Electrochemical reduction of organic compounds in the presence of carbon dioxide results in fixation of carbon dioxide with a carbon-carbon bond-forming reaction to give carboxylic acids.1,2 Carbon dioxide is an abundant, non-toxic, and inexpensive C1 carbon source for organic synthesis. From the viewpoint of recycling and reuse of carbon resources, the use of carbon dioxide for organic synthesis as a carbon source is an important and attractive project.3–5 However, it is also known that carbon dioxide is basically a stable and unreactive molecule, and highly nucleophilic organolithium or Grignard reagents are necessary for reaction with carbon dioxide to yield carboxylic acids by classical conventional methods. Electroorganic synthesis has recently been re-recognized as an environmentally benign organic synthesis from the viewpoint of green and sustainable chemistry. Electrochemical carboxylation, which involves the use of carbon dioxide and an electrochemical protocol, is a promising green and sustainable synthetic method for carboxylic acids. Recently, much attention has been paid to electrochemical carboxylation, and various organic compounds have been successfully applied to electrochemical carboxylation for synthesizing various types of carboxylic acids.1,2,6–17 Electrochemical carboxylation of benzylic halides yielding arylacetic acids including 2-arylpropanoic acids is a classical and representative example.18–20 It is well known that electrochemical carboxylation of benzylic halides occurs efficiently when electrolysis is carried out using an undivided cell and a sacrificial anode such as magnesium or aluminum.18,19,21,22 This electrochemical process has been successfully applied to the synthesis of non-steroidal anti-inflammatory agents (NSAIDs) having a 2-arylpropanoic acid skeleton such as ibuprofen and naproxen.18,19 It was also reported that esters,23 ethers,23 carbonates,23,24 sulfones,23,25,26 and trialkyl ammonium salts23,27 instead of halogens at the benzylic position were also applicable to electrochemical carboxylation as leaving groups, and these substrates were successfully converted into the corresponding arylacetic acids including NSAIDs by electrochemical carboxylation (Eq. 1 in Scheme 1). In contrast, electrochemical carboxylation of benzyl alcohols including 1-phenylethanol has been reported to proceed efficiently only when benzyl alcohols such as 1a having an electron-withdrawing group such as a methoxycarbonyl or cyano group at the ortho- or para-position on the phenyl ring are used.28 It was also reported that electrochemical carboxylation of benzyl alcohol 1b in DMF only gave a trace amount of phenylacetic acid 2b (Eq. 2 in Scheme 1).28
In conventional chemical transformations, there are several synthetic routes from benzyl alcohols to arylacetic acids as shown in Scheme 2. A representative transformation is hydrolysis of benzyl cyanides, which are generally prepared by transformation of a hydroxyl group to an appropriate leaving group followed by reaction with hazardous cyanide ion.29 However, severe reaction conditions in hydrolysis of the resulting benzyl cyanides are problematic (Eq. 3 in Scheme 2). Reaction of Grignard reagents derived from benzyl halides, prepared from benzyl alcohols, with carbon dioxide is also a useful method for synthesis of arylacetic acids,30 though the use of Grignard reagents limits the tolerance of functional groups (Eq. 4 in Scheme 2). Direct transformation of benzyl alcohols or their esters to arylacetic acids in one step was achieved by using a transition metal catalyst such as palladium, rhodium or nickel and hazardous pressurized carbon monoxide as a carbon source of the carboxyl group,31–33 although a high reaction temperature and strong acid and/or halide salts as reaction promoter were necessary (Eq. 5 in Scheme 2).
As shown in Eq. 2 in Scheme 1, we previously reported that electrochemical carboxylation of benzyl alcohols took place efficiently only when benzyl alcohol had an electron-withdrawing group on the phenyl ring.28 During our studies on electrochemical carboxylation, we recently found that electrochemical carboxylation of benzyl alcohols without any electron-withdrawing groups could also proceed by using constant current electrolysis in DMSO in the presence of carbon dioxide at rt to give arylacetic acids in moderate to good yields (Eq. 6 in Scheme 2). Although there have been several reports recently on synthesis of arylacetic acids from benzyl alcohols or their esters using carbon dioxide as a source of the carboxyl group,34–37 to the best of our knowledge, no example of direct substitution reaction of a hydroxyl group to a carboxyl group in benzyl alcohols without an electron-withdrawing group on the phenyl ring by an electrochemical method has been reported. Herein, we report the synthesis of arylacetic acid derivatives by electrochemical carboxylation of benzyl alcohols.
