A facile synthesis of gem-difluorinated heterocyclic compounds using anodic fluorination of 2-cyano-1-methylpyrrole as a key step

Article abstract of DOI:10.1055/s-2002-35621

Anodic fluorination of 2-cyano-1-methylpyrrole 1 using Et₃N·5HF in an undivided cell provided 5,5-difluoro-1-methyl-3-pyrrolin-2-one (5a). The Diels-Alder reaction of 5a with various dienes was successfully carried out to provide gem-difluorina

Full text of DOI:10.1055/s-2002-35621

SPECIAL TOPIC
2597
A Facile Synthesis of gem-Difluorinated Heterocyclic Compounds Using
Anodic Fluorination of 2-Cyano-1-methylpyrrole as a Key Step
E
lectrochemica
o
F
luorinatio
s
h
no-1-methyl
ipyrroleki Tajima, Toshio Fuchigami*
Department of Electronic Chemistry, Tokyo Institute of Technology, Nagatsuta, Midori-ku, Yokohama 226-8502, Japan
Fax +81(45)9245406; E-mail: fuchi@echem.titech.ac.jp
Received 23 September 2002
fluorination of organic compounds has been shown to be
a new powerful method for selective fluorination.5 How-
ever, there have been few reports of direct fluorination of
heteroaromatic compounds using electrochemical meth-
od.6 In most cases, yields of fluorinated products are ex-
tremely low or unsatisfactory. On the other hand, we
found that electron-withdrawing groups promoted the an-
odic fluorination of heterocyclic compounds.6,7 With
these facts in mind, we attempted the direct anodic fluori-
nation of 2-cyano-1-methylpyrrole (1).
Abstract: Anodic fluorination of 2-cyano-1-methylpyrrole 1 using
Et3N 5HF in an undivided cell provided 5,5-difluoro-1-methyl-3-
pyrrolin-2-one (5a). The Diels–Alder reaction of 5a with various
dienes was successfully carried out to provide gem-difluorinated
heterocyclic compounds in excellent yields.
Key words: anodic fluorination, 5,5-difluoro-1-methyl-3-pyr-
roline-2-one, gem-difluoromethylenes, Diels–Alder reaction,
dienes
Fluorine-containing heterocyclic compounds have attract-
ed increasing interest in modern bioorganic chemistry due
to their remarkable biological activity.1 Particularly, much
attention has been paid to pharmaceutical and agricultural
chemicals containing gem-difluoromethylene units in re-
cent years.2 There are two complementary approaches to
such an important unit. These are, (a) substitution of a car-
bonyl or an active methylene group by fluorine,3 and (b)
the use of gem-difluoromethylene-containing building
blocks.4 When it comes to fluorinated complex molecules,
the former approach cannot be applied because of the re-
activity, thermal instability, hazard and cost associated
with electrophilic and nucleophilic fluorinating agents.
Instead, the latter approach is mainly employed. However,
available gem-difluoromethylene-containing building
blocks are limited. Recently, electrochemical partial
At first, we investigated anodic fluorination of 2-cyano-1-
methylpyrrole (1) using various fluoride supporting salts
(1 M) in MeCN (10 mL). Constant current electrolysis (10
mA/cm2) was carried out at platinum plate electrodes
(2 2 cm2) in an undivided cell at room temperature until
1 was mostly consumed (4 F/mol). The results are sum-
marized in Table 1.
Anodic fluorination of 1 took place efficiently to provide
four fluorinated products 2, 3, 4, and 5a depending on the
fluoride salts. The use of Et3N 5HF provided difluorinated
product 5a preferentially. The product 5a has both a bio-
logically interesting gem-difluoromethylene unit and an
activated olefin in the heterocyclic ring. Therefore, we at-
tempted the Diels–Alder reaction of 5a as the dienophile
with various dienes.
Table 1 Anodic Fluorination of 2-Cyano-1-methylpyrrole (1)
Me
N
Me
N
Me
N
Me
N
Me
N
-2ne, -nH+
+
CN
+
CN
F
CN
+
F
CN
O
O
F
F-
F
F
F
F
4 F/mol
10 mA/cm2
4
1
2
3
5a
Run
Supporting Electrolyte
Yield (%)a
2
3
4
5a
trace
3
1
2
3
4
Et3N 2HF
Et3N 3HF
Et3N 5HF
Et4NF 4HF
20
5
trace
2
32
65
5
0
12
54
28
0
21
6
a Determined by 19F NMR spectroscopy.
Synthesis 2002, No. 17, Print: 02 12 2002.
Art Id.1437-210X,E;2002,0,17,2597,2600,ftx,en;C05202SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

