Direct electrochemical defluorinative carboxylation of α-CF3 alkenes with carbon dioxide

An unprecedented γ-carboxylation of α-CF3 alkenes with CO2 is reported. This approach constitutes a rare example of using electrochemical methods to achieve regioselectivity complementary to conventional metal catalysis. Accordingly, using platinum plate as both a working cathode and a nonsacrificial anode in a user-friendly undivided cell under constant current conditions, the γ-carboxylation provides efficient access to vinylacetic acids bearing a gem-difluoroalkene moiety from a broad range of substrates. The synthetic utility is further demonstrated by gram-scale synthesis and elaboration to several value-added products. Cyclic voltammetry and density functional theory calculations were performed to provide mechanistic insights into the reaction.


Introduction
The carboxylation of organic halides using CO 2 as an abundant and nontoxic C1 synthon 1 is an important strategy to access carboxylic acids, which are widely distributed in natural products and pharmaceuticals. 2 Despite good progress in the carboxylation of carbon-hetero bonds, 3 the activation of C-F bonds for reaction development is largely undeveloped. 4 This is possibly because the C-F bond is the strongest carbon-hetero bond with a high bond dissociation energy, the activation of which is kinetically unfavorable since uorine is neither a good Lewis base nor a good leaving group. 5 In this context, the selective C-F bond carboxylation of lightly uorinated compounds could facilitate access to uorinated carboxylic acids that are much sought-aer substances for organic synthesis, materials science, and medicinal chemistry. 6 However, to date, only a limited number of catalytic processes have been realized (Scheme 1A). 7 Feng and co-workers combined photoredox/Pd dual catalysis to realize an sp 2 C-F bond carboxylation of gem-diuoroalkenes with moderate Z/E selectivity. 7a A Cu-catalyzed formal carboxylation was reported by Yu 7b and by us 7c respectively, in which carboxylation of the vinylboronate intermediate yielded a-uoroacrylic acids with high Z-selectivity. Yu and co-workers also achieved a formal sp 3 C-F bond carboxylation of a-CF 3 styrenes, which was conducted at 80 C with 1.5 equivalents of diboron reagent and 3.0 equivalents of base, giving a,a-diuorocarboxylates regioselectively. 7b Because the C-F bond cleavage of a-CF 3 alkenes might lead to both aand g-carboxylation, it is interesting to develop g-carboxylation of a-CF 3 alkenes using CO 2 for the synthesis of carboxylic acids with a gem-diuoroalkene moiety. As a carbonyl bioisostere with less susceptibility to in vivo metabolism, gem-diuoroalkene is a prominent structural motif that is found widely in biologically active compounds (Scheme 1C). 8 Moreover, they are versatile uorinated building blocks in organic synthesis. 9 Therefore, the efficient g-carboxylation of a-CF 3 alkenes using CO 2 under mild conditions with broad substrate scope is highly desirable.
Recently, increasing attention has been paid to synthetic organic electrochemistry. 10 Using electricity as a driving force, the use of toxic or expensive reducing agents might be avoided, and room temperature is oen sufficient to promote the reaction. Interestingly, electrochemical processes facilitated access to high-energy species or new mediators, thus affording opportunities that conventional chemistry may not have achieved. 11 Intrigued by these attractive features, we postulated that electrochemistry might be a powerful strategy to develop direct and green deuorinative carboxylation of a-CF 3 alkenes to secure a level of g-carboxylation unattainable by copper catalysis and avoid the use of diboron reagent and bases. Here, we wish to report our results in electrochemical g-selective carboxylation of a-CF 3 alkenes with CO 2 to structurally diverse g,g-diuoro vinylacetic acids with good functional group tolerance, using platinum plate as both cathode and non-sacricial anode under mild conditions (Scheme 1B).
Currently, most electrocarboxylations are conducted with sacricial anodes and/or require (quasi-)divided cell to forestall the undesired oxidation of starting material or carboxylic acid products. 12 From the viewpoint of practicability and sustainability, the development of non-sacricial metal system is more desirable. 13 Just recently, Malkov and Buckley achieved highly regioselective electrosynthetic hydrocarboxylation of b,btrisubstituted alkenes and conjugated dienes using non-sacricial anode system. 14 Encouraged by these elegant advances in nonsacricial metal-based electrochemical carboxylation of alkenes, 15 along with the seminal study on electrochemical C-F bond carboxylation of benzotriuoride by Troupel, 16 we tried to develop electrochemical carboxylation of a-CF 3 alkenes using a nonsacricial anode, with our interest in chemical xation of CO 2 to value-added chemicals. 17 Accordingly, the reaction of a-CF 3 substituted styrene 1a and bubbling CO 2 was undertaken in DMF containing Et 4 NOTs to evaluate different nonsacricial anodes, at a constant current of 8 mA in an undivided cell, with Pt-plate as cathode (Table 1).