Screening of reaction conditions using 2-methylbenzyl alcohol (1c) as a substrate was carried out, and the results are summarized in Table 1. Electrochemical carboxylation of 2-methylbenzyl alcohol (1c) was firstly conducted under the reported optimized electrolysis conditions for electrochemical carboxylation of benzyl alcohols having an electron-withdrawing group on the phenyl ring.28 Electrolysis of 1c using an undivided cell equipped with a platinum plate cathode (2 × 2 cm2) and a magnesium rod anode (6 mmϕ) in DMF containing 0.1 mol dm−3 Bu4NBF4 in the presence of carbon dioxide under 20 mA cm−2 of constant current conditions with 6 F mol−1 of electricity at 0 °C gave 2-methylbenzoic acid (2c) only in 6 % yield as calculated from 1H NMR analysis (Entry 1). A similar result was obtained when electrolysis was carried out in DMF at rt (Entry 2). These results indicate that the reaction temperature is not affect the yield in the electrolysis in DMF. CH3CN and DMSO were used instead of DMF as solvents. While CH3CN gave a similar unacceptable result (Entry 3), electrolysis in DMSO as a solvent gave a better result at rt (ambient temperature) (Entry 4). Mixed solvents of DMSO with DMF or CH3CN were not effective for the carboxylation (Entries 5 and 6). Using DMSO as a solvent, the effects of current density and electricity were investigated. After several attempts as Entries 7–11 in Table 1, the best yield was obtained by electrolysis in the presence of carbon dioxide under 20 mA cm−2 of current density with 15 F mol−1 of electricity at rt to give 2-methylbenzoic acid (2c) in 40 % 1H NMR yield, and 2c could be isolated in 39 % yield after silica gel column chromatography (Entry 10). When electrolysis was carried out at rt, the temperature of the reaction mixture became 40 to 50 °C at the end of the electrolysis in every case due to generation of heat by electric resistance during the electrolysis.
Table 1.
Under the optimized electrolysis conditions in hand, the substrate scope was investigated. The details of the experiment are as follows. Benzyl alcohol (1, 1 mmol) in anhydrous DMSO (10 mL) containing 0.1 mol dm−3 Bu4NBF4 was electrolyzed in the presence of carbon dioxide at rt using an undivided cell equipped with a platinum plate cathode (2 × 2 cm2) and a magnesium rod anode (6 mmϕ) under the conditions shown in Scheme 3. After electrolysis, 1 mol dm−3 of hydrochloric acid (30 mL) was added to the electrolyzed solution, and then the mixture was extracted with EtOAc (20 mL × 3). Carboxylic acid 2 was extracted from the combined organic layer with saturated NaHCO3 (30 mL × 3) and the resulting aqueous solution was acidified with 3 mol dm−3 hydrochloric acid and then extracted with EtOAc (30 mL × 3). The combined solution was washed with H2O (100 mL × 1) and brine (100 mL × 1) and dried over MgSO4. Evaporation of the solvent gave carboxylic acid 2. In the case of 1b and 1e, pure carboxylic acids 2b and 2e were obtained without further purification. In the case of 1c and 1d, purification by column chromatography on silica gel was necessary to give pure carboxylic acid 2c and 2d.
