Electrochemical hydrodefluorination of trifluoromethyl groups

Abstract

The unique chemical properties and utility of C-F bonds, including those present in trifluoromethyl and difluoromethyl groups, in the context of bioactive pharmaceuticals and agrochemicals is discussed in Chapter 1. General C-F activation methodology is also introduced, including reductive routes for C-F activation.

Difluoromethyl ketones are a relatively underdeveloped class of fluoromethyl ketones that have a unique ability to hydrogen bond, in contrast to the more common trifluoromethyl ketones. Development of a direct mono-selective reductive electrochemical hydrodefluorination protocol utilising trifluoromethyl ketones as starting materials for efficient access into difluoromethyl ketones is discussed in Chapter 2. Enabled by electrochemical reduction, direct C-F to C-H replacement could be achieved in a single step with high Faradaic efficiency and up to 97% yield.

Similarly, difluoromethyl arenes have been reported to undergo unique hydrogen bond donor interactions and have found use as non-nucleophilic bioisosteres of both phenols and thiophenols. The activation of (traditionally inert) trifluoromethyl arenes is challenging due to very negative reduction potentials required. Common C-F activation methodology for trifluoromethyl arenes is unselective and affords exhaustive defluorination or the scope is limited by the use of chemical or photochemical reductants. Electrochemical trifluoromethyl arene mono- and di-hydrodefluorination is discussed in Chapter 3. The use of a Ni cathode was found to be crucial for selectivity and comparison to the state of the art shows an ambivalence towards substrate electronics, enabled through the control of cell potential using electrochemistry.

Chapter 4 discusses the synthesis, both electrochemically and chemically, of
pronucleophiles for the functionalisation of reductively-activated trifluoromethyl arenes. A novel platform for the di-defluorosilylation of trifluoromethyl arenes to install two different silyl protecting groups is discussed. Methodology to then functionalise the two groups sequentially is disclosed, with a view to developing similar compounds as building blocks for modular construction of densely functionalised benzyl fluoride products.

The results in this thesis have been communicated:
J. R. Box, A. P. Atkins, A. J. J. Lennox, Chem. Sci. 2021, 12, 10252–10258
J. R. Box, M. E. Avanthay, D. L. Poole, A. J. J. Lennox, Angew. Chem. Int. Ed. 2023, 62, e202218195

Date of Award	9 May 2023
Original language	English
Awarding Institution	University of Bristol
Supervisor	Alastair J J Lennox (Supervisor) & Craig P Butts (Supervisor)