Electrochemical Carboxylation of α,α-Difluorotoluene Derivatives and Its Application to the Synthesis of α-Fluorinated Nonsteroidal Anti-Inflammatory Drugs

Yusuke Yamauchi; Tsuyoshi Fukuhara; Shoji Hara; Hisanori Senboku

doi:10.1055/s-2008-1032069

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Synlett 2008(3): 438-442
DOI: 10.1055/s-2008-1032069

LETTER

Electrochemical Carboxylation of α,α-Difluorotoluene Derivatives and Its Application to the Synthesis of α-Fluorinated Nonsteroidal Anti-Inflammatory Drugs

Yusuke Yamauchi, Tsuyoshi Fukuhara, Shoji Hara, Hisanori Senboku*
Laboratory of Organic Reaction, Division of Chemical Process Engineering, Graduate School of Engineering, Hokkaido University, Sapporo 060-8628, Japan
Fax: +81(11)7066555; e-Mail: senboku@eng.hokudai.ac.jp;

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Publication History

Received 12 November 2007
Publication Date:
23 January 2008 (online)

Abstract
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Abstract

Electrochemical carboxylation of α,α-difluorotoluene derivatives resulted in an efficient fixation of carbon dioxide to give the corresponding α-fluorophenylacetic acids in good yields, and this reaction was successfully applied to the synthesis of α-fluorinated nonsteroidal anti-inflammatory drugs (NSAIDs).

Key words

carboxylic acids - fluorine - magnesium - electrochemical carboxylation - NSAIDs

References and Notes

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26

The structures of compounds were determined by ¹H NMR, ¹³C NMR, and ¹⁹F NMR and HRMS. Spectral data are shown in ref. 33.

27

General Procedure for the Electrochemical Carboxylation of α,α-Difluoroethylarenes: A solution of difluoroethylarene (1.0 mmol) in DMF (10 mL) containing Bu₄NBF₄ (0.1 M) was electrolyzed at 0 °C with a constant current (15 mA/cm²) under an atmospheric pressure of bubbling carbon dioxide. An undivided cell equipped with a Pt plate cathode (2 × 2 cm²) and a Mg rod anode (φ 6 mm) was used for electrolysis. After an appropriate amount of electricity was passed (shown in schemes), the electrolyzed solution was poured into 1 M HCl (100 mL) and then extracted with Et₂O (3 × 30 mL). In the case of 15 and 16, 6 M HCl, instead of 1 M HCl, was used and the resulting mixture was stirred for 2 h at r.t. before extraction. The combined ethereal solution was washed with sat. NaHCO₃ (3 × 40 mL). The resulting aqueous solution was acidified with 3 M HCl, and then extracted with Et₂O (3 × 30 mL). The combined ethereal solution was washed with sat. brine and dried over MgSO₄. Evaporation of the solvent gave an almost pure 2-fluoro-2-arylpropanoic acid. Spectral data of the products were in good agreement with the data reported in ref. 21 in every respect, except for the new compound 21.

31

There would be some possible explanations for this overcarboxylation in EC of 14a although they are not fully examined at this stage. Since biphenyl is known to work as an electron-transfer mediator (see ref. 34), biphenyl moiety in the reaction medium is likely to work as an electron-transfer mediator to induce the over-reduction producing dicarboxylic acid 18. Similarly to the substrate 14a, products 17 and 18, which exist as a mixture of magnesium salts in the reaction medium, also have a biphenyl moiety that would work as a mediator.

