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Article

Synthesis of α-Chloroarylacetic Acid via Electrochemical Carboxylation of α,α-Dichloroarylmethane Derivatives

by
Corentin Maret
1,
Nicolas David
1,
David Pierrot
1,
Eric Léonel
2,
Vincent Levacher
1,
Jean-François Brière
1 and
Sylvain Oudeyer
1,*
1
Univ Rouen Normandie, INSA Rouen Normandie, CNRS, Normandie Univ, COBRA UMR 6014, INC3M FR 3038, F-76000 Rouen, France
2
Université Paris-Est Créteil, ICMPE (UMR 7182), CNRS, UPEC, F-94320 Thiais, France
*
Author to whom correspondence should be addressed.
Molecules 2023, 28(18), 6704; https://doi.org/10.3390/molecules28186704
Submission received: 31 August 2023 / Revised: 12 September 2023 / Accepted: 18 September 2023 / Published: 20 September 2023
(This article belongs to the Section Organic Chemistry)
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Versions Notes

Abstract

:
The electrocarboxylation of α,α-dichloroarylmethane derivatives in the presence of CO2 was achieved, providing several α-chloroarylacetic acid derivatives with modest yields but high selectivity (chlorinated vs. non-chlorinated or dicarboxylic acid products). The obtained products were then involved in several chemical transformations, underlining their potential as versatile intermediates in synthetic chemistry. A mechanism was also proposed based upon a control experiment and cyclic voltammetry (CV) study.

Graphical Abstract

1. Introduction

α-chlorophenylacetic acid derivatives 1 are versatile synthetic intermediates involved in the synthesis of several drugs such as (1) amides or thioureas derivatives 2 used in the treatment of diseases that are at least partially mediated by vanilloid receptors 1 (VR1/TRPV1 receptors) [1] or (2) M-14659 3, cephalosporin, obtained by semi-synthesis, exhibiting a broad spectrum of antibacterial activity (Scheme 1a) [2]. Therefore, several chemical methods were reported to have access to α-chlorophenylacetic acids (mainly oxidation of α-chloroaryl acetaldehydes [3] or chlorination of α-hydroxyarylacetic acid [4]) but none of them proved to be general (Scheme 1b). As far as electrochemical approaches are concerned, the electrocarboxylation reaction of α-chlorobenzyl derivatives has been extensively studied [5,6,7,8,9,10,11]. Contrariwise, the electrocarboxylation of α,α-dihalobenzyl species [12] and, more particularly, α,α-dichlorobenzyl species remains more elusive. To the best of our knowledge, only two articles from the group of Silvestri (one original article and a review) deal with the electrocarboxylation reaction of α,α-dichloroarylmethane derivatives 4 [13,14]. In addition to being limited to only one example (α-chlorophenylacetic acid 1a from α,α-dichlorophenylmethane 4a), the experimental conditions and the electrochemical set-up are not properly described (diaphragmless cell, Al anode, Zn cathode, DMF, n-Bu4NBr (0.1 M), 100 A.m−2, 1.87 F.mol−1), no isolated yield (52% vs. converted substrate) was given for 1a and no spectral data were provided. Moreover, the reaction proceeded with a poor selectivity (s), thus affording a 64/36 mixture of α-chlorophenylacetic 1a acid and phenylacetic acid 5a. Therefore, the selective reduction in one of the two benzylic geminal chlorine atoms remains a challenging task. Since the publication of these articles, electrosynthesis has undergone a rebirth, mainly during the last ten years, providing easily accessible and reproducible conditions for synthetic chemists [15,16,17,18,19,20]. We thus would like to report our contribution to the electrocarboxylation reaction of α,α-dichloroarylmethane 4 derivatives in order to provide an efficient and selective synthesis of α-chloroarylacetic acid derivatives 1 (Scheme 1c).

2. Results

2.1. Influence of Reaction Parameters

In order to investigate this transformation, we first turned our attention to the simple commercially available α,α-dichlorodiphenylmethane 4b as a substrate in order to study the main reaction parameters (For a complete study of the reaction parameters, see Supporting Information). For the purpose of clarity, we have used the selectivity value which consists of the percentage obtained by dividing the NMR yield of the desired α-chlorophenylacetic acid methyl ester 6b (obtained after an esterification step with trimethylsilyl diazomethane) by the sum of the NMR yields of 6b and the over-reduced product 7b. Starting from the aluminum anode as reported by Silvestri et al. [13] but in acetonitrile as a solvent instead of DMF, we have obtained a 66/34 mixture of α-chlorodiphenylacetic methyl ester 6b and the over-reduced diphenylacetic methyl ester 7b (s = 66%) in low (23% and 12%) NMR yields, respectively (Table 1, entry 1). As we were aware of the crucial role of the consumable anode in this type of reaction [21,22,23,24], we then examined the nature of this metallic electrode (Table 1, entries 2–4). Other metals such Co, Zn or Mg provided lower NMR yields, along with a significant amount of diphenylacetic methyl ester 7b. Whereas in THF no reaction occurred (Table 1, entry 5), other aprotic polar solvents such as DMF and DMA (Table 1, entries 6 and 7) allow the reaction to proceed in 17% and 42% NMR yields, respectively, of 6b, along with non-negligible amounts of 7b (11% and 20% NMR yields, respectively). DMA was thus chosen as the solvent to study the influence of the cathode on the reaction performances (Table 1, entries 8–11). Among all cathodes tested, only stainless steel (SS) improved the NMR yield of 6b to 54%, while reducing the NMR yield of 7b to only 5% (s = 91%). As long as the charge is concerned, a 1.8 F/mol charge resulted in the complete selectivity of 6b (s > 99%, only traces of 7b), but at the expense of a lower, 33%, NMR yield (Table 1, entry 12), whereas a 3.2 F/mol charge provided a higher amount of 7b (11% NMR yield) without improving the NMR yield of 6b (54%, Table 1, entry 13). Regarding the intensity of the electrolysis, higher or lower intensities (10 or 30 mA instead of 20 mA) did not improve the NMR yield of 6b (39% and 50%, respectively, Table 1, entries 14–15). Finally, the reduction in the concentration of 4b from 83 mM to 35 mM had a positive impact on both the NMR yield of 6b (55%) and the selectivity, delivering only a 5% NMR yield of 7b (s > 92%). Under these conditions, a Faraday efficiency of 36.2% was calculated (see Supplementary Materials for calculations detail). In conclusion, after a careful study of the reaction parameters, we have found that the nature of the cathode, the solvent and the concentration has a major influence on the reaction, improving the results obtained by Silvestri [13] for compound 1a in terms of the yield and selectivity.