2598
T. Tajima, T. Fuchigami
SPECIAL TOPIC
In the [2+4] pericyclic cycloaddition reaction known as
the Diels–Alder reaction, compounds having a mono-
fluoro or trifluoromethyl group have been widely used as
dienes, dienophiles, or both. However, a few compounds
having a gem-difluoromethylene unit have been used as
dienes, dienophiles, or both.8 To understand the effect of
fluorine on the reactivity of dienophiles and dienes in the
Diels–Alder reaction, one must recognize that electron-
deficient dienophiles and electron-rich dienes are general-
ly most reactive in 1,3-dipolar cycloaddition. With direct
fluorine-substitution not affecting significantly the
HOMO or LUMO energies,9 one would predict that the
reactivity of dienes or dienophiles should not be affected
drastically by vinylic fluorine substitution. On the other
hand, with allylic fluorine-substitution lowering the ener-
gies of both HOMO and LUMO, one would expect an en-
hancement of dienophilic reactivity when a system has
perfluoroalkyl substituents. With these facts in mind, we
calculated the HOMO and LUMO energies of 5a and the
corresponding nonfluorinated equivalent 5b. The calcula-
tions were carried out with the MOPAC 2000 program us-
ing the AM1. From the calculations, the HOMO and
LUMO of 5a were –10.490 and –0.652 eV, respectively.
On the other hand, the HOMO and LUMO of 5b were
–9.564 and 0.076 eV, respectively. Thus, as expected, the
difluoromethylene unit was found to have an electron-
withdrawing effect, since the HOMO and LUMO energies
of 5a are lower than that of 5b.
Me
N
Me
N
O
O
F
F
5a
5b
HOMO
LUMO
-10.490 eV
-0.652 eV
-9.564 eV
0.076 eV
Figure 1 Calculated HOMO and LUMO energies for 5a
At first, we carried out the Diels–Alder reaction of 5a with
open-chain dienes (Table 2). A mixture of 5a and a large
excess amount (100 equiv) of isoprene was heated at
60 °C for 4 days to give 94% yield of the desired products
(6a and 6b) as a regioisomeric mixture. The reaction time
was reduced to about half under reflux in toluene, and the
almost same yield and regioselectivity were obtained. The
Diels–Alder reaction of 5a with 2,3-dimethylbuta-1,3-di-
ene (5 equiv) was carried out similarly in toluene to afford
7 in quantitative yield.
Next, we extended the Diels–Alder reaction to various cy-
clic dienes. As shown in Table 3, the reaction proceeded
quite smoothly, regardless of the structure of cyclic
dienes, to provide the cycloaddition products 8–10 in ex-
cellent yields. The reaction with furan gave the endo-form
preferentially while the reaction with cyclopentadiene and
cyclohexa-1,3-diene produced the endo-form solely.
Thus, 5a was found to be a highly useful building block
containing a gem-difluoromethylene unit.
Table 2 The Diels-Alder Reaction of 5a with Open-Chain Dienes
Me
Open-Chain
N
Dienes
O
F
Cycloaddition Products
F
5a
Diene
Solvent
Temp (°C)
Time (d)
4
Cycloaddition Products
Yield (%)a,b
–
60
94 (91) (13:7)c
F
F
N Me
(100 equiv)
O
6a
F
F
N Me
O
6b
6a/6b
toluene
toluene
reflux
reflux
2.2
2
93 (88) (3:2)c
quant. (96)
(5 equiv)
(5 equiv)
F
F
N Me
O
7
a Determined by 19F NMR Spectroscopy.
b Isolated yields are given in parenthesis.
c Regioisomeric Ratio.
Synthesis 2002, No. 17, 2597–2600 ISSN 0039-7881 © Thieme Stuttgart · New York

