Synthesis of 2-aryl-2,3,3,3-tetrafluoropropanoic acids, tetrafluorinated fenoprofen and ketoprofen by electrochemical carboxylation of pentafluoroethylarenes

Article abstract of DOI:10.1055/S-0029-1216993

Synthesis of 2,3,3,3-tetrafluoro-2-(3-phenoxyphenyl)propanoic acid and 2-(3-benzoylphenyl)-2,3,3,3-tetrafluoropropanoic acid (tetrafluorinated fenoprofen and ketoprofen) was achieved by electrochemical carboxylation of pentafluoroethylarenes.

Full text of DOI:10.1055/S-0029-1216993

SHORT PAPER
3375
Synthesis of 2-Aryl-2,3,3,3-tetrafluoropropanoic Acids, Tetrafluorinated
Fenoprofen and Ketoprofen by Electrochemical Carboxylation of
Pentafluoroethylarenes
Electrochemical
C
u
arboxylation
s
of
P
entaf
u
luoroethylare
k
nes e Yamauchi, Kanae Sakai, 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
Received 14 May 2009; revised 6 July 2009
the previous EC of a,a-difluorotoluene derivatives, the
EC of pentafluoroethylarenes would be generally compli-
cated, because it is well known that b,b,b-trifluoroethyl
carbanion species would mostly release a fluoride ion
spontaneously to give difluoroalkenes.10 We report herein
the synthesis of tetrafluorinated fenoprofen and ketopro-
fen by EC of pentafluoroethylarenes. Although there are
several methods for synthesizing perfluoroalkanoic acids
by reaction with CO2,11 the synthesis reported here is the
first successful synthesis of tetrafluorinated NSAIDs.
Abstract: Synthesis of 2,3,3,3-tetrafluoro-2-(3-phenoxyphenyl)-
propanoic acid and 2-(3-benzoylphenyl)-2,3,3,3-tetrafluoropro-
panoic acid (tetrafluorinated fenoprofen and ketoprofen) was
achieved by electrochemical carboxylation of pentafluoroethyl-
arenes.
Key words: carboxylic acids, fluorine-containing compounds,
magnesium anode, electrochemical carboxylation, NSAIDs
Carbon dioxide (CO2) is a useful and important carbon re-
source that is not only abundant and economical but also
nontoxic and attractive as an environmentally benign C1
chemical reagent for organic synthesis.1 Electrochemical
carboxylation (EC) is a useful and efficient method for
fixation of CO2 into organic compounds with C–C bond
formation. The fixation can readily proceed in high yields
under quite mild conditions even under an atmospheric
pressure of CO2 when a reactive metal, such as magne-
sium or aluminum, is used as an anode.2,3 Various organic
compounds have already been carboxylated by using
these methods. On the other hand, it is well known that in-
corporation of fluorine atoms into biologically-active
molecules often causes remarkable modification of their
original activities.4 Fluorine-containing organic com-
pounds are also known to have unique chemical and phys-
ical properties. Therefore, considerable attention has been
paid to their efficient and selective preparation methods.5
Although the EC of organofluorine compounds would
provide fluorinated carboxylic acids, probably due to their
low reactivity, only a,a,a-trifluorotoluene6 and (perfluo-
roalkyl)alkenes with a nickel catalyst7 have been used as
substrates for the EC. We previously reported the efficient
EC of a,a-difluorotoluene derivatives to afford a-fluo-
rophenylacetic acids and its application to the synthesis of
a-fluorinated nonsteroidal anti-inflammatory drugs
(NSAIDs).8 During the course of our studies on EC to ob-
tain useful carboxylic acids,8,9 we recently found that elec-
trochemical fixation of CO2 is also effective for
pentafluoroethylarenes to give 2-aryltetrafluoropropanoic
acids, and the present EC was successfully applied to the
synthesis of two tetrafluorinated NSAIDs. In contrast to
Pentafluoroethylarenes 2 were prepared from the corre-
sponding aryl bromides 1a12a and 1b12b according to the
reported procedure.13 Thus, the reaction of 1 with sodium
pentafluoropropanoate in NMP in the presence of CuI at
170 °C for 22 hours gave pentafluoroethylarenes 2 in the
yields as shown in Scheme 1.
