Reaction optimization. First, we used 4-iodobiphenyl and sodium difluoromethanesulfinate (NaSO2CF2H) to investigate the reaction conditions (Table 1). After a thorough screening of nickle catalysts and ligands, the difluoromethylated arene product could be realized in 85% 19F NMR yield with NiBr2 diglyme (20 mol%) and L9 (15 mol%) in an undivided cell (graphite cathode/anode, 3.5 V cell voltage, entry 1). The reaction was terminated in the absence of K2CO3 (entry 2). The addition of DMAP was found curial for the cross-coulping, which acting as a co-ligand and base (entry 3). A small amounts of tetrabutylammonium hydrogen difluoride (TBABF4) was able to further assist the electron transfer reaction system (entry 4). When other nickel sources or electrode materials were used, the reaction could not proceed. (entries 5 & 6). Reduced yields were obtained with other solvents (entries 7 & 8).
Scope of the cross-coupling of NaSO 2 CF 2 H with aryl iodide. Under the optimized reaction conditions, this paired electrolysis protocol could be extended to a wide variety of iodobenzenes (Fig. 2). Arenes bearing electron-donating substituents such as phenyl (3a), tert-butyl (3b), methoxy (3c), dioxolane (3r) and electron-withdrawing substituents such as cyano (3d) and carbonyl (3e & 3f) were perfectly accommodated. Notably, p-, m- and o-esterificated coupling products (3g-3i) were furnished in high yields. Amides (3k & 3m), benzyl alcohol (3l) or substituted piperazine (3s) were all well-tolerated. Polycyclic electron-rich aromatics including naphthyl, fluorenyl, phenanthryl (3n-3q) resulted in moderate yields. Remarkably, the dual coupling of disubstituted aryl iodide could be realized by increasing the NaSO2CF2H and extension of the reaction time (3t, 54%). Furthermore, heteroarenes including indole, pyridine, carbazole, quinoline underwent the reaction smoothly, leading to corresponding difluoromethylated heterocycles in good yield (3u-3z). As biological isostere and hydrogen bond donor, difluoromethyl moiety being widely used in drug design, we have applied this strategy to the late functionalization of natural products and drugs. Cedrol, Probenecid, Gemfibrozil and Dehydroabietylamine (DHAA) underwent the electrochemical process smoothly to afford the corresponding difluoromethylated derivatives (3aa-3ae).
Scope of the cross-coupling of NaSO 2 CFH 2 with aryl iodide. The CH2F group as the crucial motif contains in many biologically active molecules, such as afloqulone, fluticasone propionate, and the anesthetic sevofurane. 42–44 The modification of functional molecules with the CH2F group is potentially useful to improve their bioactivities. Therefore, we sought to the CH2F group is potentially useful to improve their bioactivities. Therefore, we sought to explore the generality of this approach with sodium monofluoromethylsulfonate (NaSO2CFH2) for the corresponding electrochemical couplings. By using NiCl2 glyme (10 mol%) and L3 (15 mol%), the monofluoromethylated products have been obtained (Fig. 3). Both electron-rich or electron-deficient aromatic rings all demonstrated good reactivity (4a-4f). Bioactive molecules including Lumacator, Lbuproben and Diactone-D-glucose resulted the momofluoromethylated products in good yields (4g-4i)
Synthetic applications and Mechanistic investigation. To further demonstrate the practicality of this reaction, bromonated benzothiophene was applied the standard conditions and difluoromethyl benzothiophene (5a) was obtained in a reduced yield (Fig. 4A). The reaction could also be performed in gram scale, affording 3a in 54% yield (Fig. 4B). To investigate the reaction mechanism, a series of control experiments have been carried out. First, when adding the radical-trapping agent diphenylethylene (2.0 equiv), the reaction was greatly suppressed and difluoromethyl diphenyethylene 6 was afforded in 5% yield. Subsequently, N-tert-butyl-2-phenylnitrone (PBN, 2.0 equiv) was added to the reaction mixture, significant electron spin resonance (EPR) signal was captured after 15 mins. The above results suggested that the reaction underwent a difluoromethyl radical path. Next, when Ni(COD)2 was used instead of Ni(II) catalyst under the standard conditions, 3g still gave 20% 19F NMR yield (Fig. 4C, see SI for details).
From the above experiments, it is believed that Ni(0) and iodobenzene undergo oxidative addition to form an Ar-NiII-I intermediate. The fluoroalkyl radical intermediate produced by anodic oxidation the attack the Ni(II) species to form the Ar-NiIII-Rf intermediate. The Ni(III) is quickly reduced and reductive elimination furnished the target fluoroalkyl coupling product and Ni(I), which is reduced to Ni(0) by the cathode and participates in the next cycle (Scheme 4D). Furthermore, we studied the redox potentials of two fluoroalkylating reagents by cyclic voltammetry (CV) experiments in DMF (10 mM) with n-Bu4NBF4 (0.2 M) at a scan rate of 0.2 V·s−1. The oxidation peak of NaSO2CF2H was observed at 0.577 V and NaSO2CH2F at 0.306 V. This indicated that NaSO2CH2F was more prone to oxidize on anode than NaSO2CF2H, which rapidly decomposed at higher potential and explained the decreased efficiency for the monofluoromethylation compared with difluoromethylation (Scheme 4E).