents in the synthesis of a series of tertiary N-CF3 amines bearing a range of functionality. Application of this method to more challenging substrates such as secondary amines, amides, sulfonamides, anilines, and heterocycles was unsuccessful despite extensive reaction modification. Nevertheless, these studies also identified common side products such as imines and carbamoyl fluorides, thus providing more insight into the stability and utility of N-CF3 compounds. The use of high-throughput experimentation enables the rapid optimisation of synthetic routes and can be used to accelerate compound synthesis for applications to medicinal chemistry. The second part of this study was, therefore, focused on the development of a high-throughput experimentation methodology applied to a Pd/Cu co-catalysed C-H activation reaction of oxazoles. The methodology enabled the direct isolation of products from the screening plates thus removing any requirements for scale-up reactions. The methodology was also used to rapidly develop a complex substrate scope, which displayed advantages over a classical one-condition multisubstrate approach, and enabled the generation of large amounts of reactivity data which was used for early-stage reaction prediction studies.
- Advisor / supervisor
- Mason, Joseph
- Fazakerley, Neal
- Kerr, William
- Resource Type
- Note
- This thesis was previously held under moratorium in the Chemistry Department (GSK) from 24/5/24 until 8/7/26.
- DOI
- Funder
- Embargo Note
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