PhO
Br
PhO
CF2CF3
C2F5CO2Na, CuI
NMP, 170 °C, 22 h
1a
2a
65%
O
O
O
O
Br
CF2CF3
C2F5CO2Na, CuI
Ph
Ph
NMP, 170 °C, 22 h
1b
2b
71%
Scheme 1 Preparation of pentafluoroethylarenes 2
The EC of 2 was carried out with a constant current (15
mA/cm2) at 0 °C in DMF containing 0.1 M Bu4NBF4 un-
der an atmospheric pressure of CO2 by bubbling CO2
through the solution (Scheme 2). A one-compartment cell
F
CO2H
CF3
CO2
PhO
CF2CF3
Pt
Mg
,
PhO
0.1 M Bu4NBF4 in DMF
15 mA/cm2, 6 F/mol
0 °C
82%
2a
tetrafluorofenoprofen (3a)
O
Ph
O
O
F
CO2H
CF3
CO2
CF2CF3
Pt
Mg ,
Ph
0.1 M Bu4NBF4 in DMF
15 mA/cm2, 6 F/mol
0 °C
79%
tetrafluoroketoprofen (3b)
SYNTHESIS 2009, No. 20, pp 3375–3377
x
x.
x
x
.
2
0
0
9
2b
Advanced online publication: 08.09.2009
DOI: 10.1055/s-0029-1216993; Art ID: F10109SS
© Georg Thieme Verlag Stuttgart · New York
Scheme 2 Synthesis of 3 by EC of pentafluoroethylarenes 2

3376
Y. Yamauchi et al.
SHORT PAPER
equipped with a platinum plate cathode (2 × 2 cm2) and a
magnesium rod anode (Δ 6 mm) was used. Supplying ap-
propriate electricity followed by the usual workup gave 3.
spectra were determined using a JEOL JMS FAB-mate. All re-
agents and solvents were commercially available and were used as
received.
Pentafluoroethylarenes 2; General Procedure13
When 1-pentafluoroethyl-3-phenoxybenzene (2a) was
electrolyzed as mentioned above with 6 F/mol of electric-
ity, the reductive cleavage of the C–F bond followed by
carboxylation proceeded efficiently to afford 2,3,3,3-tet-
rafluoro-2-(3-phenoxyphenyl)propanoic acid (tetrafluo-
rofenoprofen, 3a) in 82% yield (Scheme 2). A similar EC
of 2b with 6 F/mol of electricity also gave 2-(3-ben-
zoylphenyl)-2,3,3,3-tetrafluoropropanoic acid (tetrafluo-
roketoprofen, 3b) in 79% yield, after treatment with 6 M
HCl in workup to reproduce the ketone moiety
(Scheme 2). On the other hand, unsatisfied results were
obtained in synthesis of other tetrafluorinated NSAIDs,
such as ibuprofen and loxoprofen.14
To a solution of aryl bromide 112 (10 mmol) in N-methylpyrrolidin-
2-one (30 mL) were added CuI (30 mmol) and sodium pentafluoro-
propanoate (30 mmol). After stirring at 170 °C for 22 h, the mixture
was poured into sat. aq NH4Cl (100 mL) and then extracted with
hexane (3 × 30 mL). The combined organic layer was washed with
H2O (3 × 30 mL), dried (MgSO4), and concentrated under reduced
pressure. The crude product was purified by column chromatogra-
phy on silica gel to give the respective pentafluoroethylarene 2.
1-Pentafluoroethyl-3-phenoxybenzene (2a)
Yield: 65%.
IR (neat): 1588, 1489, 1445, 1338, 1296, 1208, 1186, 1146, 1099,
1080, 1010 cm–1.
1H NMR (270 MHz, CDCl3): d = 7.03 (d, J = 5.4 Hz, 2 H), 7.16–
7.19 (m, 2 H), 7.24 (br s, 1 H), 7.32 (d, J = 5.4 Hz, 1 H), 7.36–7.40
(m, 2 H), 7.45 (t, J = 5.4 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 113.1 (tq, J = 255.0, 38.3 Hz),
119.0 (qt, J = 289.0, 40.5 Hz), 116.6 (t, J = 6.5 Hz), 119.4, 120.8 (t,
J = 6.5 Hz), 121.6, 124.2, 130.4, 130.2, 130.4 (t, J = 23.9 Hz),
156.2, 157.9.
19F NMR (376 MHz, CDCl3): d = –115.5 (br s, 2 F), –85.3 (br s,
3 F).
HRMS (EI): m/z [M]+ calcd for C14H9F5O: 228.0573; found:
288.0568.
A probable reaction pathway is shown in Scheme 3. Two-
electron reduction of the substrate 2 at cathode results in
reductive C–F bond cleavage at the benzylic position to
generate benzyl anion A as an intermediate. Competitive
reduction of CO2 would result in a decrease in the reduc-
tion efficiency. Benzyl anion A attacks CO2 to give car-
boxylate ion B. The capture of carboxylate ion B by
magnesium ion, which is generated by dissolution of the
magnesium anode, would give magnesium carboxylate.
