Electrolytic partial fluorination of organic compounds. 83. Anodic fluorination of N-substituted pyrroles and its synthetic applications to gem-difluorinated heterocyclic compounds

Article abstract of DOI:10.1021/jo0520745

Anodic fluorination of N-substituted pyrroles was carried out in MeCN containing supporting fluoride salts such as Et₃N-nHF (n = 2-5) and Et₄NF-4HF with use of platinum electrodes under constant current conditions. Anodic fluorinatio

Full text of DOI:10.1021/jo0520745

Electrolytic Partial Fluorination of Organic Compounds. 83. Anodic
Fluorination of N-Substituted Pyrroles and Its Synthetic
Applications to gem-Difluorinated Heterocyclic Compounds
Toshiki Tajima, Atsushi Nakajima, and Toshio Fuchigami*
Department of Electronic Chemistry, Tokyo Institute of Technology, 4259 Nagatsuta, Midori-ku,
Yokohama 226-8502, Japan
fuchi@echem.titech.ac.jp
ReceiVed October 4, 2005
Anodic fluorination of N-substituted pyrroles was carried out in MeCN containing supporting fluoride
salts such as Et3N-nHF (n ) 2-5) and Et4NF-4HF with use of platinum electrodes under constant
current conditions. Anodic fluorination of N-methyl- and N-p-tosylpyrroles having an electron-withdrawing
cyano group proceeded smoothly to provide the corresponding fluorinated products in moderate to excellent
yields, while anodic fluorination of N-methylpyrrole devoid of an electron-withdrawing cyano group did
not take place and a polymeric product was formed at the anode surface. In sharp contrast to the cases
of N-methylpyrroles, even N-p-tosylpyrrole devoid of an electron-withdrawing cyano group underwent
anodic fluorination efficiently. Diels-Alder reaction of 5,5-difluoro-1-methyl-3-pyrrolin-2-one (2e) derived
from anodic fluorination of 2-cyano-1-methylpyrrole (2a) with various dienes was carried out to provide
the cycloaddition products in excellent yields. Furthermore, Michael reaction of 2e with various
nucleophiles was also successfully carried out to provide the Michael addition products in good to excellent
yields.
Introduction
techniques because many fluorinating reagents are usually
explosive, toxic, unstable, or hygroscopic.2 In addition, although
the chemical fluorination of five-membered heteroaromatic
compounds has been attempted, the yields and selectivity were
extremely low in all cases.3 On the other hand, recently, much
attention has also been paid to pharmaceuticals and agricultural
chemicals containing a gem-difluoromethylene unit because it
is isopolar and isosteric with an ether oxygen.4 There are two
complementary approaches to such an important unit. One is
Fluorine-containing heterocyclic compounds have attracted
much interest because of their unique chemical, physical, and
biological activities.1 In particular, fluorine-containing five-
membered heteroaromatic compounds, such as fluoropyrroles,
fluorothiophenes, and fluorofurans, are useful precursors of
various biologically active compounds and conducting polymers.
Direct selective fluorination is the most ideal method for the
preparation of these compounds from the viewpoint of atom
economy. However, it generally requires special equipment and
(2) (a) Haufe, G. J. Prakt. Chem. 1996, 338, 99-113. (b) McClinton,
M. A. Aldrichim. Acta 1995, 28, 31-35. (c) Wilkinson, J. A. Chem. ReV.
1992, 92, 505-519.
(3) (a) Gozzo, F. C.; Ifa, D. R.; Eberlin, M. N. J. Org. Chem. 2000, 65,
3920-3925. (b) Cerichelli, G.; Crestoni, M. E.; Fornarini, S. Gazz. Chim.
Ital. 1990, 120, 749-755. (c) Crestoni, M. E.; Fornarini, S. Gazz. Chim.
Ital. 1989, 119, 203-204.
(1) (a) Hiyama, T. Organofluorine Compounds; Springer-Verlag: Berlin,
2000. (b) Fluorine in Bioorganic Chemistry; Welch, J. T., Eswarakrishnan,
S., Eds.; Wiley: New York, 1991. (c) Biomedicinal Aspects of Fluorine
Chemistry; Filler, R., Kobayashi, Y., Eds.; Kodansha & Elsevier Biomedi-
cal: Tokyo, Japan, 1982.
10.1021/jo0520745 CCC: $33.50 © 2006 American Chemical Society
Published on Web 01/14/2006
1436
J. Org. Chem. 2006, 71, 1436-1441

