Electrolytic partial fluorination of organic compounds. Part 48: Anodic fluorination of 2-cyano-1-methylpyrrole

Article abstract of DOI:10.1016/S0040-4039(01)00866-8

Anodic fluorination of 2-cyano-1-methylpyrrole using Et₃N·2HF in an undivided cell provided the corresponding 5-fluoropyrrole and 2,5,5-trifluoro-1-methyl-3-pyrrolin-2-carbonitrile while the use of Et₃N·3HF afforded selectively the latter product, which was readily hydrolyzed to isolable 5,5-difluoro-1-methyl-3-pyrroline-2-one. This is the first report of successful anodic fluorination of a pyrrole derivative.

Full text of DOI:10.1016/S0040-4039(01)00866-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 4857–4860
Electrolytic partial fluorination of organic compounds. Part 48:
Anodic fluorination of 2-cyano-1-methylpyrrole†
Toshiki Tajima, Hideki Ishii and Toshio Fuchigami*
Department of Electronic Chemistry, Tokyo Institute of Technology, Nagatsuta, Midori-ku, Yokohama 226-8502, Japan
Received 20 April 2001; revised 14 May 2001; accepted 18 May 2001
Abstract—Anodic fluorination of 2-cyano-1-methylpyrrole using Et3N·2HF in an undivided cell provided the corresponding
5-fluoropyrrole and 2,5,5-trifluoro-1-methyl-3-pyrrolin-2-carbonitrile while the use of Et3N·3HF afforded selectively the latter
product, which was readily hydrolyzed to isolable 5,5-difluoro-1-methyl-3-pyrroline-2-one. This is the first report of successful
anodic fluorination of a pyrrole derivative. © 2001 Elsevier Science Ltd. All rights reserved.
Fluorinated aromatic heterocyclic compounds have
been of much interest because of their unique biological
properties.2 Although direct fluorination of heteroaro-
matic rings is the simplest way to prepare fluorinated
heterocycles, successful examples of the fluorination are
limited. For example, the chemical fluorination of five-
membered heteroaromatic compounds such as pyrroles,
thiophenes and furans were attempted; however, the
yields were extremely low (less than 6%) and the selec-
tivity was also unsatisfactory in all cases.3 Recently,
electrochemical partial fluorination of organic com-
pounds has been shown to be a new powerful method
for selective fluorination.4 However, there have been
few reports of direct fluorination of heteroaromatic
compounds using an electrochemical method.5 In most
cases, yields of the fluorinated product are extremely
Table 1. Anodic fluorination of 2-cyano-1-methylpyrrole (1)
Me
N
Me
N
Me
N
Me
N
Me
N
-2ne, -nH+
NC
NC
NC
F
NC
F
O
O
F
+
+
+
F-
4 F/mol
F
F
F
F
5
2
3
4
1
Run
Solvent
Supporting electrolyte
Yield (%)a
2
3
4
5
1
2
3
MeCN
MeCN
MeCN
MeCN
DME
Et3N·2HF
Et3N·3HF
Et3N·5HF
Et3N·4HF
Et3N·2HF
Et3N·3HF
Et3N·2HF
Et3N·3HF
Et3N·5HF
Et3N·4HF
20
5
0
0
20
8
19
0
0
Trace
2
12
21
0
Trace
3
47
28
Trace
2
Trace
Trace
0
32
65
5
4
6
5b
6
12
51
51
60
0
DME
0
7
8
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Trace
Trace
17
9c
10c
0
25
0
0
a Determined by 19F NMR spectroscopy.
b A large amount of starting 1 was recovered.
c Large amounts of unidentified polymeric products were formed.
* Corresponding author. Tel./fax: +81-45-924-5406; e-mail: fuchi@echem.titech.ac.jp
†
For Part 47, see: Ref. 1.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00866-8