33

4-(1,1-Difluoroethyl)isobutylbenzene (9): ¹H NMR (400 MHz, CDCl₃): δ = 0.90 (d, J = 6.6 Hz, 6 H), 1.80-2.08 (m, 1 H), 1.92 (t, J = 18.1 Hz, 3 H), 2.50 (d, J = 6.6 Hz, 2 H), 7.19 (d, J = 7.9 Hz, 2 H), 7.41 (d, J = 7.9 Hz, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 22.3, 25.9 (t, J = 30.0 Hz), 30.2, 45.1, 122.0 (t, J = 238.5 Hz), 124.4 (t, J = 6.0 Hz), 129.1, 135.6 (t, J = 26.7 Hz), 143.4 (t, J = 1.7 Hz). ¹⁹F NMR (372.5 MHz, CDCl₃): δ = -87.31 (q, J = 18.1 Hz, 2 F). HRMS (EI): m/z calcd for C₁₂H₁₆F₂: 198.1220; found: 198.1220.
2-Fluoro-4-(1,1-difluoroethyl)biphenyl (14a): ¹H NMR (400 MHz, CDCl₃): δ = 1.96 (t, J = 18.1 Hz, 3 H), 7.28-7.58 (m, 8 H). ¹³C NMR (100 MHz, CDCl₃): δ = 25.8 (d, J = 29.6 Hz), 112.9 (dt, J = 6.2, 25.3 Hz), 120.5-120.7 (m), 121.0 (dt, J = 1.9, 239.0 Hz), 128.1, 128.6, 129.0 (d, J = 3.1 Hz), 130.5 (dt, J = 1.7, 13.6 Hz), 131.0 (d, J = 3.8 Hz), 134.9 (d, J = 1.2 Hz), 159.4 (d, J = 248.9 Hz). ¹⁹F NMR (372.5 MHz, CDCl₃): δ = -117.33 (m, 1 F), -88.24 (q, J = 18.1 Hz, 2 F). HRMS (EI): m/z calcd for C₁₄H₁₁F₃: 236.0813; found: 236.0819.
3-(1,1-Difluoroethyl)diphenylether (14b): ¹H NMR (400 MHz, CDCl₃): δ = 1.90 (t, J = 18.2 Hz, 3 H), 6.96-7.46 (m, 9 H). ¹³C NMR (100 MHz, CDCl₃): δ = 25.9 (t, J = 29.8 Hz), 115.1 (t, J = 6.2 Hz), 119.1, 119.3 (t, J = 6.0 Hz), 119.7 (t, J = 1.7 Hz), 121.4 (t, J = 239.4 Hz), 123.7, 129.9, 129.9, 140.0 (t, J = 27.0 Hz), 156.6, 157.5. ¹⁹F NMR (372.5 MHz, CDCl₃): δ = -88.26 (q, J = 18.2 Hz, 2 F). HRMS (EI): m/z calcd for C₁₄H₁₂F₂O: 234.0856; found: 234.0857.
3-(1,1-Difluoroethyl)benzophenone (14c): ¹H NMR (400 MHz, CDCl₃): δ = 1.96 (t, J = 18.1 Hz, 3 H), 7.46-7.66 (m, 4 H), 7.72-7.77 (m, 1 H), 7.78-7.88 (m, 3 H), 7.96 (s, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 25.9 (t, J = 30.0 Hz), 121.4 (t, J = 239.4 Hz), 126.1 (t, J = 6.0 Hz), 128.4 (t, J = 5.8 Hz), 128.7, 130.0, 131.3 (t, J = 1.7 Hz), 137.1, 132.8, 137.9, 138.5 (t, J = 27.2 Hz), 195.9. ¹⁹F NMR (372.5 MHz, CDCl₃): δ = -88.37 (q, J = 18.1 Hz, 2 F). HRMS (EI): m/z calcd for C₁₅H₁₂F₂O: 246.0856; found: 246.0856.
