MURRAY, BEN,JAMES (2021) Exploring the synthetic utility of HFO-1234yf. Doctoral thesis, Durham University.
The trifluoromethyl group is a common motif in pharmaceuticals, agrochemicals and organic materials due to its potential myriad beneficial effects on the properties of such molecules. However, the synthesis of compounds bearing a trifluoromethyl groups relies on the use of either a limited number of building blocks, notably trifluoroacetic acid and trifluorotoluene derivatives, or late stage trifluoromethylating reagents, which are often prohibitively costly on manufacturing scales. This thesis explores the utility of the low global warming potential refrigerant gas 2,3,3,3-tetrafluoropropene, also known as HFO-1234yf (1), as a new building block for the synthesis of pharmaceutically relevant trifluoromethylated compounds.
The reactivity of 1 towards nucleophiles was first investigated, using various mechanistic studies to resolve a discrepancy in previous literature and a range of differently substituted α-trifluoromethyl enol ethers and β-trifluoromethyl vinyl sulfides were then synthesised. Attempted reaction of 1 with carbon-centred nucleophiles led to the discovery of a rapid dehydrofluorination process to form 3,3,3-trifluoropropyne. Addition of this alkyne to aldehydes followed by oxidation afforded a range of trifluoromethyl ynones, which in turn reacted both as Michael acceptors with nucleophiles and as dienophiles in Diels-Alder reactions, both proving to be fast and efficient processes. Furthermore, reactions of trifluoromethyl ynones with dinucleophiles to give CF3-substituted heterocycles were developed, exemplified by a novel synthesis of the anti-arthritis drug celecoxib.
Addition of the trifluoroalkynide formed in situ from 1 to ketones instead of aldehydes afforded tertiary alcohols that acted as building blocks for the synthesis of oxygen-rich trifluoromethylated heterocycles along with some promising initial results for use as bench-stable trifluoropropynylating reagents. 1,3-Dipolar cycloaddition of 1 with an azomethine ylide gave a new route to tetrafluorinated pyrrolidine systems. Finally, reactions with electrophiles were explored and, at room temperature, bromination of 1 was found to be facile. The resulting dibromoalkane underwent dehydrobromination followed by palladium-catalysed cross-coupling with aryl boronic acids and alkynes to afford tetrafluorinated styrenes and enynes, respectively.
|Item Type:||Thesis (Doctoral)|
|Award:||Doctor of Philosophy|
|Keywords:||fluorine; trifluoromethyl; refrigerant|
|Faculty and Department:||Faculty of Science > Chemistry, Department of|
|Copyright:||Copyright of this thesis is held by the author|
|Deposited On:||14 Dec 2021 16:42|