Electrochemical partial fluorination of phenylacetic acids esters and 1-tetralone

Article abstract of DOI:10.1016/S0022-1139(03)00037-X

Anodic oxidation of some benzyl derivatives (phenylacetic acids esters) 1, and 1-tetralone 4, using ammonium fluorides or ammonium tetrafluoroborate as fluorine sources and supporting electrolytes and CH₂Cl₂ as solvent, allowed the i

Full text of DOI:10.1016/S0022-1139(03)00037-X

Journal of Fluorine Chemistry 121 (2003) 227–231
Electrochemical partial fluorination of phenylacetic acids esters
and 1-tetralone
Vasile Dinoiu*, Tsuyoshi Fukuhara, Kaori Miura, Norihiko Yoneda
Division of Molecular Chemistry, Graduate School of Engineering, Hokkaido University, Sapporo 060-8628, Japan
Received 17 July 2002; received in revised form 21 January 2003; accepted 30 January 2003
Abstract
Anodic oxidation of some benzyl derivatives (phenylacetic acids esters) 1, and 1-tetralone 4, using ammonium fluorides or ammonium
tetrafluoroborate as fluorine sources and supporting electrolytes and CH2Cl2 as solvent, allowed the introduction of a fluorine atom in the a
position of an electron withdrawing group via carbocation (C), (ECBECN mechanism).
# 2003 Elsevier Science B.V. All rights reserved.
Keywords: Electrochemical partial fluorination; Phenylacetic acids esters; Amine–HF complexes
1. Introduction
Continuing our efforts on the regioselective anodic
fluorination of organic compounds, we report in this
paper the anodic fluorination of benzyl derivatives 1 and
1-tetralone 4, using Et3NꢀnHF (n ¼ 3–5), Et4NꢀBF4 and
Et4NFꢀnHF (n ¼ 1–3) as fluorine sources. The influence
of the nature of fluorine sources and of the electrolytic
temperature on anodic oxidation of benzyl derivatives was
studied.
The selective fluorination of organic molecules has
attracted much interest because a number of partially fluori-
nated organic molecules are reported to show special che-
mical and physical properties and, in some cases, biological
activities [1–5].
Electrochemical partial fluorination (ECF) has become a
more attractive method by using as a fluorine source, HF
combined with an organic base [6].
The electrochemical partial fluorination of organic com-
pounds using Et3NꢀnHF (n ¼ 2–3) as a fluorine source and
supporting electrolyte has been developed in the last few
years [7]. Recently, a new electrolyte, Et3Nꢀ5HF, has been
found to be electrochemically highly stable and an excellent
agent for the electrochemical fluorination of aldehydes and
ketones to produce the corresponding acylfluorides and
alkylfluorides in good yields [8].
The mono- and difluorination of benzylic groups was
reported by Laurent et al. [9], using CH3CN as a solvent and
Et3Nꢀ3HF as fluorine source. This anodic fluorination
allowed the introduction of a fluorine atom in the a position
of an electron withdrawing group; by raising the potential of
working electrodes after the monofluorination step, gem-
difluorides can be directly prepared.
2. Results and discussion
The anodic fluorinations of phenylacetic acids esters 1
were investigated toward various fluorine agents and sup-
porting electrolytes in CH2Cl2 as electrolytic solvent
(Scheme 1) and the results are summarized in Table 1. It
was found that the anodic fluorination of 1 proceeds highly
regioselectively and the fluorine atom was exclusively intro-
duced at the a position to the ester group, giving the a-
monofluorinated esters 2. (Compounds 2b, and 2c, were
previously obtained by Laurent et al. [9], using CH3CN as
electrolytic solvent.)
A subsequent oxidation of fluorinated derivative 2b, using
Et4NFꢀ2HF as fluorine source and CH2Cl2 as solvent, yields
geminal difluoro compound 3 (obtained also by Laurent et al.
[9], in other anodic fluorination conditions), as shown in
Scheme 2.
* Corresponding author. Present address: Department of Organic
Chemistry, University ‘‘Politehnica’’ of Bucharest, Spl. Independentei
313, Bucharest 76202, Romania.