When benzyl alcohol (1b) was subjected to the present electrochemical carboxylation with 6 F mol−1 of electricity, phenylacetic acid (2b) was obtained in 38 % yield. Under the reaction conditions for benzyl alcohols with an electron-withdrawing group on the phenyl ring reported by us, only a trace amount of 2b was produced by electrochemical carboxylation of 1b.28 In a manner similar to that for 2-methylbenzyl alcohol (1c), electrochemical carboxylation of 3-methoxybenzyl alcohol (1d) also gave the corresponding carboxylic acid 2d in 32 % isolated yield. Surprisingly, electrochemical carboxylation of benzhydrol (1e) proceeded more efficiently than the others to afford diphenylacetic acid (2e), which is a useful precursor of cannabinoid CB1 receptor ligands,38 in 81 % yield. These results indicated that the present electrochemical carboxylation of benzyl alcohol is a useful, convenient, and eco-friendly synthetic protocol for synthesis of arylacetic acids from benzyl alcohols, although the present scope is narrow and further investigations to improve the yield and efficiency are necessary.
One plausible reaction mechanism is shown in Scheme 4, although details including the solvent effect are still unclear at present. At the cathode, one-electron reduction of the hydroxyl group in benzyl alcohol generates hydrogen and benzyl alkoxide ion A, which reacts with carbon dioxide to produce benzyl carbonate ion B. Further two-electron reduction of the resulting benzyl carbonate ion B at the cathode generates benzyl anion C and carbonate ion D. We speculate that this step would be a rate-determining step. Benzyl anion C and carbon dioxide react by a carbon-carbon bond-forming reaction to produce the corresponding carboxylate ion E. At the anode, in contrast, dissolution of magnesium metal used as an anode takes place by electrochemical oxidation to generate magnesium ion. In the reaction medium, carboxylate ion E, carbonate ion D and magnesium ion form salts. Acid treatment in the workup gives carboxylic acid 2. Since competitive electrochemical reduction of carbon dioxide also takes place at the cathode to generate an anion radical of carbon dioxide, a large amount of electricity would be necessary for acceptable conversion and yield. Although the effect of the solvent, i.e., the exact role of DMSO, is still unclear, one possibility is that DMSO has a higher potential than that of DMF and CH3CN to dissolve the generated salts. Electrochemical reduction of benzyl carbonate ion B cannot proceed if benzyl carbonate ion B is precipitated in the reaction medium under the electrolysis conditions. Several kinds of salts, generated from carbonate D, carboxylate E, oxalate, and magnesium cation, would be formed during the electrolysis. Precipitation of them in the reaction medium can easily be checked by the naked eye in the second half of the electrolysis. While the exact solubility of each salt generated in situ in DMSO is unknown, dissolution of benzyl carbonate ion B would be essential for the generation of benzyl anion species C to produce carboxylate ion E. DMSO would be superior to DMF and CH3CN for dissolving salts that have formed including benzyl carbonate ion B under the electrolysis conditions. An increase of the conversion of 1b and the yield of 2b in electrochemical carboxylation of unsubstituted benzyl alcohol (1b) in DMSO compared to ones in DMF could be explained by these hypotheses. On the other hand, the effects of a substituent on the phenyl ring are also unclear at present. We reported that an electron-withdrawing group such as a methoxycarbonyl or cyano group at the ortho- or para-position on the phenyl ring of benzyl alcohols was effective in electrochemical carboxylation while one at the meta-position was ineffective.28 From these results, we thought that the location of an electron-withdrawing group on the phenyl ring of benzyl alcohols is critical, and that a resonance effect of an electron-withdrawing group on the phenyl ring might be contributed to an electron transfer process. Even though DMSO would be superior to DMF for dissolving the salts, a decrease in current efficiency of electrochemical carboxylation of benzyl alcohols having no electron-withdrawing group in DMSO supports this hypothesis. Investigation of other factors involved in the solvent effects is in progress.
In conclusion, we found that electrochemical reduction of benzyl alcohols in DMSO in the presence of carbon dioxide resulted in direct electrochemical substitution of a hydroxyl group by a carboxyl group at the benzylic position to give the corresponding arylacetic acids in moderate to good yields. This is the first example of electrochemical carboxylation of benzyl alcohols without an electron-withdrawing group on the phenyl ring. At the present stage, although the exact reaction mechanism including the effect of DMSO as a solvent is still unclear and sufficient wide scope is not indicated yet, the results indicate the potential for a useful, convenient, and eco-friendly synthetic method for arylacetic acids from benzyl alcohols. Further investigations to increase the substrate scope and improve the yields and efficiency are in progress.