SPECIAL TOPIC
Electrochemical Fluorination of 2-Cyano-1-methylpyrrole
2599
Table 3 The Diels-Alder Reaction of 5a with Cyclic Dienes
Diene
Solvent
–
Temp (°C)
60
Time (d)
3
Cycloaddition Products
Yield (%)a
quant.
O
O
F
F
(endo/exo = 20:13)
N
(100 equiv)
(5 equiv)
Me
O
8
toluene
toluene
reflux
reflux
0.5
1.5
quant. (92)b
(endo only)
F
F
N
Me
O
9
quant. (96)
(endo only)
F
F
N
(5 equiv)
Me
O
10
a Determined by 19F NMR Spectroscopy.
b Isolated yields are given in parenthesis.
2-Cyano-5-fluoro-1-methylpyrrole (2)
1H NMR: = 6.66 (m, 1 H), 5.59 (m, 1 H), 3.61 (s, 3 H).
product 5a. Thus, an effective, facile synthetic method of 13C NMR: = 148.2 (d, J = 267.2 Hz), 117.9 (d, J = 3.9 Hz), 113.3,
In conclusion, we have successfully carried out the Diels–
Alder reaction using the anodically gem-difluorinated
96.3 (d, J = 2.8 Hz), 88.3 (d, J = 11.7 Hz), 30.1 (d, J = 1.7 Hz).
19F NMR: = –53.96 (m).
MS: m/z = 124 (M+), 109, 84.
gem-difluoromethylated heterocyclic compounds was es-
tablished in 2 steps, consisting of an anodic gem-difluori-
nation and the construction of a heterocyclic skeleton by
the Diels–Alder reaction. The products 6a, 6b, and 7 are
precursors of phthalimidine derivatives,10 which are phys-
iogically active, prospective isoindole derivatives. In this
way, novel synthesis of heterocyclic compounds contain-
HRMS: m/z calcd for C6H5FN2: 124.0437. Found: 124.0443.
5-Cyano-5-fluoro-1-methyl-3-pyrrolin-2-one (3)
1H NMR: = 7.08 (d, J = 5.8 Hz, 1 H), 6.48 (d, J = 5.8 Hz, 1 H),
ing a gem-difluoromethylene unit was achieved using an- 3.09 (s, 3 H).
13C NMR: = 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.
odic fluorination of 2-cyano-1-methylpyrrole (1) as a key
step.
19F NMR: = –46.41 (s).
MS: m/z = 140 (M+), 111, 84.
1H NMR, 13C NMR, and 19F NMR spectra were recorded in CDCl3
1
at 270, 254 and 68 MHz, respectively. The chemical shifts for H
HRMS: m/z calcd for C6H5FN2O: 140.0386. Found: 140.0386.
and 19F NMR are given in (ppm) from internal TMS and monof-
luorobenzene (–36.5 ppm), respectively. Mass spectra were ob-
tained with a Shimadzu GC-MSQP-2000A mass spectrometer.
High resolution mass spectra were obtained with a Jeol JMS-700
mass spectrometer.
2,5,5-Trifluoro-1-methyl-3-pyrrolin-2-carbonitrile (4)
19F NMR: = –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+).
Anodic Fluorination of 2-Cyano-1-methylpyrrole (1)
Electrolysis was carried out at a platinum anode and cathode (2
5,5-Difluoro-1-methyl-3-pyrrolin-2-one (5a)
1H NMR: = 6.92 (d, J = 5.8 Hz, 1 H), 6.30 (d, J = 5.8 Hz, 1 H),
2.94 (s, 3 H).
13C NMR: = 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: = –23.61 (s).
MS: m/z = 133 (M+), 106, 84.
2
cm2) in a solution of an appropriate fluoride salt (1 M) in CH3CN(10
mL) containing 2-cyano-1-methylpyrrole 1 (1 mmol) by using an
undivided cell under a nitrogen atmosphere at an ambient tempera-
ture. Constant current (10 mA/cm2) was applied until consumption
of 1 was mostly achieved (4 F/mol). After the electrolysis, the re-
sulting electrolytic solution was passed through a short column of
silica gel using CHCl3 as eluent. The collected solution was evapo-
rated under vacuum. Then, the yields of the fluorinated products 2–
5a were calculated by means of 19F NMR by using a known amount
of monofluorobenzene as an internal standard. After that, 2–5a were
isolated by column chromatography on silica gel using CHCl3.
HRMS calcd for C5H5F2NO: 133.0339. Found: 133.0335.
Diels–Alder Reaction of 5a with Dienes; General Procedure
To a solution of the 5,5-difluoro-1-methyl-3-pyrrolin-2-one 5a (1
mmol) in toluene (10 mL) was added a diene (5 mmol). The reaction
mixture was stirred for 0.5–4 d under reflux. After the reaction was
complete, the reaction mixture was passed through a short column
Synthesis 2002, No. 17, 2597–2600 ISSN 0039-7881 © Thieme Stuttgart · New York

