Date: 19 June 2025 | Category: News
Authors: Patrick Ryan, Dhananjay Bhattacherjee, Thomas Wirth, Luke Hunter and Giancarlo Pascali*
The Pascali group at the University of New South Wales, and the Wirth group, from Cardiff University, have successfully used the Vapourtec Ion Electrochemical Reactor to achieve electrochemical fluorination of proline cores, leading to either mono-fluorination or gem-difluorination, Scheme 1 [1].
Scheme 1: Mild, electrochemical method for the late-stage fluorination of proline derivatives.
Fluorinated proline derivatives have many applications
Fluorinated proline derivatives have applications across a broad range of industries, including protein engineering, medicinal chemistry and catalysis [2, 3, 4]. Installation of a fluorine atom onto a proline ring can provide many advantages, including metabolism resistance, control of ring puckering and the opportunity to interrogate biomolecular function using 19F NMR techniques. Alongside this, the rapid late-stage installation of 18F can lead to applications within radiochemistry and PET imaging.
Electrochemical mono-fluorination
Standard gem-difluorination strategies can be limited by their use of strong nucleophilic fluoride sources [1]. Electrochemistry offers an alternative approach, with the added benefit of increased selectivity due to a simplified solution phase and tunable solid phase oxidation conditions. Nevertheless, the development of electrochemical gem-difluorination is underexplored.
Initial studies into the mono-fluorination of para-methoxythiophenyl-containing derivative 1 were very successful, with the metastable monofluorinated species 2 forming rapidly in 91% yield under batch conditions, Scheme 2. Moving forwards, preparation of the requisite gem-difluoride 3 under fluoro-Pummerer conditions was explored. While trace quantities of the desired product were observed, several species were present, including the diastereomeric monofluorinated proline 2 and a substantial quantity of sulfoxide 4, which was a mechanistic endpoint.
Scheme 2: Electrochemical fluorination of dithioproline 1, showing monofluorinated intermediate 2, desired difluorination product 3 and the sulfone mechanistic endpoint 4.
Flow conditions were therefore implemented, as it was thought that formation of the undesired sulfoxide 3 could be minimised through enhanced control of electrolysis. Use of the Vapourtec Ion electrochemical reactor, with the ability of flow rate variation, allowed for the lower flow rate and longer electrolysis time required. Overall, it was possible to tune the reaction such that less sulfoxide by-product was formed, with a higher yield of the desired gem-difluorinated product attained (9% in flow versus 6% in batch).
Although high yields of gem-difluorination were not achieved, this work provides proof-of-concept for efficient monofluorination of para-methoxythiophenyl derivatives, and showcases the superiority of flow electrochemistry over traditional batch methods for tuning reaction conditions. Further work towards preparing 4,4-gem-difluoroprolines is ongoing, potentially exploring alternative substrates that better promote the second fluorination step.
References:
[1] Electrochemical Fluorination of Proline Derivatives. (P. Ryan, D. Bhattacherjee, T. Wirth, L. Hunter, G. Pascali, Eur. J. O. C., 2025, e202500264). https://doi.org/10.1002/ejoc.202500264
[2] Fluorine-Containing Prolines: Synthetic Strategies, Applications, and Opportunities. (P. K. Mykhailiuk, J. Org. Chem. 2022, 87(11), 6961). https://doi.org/10.1021/acs.joc.1c02956
[3] Tinker, Tailor, Soldier, Spy: The Diverse Roles That Fluorine Can Play within Amino Acid Side Chains. (S. A. Miles, J. A. Nillama, L. Hunter, Molecules, 2023, 28 (17), 6192). https://doi.org/10.3390/molecules28176192
[4] Biochemistry of fluoroprolines: the prospect of making fluorine a bioelement. (V.Kubyshkin, R. Davis, N. Budisa, Belstein J. Org. Chem., 2021, 17, 439). https://doi.org/10.3762/bjoc.17.40