2.2. Scope and Limitations

With these optimal conditions in hand, we then moved to the study of the scope and limitations of our methodology. Since only a few α,α-dichloroarylmethane derivatives 4 are commercially available, we put some efforts in their synthesis. By using conditions reported by Hegarty et al. starting from commercially available aromatic aldehydes 8 (PCl5, toluene, rt; see Section 3 below and Supplementary Materials for more details) [25], we were able to obtain several α,α-dichloroarylmethane derivatives 4. Next, the scope and limitations of the electrochemical carboxylation reaction were studied (Scheme 2).
Generally speaking, even if a complete conversion was observed, modest yields of around 50% were obtained, but a high selectivity (Cl (1 or 6) vs. H (5 or 7) and/or dicarboxylated product (8 or 9)) were observed (s = 60–96%). Regarding the modulation of the Ar part, electron-withdrawing or -donating groups can be introduced, with electro-donating groups providing higher isolated yields (1e, 37% vs. 1i, 55%) and selectivities (1e, s = 60% vs. 1i, s = 78%). Fluoride and bromine at the para position are also well-tolerated (1d, 53% and 1g, 48%, respectively). The introduction of a methyl substituent at the para or ortho position afforded the desired product in acceptable yields (1c, 54% and 1j, 48%), whereas a methyl at the meta position resulted in a drop of the yield to 36% for compound 1h. As far as the methyl substituent is concerned, an ortho substitution gave a lower selectivity than a meta and para substitution (s = 63% for 1j vs. s = 90 and 86% for 1c and 1h, respectively). The phenyl group at the para position provided the desired product in a low yield and modest selectivity (1f, 32%, s = 67%). It is worthy of note that during the silica gel purification of 1l, the chlorine atom was substituted by a methoxy group due to the presence of methanol in the mobile phase, affording compound 10 in a 24% isolated yield. We have also tried to vary the R1 substituent. Accordingly, a phenyl can be introduced, affording a decent 48% yield and excellent selectivity (s = 96%) for compound 6b. Starting from α,α,α-trichlorotoluene, methyl ester 6k bearing a gem-dichloro group was successfully obtained in a modest 23% yield but a good level of selectivity (s = 81%). However, some products remain problematic with otherwise improved methodology. In the case of thiophene derivatives, a complex mixture was obtained, whereas the formation of the product with an N-Ts indole moiety was not observed. Finally, compound 1m was formed but as an inseparable mixture with 5m (25% NMR yield, s = 45%).

2.3. Versatile Transformations of the α-Chlorophenylacetic Acid 1a

In order to demonstrate the synthetic utility of the α-chloroarylacetic acids, we have turned our attention to several chemical transformations (Scheme 3).
First, the acid moiety was submitted to an amidation reaction via the corresponding acid chloride in the presence of benzyl amide, affording the amide derivatives 11 in 59%. An esterification was also possible by using trimethylsilyldazomethane in a mixture of toluene and methanol to give the chlorinated ester 6a in almost quantitative yields. More interestingly, the chlorine atom of 6a can be submitted to nucleophilic substitution in the presence of sodium azide under liquid/liquid phase-transfer conditions, leading to 12 in an excellent yield. The product 12 is of particular interest as it paves the way to the access of non-proteogenic α-amino acid derivatives [26,27].

2.4. Mechanistic Considerations

Finally, control experiments and CV analyses were performed to gain insight into the mechanism (Scheme 4). We first checked whether the reaction proceeded exclusively under electrochemical conditions by performing the reaction without a current for 1.5 h. No product was detected by an NMR analysis of the crude mixture (Scheme 4a). Then, the reaction was performed at 20 mA for 36 min (1.8 F/mol) and, then, the mixture was stirred for one additional hour without a current. The result was almost identical to that obtained when the reaction was stopped after the 1.8 F/mol electrolysis (see also Table 1, entry 12), indicating that the presence of Al3+ presumably formed at the anode during electrolysis is not involved in the reaction.
According to previous reports [13,14] and our own study (see Supplementary Materials for CV experiments) ((a) The reduction potential of PhCHCl2 in DMA (Ered = −2.2 V/SCE) was found to be similar to previously reported value in DMF, see ref [28] and supporting information. (b) Our attempts to determine the reduction potential of CO2 in DMA failed (see supporting information). (c) Our attempts to clarify the exact role of the Al3+ by CV have not been conclusive (see Supporting Information)), we have proposed a plausible mechanism (Scheme 4b). First, the α,α-dichloroarylmethane derivatives PhRCCl2 4 would be reduced at the cathode (Ered = −2.2 V/SCE for R = H and Ered = −1.8 V/SCE for R = Ph in DMF) [28] thanks to a two electron process to provide the corresponding α-chloro anion A which then would add to CO2 (Ered = −2.2 V/SCE in DMF) [29] to give the α-chlorophenylacetic carboxylate B flanked by an aluminum counter-ion. Simultaneously, the aluminum anode plate would be oxidized to afford the corresponding aluminum (III) cation in solution. This aluminum counter-ion is expected to stabilize the carboxylate anion generated during the electrolysis which is generally unstable under the electrochemical conditions [7] and also to avoid its possible transformation into mandelic acid [13]. Finally, the expected product 1 would be obtained after aqueous work-up. The by-product 5 could be obtained by the further reduction in B at the cathode followed by aqueous work-up. Nevertheless, due the close proximity between the reduction potential of CO2 and that of some of the α,α-dichloroarylmethane derivatives 4, a mechanism first involving the reduction in CO2 to form the corresponding radical anion followed by the radical coupling with 4• (resulting from the one electron reduction in 4 at the cathode) cannot totally be ruled out (Scheme 4c).