Monofluorination of ester 1a in the presence of Et3Nꢀ5HF
as fluorine source and supporting electrolyte gave the cor-
responding a-monofluorinated ester 2a in a low yield (17%),
E-mail address: vdinoiu@mmc.ro (V. Dinoiu).
0022-1139/03/$ – see front matter # 2003 Elsevier Science B.V. All rights reserved.
doi:10.1016/S0022-1139(03)00037-X

228
V. Dinoiu et al. / Journal of Fluorine Chemistry 121 (2003) 227–231
Scheme 1.
Scheme 2.
(Table 1, entry 1). Next, we investigated the anodic fluor-
ination of the benzylic derivative 1b, which contains a
para-methoxy group in the aromatic ring, toward various
fluorine sources (Table 1, entries 2–8). The anodic fluorina-
tion of ester 1b had been previously attempted in Et4NꢀBF4/
CH2Cl2 but no fluorine derivative was found and the sub-
strate was recovered (Table 1, entry 2). We re-examined
the fluorination of 1b in various fluorine sources and the
desired a-monofluorinated esters 2b were obtained (Table 1,
entries 3–12).
The influence of the nature of the fluorine sources on the
anodic fluorination of benzyl derivatives 1b at 0 8C was
studied (Table 1, entries 3–8). It was found that, Et4NFꢀ1HF,
Et4NFꢀ2HF and Et3Nꢀ3HF are good fluorine sources and
Table 1
Anodic fluorination of phenylacetic acids esters 1 and ethyl fluoro-[4-methoxyphenyl]acetic acid ester 2b
Entry
Compound
Electrolyte
Potential
V vs. Ag/Agþ
Charge passed
(F molꢁ1
Temperature (8C)
Time (h)
Product yielda
)
(%) 2 and 3
1
2
1a
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1c
1c
1d
2b
Et3Nꢀ5HF
Et4NꢀBF4
2.10
1.90
1.45
1.40
1.40
1.45
1.30
1.40
1.45
1.45
1.35
1.35
1.00
1.10
1.10
1.65
3.0
1.4
3.6
4.6
2.6
2.6
2.6
2.6
3.6
2.6
5.3
3.7
2.6
3.0
4.0
4.0
ꢁ46
RT
0
4.5
6
17
0c
3
Et4NFꢀHF
Et4NFꢀ2HF
Et4NFꢀ3HF
Et3Nꢀ3HF
Et3Nꢀ4HF
Et3Nꢀ5HF
Et4NFꢀ2HF
Et4NFꢀ2HF
Et4NFꢀ2HF
Et4NFꢀ2HF
Et4NFꢀ2HF
Et4NFꢀ2HF
Et4NFꢀ2HF
Et4NFꢀ2HF
4
54
60
34
61
8
Tracesb
50
50
44
57
63
62
50
46
4
0
6
5
0
4
6
0
3
7
0
4.5
3
8
0
9
ꢁ46
ꢁ15
ꢁ15
RT
0
6
10
11
12
13
14
15
16
3
8
4
3
RT
0
3.5
6.5
6
0
a Isolated yield.
b The substrate was recovered.

V. Dinoiu et al. / Journal of Fluorine Chemistry 121 (2003) 227–231
229
Scheme 4.
Scheme 3.
quent oxidation of (B) yielded the carbocation (C). Finally,
a-monofluorinated ester 2 was formed by the attack of the
fluoride ion toward (C).
support electrolytes for these reactions that produce the
corresponding a-monofluorinated esters 2b in good yields
(Table 1, entries 3, 4 and 6). Using Et3Nꢀ4HF and Et3Nꢀ5HF
gave low yields and the substrate was recovered (Table 1,
entries 7 and 8).
The study of the influence of electrolytic temperature on
the anodic fluorination of benzylic derivatives 1b in the
presence of Et4NFꢀ2HF as fluorine source and supporting
electrolyte (Table 1, entries 9–12) shows that similar results
were obtained at different temperatures. Good yields were
obtained when the substrates in anodic fluorination con-
tained two or three methoxy groups in aromatic ring (Table 1,
entries 13–15).