Electrolytic Partial Fluorination of Organic Compounds
TABLE 1. Oxidation Potentials of N-Substituted Pyrroles
the substitution of a carbonyl or an active methylene group by
various fluorinating reagents derived from fluorine gas,5 and
the other is the use of gem-difluoromethylene-containing
building blocks.6 The former approach cannot be applied to
complex molecules because of the low selectivity of fluorinating
reagents such as SF4 and diethylaminosulfur trifluoride (DAST).
Instead, the latter approach is mainly employed despite the
limited availability of gem-difluoromethylene-containing build-
ing blocks.
Recently, electrochemical fluorination has been shown to be
a useful alternative method for selective direct fluorination
because the electrochemical fluorination can be carried out under
mild and safe conditions with relatively simple equipment.
Therefore, there have been many reports on anodic fluorination
of organic compounds such as organosulfur, organonitrogen,
and heterocyclic compounds.7 However, there have been few
reports on anodic fluorination of heteroaromatic compounds.
On the other hand, we found that electron-withdrawing groups
promoted the anodic fluorination of heteroatom compounds.8
With these facts in mind, we attempted anodic fluorination of
N-substituted pyrroles and its synthetic applications to gem-
difluorinated heterocyclic compounds. The results are reported
and discussed in this paper.
R1
R2
Epox (V vs SCE)a
1a
2a
3a
4a
Me
Me
Ts
H
CN
H
1.40
1.95
1.96
2.56
Ts
CN
a Oxidation potentials (Epox) of 1a-4a (0.01 M) were measured in 0.1
M n-Bu4NBF4/MeCN, recorded at a Pt disk electrode (φ ) 8 mm). The
scan rate was 100 mV s-1
.
provide the fluorinated products 2c, 2d, and 2e depending on
the supporting fluoride salts (entries 3-5). Anodic fluorination
of 3a was also carried out to provide the corresponding
difluorinated product 3b in excellent yield (entry 6). Interest-
ingly, anodic fluorination of 3a proceeded smoothly despite an
absence of a substituent at the 2-position. From these results of
anodic fluorination of 1a-3a, anodic fluorination of N-
substituted pyrroles seems to be greatly affected not by steric
hindrance at the 2-position but by the reactivity of the cation
radical intermediates derived from one-electron oxidation of
N-substituted pyrroles. Furthermore, anodic fluorination of 4a
with Et4NF-4HF took place to provide the corresponding
difluorinated product 4b in high yield. On the other hand, 4b
was obtained in moderate yields with use of Et3N-3HF and
Et3N-5HF, because the oxidation potential of 4a (Epox ) 2.56
V vs SCE) is much higher compared with those of Et3N-3HF
(Edox ) 2.0 V vs SCE) and Et3N-5HF (Edox ) 2.4 V vs SCE).
To learn about the reaction mechanism, in the case of 2a,
the relationship between the electricity and the yields of the
fluorinated products 2c and 2d was investigated in Et3N-3HF/
MeCN. As shown in Figure 1, the maximum yield of 2c was
obtained at 2 F/mol, and then the yield decreased with the
amount of electricity. On the other hand, the yield of 2d
increased linearly to 65% yield with the amount of electricity.
This near-linear formation of 2d and the course of the yield of
2c suggest that 2d is formed via 2c. Then, the oxidation potential
of 2c was measured. The oxidation potential of 2c (Epox ) 1.90
