Direct electrochemical hydrodefluorination of trifluoromethylketones enabled by non-protic conditions

Abstract

CF₂H groups are unique due to the combination of their lipophilic and hydrogen bonding properties. The strength of H-bonding is determined by the group to which it is appended. Several functional groups have been explored in this context including O, S, SO and SO₂ to tune the intermolecular interaction. Difluoromethyl ketones are under-studied in this context, without a broadly accessible method for their preparation. Herein, we describe the development of an electrochemical hydrodefluorination of readily accessible trifluoromethylketones. The single-step reaction at deeply reductive potentials is uniquely amenable to challenging electron-rich substrates and reductively sensitive functionality. Key to this success is the use of non-protic conditions enabled by an ammonium salt that serves as a reductively stable, masked proton source. Analysis of their H-bonding has revealed difluoromethyl ketones to be potentially highly useful dual H-bond donor/acceptor moieties.

Fig. 1. H-Bonding in DFMKs and their synthesis via hydrodefluorination.

Fig. 2. Reaction of 1a to 3a with 3 different Br⁻ concentrations.

Fig. 3. Isolated yields of DFMKs tested under the reaction conditions at 0.5 mmol scale. NMR yields in parentheses. ^aReaction run at 10 mA; ^breaction run in IKA Divided ProSyn: quantitative yield based on RSM; ^c5 mmol scale, Ni foil:Gr (cath:an); ^disolated as the corresponding ketone following purification on silica.

Fig. 4. [A] Derivatization of DFMKs. X = H (3a) for 4, 7, and 8, X = Br (3ae) for others; [B] H-bond strength (A-value) correlated to σ_m Hammett parameter; [C] intermolecular H-bond revealed in X-ray crystal structure of 3ae; [D] DFT calculated (B3LYP/6-311+g(d)) relative energies of conformers with rotation around HC–CO bond. Brown arrows indicate direction of dipole.