2600
T. Tajima, T. Fuchigami
SPECIAL TOPIC
of silica gel using CHCl3 as eluent. The collected solution was evap-
orated under vacuum. Then, the yields of the fluorinated products
6a–10 were calculated by means of 19F NMR similarly to the cases
of 2–5a. After that, 6a–10 were isolated by column chromatography
on silica gel using CHCl3.
Acknowledgment
This work was supported by Grant-in-Aid for Scientific Research
on Priority Areas (A) ‘Exploitation of Multi-Element Cyclic Mole-
cules’ from the Ministry of Education, Culture, Sports, Science and
Technology, Japan.
A mixture of 6a and 6b was easily isolated. However, their separa-
tion failed although 6a and 6b appeared separately by GC-MS. We
could not separately identify them by 1H and 19F NMR spectrosco-
py.
References
(1) (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:
Berlin, 2000.
3,3-Difluoro-2,5-dimethyl-3a,4,6,7,7a-pentahydroisoindole-1-
one and 3,3-Difluoro-2,6-dimethyl-3a,4,5,7,7a-pentahydro-
isoindole-1-one (6a/b)
1H NMR: = 5.48 (br s, 1 H), 3.05–2.77 (m, 5 H), 2.48–2.10 (m, 4
H), 1.72 (s, 3 H).
(2) (a) Takahashi, L. H.; Radhakrishnan, R.; Rosenfield, R. E.
Jr.; Meyer, E. F. Jr.; Trainor, D. A. J. Am. Chem. Soc. 1989,
111, 3368. (b) Sham, L. H. In Fluorine-Containing Amino
Acids; Kuhahr, V. P.; Soloshonok, V. A., Eds.; Wiley:
Chichester, 1995, 333. (c) Witkowski, S.; Rao, Y. K.;
Premchandran, R. H.; Halushka, P. V.; Fried, J. J. Am.
Chem. Soc. 1992, 114, 8464. (d) Chambers, R. D.; Jaouhari,
R.; O’Hagan, D. Tetrahedron 1989, 45, 5101.
19F NMR: = –1.30 (dd, J = 185.0, 14.8 Hz), –0.96 (dd, J = 185.0,
12.9 Hz), –15.7 (d, J = 185.0 Hz), –17.5 (d, J = 185.0 Hz).
MS: m/z = 201 (M+), 186, 181, 138.
HRMS: m/z calcd for C10H13F2NO: 201.0965. Found. 201.0944,
201.0935.
3,3-Difluoro-2,5,6-trimethyl-3a,4,7,7a-tetrahydroisoindole-1-
(3) Middleton, W. J. J. Org. Chem. 1975, 40, 574.
(4) (a) Tozer, M. J.; Herpin, T. F. Tetrahedron 1996, 52, 8619.
(b) Percy, J. M. Top. Curr. Chem. 1997, 193, 131.
(5) (a) Fuchigami, T. In Organic Electrochemistry, 4 th ed.;
Lund, H.; Hammerich, O., Eds.; Marcel Dekker: New York,
2001, Chap. 25. (b) Fuchigami, T. In Advances in Electron-
Transfer Chemistry, Vol. 6; Mariano, P. S., Ed.; JAI Press:
Conneticut, 1999, 41. (c) Fuchigami, T. Top. Curr. Chem.
1994, 170, 1. (d) Fuchigami, T. J. Synth. Org. Chem. Jpn.
1994, 52, 1063.
(6) (a) Huba, F.; Yeager, E. B. Electrochim. Acta 1979, 24, 489.
(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.
one (7)
1H NMR: = 2.94 (m, 2 H), 2.85 (s, 3 H), 2.38–2.08 (m, 4 H), 1.67
(s, 6 H).
19F NMR: = 0.98 (dd, J = 186.8, 14.8 Hz), –15.6 (d, J = 186.8
Hz).
MS: m/z = 215 (M+), 200, 195, 152.
HRMS: m/z calcd for C11H15F2NO: 215.1122. Found: 215.1097.
Selected Spectroscopic Data
5,5-Difluoro-4-methyl-10-oxa-4-azatricyclo[5,2,1,02,6]dec-8-
ene-3-one (8)
endo-8:
1H NMR: = 6.47–6.21 (m, 2 H), 5.27–5.15 (m, 2 H), 3.61–3.47
(m, 1 H), 3.42–3.28 (m, 1 H), 2.73 (s, 3 H).
19F NMR: = 5.54 (dd, J = 196.0, 14.8 Hz), –13.7 (d, J = 196.0
Hz).
(7) (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.
(8) Dolbier, W. R. In Chemistry of Organic Fluorine
Compounds, Vol. 2; Hudlicky, M.; Pavlath, A. E., Eds.;
American Chemical Society: Washington D.C., 1995, 797–
839.
MS: m/z = 201 (M+), 172, 132, 114, 95.
HRMS: m/z calcd for C9H9F2NO2: 201.0601. Found: 201.0588.
exo-8:
1H NMR: = 6.56–6.42 (m, 2 H), 5.32 (s, 1 H), 5.23 (s, 1 H), 2.99–
2.85 (m, 4 H), 2.76–2.67 (m, 1 H).
19F NMR: = 5.12 (dd, J = 188.7, 14.8 Hz), –14.9 (d, J = 188.7 Hz)
MS: m/z = 201 (M+), 132, 114, 95.
(9) Brundle, C. R.; Robin, M. B.; Kuebler, N. A.; Basch, H. J.
Am. Chem. Soc. 1972, 94, 1451.
(10) Takahashi, I.; Hatanaka, M. Heterocycles 1997, 45, 2475.
HRMS: m/z calcd for C9H9F2NO2: 201.0601. Found: 201.0601.
Synthesis 2002, No. 17, 2597–2600 ISSN 0039-7881 © Thieme Stuttgart · New York