Results and Discussion
At first, the oxidation potentials of N-methyl- and N-p-
tosylpyrrole (1a, 3a) and their 2-cyano derivatives 2a and 4a
were measured. As shown in Table 1, the oxidation potential
of 2a having a strongly electron-withdrawing cyano group was
much higher compared with that of 1a devoid of an electron-
withdrawing cyano group. The oxidation potential of 4a having
a strongly electron-withdrawing cyano group was also much
higher compared with that of 3a devoid of an electron-
withdrawing cyano group. Interestingly, 2a and 3a have similar
oxidation potentials.
Next, anodic fluorination of 1a-4a was carried out with
various supporting fluoride salts in acetonitrile (MeCN). As
show in Table 2, anodic fluorination of 1a did not take place at
all and a polymeric product was formed at the anode surface
regardless of supporting fluoride salts (entries 1 and 2). On the
other hand, anodic fluorination of 2a proceeded smoothly to
ox
V vs SCE) was slightly lower compared with that of 2a (Ep
) 1.95 V vs SCE) because of the resonance effect of the fluorine
atom of 2c. These facts indicate that the further oxidation of 2c
gives 2d after 2c is once formed during the electrolysis. Then,
anodic fluorination of 2c was investigated. As shown in eq 1,
(4) (a) Sham, L. H. In Fluorine-containing Amino Acids; Kuhahr, V. P.,
Soloshonok, V. A., Eds.; John Wiley & Sons: Chichester, UK, 1995; p
333. (b) Witkowski, S.; Rao, Y. K.; Premchandran, R. H.; Halushka, P. V.;
Fried, J. J. Am. Chem. Soc. 1992, 114, 8464-8472. (c) Takahashi, L. H.;
Radhakrishnan, R.; Rosenfield, R. E., Jr.; Meyer, E. F., Jr.; Trainor, D. A.
J. Am. Chem. Soc. 1989, 111, 3368-3374. (d) Chambers, R. D.; Jaouhari,
R.; O’Hagan, D. Tetrahedron 1989, 45, 5101-5108.
(5) Middleton, W. J. J. Org. Chem. 1975, 40, 574-578.
(6) (a) Percy, J. M. Top. Curr. Chem. 1997, 193, 131-195. (b) Tozer,
M. J.; Herpin, T. F. Tetrahedron 1996, 52, 8619-8683.
(7) (a) Fuchigami, T.; Tajima, T. In Fluorine-Containing Synthons;
Soloshonok, V. A., Ed.; ACS Symp. Ser. No. 911; Oxford University Press/
American Chemical Society: Washington, DC, 2005; Chapter 15. (b)
Fuchigami, T. In Organic Electrochemistry, 4th ed.; Lund, H., Hammerich,
O., Eds.; Marcel Dekker: New York, 2001; Chapter 25. (c) Fuchigami, T.
In AdVances in Electron-Transfer Chemistry; Mariano, P. S., Ed.; JAI
Press: Greenwich, CT, 1999; Vol. 6, pp 41-130. (d) Noel, M.; Surya-
narayanan, V.; Chellammal, S. J. Fluorine Chem. 1997, 83, 31-40. (e)
Fuchigami, T. In Topics in Current Chemistry, 170; Steckhan, E. ,Ed.;
Electrochemistry, Vol. 5; Springer-Verlag: Berlin, 1994; pp 1-37.
(8) (a) Fuchigami, T.; Konno, A.; Nakagawa, K.; Shimojo, M. J. Org.
Chem. 1994, 59, 5937-5941. (b) Fuchigami, T.; Hayashi, T.; Konno, A.
Tetrahedron Lett. 1992, 33, 3161-3164. (c) Konno, A.; Nakagawa, K.;
Fuchigami, T. J. Chem. Soc., Chem. Commun. 1991, 1027-1029. (d)
Fuchigami, T.; Shimojo, M.; Konno, A.; Nakagawa, K. J. Org. Chem. 1990,
55, 6074-6075.
anodic fluorination of 2c in Et3N-3HF/MeCN was carried out
to provide the fluorinated product 2d in good yield. Thus, it
was clarified that 2d is generated from 2c. Furthermore, to
clarify the oxygen source of 2e, excess amounts of water were
added to the electrolytic solution after the electrolysis of 2a in
J. Org. Chem, Vol. 71, No. 4, 2006 1437

