LETTER
Electrochemical Carboxylation of a,a-Difluorotoluene Derivatives
441
(16) Furuya, T.; Fukuhara, T.; Hara, S. J. Fluorine Chem. 2005,
126, 721.
(17) Schlosser, M.; Michel, D.; Guo, Z.-W.; Sih, C. J.
Tetrahedron 1996, 52, 8257.
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): d = –87.31 (q, J = 18.1 Hz, 2 F). HRMS (EI): m/z
calcd for C12H16F2: 198.1220; found: 198.1220.
(18) Goj, O.; Kotila, S.; Haufe, G. Tetrahedron 1996, 52, 12761.
(19) Rozen, S.; Hagooly, A.; Harduf, R. J. Org. Chem. 2001, 66,
7464.
(20) Laurent, E.; Marquet, B.; Roze, C.; Ventalon, F. J. Fluorine
Chem. 1998, 87, 215.
(21) Fujisawa, H.; Fujiwara, T.; Takeuchi, Y.; Omata, K. Chem.
Pharm. Bull. 2005, 53, 524.
(22) Bellezza, F.; Cipiciani, A.; Ricci, G.; Ruzziconi, R.
Tetrahedron 2005, 61, 8005.
(23) Takeuchi, Y.; Fujisawa, H.; Fujiwara, T.; Matsuura, M.;
Komatsu, H.; Ueno, S.; Matsuzaki, T. Chem. Pharm. Bull.
2005, 53, 1062.
(24) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 3769.
(25) Olah, G. A.; Nojima, M.; Kerekes, I. Synthesis 1973, 779.
(26) The structures of compounds were determined by 1H NMR,
13C NMR, and 19F NMR and HRMS. Spectral data are shown
in ref. 33.
2-Fluoro-4-(1,1-difluoroethyl)biphenyl (14a): 1H NMR
(400 MHz, CDCl3): d = 1.96 (t, J = 18.1 Hz, 3 H), 7.28–7.58
(m, 8 H). 13C NMR (100 MHz, CDCl3): d = 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):
d = –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): d = 1.90 (t, J = 18.2 Hz, 3 H), 6.96–7.46 (m,
9 H). 13C NMR (100 MHz, CDCl3): d = 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): d = –88.26 (q, J = 18.2 Hz, 2 F). HRMS (EI): m/z
calcd for C14H12F2O: 234.0856; found: 234.0857.
(27) General Procedure for the Electrochemical
Carboxylation of a,a-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 (f 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.
(28) Hiyama, T.; Wakasa, N.; Ueda, T.; Kusumoto, T. Bull.
Chem. Soc. Jpn. 1990, 63, 640.
(29) (a) Silvestri, G.; Gambino, S.; Filardo, G. Tetrahedron Lett.
1986, 27, 3429. (b) Mcharek, S.; Heintz, M.; Troupel, M.;
Périchon, J. Bull. Soc. Chim. Fr. 1989, 95. (c) Chan, A. S.
C.; Huang, T. T.; Wagenknecht, J. H.; Miller, R. E. J. Org.
Chem. 1995, 60, 742.
(30) Karimi, B.; Golshani, B. Synthesis 2002, 784.
(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.
3-(1,1-Difluoroethyl)benzophenone (14c): 1H NMR (400
MHz, CDCl3): d = 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): d = 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): d = –
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): d = 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): d = 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): d = –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): d = 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): d = 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): d = –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): d = 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): d = 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)d = –87.29 (q, J = 18.2 Hz, 2 F). HRMS (EI): m/z
calcd for C17H22F2O2: 296.1588; found: 296.1580.
(32) Terao, Y.; Ijima, Y.; Kakidani, H.; Ohta, H. Bull. Chem. Soc.
Jpn. 2003, 76, 2395.
(33) 4-(1,1-Difluoroethyl)isobutylbenzene (9): 1H NMR (400
MHz, CDCl3): d = 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): d = 22.3, 25.9 (t, J = 30.0 Hz), 30.2, 45.1,
a-Fluoroloxoprofen (21): 1H NMR (400 MHz, CDCl3): d =
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
Synlett 2008, No. 3, 438–442 © Thieme Stuttgart · New York