Nickel-catalyzed oxidative uoroalkylation of aryl halides via paired electrolysis

The paired electrolysis triggers multiple oxidative and reductive processes to occur simultaneously, which ensures the steady transformation of the intermediates to the desired coupling products. However, uoroalkyl radicals have not been harnessed for metal-catalyzed cross-coupling with aryl halides under electrochemical conditions. This work describes a general strategy for rapid access to various uoromethyl and diuoromethyl aromatics by paired electrolysis. The contradiction between anodic oxidation of uoroalkyl sulnates and cathodic reduction of low-valent nickel catalysts can be well addressed under mild cell conditions, allowing for direct introduction of uorinated functionalities into aromatic systems.


Introduction
The wide application of uoromethyl and di uoromethyl groups in agrochemical, pharmaceutical, and material science has triggered every endeavor for selective incorporation of uoroalkyl groups into organic molecules. [1][2][3][4] The transmetallation of organometallic di uoromethylating reagents (LnMCF 2 H) [5][6][7][8][9][10] has been developed for selective introduction of CF 2 H motif into arenes 13 (Fig. 1A). Meanwhile, cross reductive coupling of di uoromethyl halomethanes provided a new route for the activation of inert uorinated gases (Fig. 1B, left). 11,12 However, the use of instable organometallic reagents, the stoichiometric reductants, 6,9,14,15 and gaseous uorine sources 16 could not be avoided. The readily accessible and operationally simple oxidative di uoromethylating reagents are promising candidate to address the above issues. However, since the low-valent metal catalysts (such as Ni 0 ) that required in most of the cross-coupling reactions with organic halides can not survive under oxidative conditions (Fig. 1B, right), the search of suitable conditions for oxidative di uoromethylation strategy remains fruitless and represents unmet challenge. Electrochemically initiated radical cross-coupling has drawn much attention for the redox-e ciency, innate scalability and compatibility of electrolytic process. 17 The combination of uorination and electrochemistry opens a new arena for the development of organo uorine methodology 18 . Recently, various electrochemically mediated approaches for uoroalkylation of organic molecules through radical addition pathway have been reported. [19][20][21][22] However, the metal-catalyzed electrochemical cross-coupling of uoroalkyl radicals with aryl halides remain unsolved task, which was plagued by mismatched active intermediates and lack of suitable oxidative uorinating sources. Paired electrolysis utilizes the expenditure of electrical power to oxidize/reduce the active species, maximizing the congeniality through performing simultaneously two half reactions and displays pronounced advances in the kinetic control of radical and catalyst reactivity. [23][24][25] Achievements have been made for metal-catalyzed C-C 26-31 , C-N 32,33 , C-S 34,35 and C-P 36,37 bond formations. In the eld of electrochemical uorination, uoroalkyl sulfonates have been widely employed as ideal oxidative di uoromethylating agents. Owing to the low oxidative potential and high reactivity under cell conditions, uoroalkyl radicals could be readily produced by anodic oxidation of the corresponding sulfonates. 38- 41 We envisioned that the harmonic merge of the oxidative process of uoroalkyl sul nate with the reductive nickel catalytic path could realize the desired cross-coupling sequence through paired electrolysis. Herein, a nickel-catalyzed redox neutral electrochemical cross-coupling is described for the rapid access of a broad range of mono-and di uoroalkylated (hetero)arenes (Fig. 1C).