A subsequent anodic fluorination of monofluoro-ester 2b
yielded geminal difluoro compound 3, in the presence of
Et4NFꢀ2HF as fluorine source and CH2Cl2 as electrolytic
solvent in 46% yield (Table 1, entry 16).
An ECBECN (electrochemical–chemical–electrochemi-
cal–chemical) mechanism is widely accepted for that type
of electrochemical partial fluorination reactions [9,10], and
most likely the reactions in our study follow the same
pathway (Scheme 3).
Next, we turned our attention to the anodic fluorination of
1-tetralone (Scheme 4) in CH2Cl2 as solvent. Using
Et3Nꢀ5HF as fluorine source, and 0 8C as electrolytic tem-
perature, no fluorination occurred when the charge passed
was 2.1 F molꢁ1. Increasing the amount of electricity to
3.7 F molꢁ1, fluorination took place at the benzylic position
and monofluoro derivative 5 was obtained with 28% isolated
yield (Table 2, entry 2). A better yield was obtained when the
electrolyte temperature was ꢁ46 8C (Table 2, entry 3). The
anodic fluorination of 1-tetralone in the presence of
Et4NFꢀ2HF as supporting electrolyte and fluorinating agent,
in CH2Cl2 as electrolytic solvent, gave monofluoro product 5
with 65% yield when charge passed was 5.2 F molꢁ1
(Table 2, entry 6); the yield decreases to 18% when only
2.6 F molꢁ1 were used (Table 2, entry 5).
In summary, we have reported a selective electrochemical
fluorination of benzyl derivatives 1 and 1-tetralone 4, using
different fluoride supporting electrolytes such as Et3NꢀnHF
(n ¼ 3–5) and Et4NFꢀ2HF in CH2Cl2, which allowed the
introduction of a fluorine atom in benzyl position. The
highest yields were obtained when Et4NFꢀ2HF and
Et3Nꢀ3HF were used as fluorine sources in the ECF of
benzyl derivatives 1 and when Et4NFꢀ2HF and Et3Nꢀ5HF
were used in ECF of 1-tetralone 4.
The one-electron oxidation of the substrate 1 gave the
radical cation species (A), which was deprotonated by a
fluoride ion to afford the benzylic radical (B). The subse-
Table 2
Anodic fluorination of 1-tetralone
Entry
Substrate
Electrolyte
Anodic potential
V vs. Ag/Agþ
Charge passed
(F molꢁ1
)
Temperature (8C)
Product yielda (%) 5
1
2
3
4
5
6
4
4
4
4
4
4
Et3Nꢀ5HF
Et3Nꢀ5HF
Et3Nꢀ5HF
Et3Nꢀ4HF
Et4NFꢀ2HF
Et4NFꢀ2HF
2.0
2.0
2.0
2.1
2.1
2.1
2.1
3.7
3.8
3.7
2.6
5.2
0
0
–
28
56
35
18
65
ꢁ46
ꢁ46
ꢁ15
ꢁ15
a Isolated yield.

230
V. Dinoiu et al. / Journal of Fluorine Chemistry 121 (2003) 227–231
3. Experimental
3.1. General
7:1 mixture of hexane and ethyl acetate to give a colorless
oil.
1H NMR: 1.26 (t, J ¼ 7:3 Hz, 3H); 3.88 (s, 3H); 4.25
(q, J ¼ 7:3 Hz, 2H); 5.73 (d, J ¼ 48:2 Hz, 1H); 6.92 and
7.38 (2d, AB, J ¼ 8:5 Hz, 4H); 19F NMR: ꢁ12.88
(d, J ¼ 48:2 Hz, 1F); IR (neat, cmꢁ1) 1760 (nC¼O); MS
(m/z): 212 (Mþ þ Hþ). HRMS. Calcd. for C11H13FO3 (m/e):
212.0849; Found: 212.0832.
