Electrochemical C−C bond cleavage of cyclopropanes towards the synthesis of 1,3-difunctionalized molecules

Electrochemistry has a lot of inherent advantages in organic synthesis and many redox reactions have been achieved under electrochemical condition. However, the electrochemical C−C bond cleavage and functionalization reactions are less studied. Here we develop electrochemical C−C bond cleavage and 1,3-difuntionalization of arylcyclopropanes under catalyst-free and external-oxidant-free conditions. 1,3-difluorination, 1,3-oxyfluorination and 1,3-dioxygenation of arylcyclopropanes are achieved with a high chemo- and regioselectivity by the strategic choice of nucleophiles. This protocol has good functional groups tolerance and can be scaled up. Mechanistic studies demonstrate that arylcyclopropane radical cation obtained from the anode oxidation and the subsequently generated benzyl carbonium are the key intermediates in this transformation. This development provides a scenario for constructing 1,3-difunctionalized molecules.

C -C bonds are the basic skeleton of organic compounds and the direct functionalization via C-C bond deconstruction is quite meaningful for synthesis of complex molecules 1,2 . Cyclopropanes are important building blocks. The ring-opening of cyclopropanes driven by the release of ring strain has been widely applied in total synthesis 3,4 . Donor-acceptor cyclopropanes (DACs), which are activated by vicinal electrondonating and electron-withdrawing groups are predisposed to ring-opening under Lewis acid catalysis due to the inherent electronic bias [5][6][7] , whereas non-activated cyclopropanes, which are more regular in nature, are reluctant to ring-opening due to insufficient electronic bias. There are two methods for ringopening of non-activatied cycolpropanes. One relies on oxidative addition by transition metals. However, these reaction are limited to ring-opening rearrangement or cycloaddition reactions and requires specific directing groups for regioselective ring-opening functionalization 8 . The other one relies on electrophilic activation with Lewis acidic species. However, most of the transformations are limited to electrophilic addition reactions [9][10][11][12][13][14][15][16][17] . Ring-opening functionalization of arylcyclopropanes initiated through the single electron oxidation followed by the yield of corresponding radical cations was discovered in the 1970s 18,19 . In recent years, this strategy was further applied in 1,3-aminofunctionalization, 1,3-oxoamination, and 1,3-oxochlorination of arylcycropropanes in the presence of oxidants or light. However, in most cases, its large scalability application was not studied and arylcycropropanes with electron-withdrawing groups could not be well compatible due to their high oxidative potential (Fig. 1a) [20][21][22][23][24] .
Organic electrochemistry is reviving due to their effortlessness of scalability, avoidance of stoichiometric oxidants or reducing agents, and flexible reaction tunability 25 . Various redox reactions have been achieved by the comsumption of traceless electrons under constant potential or current conditions [26][27][28][29][30][31][32][33][34][35][36][37][38] . As a main part of preparative electrosynthesis, anode processes such as C-H functionalization, oxidative coupling, decarboxylation, and olefin functionalization has been developed [39][40][41][42][43][44][45][46][47][48] . However, electrochemical oxidative C−C bond cleavage/functionalization are rarely developed due to the inertness and weak electronic bias of C−C bonds, which are always encumbered by other bonds 8,48,49 . Pioneering work was disclosed by Shono and coworkers who reported anodic oxidation of arylcyclopanes in methanol 50 . But only six examples were presented in this report (Fig. 1b). Our design for electrochemical C−C bond cleavage/ functionalization based on the following mechanistic proposal (Fig. 1c): Firstly, arylcyclopropane is oxidized to a radical cation by anode, which results in the weakening of the C α -C β bond, as the BDE of C α -C β bond decreases more than 30 kcal/mol from the neutral cyclopropane to the corresponding radical cation 51 . Then the radical cation undergoes three-electron S N 2 reaction to generate a benzyl radical 52 . Different from reported thermochemical and photochemical strategy, the benzyl radical can further lose one electron at anode and converted to a benzyl carbonium under electrochemical conditions 43 . The following nucleophilic attack to the benzyl carbonium can finally yield the 1,3-difunctionalization product. Fluorinated products could be prepared by employing Et 3 N·3HF as nucleophilic fluorine source [53][54][55][56][57][58] . In this work, we develop the electrochemical 1,3-difluorination, 1,3-oxyfluorination, and 1,3-dioxygenation of arylcyclopropanes with a high chemoselectivity and regioselectivity by the strategic choice of nucleophiles. Moreover, a wide variety of arylcyclopropanes with electrondonating and electron-withdrawing groups could be converted to the 1,3-difunctionalized molecules by following this protocol.