Results and discussion
First, we evaluated graphite, RVC and Pt anodes, and found that the reaction indeed proceeded at room temperature for 4 hours, with a total charge of 6 Faraday/mol to yield the g-carboxylation product 2a in 32, 14, and 57% yields, respectively, and no acarboxylation adducts were detected (entries 1-3). This result unambiguously supported our working hypothesis and encouraged us to conduct further optimization studies using the Pt anode. Varying the cathode from Pt-plate to graphite or RVC gave no better results (entries 4 and 5). Increasing the current to 10 mA resulted in almost no change in yield but decreasing the current to 6 mA led to a reduction in the yield to 42% due to incomplete reaction (entries 6 and 7). Since the supporting electrolyte could affect the local environment near the electrode as part of the electrical double-layer, 18 we next evaluated its inuence. Using n Bu 4 NClO 4 as the electrolyte, the yield of 2a improved signicantly to 72% (entry 9). The solvent effects were also investigated, but DMF still proved to be the solvent of choice (entries 10-12 vs. 9). Finally, by increasing the electrolyte concentration to 0.07 M and performing the reaction with an ElectraSyn 2.0 instrument (see ESI †), the desired carboxylic acid, 2a could be obtained in 83% yield (entry 13). To investigate the stability of the carboxylation product under constant current conditions in an undivided cell, 19 we extended the reaction time to 7 hours and found that almost the same yield of 2a was obtained as that aer 4 hours (entry 14 vs. 13). This indicated the carboxylation product was sufficiently stable and did not decompose during the reaction (for detail of optimization, see ESI †).
Having established the optimal reaction conditions, we next evaluated the scope of the reaction with respect to a-CF 3 styrene derivatives. With various substituents on the phenyl rings, including methyl, tert-butyl, phenyl, terminal alkene, halogen, ether, cyano, and ester groups, alkenes 1b-r readily afforded the corresponding g,g-diuoro vinylacetic acids, 2b-r in 45-84% yields. The electronic and steric effects of the phenyl substituents had little impact on the carboxylation. For instance, the reaction of isomeric substrates with a methyl, chloro, uoro, or OCF 3 group at the para-or meta-position proceeded smoothly to afford the corresponding products 2b, 2c, 2j-l and 2p-r in similarly good to high yields. The a-CF 3 alkene derivatives  bearing 2-naphthyl, 2-thiophenyl, or 2-benzofuranyl group also worked well to furnish 2s-u in 40-62% yields.
Notably, a-CF 3 alkenes with a-alkyl substituents were also viable substrates. For example, alkenes bearing an a-phenethyl, phenylpropyl, or n-nonyl group produced the g-carboxylation products 3a-c in 46-57% yields. Furthermore, alkenes with an a-alkynyl moiety worked well to give the desired acids, 3d and 3e in 48 and 65% yields, respectively. Trisubstituted alkenes were further investigated, furnishing corresponding acids 3f-i in 40-56% yields. Cyclic alkenes based on 1,2-dihydronaphthalene skeleton were amenable, giving 3j and 3k in 52 and 55% yields, respectively. To our delight, several complex substrates derived from b-D-glucose, estrone and fructose also reacted well, affording the desired adducts 4a-c in reasonable yields. These results clearly demonstrated the good functional group tolerance of our method. For some substrates indicated in Table 2, the addition of H 2 O was benecial for the reaction yield, but the reason for this is not clear. 20 Given that a wide range of functional groups are tolerated, such as alkene, alkyne, and halogen groups, this methodology should be orthogonal to classical cross-coupling chemistry, which would further extend its synthetic utility. Also noteworthy was the perfect regioselectivity: only g-carboxylation occurred for all the reactions discussed above, and no a-carboxylation products were detected. In addition, for substrates bearing a uoro, CF 3 , or OCF 3 group, possessing different sp 2 or sp 3 C-F bonds, the deuorinative carboxylation occurred at the a-CF 3 alkenes moiety exclusively.
To further demonstrate the practicability of the developed electrochemical carboxylation, a gram-scale reaction of 1a was conducted on a 6.0 mmol scale, and the product 2a was isolated in 0.93 g with comparable yield (78%; Scheme 2). Moreover, the thus obtained carboxylic acid could be readily elaborated to valuable uorine-containing molecules. Under Pd/C catalysis, the alkene moiety of 2a could be readily hydrogenated to give b-diuoromethyl carboxylic acid 5 in 90% yield. The methylation and subsequent TBAF promoted olen isomerization delivered 6 in 78% yield. Condensation with amine afforded direct access to amide 7 in 92% yield, and reduction of the carboxylic acid moiety with LiAlH 4 delivered alcohol 8 in 82% yield. The a-uoro dihydrofuran 9 could be obtained in 40% yield via LiAlH 4 -mediated reduction and base-promoted deuorinative cyclization.
