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. 2023 Jan 27;62(12):e202218195.
doi: 10.1002/anie.202218195. Online ahead of print.

Electronically Ambivalent Hydrodefluorination of Aryl-CF3 groups enabled by Electrochemical Deep-Reduction on a Ni Cathode

John R Box  1 , Mickaël E Avanthay  1 , Darren L Poole  2 , Alastair J J Lennox  1
Affiliations

Electronically Ambivalent Hydrodefluorination of Aryl-CF3 groups enabled by Electrochemical Deep-Reduction on a Ni Cathode

John R Box et al. Angew Chem Int Ed Engl. .

Abstract
in English, German

We report a general procedure for the direct mono- and di-hydrodefluorination of ArCF3 compounds. Exploiting the tunability of electrochemistry and the selectivity enabled by a Ni cathode, the deep reduction garners high selectivity with good to excellent yields up to gram scale. The late-stage peripheral editing of CF3 feedstocks to construct fluoromethyl moieties will aid the rapid diversification of lead-compounds and compound libraries.

The Ar-CF2 H moiety is featured in an increasing number of bioactive compounds due to its unique combination of properties. The hydrodefluorination of Ar-CF3 compounds is a direct and efficient route toward this motif. As reported methods for this transformation have focused on specific substrate families, herein we describe a general-electronically ambivalent-procedure for the single-step direct mono-hydrodefluorination of a variety of feedstock and functionalized Ar-CF3 compounds. Exploiting the inherent tunability of electrochemistry and the selectivity enabled by a Ni cathode, the deep reduction garners high selectivity for ArCF2 H products, with good to excellent yields up to gram scale. The protocol has been extended to a single-step di-hydrodefluorination yielding benzyl fluorides. The late-stage peripheral editing of a single CF3 feedstock to construct fluoromethyl (CF2 H, CFH2 ) moieties will aid the rapid diversification of lead-compounds and compound libraries.

Keywords: Defluorination; Electrochemistry; Fluorine; Nickel; Reduction.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
[A–C]: The utility of CF2H groups, their synthesis and challenges; [D]: Electrochemical defluorination strategy. CV of 1 a–d (averaged forward and return currents). ‐Ni||+Pt, 5 mM [1 a–d], degassed DMF, 0.1 V/s, NBu4PF6, N2. See Supporting Information for CVs run in with different electrode materials and in MeCN.
Figure 2
Figure 2
[A]: Substrate scope. Isolated yields of ArCF2H, unless indicated. Ratios in brackets correspond to CF2H:CFH2 determined from crude 19F NMR, n.d.=not‐detected. CP=Chronopotentiometry. Benchmarking yields are 19F NMR yields, except where noted ‘b’. a 19F NMR yield, not isolated due to volatility. b % conversion, c CF2H observed in 19F NMR of crude mixture, product hydrolysed to corresponding aldehyde on silica, d reaction run without TMSCl. [B]: Summed Hammett σ value of successful substrates (see Supporting Information for details).
Figure 3
Figure 3
[A] control experiments to probe for radical or anionic intermediates. [B] ArCFH2 scope, isolated yields of ArCFH2, with 19F NMR yields given in parentheses, ratio is CFH2 : CF2H. a NMR yield given due to volatility of product.
See this image and copyright information in PMC

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