Results And Discussion
Reaction optimization. First, we used 4-iodobiphenyl and sodium di uoromethanesul nate (NaSO 2 CF 2 H) to investigate the reaction conditions (Table 1). After a thorough screening of nickle catalysts and ligands, the di uoromethylated arene product could be realized in 85% 19 F NMR yield with NiBr 2 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 K 2 CO 3 (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 di uoride (TBABF 4 ) 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).
Remarkably, the dual coupling of disubstituted aryl iodide could be realized by increasing the NaSO 2 CF 2 H and extension of the reaction time (3t, 54%). Furthermore, heteroarenes including indole, pyridine, carbazole, quinoline underwent the reaction smoothly, leading to corresponding di uoromethylated heterocycles in good yield (3u-3z). As biological isostere and hydrogen bond donor, di uoromethyl moiety being widely used in drug design, we have applied this strategy to the late functionalization of natural products and drugs. Cedrol, Probenecid, Gem brozil and Dehydroabietylamine (DHAA) underwent the electrochemical process smoothly to afford the corresponding di uoromethylated derivatives (3aa-3ae). Scope of the cross-coupling of NaSO 2 CFH 2 with aryl iodide. The CH 2 F group as the crucial motif contains in many biologically active molecules, such as a oqulone, uticasone propionate, and the anesthetic sevofurane. [42][43][44] The modi cation of functional molecules with the CH 2 F group is potentially useful to improve their bioactivities. Therefore, we sought to the CH 2 F group is potentially useful to improve their bioactivities. Therefore, we sought to explore the generality of this approach with sodium mono uoromethylsulfonate (NaSO 2 CFH 2 ) for the corresponding electrochemical couplings. By using NiCl 2 glyme (10 mol%) and L3 (15 mol%), the mono uoromethylated products have been obtained (Fig. 3). Both electron-rich or electron-de cient aromatic rings all demonstrated good reactivity (4a-4f).
Bioactive molecules including Lumacator, Lbuproben and Diactone-D-glucose resulted the momo uoromethylated 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 di uoromethyl 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 di uoromethyl diphenyethylene 6 was afforded in 5% yield. Subsequently, N-tert-butyl-2-phenylnitrone (PBN, 2.0 equiv) was added to the reaction mixture, signi cant electron spin resonance (EPR) signal was captured after 15 mins. The above results suggested that the reaction underwent a di uoromethyl radical path. Next, when Ni(COD) 2 was used instead of Ni(II) catalyst under the standard conditions, 3g still gave 20% 19 F NMR yield (Fig. 4C, see SI for details). The oxidation peak of NaSO 2 CF 2 H was observed at 0.577 V and NaSO 2 CH 2 F at 0.306 V. This indicated that NaSO 2 CH 2 F was more prone to oxidize on anode than NaSO 2 CF 2 H, which rapidly decomposed at higher potential and explained the decreased e ciency for the mono uoromethylation compared with di uoromethylation (Scheme 4E).

Conclusion
In summary, a paired electrolysis protocol of Ni-catalyzed uoroalkylation of (hetero)arenes has been developed. The paradox between anodic oxidation of uoroalkyl sul nates and cathodic reduction of lowvalent nickel species can be conciliated under mild cell conditions, which is di cult to proceed in batch reaction with chemical oxidants. Further studies in electrochemical uorination is underway in our laboratory.

Methods
General procedure of the Condition A In glovebox, NiBr 2 diglyme (0.04 mmol, 20 mol%) and L9 (0.03 mmol, 15 mol%) were dissolved in 4 mL of DMSO. The solution was stirring for 1 h before usage. Next, an oven-dried undivided reactor (10 mL) Competing interests equipped with (hetero)aryl iodides (0.2 mmol), NaSO 2 CF 2 H (0.4 mmol), K 2 CO 3 (0.4 mmol), DMAP (0.08 mmol), n-Bu 4 NBF 4 (0.02mmol) and a stir bar. The reactor was equipped with graphite felt electrode (20× 10× 1 mm) as the anode and the cathode. The pre-mixed solution (4 mL) of ligand and nickel was then added and the reaction mixture was stirred and electrolyzed at a Cell voltage of 3.5 V (The dual display potentiostat was operating in constant voltage mode) under 30 o C for 8 h. When the reaction was completed, the solution was extract by EtOAc (3×10 mL), and the combined organic layers were concentrated with a rotary evaporator. The product was puri ed by ash column chromatography on silica gel.
General procedure of the Condition B In glovebox, NiCl 2 glyme (0.02 mmol, 10 mol%) and L3 (0.03 mmol, 15 mol%) were dissolved in 4 mL of DMSO. The solution was stirring for 1 h before usage. Next, an oven-dried undivided reactor (10 mL) equipped with (hetero)aryl iodides (0.2 mmol), NaSO 2 CFH 2 (0.4 mmol), K 2 CO 3 (0.4 mmol), DMAP (0.08 mmol), n-Bu 4 NBF 4 (0.02mmol) and a stir bar. The reactor was equipped with graphite felt electrode (20× 10× 1 mm) as the anode and the cathode. The pre-mixed solution (4 mL) of ligand and nickel was then added and the reaction mixture was stirred and electrolyzed at a Cell voltage of 3.5 V (The dual display potentiostat was operating in constant voltage mode) under 30 o C for 8 h. When the reaction was completed, the solution was extract by EtOAc (3×10 mL), and the combined organic layers were concentrated with a rotary evaporator. The product was puri ed by ash column chromatography on silica gel.