Stereoselective Synthesis of Monofluoroalkenes

Abstract

Monofluoroalkenes are effective bioisosteres of amides, and the development of methods towards their synthesis has been an enduring goal in the domain of organofluorine chemistry. An overview of these synthetic methods is included in Chapter 1, outlining their limitations in stereoselectivity, scope, and step-inefficiency. The literature surrounding hypervalent-iodine reagents is also
discussed, with the emphasis of this thesis directed towards the use of β-fluorovinyl-iodonium salts (FVIs) as fluoroalkene coupling reagents to solve these aforementioned limitations. Although efficient syntheses of E-β-fluorovinyl-iodonium salts have been previously reported, methods for accessing the Z-isomer suffer from many drawbacks, particularly multi-step syntheses, low yields, and limited scope. The research described in Chapter 2 achieves the regio- and stereoselective synthesis of Z-FVIs in a single step from alkynes via a silver-catalysed process. A wide scope is accessible with this method, both with respect to the alkene and (aryl)-iodonium components. Through control experiments, a preliminary mechanism for this transformation is outlined. Additionally, the results from a computational study on the key postulated steps help rationalise the role of silver, together with the observed regio- an stereochemical outcome. Finally, stereo-retentive functionalisations using Z-FVIs are demonstrated, enabling the efficient synthesis of a diverse range of Z-monofluoroalkenes, and enabling access to interesting novel/under-explored fluoroalkene structures in subsequent chapters.

Z-1,2-Fluoro-trifluoromethyl alkenes are rare fluoroalkene structures, with potential applications in medicinal chemistry and as synthetic precursors to multiply-fluorinated organic compounds. Only one method has been reported for their synthesis, which is limited to styrenes. To expand this narrow scope, a copper-mediated trifluoromethylation of Z-FVIs has been developed (Chapter 3). A wide scope of ’non-styrenyl’ 1,2-fluoro-trifluoromethyl alkenes is accessible with this method, with complete retention of the Z-stereochemistry.

By exploring further the versatile reactivity of Z-FVIs, Chapter 4 describes the C-S bond formation reactions of Z-FVIs with thiol and thiourea coupling partners, using copper-catalysis. Notably, Z-1,2-thiofluoroalkenes have only been sparsely reported in the literature, for which no general and stereoselective synthetic methods exist. Additionally, such thiourea-coupled products (Z-fluorovinyl isothiouronium salts) are entirely unreported. Successful preliminary results from the optimisation studies are disclosed: both coupling reactions demonstrate good yields, complete retention of the Z-stereochemistry, and employ mild reaction conditions.

Date of Award	3 Oct 2023
Original language	English
Awarding Institution	University of Bristol
Supervisor	Alastair J J Lennox (Supervisor)