3. Materials and Methods

3.1. General Information

Reactions were performed using oven dried glassware under an inert atmosphere of nitrogen. Unless otherwise noted, all reagent-grade chemicals and solvents were obtained from commercial suppliers and were used as received. Toluene was dried over an MBRAUN MB SPS-800 apparatus (MBRAUN inertgas-system gmbh, Garching, Germany). Reactions were monitored by thin-layer chromatography with silica gel 60 F254 pre-coated aluminum plates (0.25 mm). Visualization was performed under UV light, phosphomolybdic acid or KMnO4 oxidation. Chromatographic purification of compounds was achieved with 60 silica gel (40–63 μm). Melting points were measured on a WME Köfler hot-stage (Stuart SMP3) and are uncorrected (Barloworld Scientific France SAS, Nemours, France). Infrared spectra (IR) were recorded on a PerkinElmer Spectrum 100 Series FT-IR spectrometer. Liquids and solids were applied on the Single Reflection Attenuated Total Reflectance (ATR) Accessories (PerkinElmer, Wellesley, MA, USA). Data are reported in cm−1. 1H Spectra (300 MHz) and 13C NMR spectra (75 MHz) were recorded on a Bruker Advance 300 (Bruker, Billerica, MA, USA). Processing and analysis of the spectra were performed with the Topspin 3.6 software (Bruker, Billerica, MA, USA) on a PC workstation. Data appear in the following order: chemical shifts in ppm which were referenced to the internal solvent signal, number of protons, multiplicity (s, singlet; d, doublet; t, triplet; q, quadruplet; dd, doublet of doublet, ddd, doublet of doublet of doublet, dt, doublet of triplet; ddt, doublet of doublet of triplet, td, triplet of doublet; tdd, triplet of doublet of doublet; m, multiplet, ABq, AB system) and coupling constant J in Hertz. Accurate mass measurements (HRMS) were performed by the Mass Spectrometry Laboratory of the University of Rouen and were recorded with a Waters LCP 1er XR spectrometer (Waters, Milford, CT, USA). The electrosynthesis were carried out by means of IKAElectraSynth® 2.0 apparatus. Electrodes were all purchased from IKA® (IKA, Staufen, Germany). Cyclic Voltammetry (CV) measurements were carried out with an OrigaFlex® potentiostat/galvanostat by means of three electrodes (Origalys, Rilleux-la-Pape, France).

3.2. General Procedure for the Synthesis of α,α-Dichloro Benzyl Derivatives 4 [25]

To a dry 10 mL flask containing PCl5 (1.3 equiv), dry toluene (5 mL) was added the corresponding aldehyde (1 equiv) and the mixture was then stirred for 16 h. After completion, the reaction was diluted with 20 mL EtOAc and washed two times with 20 mL saturated NaHCO3 aqueous solution, then once with 10 mL brine. The organic layer was dried over MgSO4, filtered, and concentrated at 40 °C under 80 mbar pressure. The residue was purified by silica gel column chromatography (100/0 EP:EtOAc to 95/5) to obtain the corresponding α,α-dichloro aryl compounds 4. As mentioned by the authors and due their high reactivity, products 4 were generally used rapidly after their synthesis; 4a, 4j and 4k were commercially available and were used as received.
α,α-dichloro-4-methyltoluene 4c: Following the general procedure with 4-methylbenzaldehyde (300 mg, 2.5 mmol), the title compound 4c was obtained as a white solid (367 mg, 84%). 1H NMR (300 MHz, CDCl3) δ 7.49–7.46 (m, 2H, CHAr), 7.23–7.20 (m, 2H, CHAr), 6.70 (s, 1H, CH), 2.39 (s, 3H, CH3). 13C NMR (75 MHz, CDCl3) δ 140.3 (CAr), 137.8 (CAr), 129.6 (CHAr), 126.1 (CHAr), 72.0 (CH), 21.4 (CH3). The spectral data were in agreement with those previously reported [30].

3.3. General Procedure A for the Synthesis of α-Chloroarylacetic Acid Derivatives 1

In a dry electrochemical cell (10 mL vial from IKA) containing n-Bu4NBr (33 mg, 0.1 mmol) DMA (7 mL) was added and α,α-dichloro aryl derivates 4 (0.25 mmol) under nitrogen. The electrodes (aluminum electrode as anode and stainless steel as cathode) were installed, and carbon dioxide was bubbled through the solution for 5 min using a CO2 balloon. The reaction was carried out at room temperature for 48 min, with a constant current of 20 mA and a charge of 3.2 F.mol−1. After completion, the electrodes were rinsed subsequently with EtOAc, HCl 1M and then water. The reaction mixture was diluted with 15 mL of EtOAc and washed with 15 mL of HCl 0.5 M. The aqueous phase was washed a second time with 10 mL of EtOAc and then the combined organic extract was washed three times with 10 mL of HCl 0.5 M. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The NMR yield was measured by 1H NMR of crude by means of dimethyl terephthalate as internal standard (0.25 equiv, 12.2 mg). The residue was purified by silica gel column chromatography (5/25/70 MeOH:CH2Cl2:PE, then 1/20/79 HCOOH:Et2O:PE) to obtain the corresponding α-chloroarylacetic acid 1.