2-[4-(1,1-Difluoroethyl)benzyl]cyclopentanone (14d): ¹H NMR (400 MHz, CDCl₃): δ = 1.47-1.61 (m, 1 H), 1.67-1.82 (m, 1 H), 1.90-2.02 (m, 1 H), 1.91 (t, J = 18.1 Hz, 3 H), 2.04-2.17 (m, 2 H), 2.30-2.42 (m, 2 H), 2.58 (dd, J = 9.5, 13.9 Hz, 1 H), 3.17 (dd, J = 4.0, 13.9 Hz, 1 H), 7.22 (d, J = 8.0 Hz, 2 H), 7.42 (d, J = 8.0 Hz, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 20.5, 25.8 (t, J = 30.1 Hz), 29.1, 35.2, 38.1, 50.8, 121.8 (t, J = 238.5 Hz), 124.7 (t, J = 6.0 Hz), 128.9, 136.1 (t, J = 26.7 Hz), 141.8 (t, J = 1.7 Hz), 219.8. ¹⁹F NMR (372.5 MHz, CDCl₃): δ = -87.57 (q, J = 18.1 Hz, 2 F). HRMS (EI): m/z calcd for C₁₄H₁₆F₂O: 238.1169; found: 238.1172.
2-[3-(1,1-Difluoroethyl)phenyl]-2-phenyl-1,3-dioxane (15): ¹H NMR (400 MHz, CDCl₃): δ = 1.68-1.98 (m, 2 H), 1.90 (t, J = 18.1 Hz, 3 H), 3.98-4.10 (m, 4 H), 7.23-7.29 (m, 1 H), 7.32-7.40 (m, 4 H), 7.50-7.58 (m, 3 H), 7.72 (s, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 25.5, 26.0 (t, J = 29.8 Hz), 61.6, 100.6, 121.8 (t, J = 239.2 Hz), 122.4 (t, J = 6.2 Hz), 124.0 (t, J = 6.0 Hz), 126.5, 127.7, 127.9, 128.6, 128.6, 138.3 (t, J = 26.7 Hz), 141.7, 143.4. ¹⁹F NMR (372.5 MHz, CDCl₃): δ = -87.95 (q, J = 18.1 Hz, 2 F). HRMS (EI): m/z calcd for C₁₈H₁₈F₂O₂: 304.1275; found: 304.1281.
1-[4-(1,1-Difluoroethyl)benzyl]-6,10-dioxaspiro[4.5]de-cane (16): ¹H NMR (400 MHz, CDCl₃): δ = 1.30-1.48 (m, 2 H), 1.52-1.75 (m, 3 H), 1.80-1.98 (m, 1 H), 1.91 (t, J = 18.2 Hz, 3 H), 1.90-2.13 (m, 2 H), 2.14-2.23 (m, 1 H), 2.47 (dd, J = 11.1, 13.5 Hz, 1 H), 3.04 (dd, J = 4.0, 13.5 Hz, 1 H), 3.86-4.04 (m, 4 H), 7.25 (d, J = 7.9 Hz, 2 H), 7.40 (d, J = 7.9 Hz, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 20.6, 25.8 (t, J = 29.8 Hz), 25.9, 28.2, 30.3, 34.4, 50.6, 60.6, 62.1, 108.3, 122.0 (t, J = 237.9 Hz), 124.4 (t, J = 6.0 Hz), 129.0, 135.4 (t, J = 26.9 Hz), 143.9 (t, J = 1.9 Hz). ¹⁹F NMR (372.5 MHz, CDCl₃)δ = -87.29 (q, J = 18.2 Hz, 2 F). HRMS (EI): m/z calcd for C₁₇H₂₂F₂O₂: 296.1588; found: 296.1580.
α-Fluoroloxoprofen (21): ¹H NMR (400 MHz, CDCl₃): δ = 1.51-1.58 (m, 1 H), 1.68-1.80 (m, 1 H), 1.90-2.03 (m, 1 H), 1.96 (d, J = 22.3 Hz, 3 H), 2.01-2.16 (m, 2 H), 2.30-2.39 (m, 2 H), 2.54 (dd, J = 9.5, 13.9 Hz, 1 H), 3.15 (dd, J = 4.1, 13.9 Hz, 1 H), 7.22 (d, J = 7.9 Hz, 2 H), 7.42 (d, J = 7.9 Hz, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 20.3, 24.2 (d, J = 23.9 Hz), 28.9, 34.9, 38.0, 50.8, 94.0 (d, J = 185.1 Hz), 124.8 (d, J = 8.5 Hz), 128.9, 136.4 (d, J = 22.8 Hz), 140.6, 174.9 (d, J = 28.3 Hz), 221.5. ¹⁹F NMR (372.5 MHz, CDCl₃): δ = -151.09 (q, J = 22.3 Hz, 1 F). HRMS (EI): m/z calcd for C₁₅H₁₇FO₃: 264.1162; found: 264.1162.