Synthesis of Polyfluorobenzoic Acids By Regioselective Electrochemical Carboxylation of Polyfluoroarenes

Since carbon dioxide (CO₂) is an abundant, economical, nontoxic and environmentally benign C1 chemical reagent, fixation of carbon dioxide in organic molecules has recently become an attractive project in organic synthesis. An electrochemical method has contributed greatly to this area because it enables an efficient fixation of carbon dioxide in organic molecules even under atmospheric pressure of carbon dioxide when a reactive metal, such as magnesium or aluminum metal, is used as a sacrificial anode. There have been a number of reports on electrochemical fixation of carbon dioxide, and we have also reported synthesis of useful carboxylic acids by electrochemical carboxylation of various organic compounds. On the other hands, it is well known that fluorine-containing organic compounds have unique chemical and physical properties. The introduction of fluorine atoms into biologically-active compounds is also known to cause remarkable modification of their original activities. Therefore, considerable attention has been paid to efficient and selective preparation methods of organofluorine compounds. However, little attention has been paid to electrochemical carboxylation to afford fluorinated carboxylic acids.^1-4 During the course of our continuous studies on the synthesis of useful carboxylic acids by electrochemical fixation of carbon dioxide,⁵ we recently found that electrochemical reduction of polyfluoroarenes in the presence of carbon dioxide resulted in a regioselective cleavage of a C-F bond of the phenyl ring followed by reaction with carbon dioxide to give the corresponding mono-carboxylated products, polyfluorobenzoic acids, in moderate to good yields.⁶ We report herein the results for synthesis of polyfluorobenzoic acids by regioselective electrochemical carboxylation of polyfluoroarenes.

First, we screened reaction conditions for electrochemical carboxylation of hexafluorobenzene (1a) as a substrate. When constant current electrolysis of 1a was carried out in DMF using a one-compartment cell equipped with a Pt cathode and an Mg anode with 3 F/mol of electricity in the presence of carbon dioxide, reductive cleavage of a C-F bond on the phenyl ring followed by reaction with carbon dioxide took place to give pentafluorobenzoic acid (2a). After reaction conditions screening, 2a could be obtained in 73% ¹⁹F NMR yield by electrolysis of 1a at –40°C with 5 mA/cm² of current density. After recrystallization with hexane and acetone, pentafluorobenzoic acid (2a) was obtained in 65% isolated yield as a pure product.

We next investigated similar electrochemical carboxylations of several polyfluoroarenes, and the results are shown in Scheme. When pentafluorobenzene (1b) was subjected to the present electrochemical carboxylation under the same conditions for the reaction of 1a, C-F bond cleavage followed by carboxylation also took place efficiently to give 2,3,5,6-tetrafluorobenzoic acid (2b) in 78% ¹⁹F NMR yield and 66% isolated yield after recrystallization. It is noteworthy that C-F bond cleavage followed by carboxylation of 1b occurred at the C3 position of 1b predominantly to give 2b as a major product. Similar regioselective electrochemical carboxylation was also achieved when pentafluoroarenes 1c-f were used as substrates. Under the same conditions except for 1d, electrochemical carboxylation of 1c-f gave 4-substituted-2,3,5,6-tetrafluorobenzoic acids 2c-f in 61-84% ¹⁹F NMR yields and 49-76% isolated yields after recrystallization. It is also to note that C-F bond cleavage occurred at the para position of the substituents of Me-, AcO-, Me(RO)₂C-, and MeS- in pentafluoroethylarenes 1c-f predominantly in all cases to give 4-substituted-2,3,5,6-tetrafluorobenzoic acids 2c-f as major products.

<Scheme>

Other results of electrochemical carboxylation of polyfluoroarenes and proposed reaction mechanism including regioselectivity of the carboxylation will be presented.

References:

1. O. Sock, M. Troupel, J. Périchon, Tetrahedron Lett. 1985, 26, 1509.

2. M. Heintz, O. Sock, C. Saboureau, J. Périchon, Tetrahedron 1988, 44, 1631.

3. C. Saboureau, M. Troupel, S.  Sibille, J.  Périchon , J. Chem. Soc., Chem. Commun. 1989, 1138.

4. E. Chiozza, M. Desigaud, J. Greiner, E. Dunach, Tetrahedron Lett. 1998, 39, 4831.

5. (a) Y. Yamauchi, T. Fukuhara, S. Hara, H. Senboku, Synlett 2008, 438; (b) Y. Yamauchi, K. Sakai, T. Fukuhara, S. Hara, H. Senboku, Synthesis 2009, 3375; (c) Y. Yamauchi, S. Hara, H. Senboku, Tetrahedron 2010, 66, 473; (d) M. Ohkoshi, J. Michinishi, S. Hara, H. Senboku, Tetrahedron, 2010, 66, 7732; (e) H. Senboku, J. Michinishi, S. Hara, Synlett, 2011, 1567; (f) H. Senboku, Y. Yamauchi, N. Kobayashi, A. Fukui, S. Hara, Electrochemistry 2011, 79, 862; (g) H. Senboku, Y. Yamauchi, N. Kobayashi, A. Fukui, S. Hara, Electrochim. Acta 2012, 82, 450.

6. H. Senboku, K. Yoneda, S. Hara, Electrochemistry 2013, 81, 380.