1 mmol Procedure

In a dry electrochemical cell (20 mL vial from IKA) containing n-Bu4NBr (110 mg, 0.34 mmol) DMA was added (16 mL) and α,α-dichlorotoluene 4a (126 mL, 1.00 mmol) under nitrogen. The electrodes (aluminum electrode as anode and stainless steel as cathode) were installed, and carbon dioxide was bubbled through the solution for 5 min using a CO2 balloon. The reaction was carried out at room temperature for 48 min, with a constant current of 20 mA and a charge of 3.2 F.mol−1. After completion, the electrodes were rinsed subsequently with EtOAc, HCl 1M and then water. The reaction mixture was diluted with 30 mL of EtOAc and washed with 30 mL of HCl 0.5 M. The aqueous phase was washed a second time with 20 mL of EtOAc and then the combined organic extract was washed three times with 20 mL of HCl 0.5 M. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5/25/70 MeOH:CH2Cl2:PE, then 1/20/79 HCOOH:Et2O:PE) to obtain the corresponding 2-chloro-2-phenylacetic acid 1a as a white solid (75 mg, 44%).
2-chloro-2-(4-methylphenyl)acetic acid 1c: Following the general procedure A with 4c (46 mg, 0.26 mmol), the title compound 1c was obtained as a white solid (26 mg, 54%). mp = 89–90 °C. 1H NMR (300 MHz, CDCl3) δ 10.55 (bs, 1H, CO2H), 7.40–7.38 (d, J = 8.2 Hz, 2H, CHAr), 7.21–7.19 (d, J = 8.2 Hz, 2H, CHAr), 5.35 (s, 1H, CH), 2.36 (s, 3H, CH3). 13C NMR (75 MHz, CDCl3) δ 174.3 (CO2H), 139.8 (CAr), 132.0 (CAr), 129.7 (CHAr), 127.9 (CHAr), 58.6 (CH), 21.3 (CH3). IR (neat) n 2323, 1721, 1512, 1412, 1286, 1201, 912, 804, 787 cm−1. HRMS (TOF-ESI−): calcd for C9H8Cl2O2 [(M-H)−]: 183.0218; found: 183.0206.

3.4. Synthesis of Methyl Methyl 2-Chloro-2-phenylacetate 6a

The 2-chloro-2-phenylacetic acid 1a (1.00 g, 5.86 mmol) was then dissolved in toluene/methanol mixture (10 mL, 7:3 v/v) and cooled to 0 °C. TMS diazomethane (2M in hexanes, 2.17 mL, 14.7 mmol) was then added until a yellow coloration persisted in the solution. The solution was then stirred for 30 min at 0 °C and then 30 min at r.t. The solution was then quenched with acetic acid (0.1 mL), MeOH was evaporated and the residual toluene solution was diluted with ethyl acetate. The organic phase was washed with HCl 1M and saturated with aqueous NaHCO3 solution and then water. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. Methyl 2-chloro-2-phenylacetate derivatives 6 (1.06 g, 5.74 mmol, 98%) was obtained as a transparent oil. 1H NMR (300 MHz, CDCl3) δ 7.51–7.48 (m, 2H, CHAr), 7.40–7.36 (m, 3H, CHAr), 5.37 (s, 1H, CH), 3.78 (s, 3H, CH3). Spectroscopic data were in agreement with those previously reported [31].

3.5. General Procedure B for the Synthesis of Methyl 2-Chloro-2-phenylacetate Derivatives 6b,k

In a dry electrochemical cell (10 mL vial from IKA) containing n-Bu4NBr (33 mg, 0.1 mmol), DMA was added (7 mL) and α,α-dichloro aryl derivates 4 (0.25 mmol) under nitrogen. The electrodes (aluminum electrode as anode and stainless steel as cathode) were installed, and carbon dioxide was bubbled through the solution for 5 min using a CO2 balloon. The reaction was carried out at room temperature for 48 min, with a constant current of 20 mA and a charge of 3.2 F.mol−1. After completion, the electrodes were rinsed subsequently with EtOAc, HCl 1M and then water. The reaction mixture was diluted with 15 mL of EtOAc and washed with 15 mL of HCl 0.5 M. The aqueous phase was washed a second time with 10 mL of EtOAc and then the combined organic extract was washed three times with 10 mL of HCl 0.5 M. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The crude mixture was then dissolved in toluene/methanol mixture (7:3 v/v) and cooled to 0 °C. TMS diazomethane was then added until a yellow coloration persisted in the solution. The solution was then stirred for 15 min at 0 °C and then 15 min at r.t. The solution was then quenched with acetic acid and extracted with ethyl acetate and washed with saturated aqueous NaHCO3 solution, HCl 1M and then water. The NMR yield was measured by 1H NMR of crude by means of dimethyl terephthalate as internal standard (0.25 equiv, 12.2 mg). The residue was purified by silica gel column chromatography (5/25/70 MeOH:CH2Cl2:PE, then 1/20/79 HCOOH:Et2O:PE) to obtain the corresponding methyl 2-chloro-2-phenylacetate derivatives 6.
Methyl 2-chloro-2,2-diphenylacetate 6b: Following the general procedure B with 4b (59 mg, 0.25 mmol), the title compound 6b was obtained as colorless oil (31 mg, 48%). 1H NMR (300 MHz, CDCl3) δ 7.42–7.26 (m, 10H, CHAr), 3.78 (s, 3H, CH3). Spectroscopic data were in agreement with those previously reported [32].