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T. Tajima et al. / Tetrahedron Letters 42 (2001) 4857–4860
carried out anodic fluorination of 1 in Et3N·3HF/MeCN
low or unsatisfactory. On the other hand, we found that
electron-withdrawing groups promoted the anodic fluori-
nation of heterocyclic compounds.5,6 With these facts in
mind, we attempted the direct anodic fluorination of
pyrroles having an electron-withdrawing cyano group.
in the presence of water (Scheme 1).
In the presence of an equimolar amount of water, the
yield of trifluorinated product 5 decreased drastically
while that of 4 increased. In this case, a considerable
amount of N-methylmaleimide was formed. Moreover,
after the electrolysis of 1 in Et3N·3HF/MeCN, excess
water was added to the electrolytic solution and then the
reaction mixture was stirred for 4 h to give the difluori-
nated product 4 in 54% yield (ca. 83% yield from 5 in
consideration of run 2) as shown in Scheme 2. These
results clearly indicate that 5 was readily hydrolyzed to
form 4 efficiently. Therefore, 5 is a precursor to 4.
At first, we investigated anodic fluorination of 2-cyano-1-
methylpyrrole (1) using various fluoride supporting salts
and solvents. Constant current electrolysis was carried
out at platinum plate electrodes in an undivided cell at
room temperature until 1 was mostly consumed (4
F/mol). The results are summarized in Table 1.
Anodic fluorination of 1 took place efficiently to provide
four fluorinated products 2,7 3,8 49 and 510 depending on
the fluoride salts and solvents. When Et3N·3HF was
used, trifluorinated product 5 was selectively (runs 2 and
6) or exclusively formed (run 8) depending on the solvent
used. On the other hand, the use of Et3N·5HF/MeCN or
Et4NF·4HF/MeCN provided difluorinated product 4
preferentially (runs 3 and 4), while the use of the same
fluoride salts in CH2Cl2 afforded 3 exclusively (runs 9 and
10). It is noted that monofluorinated pyrrole 2 was
formed in considerable amount along with 5 by using
Et3N·2HF regardless of the solvents (runs 1, 5 and 7).
The product 2 was easily isolated by column chromatog-
raphy (hexane/AcOEt, 3:1). In all cases, the N-methyl
group was not fluorinated at all. This is in sharp contrast
to the anodic fluorination of 1-methylpyrazole-4-car-
boxylates to provide both ring-fluorinated and N-methyl
fluorinated products.5c Thus, the product selectivity was
found to be controlled mainly by the fluoride salts used.
The oxygen source of the products 3 and 4 seems to be
water contaminated in the fluoride salts. Therefore, we
Figure 1. Dependence of yields of 2 and 5 on the charge
passed during the anodic fluorination of 1 in Et3N·3HF/
MeCN.
Me
N
Me
N
Me
N
Me
N
Me
N
-4e
NC
NC
F
NC
O
O
O
F
O
+
+
+
F
F
F
F
Et3N•3HF/MeCN
H2O (1 eq.)
1
4
5
3
4 F/mol
trace
7%
34%
28%
Scheme 1.
Scheme 2.
Scheme 3.
Me
Me
N
Me
N
H2O (100 eq.)
4 h
N
-4e
NC
NC
F
O
O
+
Et3N•3HF/MeCN
F
F
1
4 F/mol
4
3
trace
54%
Me
N
Me
Me
N
-2e
N
F
F
NC
O
NC
F
F
+
Et3N•3HF/MeCN
F
F
4
2 F/mol
5
2
trace
66%

T. Tajima et al. / Tetrahedron Letters 42 (2001) 4857–4860
4859
Me
N
Me
N
Me
N
Me
N
-e
-e, -H+
F-
NC
NC
NC
NC
F
F
H
1
A
2
H2O, -H+
-2e, 2F-
Me
Me
N
Me
N
H2O
N
NC
NC
OH
NC
F
F
F
O
H
F
F
4
5
-e, -H+
Me
Me
Me
-e, -H+
-e, F-
N
N
N
NC
NC
OH
O
O
F
3
Scheme 4.
In order to clarify the reaction mechanism, the oxida-
tion potentials of 1 and 2 were measured. The oxidation
potential of 2 (EOP X=1.72 V versus SEC) was found to
be slightly less positive compared with 1 (EOP X=1.77 V
versus SCE). It was also confirmed that anodic fluori-
nation of 2 in MeCN/Et3N·3HF provided 5 selectively
in good yield (Scheme 3).
In sharp contrast to the case of 1, the anodic fluorina-
tion of pyrrole and 1-methylpyrrole gave only a poly-
merized product and no fluorinated product was
formed.
In conclusion, we have successfully carried out for the
first time anodic fluorination of 2-cyano-1-
methylpyrrole. The product 4 has a biologically inter-
esting gem-difluoromethylene unit in the heterocyclic
ring and 2 has also a versatile cyano group and a
fluorine atom. Therefore, 2 and 4 seem to be useful
fluorinated building blocks. Work on further applica-
tion and the scope and limitation of the methodology
for anodic fluorination is now in progress.
Furthermore, the relationship between the product
yields and the charge passed was investigated. As
shown in Fig. 1, trifluorinated product 5 was formed
even at an early stage of the electrolysis, and the yield
of 5 increased linearly to 65% with the amount of
electricity. In contrast, the yield of 2 is rather low and
did not change with the electricity. These facts suggest
that 2 is easily oxidized to give 5 immediately after 2 is
formed during the electrolysis.
References
From these results, a possible reaction mechanism was
proposed as shown in Scheme 4. This reaction sequence
can be explained by a conventional ECEC process.
Since 2 is more easily oxidized than 1, the trifluorinated
product 5 is preferentially formed by the further elec-
trochemical oxidation of 2 once formed during the
electrolysis. However, since Et3N·2HF is easily oxi-
dized, the further oxidation of 2 seems to be suppressed
by simultaneous oxidation of Et3N·2HF. In support of
this hypothesis, the use of Et3N·5HF and Et4NF·4HF,
which are stable for oxidation, did not provide 2. The
trifluorinated product 5 is unstable; however, it is easily
converted to the difluoro compound 4 efficiently by the
hydrolysis of 5. As already mentioned, the use of
Et3N·5HF/MeCN and Et4NF·4HF/MeCN gave 3 and
4, while the use of CH2Cl2 instead of MeCN provided
3 solely. The reason for such product selectivity is not
clear at present. The monofluorinated product 3 seems
to be formed by the addition of water to the radical
cation A (Scheme 4).
1. Shaban M. R.; Ishii, H.; Fuchigami, T. J. Org. Chem., in
press.
2. (a) Biomedicinal Aspects of Fluorine Chemistry; Filler, R.,
Kobayashi, Y., Eds.; Kodansha & Elsevier Biomedical:
Tokyo, 1982; (b) Fluorine in Bioorganic Chemistry;
Welch, J. T.; Eswarakrishnan, S., Eds.; Wiley: New York,
1991; (c) Organofluorine Compounds; Hiyama, T., Ed.;
Springer-Verlag: Berlin, 2000.
3. (a) Gozzo, F. C.; Ifa, D. R.; Eberlin, M. N. J. Org.
Chem. 2000, 65, 3920; (b) Cerichelli, G.; Crestoni, M. E.;
Fornarini, S. Gazz. Chim. Ital. 1990, 120, 749.
4. (a) Fuchigami, T. In Organic Electrochemistry, 4th ed.;
Lund, H.; Hammerich, O., Eds.; Marcel Dekker: New
York, 2001; Chapter 25; (b) Fuchigami, T. In Topics in
Current Chemistry 170: Electrochemistry; Steckhan, E.,
Ed.; Springer-Verlag: Berlin, 1994; Vol. 5, p. 1; (c)
Fuchigami, T. In Advances in Electron-Transfer Chem-
istry; Mariano, P. S., Ed.; JAI Press: Conneticut, 1999;
Vol. 6, p. 41; (d) Fuchigami, T. J. Synth. Org. Chem. Jpn.
1994, 52, 1063.