Ethyl fluoro-[3,4-dimethoxyphenyl]acetate (2c) was pur-
ified by flash chromatography on silica gel, eluting with 10:3
mixture of hexane and ethyl acetate to give a colorless oil.
1H NMR: 1.29 (t, J ¼ 7:3 Hz, 3H); 3.89 (s, 6H); 4.26
(q, J ¼ 7:3 Hz, 2H); 5.70 (d, J ¼ 48:8 Hz, 1H); 6.88
(d, J ¼ 8:0 Hz, 2H); 6.98 (m, 1H); 19F NMR: ꢁ13.54
(d, J ¼ 48:8 Hz, 1F); IR (neat, cmꢁ1) 1757 (nC¼O); MS
(m/z): 242 (Mþ þ Hþ). HRMS. Calcd. for C12H15FO4 (m/e):
242.0954; Found: 242.0953.
Caution: Et3NꢀnHF and Et4NFꢀ2HF are toxic; if they
come in contact with skin, they cause a serious burn. There-
fore, it is recommended that rubber gloves be used.
Typical anodic difluorination conditions were as follows.
Anodic oxidations of 1 (1 mmol) and 4 (1 mmol), were
carried out with an undivided cell with a platinum anode and
cathode (2 cm ꢂ 2 cm) in 15 ml fluorine source or in 8 ml
fluorine source and 8 ml CH2Cl2. Anodic potentials were
determined by cyclic voltammertry. The reference electrode
was Ag/AgNO3 (0.01 M) in MeCN containing Et4NꢀBF4
(0.1 M).
Since positive oxidative potentials were involved, careful
handling of the solvent supporting electrolyte system was
needed, moisture avoided, to ensure polymerization-free
electrolysis. IR spectra were obtained on a FT/IR-410 Jasco
Ethyl fluoro-[3,4,5-trimethoxyphenyl]acetate (2d) was
purified by flash chromatography on silica gel, eluting with
2:1 mixture of hexane and diethyl ether to give a colorless
oil.
1
spectometer. H and 19F NMR spectra were recorded, in
CDCl3 as a solvent, on a JEOL Datum (400 MHz) spectro-
meter.
1H NMR: 1.29 (t, J ¼ 7:1 Hz, 3H); 3.85–3.95 (m, 9H);
4.29 (q, J ¼ 7:1 Hz, 2H); 5.70 (d, J ¼ 47:8 Hz, 1H); 6.68
(s, 2H); 19F NMR: ꢁ16.23 (d, J ¼ 47:8 Hz, 1F); IR (neat,
cmꢁ1) 1758 (nC¼O); MS (m/z): 272 (Mþ þ Hþ). HRMS.
Calcd. for C13H17FO5 (m/e): 272.1060; Found: 272.1043.
Ethyl difluoro-[4-methoxyphenyl]acetate (3) was purified
by flash chromatography on silica gel, eluting with 7:1
mixture of hexane and ethyl acetate to give a colorless oil.
1H NMR: 1.32 (t, J ¼ 8 Hz, 3H); 3.83 (s, 3H); 4.29
(q, J ¼ 8 Hz); 6.94 (d, J ¼ 8:5 Hz, 2H); 7.53 (d, J ¼
8:5 Hz, 2H); 19F NMR: 59.17 (s, 2F); IR (neat, cmꢁ1):
1764 (nC¼O); MS (m/z): 230 (Mþ þ Hþ). HRMS. Calcd.
for C10H9FO (m/e): 230.0754; Found: 230.0748.
1
The chemical shifts for H NMR are reported in d ppm
downfield from internal TMS, and those for 19F NMR are
given in d ppm downfield from internal C6F6, d(CFCl3) of
the C6F6 reference being ꢁ162.2 ppm.
All reactions with air-sensitive compounds were carried
out under a dinitrogen atmosphere. Column chromatography
was conducted with silica gel. GC Analyses were performed
using a Hitachi G-5000 instrument (flame ionization detec-
tor, FID) with a 30 m column Neutra Bond.
3.2. Materials
The electrolytes, Et3NꢀnHF and Et4NFꢀnHF, and
Et4NFꢀBF4, were kind gifts of Morita Chemical Industries
Co. Ltd. (Japan) and were used without purification.