3.6. Procedure for the Synthesis of 2-Methoxy-2-(4-methoxyphenyl)acetic Acid 10

Compound 10 was obtained after a slight modification of the general procedure A. The crude product was dissolved in MeOH, SiO2 was added and the resulting mixture was stirred overnight at room temperature. After filtration and evaporation of MeOH, the resulting mixture was purified according to general procedure A. Starting from 1l (48 mg, 0.25 mmol), the title compound 10 was obtained as a white solid (12 mg, 24%). 1H NMR (300 MHz, CDCl3) δ 7.37–7.32 (m, 2H, CHAr), 6.93–6.88 (m, 2H, CHAr), 4.73 (s, 1H, CH), 3.81 (s, 3H, CH3), 3.39 (s, 3H, CH3). Spectroscopic data were in agreement with those previously reported [33].

3.7. Procedure for the Synthesis of N-Benzyl-2-chloro-2-phenylacetamide 11

Product 11 was synthesized following the procedure reported in the literature [34], as follows: oxalyl chloride (273 mL, 3.22 mmol, 1.1 equiv) and DMF (5 drops) were added to a 0 °C solution of 2-chloro-2-phenylacetic acid 1a (500 mg, 2.93 mmol, 1 equiv) in anhydrous CH2Cl2 (5 mL) in an oven-dried schlenk tube. The reaction mixture was allowed to warm to room temperature, stirring for 1 h. The solution was then transferred by cannula to a solution of benzyl amine (417 mL, 3.81 mmol, 1.3 equiv) and triethylamine (514 mL, 3.81 mmol, 1.3 equiv) in anhydrous CH2Cl2 (5 mL) at 0 °C. The suspension was stirred for 4 h and then the reaction was quenched by the addition of HCl (1 M). The reaction mixture was extracted with CH2Cl2 (25 mL × 3) and the combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The residue was purified by flash chromatography (hexane/dichloromethane = 2/1) which furnished the desired product (450 mg, 59%) as white solid. 1H NMR (300 MHz, CDCl3) δ δ 7.46–7.27 (m, 10H, CHAr), 7,00 (br s, 1H, NH) 5.43 (s, 1H, CH), 4.52 (d, 3J = 5.8 Hz, 2H, CH2). Spectroscopic data were in agreement with those previously reported [35].

3.8. Procedure for the Synthesis of Methyl 2-Azido-2-phenylacetate 12

The title product was synthesized according to a reported procedure [36], as follows: Methyl 2-chloro-2-phenylacetate 6a (194 mg, 1 mmol) was mixed with NaN3 (130 mg, 2 mmol) and tetrabutylammonium hydrogensulfate (50 mg, 0.15 equiv) in a mixture of water (1 mL) and chloroform (1 mL). The reaction was allowed to stir at room temperature for 24 h in the dark, after which time the aqueous layer was removed and the organic layer was washed with water (3 × 10 mL) and dried over sodium sulfate. The solvent was removed carefully by rotary evaporation under reduced pressure without heating. The title compound 12 was obtained as a colorless oil (191 mg, 99%). 1H NMR (300 MHz, CDCl3) δ 7.41–7.37 (m, 5H, CHAr), 4.99 (s, 1H, CH), 3.76 (s, 3H, CH3). Spectroscopic data were in agreement with those previously reported [37].

4. Conclusions

In conclusion, we have reported on an efficient and selective electrocarboxylation reaction of α,α-dichlorobenzyl compounds 4 to afford the corresponding α-chloroaryl acetic acid derivatives 1 with moderate isolated yields but high selectivity (the other chlorine atom is not affected by the reduction process). Several α-chloroaryl acetic acid derivatives with different substitution patterns, both on the methylene carbon at the benzylic position and the aromatic ring, were obtained. Moreover, we have demonstrated the versatility of the obtained products by modulating either the carboxylic acid part (ester or amide formation) or the chlorine atom (introduction of an azide moiety en route to the synthesis of non-proteogenic α-amino acids). Finally, thanks to control experiments and a cyclic voltammetry study, a plausible mechanism was proposed.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules28186704/s1; complete study of reaction parameters, cyclic voltammetry analyses, faraday efficiency calculations, general procedure for the synthesis of all compounds, spectral data and copies of NMR for compounds 1a,c–j,l–m, 4c–j,l–m, 6a,b,k, 10, 11, 12. Refs. [38,39,40,41] are cited in Supplementary Materials.

Author Contributions

Conceptualization, S.O. and E.L.; methodology, C.M.; formal analysis, C.M. and N.D.; investigation, C.M., D.P. and N.D.; writing—original draft preparation, S.O.; writing—review and editing, S.O., J.-F.B., V.L. and E.L.; supervision, S.O. and J.-F.B.; project administration, S.O.; funding acquisition, S.O. All authors have read and agreed to the published version of the manuscript.

Funding

This work has been partially supported by University of Rouen Normandy, INSA Rouen Normandy, the Centre National de la Recherche Scientifique (CNRS), European Regional Development Fund (ERDF), Labex SynOrg (ANR-11-LABX-0029), Carnot Institute I2C, the graduate school for research XL-Chem (ANR-18-EURE-0020 XL CHEM). This work is part of the EFLUX project funded by the European Union through the European Regional Development Fund (ERDF).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data is contained within the article or Supplementary Materials.

Conflicts of Interest

The authors declare no conflict of interest.

Sample Availability

Not applicable.