The reaction mechanism was then studied experimentally and computationally to shed light on the two attractive features of our protocol: the g-carboxylation complementary to the acarboxylation obtained by copper catalysis, 7b and the obviation of a sacricial anode. First, cyclic voltammetry (CV) analyses were conducted to investigate the electrochemical process on the cathode (Fig. 1).
For the CV of a-CF 3 styrene 1a, a one-electron reduction peak in the potential at À2.69 V and a second at À2.94 V was observed (green line), whereas at a potential of À2.69 V, the reduction current of CO 2 was less than 0.1 mA (blue line), indicating that 1a is easier to reduce than CO 2 . Aer the solution of 1a was saturated with CO 2 (pink line), only one reduction peak was observed at À2.81 V with an associated peak current increase from 0.21 to 0.36 mA (ca. 1.7 times). The inuence of potential on the reaction was further studied by constant potential electrolysis. When the reaction was conducted with cathode potential less than À2.70 V, the yield decreased gradually (Table  S7 in ESI †). These results suggested that an ECEC process might be involved, in which a radical anion that could react immediately with CO 2 might be generated aer the rst one-electron electroreduction, then the second electron transfer is facilitated at a less negative potential thus leading to a signicant increase in current observed. Accordingly, since a different species is being reduced in the presence of CO 2 , the second peak at À2.94 V is not observed. 21 Due to the higher stability of the tertiary alkyl radical, aer the rst one-electron electroreduction, carboxylation at the less substituted carbon of the alkene moiety should be favored.
To gain more evidence for the intermediacy of a radical anion, we subjected 1a to electrocarboxylation conditions in the presence of several known radical traps. Unfortunately, we were unable to trap the putative radical anion generated via the single-electron reduction or tertiary alkyl radical formed aer the addition of CO 2 . This might be because the radical Scheme 2 Synthetic elaboration of 2a. reduction and subsequent deuorination are favored under electroreduction conditions. However, the addition of 2.0 equivalents of TEMPO to the reaction in the absence of CO 2 led to the formation of TEMPO adduct 10, in 40% yield. Furthermore, when the reaction was conducted in the absence of TEMPO and CO 2 , the allylic radical dimerization product 11, was obtained in 33% yield (Scheme 3). These results suggested that the radical anion was involved during the reaction and that its deuorination produced the allylic radical.
Subsequently, density functional theory (DFT) calculations were performed as shown in Fig. 2. The results revealed that the reaction of CO 2 with radical anion I, generated via one-electron reduction of a-CF 3 alkene, was thermodynamically spontaneous with a low free-energy barrier of 8.4 kcal mol À1 . Deuorination or protonation of radical anion I had higher free energy barriers of 13.3 and 19.3 kcal mol À1 , respectively. These results are consistent with the experimental data and give a good explanation for the high regioselectivity and chemical selectivity of the reaction process.
To identify the sacricial reductant on the anode, we analyzed the reaction mixture of 1a with CO 2 directly without acidication, and detected a DMF-protected carboxylate 12 (Scheme 3). This result suggested that a Shono oxidation of DMF might occur. 22 Considering that water has a lower oxidation potential than DMF (1.23 and 1.9 V vs. SHE, respectively), 23 it was more likely to act as sacricial reductant. 14b Inspired by Chen's work, 24  Based on the above investigation of the mechanism, a putative reaction pathway was proposed, as shown in Fig. 3. Initially, a one-electron reduction of a-CF 3 alkene generated the corresponding radical anion I, which reacted immediately with CO 2 at the g-position to give tertiary alkyl radical II. The secondary, one-electron reduction was then followed by a deuorination process to form carboxylate anion V. Meanwhile, the oxidation of DMF or H 2 O occurred at the anode, delivering the imine cation or hydrogen cation, both of which can interact with carboxylate anion V to yield the protected carboxylates or deliver the carboxylic acids directly.

Conclusions
In summary, we have developed a regioselective electrochemical g-carboxylation of a-CF 3 alkenes using CO 2 in a user-friendly undivided cell under constant current conditions, without the sacrice of the anode. Both di-and trisubstituted a-CF 3 alkenes work well to afford structurally diverse vinylacetic acids bearing a gem-diuoroalkene moiety in acceptable yields under mild conditions, with good tolerance of functional groups. Notably, this protocol constitutes a rare example of using an electrochemical process to secure regioselectivity that differs from that of the metal-catalyzed process, suggesting the potential of the electrochemistry approach for divergent synthesis. The application of this atom-economical electrochemical method for the synthesis of a diverse range of uorine-containing carboxylic   acids from well-known greenhouse gases CO 2 and hydro-uorocarbons, 25 is now in progress.

Conflicts of interest
There are no conicts to declare.