Acid treatment in workup gives carboxylic acid 3.15
F
2-[3-(Pentafluoroethyl)phenyl]-2-phenyl-1,3-dioxolane (2b)
F
F
+ 2 e
– F
Yield: 71%.
R
R
CF3
CF3
IR (neat): 2893, 1490, 1450, 1338, 1302, 1206, 1145, 1089, 1018,
987, 957 cm–1.
2
A
1H NMR (270 MHz, CDCl3): d = 4.05–4.10 (m, 4 H), 7.30–7.38 (m,
3 H), 7.42–7.51 (m, 4 H), 7.68 (d, J = 7.7 Hz, 1 H), 7.83 (s, 1 H).
13C NMR (100 MHz, CDCl3): d = 65.0, 108.8, 113.4 (tq, J = 254.7,
38.3 Hz), 119.1 (qt, J = 286.8, 39.3 Hz), 124.0 (t, J = 6.3 Hz), 126.0,
126.1 (t, J = 6.3 Hz), 128.3, 128.4, 128.6 (t, J = 23.9 Hz), 128.7,
130.0, 141.4, 143.4.
F
CO2
CF3
F
CO2H
CF3
CO2
R
R
B
3
Scheme 3 A probable reaction pathway to tetrafluoropropanoic
19F NMR (376 MHz, CDCl3): d = –115.3 (br s, 2 F), –85.3 (br s,
3 F).
acids
HRMS (EI): m/z [M]+ calcd for C17H13F5O2: 344.0835; found:
344.0825.
In conclusion, we have succeeded in the first synthesis of
2,3,3,3-tetrafluoro-2-(3-phenoxyphenyl)propanoic acid
and
2-(3-benzoylphenyl)-2,3,3,3-tetrafluoropropanoic
2-Aryltetrafluoropropanoic Acids 3 by Electrochemical Car-
boxylation of Pentafluoroethylarenes 2; General Procedure
A solution of pentafluoroethylarene 2 (1.0 mmol) in anhyd 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
CO2 by bubbling CO2 through the solution. An undivided cell
equipped with a Pt plate cathode (2 × 2 cm2) and a Mg rod anode (Δ
6 mm) was used for the electrolysis. After an appropriate amount of
electricity had been passed (shown in Scheme 2), the electrolyzed
solution was poured into aq 1 M HCl (100 mL) and then extracted
with Et2O (3 × 30 mL). In the case of 1b, aq 6 M HCl instead of aq
1 M HCl, was used and the resulting mixture was stirred for 2 h at
r.t. before extraction. The combined ethereal extracts were washed
with aq sat. NaHCO3 (3 × 40 mL). The resulting aqueous solution
was acidified with aq 3 M HCl (150 mL) and then extracted with
Et2O (3 × 30 mL). The combined ethereal extracts were washed
with brine (3 × 30 mL) and dried (MgSO4). Evaporation of the sol-
vent gave an almost pure 2-aryl-2,3,3,3-tetrafluoropropanoic acid 3.
acid – tetrafluorinated analogues of NSAIDs, fenoprofen
and ketoprofen – by electrochemical reduction of the cor-
responding pentafluoroethylarenes in the presence of at-
mospheric pressure of CO2 using a Pt cathode and a Mg
anode. a-Fluorination of NSAIDs is known to result in the
modification of the balance of COX-1/COX-2 inhibi-
tions,17 and the resulting a-fluorinated NSAIDs show
some aniticancer activity.16 For these reasons, biological
activities of the prepared tetrafluorinated NSAIDs 3
would be potentially anticipated.
IR spectra were determined by neat form with a JASCO FT/IR-410
spectrometer. H (270 MHz), 13C (100 MHz), and 19F (376 MHz)
1
NMR spectra were recorded in CDCl3 on JEOL EX270 and A400II
FT NMR spectrometers. The chemical shifts (d) are given in ppm
with TMS (1H, 13C) and CFCl3 (19F) as references, respectively. MS
Synthesis 2009, No. 20, 3375–3377 © Thieme Stuttgart · New York

SHORT PAPER
Electrochemical Carboxylation of Pentafluoroethylarenes
3377
Tetrafluorofenoprofen (3a)
Yield: 82%.
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IR (neat): 3079, 2924, 1742, 1585, 1489, 1442, 1262, 1216, 1165,
1123, 1083, 1022, 995 cm–1.
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Acta 1997, 42, 2117. (b) Tokuda, M.; Yoshikawa, A.;
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Chem. 2001, 507, 82. (h) Senboku, H.; Kanaya, H.; Tokuda,
M. Synlett 2002, 140. (i) Chowdhury, M. A.; Senboku, H.;
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Electrochemistry 2006, 74, 612.