References

  1. Frank, R.; Bahrenberg, G.; Christoph, T.; Schiene, K.; DeVry, J.; Damann, N.; Frormann, S.; Lesch, B.; Lee, J.; Kim, Y.-S.; et al. Preparation of Substituted Phenylamine Derivatives for Use as Vanilloid Receptor Ligands. PCT International Application WO2010/127856. 11 November 2010. [Google Scholar]
  2. Murakami, K.; Ohashi, M.; Matsunaga, A.; Yamamoto, I.; Nohira, H. Asymmetric transformation of a racemic α-(phthalimidooxy)arylacetic ester by a combination of preferential crystallization and simultaneous racemization. Chirality 1993, 5, 41–48. [Google Scholar] [CrossRef]
  3. Paraskevas, S.M.; Paraskevas, M.S. Chlorination and oxidation of some aldehydes by H2O2 and diphenic acid · CuCl2 complex. Catal. Commun. 2004, 5, 687–690. [Google Scholar] [CrossRef]
  4. Carnell, A.J.; Kirk, R.; Smith, M.; McKenna, S.; Lian, L.Y.; Gibson, R. Inhibition of human alpha-methylacyl CoA racemase (AMACR): A target for prostate cancer. ChemMedChem 2013, 8, 1643–1647. [Google Scholar] [CrossRef]
  5. Otero, M.D.; Batanero, B.; Barba, F. CO2 anion–radical in organic carboxylations. Tetrahedron Lett. 2006, 47, 2171–2173. [Google Scholar] [CrossRef]
  6. Murtaza, A.; Qamar, M.A.; Saleem, K.; Hardwick, T.; Zia Ul, H.; Shirinfar, B.; Ahmed, N. Renewable Electricity Enables Green Routes to Fine Chemicals and Pharmaceuticals. Chem. Rec. 2022, 22, e202100296. [Google Scholar] [CrossRef] [PubMed]
  7. Senboku, H.; Katayama, A. Electrochemical carboxylation with carbon dioxide. Curr. Opin. Green Sustain. Chem. 2017, 3, 50–54. [Google Scholar] [CrossRef]
  8. De Sarkar, S.; Maiti, D.; Halder, A.; Mahanty, K. Recent Developments in the Electroreductive Functionalization of Carbon–Halogen Bonds. Synthesis 2022, 55, 400–416. [Google Scholar] [CrossRef]
  9. Yu, Z.; Shi, M. Recent advances in the electrochemically mediated chemical transformation of carbon dioxide. Chem. Commun. 2022, 58, 13539–13555. [Google Scholar] [CrossRef]
  10. Wang, S.; Feng, T.; Wang, Y.; Qiu, Y. Recent Advances in Electrocarboxylation with CO2. Chem. Asian J. 2022, 17, e202200543. [Google Scholar] [CrossRef]
  11. Liu, X.-F.; Zhang, K.; Tao, L.; Lu, X.-B.; Zhang, W.-Z. Recent advances in electrochemical carboxylation reactions using carbon dioxide. Green Chem. Eng. 2022, 3, 125–137. [Google Scholar] [CrossRef]
  12. Xie, S.L.; Gao, X.T.; Wu, H.H.; Zhou, F.; Zhou, J. Direct Electrochemical Defluorinative Carboxylation of gem-Difluoroalkenes with Carbon Dioxide. Org. Lett. 2020, 22, 8424–8429. [Google Scholar] [CrossRef] [PubMed]
  13. Silvestri, G.; Gambino, S.; Filardo, G.; Greco, G.; Gulotta, A. Electrochemical carboxylation of benzal chloride. Tetrahedron Lett. 1984, 25, 4307–4308. [Google Scholar] [CrossRef]
  14. Silvestri, G.; Gambino, S.; Filardo, G.; Tiitta, M.; Sjöström, M.; Wold, S.; Berglind, R.; Karlsson, B. Use of Sacrificial Anodes in Synthetic Electrochemistry. Processes Involving Carbon Dioxide. Acta Chem. Scand. 1991, 45, 987–992. [Google Scholar] [CrossRef]
  15. Yan, M.; Kawamata, Y.; Baran, P.S. Synthetic Organic Electrochemical Methods since 2000: On the Verge of a Renaissance. Chem. Rev. 2017, 117, 13230–13319. [Google Scholar] [CrossRef]
  16. Meyer, T.H.; Choi, I.; Tian, C.; Ackermann, L. Powering the Future: How Can Electrochemistry Make a Difference in Organic Synthesis? Chem 2020, 6, 2484–2496. [Google Scholar] [CrossRef]
  17. Schotten, C.; Nicholls, T.P.; Bourne, R.A.; Kapur, N.; Nguyen, B.N.; Willans, C.E. Making electrochemistry easily accessible to the synthetic chemist. Green Chem. 2020, 22, 3358–3375. [Google Scholar] [CrossRef]
  18. Pollok, D.; Waldvogel, S.R. Electro-organic synthesis—A 21(st) century technique. Chem. Sci. 2020, 11, 12386–12400. [Google Scholar] [CrossRef]
  19. Zhu, C.; Ang, N.W.J.; Meyer, T.H.; Qiu, Y.; Ackermann, L. Organic Electrochemistry: Molecular Syntheses with Potential. ACS Cent. Sci. 2021, 7, 415–431. [Google Scholar] [CrossRef]
  20. Leech, M.C.; Lam, K. A practical guide to electrosynthesis. Nat. Rev. Chem. 2022, 6, 275–286. [Google Scholar] [CrossRef]
  21. Chaussard, J.; Folest, J.-C.; Nedelec, J.-Y.; Perichon, J.; Sibille, S.; Troupel, M. Use of Sacrificial Anodes in Electrochemical Functionalization of Organic Halides. Synthesis 1990, 369–381. [Google Scholar] [CrossRef]