Results
Investigation of reaction conditions. We began our investigation by exploring the selective synthesis of 1,3-difluorination, 1,3-oxyfluorination, and 1,3-dioxygenation products from phenylcyclopropane. After extensive screening of various conditions (for more details, see Supplementary Table 1 -5), with the use of Et 3 N·3HF as a fluorine source, 1,3-difluorination product 2 was obtained in 77% yield by conducting the electrolysis under constant current of 16 mA in an undivided cell equipped with platinum plate as both anode and cathode (Fig. 2, Entry 1). 1,3-oxyfluorination product 3 was obtained in 47% yield with the concomitant formation of other three 1,3-difuntionalization products under the existence of both Et 3 N·3HF and MeOH (Fig. 2, Entry 2). The yield of 1,3-oxyfluorination product 3 increased slightly when the reaction temperature decreased to 0°C (Fig. 2, Entry 3). An obviously improved yield was observed by using carbon cloth as anode materials (Fig. 2, Entry 4). The influence of the concentration of phencyclopropane to the reaction could be neglected (Fig. 2, Entry 5). 1,3-oxyfluorination product 3 was finally observed in 76% yield by adjusting the ratio of Et 3 N·3HF/MeOH (Fig. 2, Entry 6). The good selectivity of the 1,3oxyfluorination product 3 was speculated to be controlled by kinetics. At the first step, the reaction rate between MeOH and arylcyclopropane radical cation is larger than the reaction rate between Et 3 N·3HF and arylcyclopropane radical cation, which possibly due to the lower nucleophilicity of Et 3 N·3HF than MeOH 57 . Therefore, arylcropropane radical cation mainly reacts with MeOH instead of Et 3 N·3HF. According to the rate constant equation proposed by Mayr et al, the reaction rate of benzyl carbonium with MeOH or Et 3 N·3HF are both very fast and determined by diffusion rate 59,60 , so the fluorination is the major process in the second step because of the excess amount of fluorine source compared with methanol in the reaction system. Further condition screening demonstrated that 1,3-dioxygenation products could be obtained in 95% yield under the electrolysis in MeOH with Bu 4 NBF 4 as supporting electrolyte (Fig. 2, Entry 7).
The scalability of this method was demonstrated by using carbon cloth as anode and nickel foam as cathode instead of expensive platinum electrode with equivalent amount of Et 3 N·3HF (Fig. 3). The yields increased for most of the tested substrates when operated at gram scale. The yields increased from 75% to 90% for para-methanesulfonyl substituted phenylcyclopropane (6). The yields increased to 65% and 63% for ester (14)   and oxytrifluoromethyl (22) substituted arylcyclopropanes. The yields would decrease slightly from 67% to 63% only when it came to 4-bromocyclopropylbenzene (10).

Discussion
To gain more insights into the aforementioned transformation, several mechanistic studies were conducted. Redox potentials of the cyclopropanes were tested by cyclic voltammetry experiments (Fig. 5a). The alkyl substituted cyclopropane 1c has a high  Ag/AgCl/KCl sat ). These results illustrate that aryl group is crucial for the oxidation of the cyclopropane substrates. The charge distribution of phenylcyclopropane radical cation has been studied by DFT calculation (Fig. 5b). The results show that distal C atom in cyclopropane motif possess partial positive charge and are the potential nucleophilic attack sites. Considering the reaction between benzyl radical and dioxygen was very fast (rate constant 2.8 × 10 9 L mol −1 s −1 ) 65 , the reaction was conducted in the dioxygen atmosphere in order to trap the possible benzyl radical intermediate. The detection of the oxygenation products is highly inductive of the formation of the benzyl radical during the reaction (Fig. 5c). In addition, the existence of benzyl radical was also evidenced by the trapping experiment using BrCCl 3 66,67 . Furthermore, the electrolysis of phenylcyclopropane and Et 3 N·3HF in CH 3 CN resulted in the isolation of amidation product 59, which suggested the involvement of benzyl carbonium intermediate during the reaction (Fig. 5d) 68,69 .
In conclusion, we have developed a electrochemical C-C bond cleavage of arylcyclopropanes, enabling 1,3-difunctionalization of arylcyclopropanes to yield 1,3-difluorination, 1,3-oxyfluorination, and 1,3-dioxygenation products. Neither additional oxidant or catalyst were needed in this transformation. Productive gramscale 1,3-difluorination reaction was conducted by using stoichiometric amount of commercial available Et 3 N·3HF as fluorine source. Mechanistic studies show that arylcyclopropane radical cation and benzyl carbonium play paramount role in this reaction. This study provides a simple strategy for constructing 1,3difunctionalized molecules.

Methods
General procedure (2). An oven-dried undivided three-necked bottle equipped with a stir bar. The bottle was equipped with platinum plate (15 mm × 15 mm × 0.3 mm) as both the anode and cathode and then charged with argon gas in glove box. Phenylcyclopropane (0.5 mmol), Et 3 N·3HF (1.2 mL) and PhCF 3 (4.8 mL) were added. The reaction mixture was stirred and electrolyzed at a constant current of 16 mA at 25°C for 2 h. The reaction was diluted with water. The organic layer was extracted with CH 2 Cl 2 , dried with anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The pure product was obtained by flash column chromatography on silica gel. Full experimental details can be found in the Supplementary Methods.