4-Fluoro-1-tetralone (5) was purified by flash chromato-
graphy on silica gel, eluting with 2:1 mixture of hexane and
diethyl ether to give a colorless oil.
1H NMR: 2.50 (m, 2H); 2.61 (m, 1H); 2.95 (m, 1H); 5.75
(dt, J ¼ 49:7 Hz, J ¼ 5:4 Hz, 1H); 7.50–8.08 (m, 4H);
19F NMR: ꢁ8.8 (m, 1F); IR (neat, cmꢁ1) 1692 (nC¼O); MS
(m/z): 164 (Mþ þ Hþ). HRMS. Calcd. for C10H9FO (m/e):
164.0637; Found: 164.0654.
3.3. Separation and analysis of products
The electrolytic mixture was diluted with water and
extracted with three portions of CH2Cl2. The organic phase
was washed with brine and dried over MgSO4. After the
removal of MgSO4 by filtration, the products were isolated
by column chromatography on silica gel and identified by 1H
and 19F NMR spectra, IR-spectra, MS-spectra and HMRS.
Ethyl fluoro-phenylacetate (2a) was purified by flash
chromatography on silica gel, eluting with 10:1 mixture
of hexane and ethyl acetate to give a colorless oil.
Acknowledgements
One of the authors, V. Dinoiu, is deeply indebted to The
Japan Society for the Promotion of Science (JSPS) for
granting research fellowship (1998–2000).
1H NMR: 1.29 (t, J ¼ 7:3 Hz, 3H); 4.25 (q, J ¼ 7:3 Hz,
2H); 5.76 (d, J ¼ 48:2 Hz, 1H); 7.10–7.48 (m, 5H); 19F
NMR: ꢁ18.50 (d, J ¼ 48:2 Hz, 1F); IR (neat, cmꢁ1) 1760
(nC¼O); MS (m/z): 182 (Mþ þ Hþ). HRMS. Calcd. for
C10H11FO2 (m/e): 182.0743; Found: 182.0739.
References
[1] T. Fukuhara, M. Sekiguchi, N. Yoneda, Chem. Lett. (1994) 1011.
[2] J.T. Welch, Tetrahedron 43 (1987) 3123.
Ethyl fluoro-[4-methoxyphenyl]acetate (2b) was puri-
fied by flash chromatography on silica gel, eluting with
[3] J.T. Welch, S. Eswarakrishnan, Fluorine in Bioorganic Chemistry,
Wiley, New York, 1991.

V. Dinoiu et al. / Journal of Fluorine Chemistry 121 (2003) 227–231
231
[4] T. Fuchigami, M. Shimojo, A. Konno, K. Nakagawa, J. Org. Chem.
55 (1990) 6074.
[8] S.Q. Chen, T. Fukuhara, S. Hara, N. Yoneda, Electrochem. Acta 42
(1997) 1951.
[5] A. Erian, A. Konno, T. Fuchigami, J. Org. Chem. 60 (1995) 3459.
[6] N. Yoneda, Tetrahedron 47 (1991) 5329.
[7] (a) T. Fuchigami, M. Shimojo, A. Konno, J. Org. Chem. 60 (1995)
7654;
[9] E. Laurent, B. Marquet, R. Tardivel, Tetrahedron 45 (1989) 4431.
[10] (a) N.L. Weinberg, T.B. Reddy, J. Am. Chem. Soc. 97 (1975)
4264;
(d) I.N. Rozhkov, Russ. Chem. Rev. 45 (1976) 615;
(c) T. Fuchigami, K. Yamamoto, Y. Nakagawa, J. Org. Chem. 56
(1991) 137;
(b) T. Fuchigami, Rev. Heteroatom. Chem. 10 (1994) 155;
(c) T. Fuchigami, A. Konno, K. Nakagawa, M. Shimojo, J. Org.
Chem. 59 (1994) 5937.
(d) G. Haufe, J. Prakt. Chem. 338 (1996) 99–113.