  22. Oudeyer, S.; Léonel, E.; Paugam, J.P.; Nédélec, J.-Y. Copper-catalyzed electrosynthesis of 1-acyl-2,2-diphenylcyclopropanes and their behaviour in acidic medium. Tetrahedron 2003, 59, 1073–1081. [Google Scholar] [CrossRef]
  23. Oudeyer, S.; Léonel, E.; Paugam, J.P.; Nédélec, J.Y. Epoxide formation by indirect electroreductive coupling between aldehydes or ketones and activated gem-dichloro compounds. Synthesis 2004, 389–400. [Google Scholar] [CrossRef]
  24. Oudeyer, S.; Léonel, E.; Paugam, J.P.; Sulpice-Gaillet, C.; Nédélec, J.-Y. Formation of polysubstituted chlorocyclopropanes from electrophilic olefins and activated trichloromethyl compounds. Tetrahedron 2006, 62, 1583–1589. [Google Scholar] [CrossRef]
  25. Fergus, S.; Eustace, S.J.; Hegarty, A.F. Nitrile ylide dimerization: Investigation of the carbene reactivity of nitrile ylides. J. Org. Chem. 2004, 69, 4663–4669. [Google Scholar] [CrossRef]
  26. Rolla, F. Sodium borohydride reactions under phase-transfer conditions: Reduction of azides to amines. J. Org. Chem. 2002, 47, 4327–4329. [Google Scholar] [CrossRef]
  27. Green, J.E.; Bender, D.M.; Jackson, S.; O’Donnell, M.J.; McCarthy, J.R. Mitsunobu approach to the synthesis of optically active α,α-disubstituted amino acids. Org. Lett. 2009, 11, 807–810. [Google Scholar] [CrossRef]
  28. Sengmany, S.; Léonel, E.; Paugam, J.P.; Nédélec, J.Y. Cyclopropane formation by copper-catalyzed indirect electroreductive coupling of activated olefins and activated α,α,α-trichloro or gem-dichloro compounds. Synthesis 2002, 533–537. [Google Scholar] [CrossRef]
  29. Lamy, E.; Nadjo, L.; Saveant, J.M. Standard potential and kinetic parameters of the electrochemical reduction of carbon dioxide in dimethylformamide. J. Electroanal. Chem. 1977, 78, 403–407. [Google Scholar] [CrossRef]
  30. An, J.; Tang, X.; Moore, J.; Lewis, W.; Denton, R.M. Phosphorus(V)-catalyzed deoxydichlorination reactions of aldehydes. Tetrahedron 2013, 69, 8769–8776. [Google Scholar] [CrossRef]
  31. Kelly, B.D.; Lambert, T.H. Aromatic cation activation of alcohols: Conversion to alkyl chlorides using dichlorodiphenylcyclopropene. J. Am. Chem. Soc. 2009, 131, 13930–13931. [Google Scholar] [CrossRef]
  32. Timperley, C.M.; Bird, M.; Gore, S.J.; Lindsay, C.D.; Rice, H.; Tattersall, J.E.H.; Whitmore, C.L.; Green, A.C. 3-Quinuclidinyl-alpha-methoxydiphenylacetate: A multi-targeted ligand with antimuscarinic and antinicotinic effects designed for the treatment of anticholinesterase poisoning. Toxicol. Lett. 2020, 325, 67–76. [Google Scholar] [CrossRef] [PubMed]
  33. Li, G.; Dong, H.; Ma, Y.; Shao, K.; Li, Y.; Wu, X.; Wang, S.; Shao, Y.; Zhao, W. Structure-activity relationships study of neolamellarin A and its analogues as hypoxia inducible factor-1 (HIF-1) inhibitors. Bioorg. Med. Chem. Lett. 2019, 29, 2327–2331. [Google Scholar] [CrossRef] [PubMed]
  34. Li, B.; Aliyu, M.A.; Gao, Z.; Li, T.; Dong, W.; Li, J.; Shi, E.; Tang, W. General Synthesis of Chiral alpha,alpha-Diaryl Carboxamides by Enantioselective Palladium-Catalyzed Cross-Coupling. Org. Lett. 2020, 22, 4974–4978. [Google Scholar] [CrossRef] [PubMed]
  35. Stockhammer, L.; Weinzierl, D.; Bogl, T.; Waser, M. Enantioselective alpha-Chlorination Reactions of in Situ Generated C1 Ammonium Enolates under Base-Free Conditions. Org. Lett. 2021, 23, 6143–6147. [Google Scholar] [CrossRef]
  36. Golas, P.L.; Tsarevsky, N.V.; Matyjaszewski, K. Structure–Reactivity Correlation in “Click” Chemistry: Substituent Effect on Azide Reactivity. Macromol. Rapid Commun. 2008, 29, 1167–1171. [Google Scholar] [CrossRef]
  37. Munaretto, L.S.; Dos Santos, C.Y.; Gallo, R.D.C.; Okada, C.Y., Jr.; Deflon, V.M.; Jurberg, I.D. Visible-Light-Mediated Strategies to Assemble Alkyl 2-Carboxylate-2,3,3-Trisubstituted beta-Lactams and 5-Alkoxy-2,2,4-Trisubstituted Furan-3(2H)-ones Using Aryldiazoacetates and Aryldiazoketones. Org. Lett. 2021, 23, 9292–9296. [Google Scholar] [CrossRef]
  38. Léonel, E.; Paugam, J.-P.; Heintz, M.; Nédélec, J.-Y. A Simple and Efficient Procedure for the Preparation of Benzal Chlorides and Benzal Bromides. Synth. Commun. 1999, 29, 4015–4024. [Google Scholar] [CrossRef]