1H NMR (270 MHz, CDCl3): d = 7.01–7.03 (m, 2 H), 7.07–7.10 (m,
1 H), 7.13–7.17 (m, 1 H), 7.35–7.42 (m, 5 H).
13C NMR (100 MHz, CDCl3): d = 91.7 (dq, J = 204.0, 33.0 Hz),
116.0 (d, J = 10.3 Hz), 119.3, 120.0 (d, J = 9.0 Hz), 120.4, 121.0
(qd, J = 287.2, 29.4 Hz), 124.1, 130.0, 130.26 (d, J = 21.8 Hz),
130.30 (d, J = 1.9 Hz), 156.1, 157.9 (d, J = 1.9 Hz), 169.2 (d,
J = 25.1 Hz).
19F NMR (376 MHz, CDCl3): d = –77.7 (d, J = 7.6 Hz, 3 F), –172.9
(q, J = 7.6 Hz, 1 F).
HRMS (EI): m/z [M]+ calcd for C15H10F4O3: 314.0566; found:
314.0567.
Tetrafluoroketoprofen (3b)
Yield: 79%.
(10) Uneyama, K.; Katagiri, T.; Amii, H. Acc. Chem. Res. 2008,
IR (neat): 3069, 1760, 1662, 1598, 1577, 1448, 1283, 1203, 1002,
915 cm–1.
41, 817; and references cited therein.
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1H NMR (270 MHz, CDCl3): d = 7.47–7.65 (m, 4 H), 7.78–7.81 (m,
2 H), 7.90–7.95 (m, 2 H), 8.14 (s, 1 H).
13C NMR (100 MHz, CDCl3): d = 91.7 (dq, J = 202.6, 32.7 Hz),
121.0 (qd, J = 287.0, 29.1 Hz), 127.4 (d, J = 10.1 Hz), 128.5, 128.9,
129.7 (d, J = 9.1 Hz), 129.8 (d, J = 22.3 Hz), 130.2, 132.1, 133.2,
136.5, 137.8, 165.9 (d, J = 24.9 Hz), 196.6.
19F NMR (376 MHz, CDCl3): d = –77.7 (d, J = 7.8 Hz, 3 F), –173.4
(q, J = 7.8 Hz, 1 F).
HRMS (EI): m/z [M]+ calcd for C16H10F4O3: 326.0566; found:
326.0554.
Acknowledgment
(13) Carr, G. E.; Chambers, R. D.; Holmes, T. F.; Parker, D. G.
J. Chem. Soc., Perkin Trans. 1 1988, 921.
(14) The yield of tetrafluorinated ibuprofen and loxoprofen by
EC of the corresponding tetrafluoroethylarenes were 31%
and 32%, respectively, as determined by 19F NMR
spectroscopy.
This work was partly supported by The Akiyama Foundation. The
authors greatly acknowledge the financial support by the Global
COE Program (Project No. B01: Catalysis as the Basis for Innova-
tion in Materials Science) from the Ministry of Education, Culture,
Sports, Science and Technology, Japan.
(15) The low yields in the synthesis of tetrafluorinated ibuprofen
and loxoprofen are due to the elimination of a fluoride ion
from the intermediate A producing the corresponding
trifluorostyrenes,10,17 whose electrochemical reduction
followed by the fixation of CO2 would likely lead to several
carboxylic acids as by-products9a,f resulting in low yields of
the expected products.
(16) Takeuchi, Y.; Fujisawa, H.; Fujiwara, T.; Matsuura, M.;
Komatsu, H.; Ueno, S.; Matsuzaki, T. Chem. Pharm. Bull.
2005, 53, 1062.
(17) We independently prepared a,b,b-trifluoro-4-isobutyl-
styrene and confirmed its formation in the EC of 4-(penta-
fluoroethyl)isobutylbenzene by 19F NMR spectra of the
crude products. We also tried the EC of a,b,b-trifluoro-4-
isobutylstyrene under the same conditions as the EC of 4-
(pentafluoroethyl)isobutylbenzene and found that 19F NMR
spectra of the crude products closely resembled that of the
EC of 4-(pentafluoroethyl)isobutylbenzene. These results
indicated that similar products would be produced in both
reactions and a,b,b-trifluoro-4-isobutylstyrene would be
produced in the EC of 4-(pentafluoroethyl)isobutylbenzene.
Because both reactions were complicated and several
products were produced, isolation and identification of the
products could not be carried out.
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Synthesis 2009, No. 20, 3375–3377 © Thieme Stuttgart · New York