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T. Tajima et al. / Tetrahedron Letters 42 (2001) 4857–4860
5. (a) Huba, F.; Yeager, E. B. Electrochim. Acta 1979, 24, 489;
HRMS calcd for C6H5N2F: 124.0437. Found: 124.0443.
(b) Ballinger, J. R.; Teare, F. W. Electrochim. Acta 1985,
30, 1075; (c) Makino, K.; Yoshioka, H. J. Fluorine Chem.
1988, 39, 435; (d) Sono, M.; Toyoda, N.; Shizuri, Y.; Tori,
M. Tetrahedron Lett. 1994, 35, 9237; (e) Konno, A.;
Shimojo, M.; Fuchigami, T. J. Fluorine Chem. 1998, 87,
137; (f) Hou, Y.; Higashiya, S.; Fuchigami, T. J. Org.
Chem. 1999, 64, 3346.
8. 5-Cyano-5-fluoro-1-methyl-3-pyrrolin-2-one (3): colorless
1
oil; H NMR l 7.08 (d, J=5.8 Hz, 1H), 6.48 (d, J=5.8
Hz, 1H), 3.09 (s, 3H); 13C NMR l 167.2 (d, J=3.4 Hz),
139.2 (d, J=19.0 Hz), 131.2 (d, J=3.4 Hz), 111.5 (d,
J=56.5), 94.6 (d, J=204.6), 25.2; 19F NMR l −46.41 (s);
MS (m/z) 140 (M+), 111, 84; HRMS calcd for C6H5FN2O:
140.0386. Found: 140.0386.
6. (a) Dawood, K. M.; Fuchigami, T. J. Org. Chem. 1999, 64,
138; (b) Dawood, K. M.; Higashiya, S.; Hou, Y.;
Fuchigami, T. J. Org. Chem. 1999, 64, 7935; (c) Shaaban,
M. R.; Ishii, H.; Fuchigami, T. J. Org. Chem. 2000, 65,
8685.
9. 5,5-Difluoro-1-methyl-3-pyrrolin-2-one (4): colorless oil; 1H
NMR l 6.92 (d, J=5.8 Hz, 1H), 6.30 (d, J=5.8 Hz, 1H),
2.94 (s, 3H); 13C NMR l 166.6, 138.0 (t, J=27.4 Hz), 130.2
(t, J=3.9 Hz), 122.3 (t, J=243.7), 22.8; 19F NMR l −23.61
(s); MS (m/z) 133 (M+), 106, 84; HRMS calcd for
C5H5F2NO: 133.0339. Found: 133.0335.
1
7. 5-Fluoro-1-methyl-2-pyrrolecarbonitrile (2): yellow oil; H
NMR l 6.66 (m, 1H), 5.59 (m, 1H), 3.61 (s, 3H); 13C NMR
l 148.2 (d, J=267.2 Hz), 117.9 (d, J=3.9 Hz), 113.3, 96.3
(d, J=2.8 Hz), 88.3 (d, J=11.7 Hz), 30.1 (d, J=1.7 Hz);
19F NMR l −53.96 (m); MS (m/z) 124 (M+), 109, 84;
10. 2,5,5-Trifluoro-1-methyl-3-pyrrolin-2-carbonitrile (5): 19F
NMR l −2.54 (dd, J=205.3, 18.5 Hz), −11.31 (dd,
J=205.3, 27.7 Hz), −30.36 (dd, 27.7, 18.5 Hz); MS (m/z)
162 (M+).
.