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

Abstract

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.

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

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

[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 19}F 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

[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.