  39. Polat, E.; Cakici, M. Deoxygenative Chlorination of Aldehydes and Alcohols with Dichloromethyl Methyl Ether and TiCl4. Eur. J. Org. Chem. 2022, 2022, e202201106. [Google Scholar] [CrossRef]
  40. Zhao, Z.; Kulkarni, K.G.; Murphy, G.K. Synthesis of Aryldihalomethanes by Denitrogenative Dihalogenation of Benzaldehyde Hydrazones. Adv. Synth. Catal. 2017, 359, 2222–2228. [Google Scholar] [CrossRef]
  41. Tao, J.; Tran, R.; Murphy, G.K. Dihaloiodoarenes: α,α-dihalogenation of phenylacetate derivatives. J. Am. Chem. Soc. 2013, 135, 16312–16315. [Google Scholar] [CrossRef]
Molecules 28 06704 sch001
Scheme 1. General context of the project.
Scheme 1. General context of the project.
Molecules 28 06704 sch001
Molecules 28 06704 sch002
Scheme 2. Scope and limitations of the electrochemical carboxylation of α,α-dichloroarylmethane derivatives 4.
Scheme 2. Scope and limitations of the electrochemical carboxylation of α,α-dichloroarylmethane derivatives 4.
Molecules 28 06704 sch002
Molecules 28 06704 sch003
Scheme 3. Chemical transformations on α-chlorophenylacetic acid 1a. a (1) (COCl)2 (1.1 equiv), DMF (5 drops), CH2Cl2; (2) BnNH2 (1.3 equiv), Et3N (1.3 equiv), CH2Cl2. b TMSCHN2 (2.5 equiv), toluene/MeOH (7:3 v/v), 0 °C, rt. c NaN3 (2 equiv), n-Bu4NHSO4 (0.15 equiv), H2O/CHCl3 (1:1 v/v).
Scheme 3. Chemical transformations on α-chlorophenylacetic acid 1a. a (1) (COCl)2 (1.1 equiv), DMF (5 drops), CH2Cl2; (2) BnNH2 (1.3 equiv), Et3N (1.3 equiv), CH2Cl2. b TMSCHN2 (2.5 equiv), toluene/MeOH (7:3 v/v), 0 °C, rt. c NaN3 (2 equiv), n-Bu4NHSO4 (0.15 equiv), H2O/CHCl3 (1:1 v/v).
Molecules 28 06704 sch003
Molecules 28 06704 sch004
Scheme 4. Mechanistic considerations: (a) control experiments; (b) plausible mechanism; (c) alternative pathway. 1 1H NMR yield determined on the crude mixture by using dimethyl terephthalate as an internal standard.
Scheme 4. Mechanistic considerations: (a) control experiments; (b) plausible mechanism; (c) alternative pathway. 1 1H NMR yield determined on the crude mixture by using dimethyl terephthalate as an internal standard.
Molecules 28 06704 sch004
Table 1. Optimization of the reaction conditions.
Table 1. Optimization of the reaction conditions.
Molecules 28 06704 i001
EntryAnode/CathodeSolventConc. (mM)Charge (F/mol)i (mA)NMR Yield 6b/7b (%) 1Selectivity, s (%) 2
1Al/NiFoamACN832.62023/1266
2Co/NiFoamACN832.62013/1154
3Zn/NiFoamACN832.6204/736
4Mg/NiFoamACN832.6206/1726
5Al/NiFoamTHF832.620nr/--
6Al/NiFoamDMF832.62017/1161
7Al/NiFoamDMA832.62042/2068
8Al/Glassy CDMA832.62032/2655
9Al/GraphiteDMA832.62025/2451
10Al/NiDMA832.62036/1078
11Al/SSDMA832.62054/591
12Al/SSDMA831.82033/traces>99
13Al/SSDMA833.22054/1183
14Al/SSDMA832.61039/687
15Al/SSDMA832.63050/886
16Al/SSDMA1252.62029/781
17Al/SSDMA352.62055(48) 3/<5>92
1 NMR yields were determined on 1H NMR spectra of the crude product (after an esterification step with TMS diazomethane) in the presence of dimethyl terephthalate as an internal standard. 2 Selectivity (s) determined on crude mixture by 1H NMR using an internal standard, as follows: (NMR yield of 6b/(NMR yield of 6b + NMR yield 7b)) × 100. 3 Isolated yield. SS: stainless steel. nr: no reaction. Bold text indicates the parameter which has been modified.
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MDPI and ACS Style

Maret, C.; David, N.; Pierrot, D.; Léonel, E.; Levacher, V.; Brière, J.-F.; Oudeyer, S. Synthesis of α-Chloroarylacetic Acid via Electrochemical Carboxylation of α,α-Dichloroarylmethane Derivatives. Molecules 2023, 28, 6704. https://doi.org/10.3390/molecules28186704

AMA Style

Maret C, David N, Pierrot D, Léonel E, Levacher V, Brière J-F, Oudeyer S. Synthesis of α-Chloroarylacetic Acid via Electrochemical Carboxylation of α,α-Dichloroarylmethane Derivatives. Molecules. 2023; 28(18):6704. https://doi.org/10.3390/molecules28186704

Chicago/Turabian Style

Maret, Corentin, Nicolas David, David Pierrot, Eric Léonel, Vincent Levacher, Jean-François Brière, and Sylvain Oudeyer. 2023. "Synthesis of α-Chloroarylacetic Acid via Electrochemical Carboxylation of α,α-Dichloroarylmethane Derivatives" Molecules 28, no. 18: 6704. https://doi.org/10.3390/molecules28186704

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