Tajima et al.
TABLE 2. Anodic Fluorination of N-Substituted Pyrroles
yield (%)a
1c-4c
entry
substrate
R1
R2
supporting electrolyte (1 M)
1b-4b
1d-4d
1e-4e
1b
2b
3
4
5
1a
1a
2a
2a
2a
3a
Me
Me
Me
Me
Me
Ts
H
H
CN
CN
CN
H
Et3N-3HF
Et4NF-4HF
Et3N-2HF
Et3N-3HF
Et3N-5HF
Et3N-3HF
0
0
0
0
0
93
0
0
0
0
32
65
5
0
0
trace
3
54 (51)
0
20 (19)c
5
0
0
6
0
[34/66]d
48
[46/54]
49
[43/57]
80(55)
[45/55]
7
8
9
4a
4a
4a
Ts
Ts
Ts
CN
CN
CN
Et3N-3HF
Et3N-5HF
Et4NF-4HF
0
0
0
0
0
0
0
0
0
a Determined by 19F NMR spectroscopy. b A polymeric product was formed at the anode surface. c Isolated yield in parentheses. d Ratio of cis/trans
isomers.
tion of pyrroles, while they suppress highly efficiently anodic
polymerization. The reaction pathway seems to greatly depend
not on steric hindrance at the 2-position but on the reactivity of
the cation radical intermediate A, because anodic fluorination
of 3a devoid of a substituent at the 2-position proceeded
smoothly (entry 6 in Table 2). The difluorinated product 2b
derived from 2a eliminates a fluoride anion rapidly due to the
absence of an electron-withdrawing group on the nitrogen atom
to provide 2c. Then, since 2c is more easily oxidized than 2a,
the trifluorinated product 2d is preferentially formed by the
further oxidation of 2c once formed during the electrolysis. On
the other hand, it also seems to be possible to form 2d by the
further oxidation of 2b; however, the further oxidation of 3b
and 4b did not take place at all. Therefore, 2d is formed from
2c. Then, the trifluorinated product 2d reacts rapidly with water
to give the difluorinated product 2e.
The difluorinated product 2e derived from 2a has both a bio-
logically interesting gem-difluoromethylene unit and an activated
olefin in the heterocyclic ring. Therefore, it is expected that 2e
becomes a useful building block having a gem-difluorometh-
ylene unit. Then, at first, the Diels-Alder reaction of 2e as a
dienophile with various dienes was investigated. Several
examples of the Diels-Alder reaction are shown in Table 3.
2e reacted with open-chain dienes such as isoprene (5a) and
2,3-dimethyl-1,3-butadiene (6a) under reflux in toluene to afford
the corresponding cycloaddition products 5b and 5c in excellent
yield as a regioisomeric mixture and 6b in quantitative yield,
respectively (entries 1 and 2). The Diels-Alder reaction of 2e
with cyclic dienes such as cyclopentadiene (7a), cyclohexadiene
(8a), and furan (9a) also proceeded smoothly to provide the
cycloaddition products 7b, 8b, and 9b in quantitative yields with
endo selectivities (entries 3-5). From these results, it was found
that 2e is a highly useful dienophile having a gem-difluorom-
ethylene unit in the Diels-Alder reaction.
FIGURE 1. Relationship between the electricity and the yields of 2c
and 2d in Et3N-3HF/MeCN.
Et3N-3HF/MeCN (eq 2). The reaction mixture was stirred for
4 h to give the difluorinated product 2e in 54% yield (ca. 83%
yield from 2d in consideration of entry 4 in Table 2). This result
clearly indicates that 2d was readily hydrolyzed to form 2e
efficiently. Therefore, 2d is a precursor to 2e. Thus, the oxygen
source of 2e is water contaminated in the fluoride salts, and
there seems to be more water contamination in Et3N-5HF.
In consideration of these results, a possible reaction mech-
anism was proposed as shown in Scheme 1. At first, one-electron
oxidation of a substrate gives the corresponding cation radical
intermediate A. Then, in the case of 1a, anodic polymerization
proceeds via the radical coupling reaction of A.9 On the other
hand, in the cases of 2a, 3a, and 4a, anodic fluorination takes
place to provide the corresponding difluorinated product via a
conventional ECEC process. Therefore, interestingly, electron-
withdrawing p-tosyl and cyano groups promote anodic fluorina-
Next, the Michael reaction of 2e with various nucleophiles
was also investigated. Several examples of the Michael reaction
are listed in Table 4. In every case, the reactions proceeded
smoothly in the presence of Bu4NF at room temperature to
provide the corresponding Michael addition products in good
(9) Heinze, J. In Organic Electrochemistry, 4th ed.; Lund, H., Hammer-
ich, O., Eds.; Marcel Dekker: New York, 2001; Chapter 32.
1438 J. Org. Chem., Vol. 71, No. 4, 2006

Electrolytic Partial Fluorination of Organic Compounds
SCHEME 1. Reaction mechanism
TABLE 3. Diels-Alder Reaction of 2e with Various Dienes
TABLE 4. Michael Reaction of 2e with Various Nucleophiles
a Determined by 19F NMR Spectroscopy. b Isolated yield in parentheses.
c Regioisomeric ratio.
a Determined by 19F NMR Spectroscopy. b Isolated yield in parentheses.
to quantitative yields. Thus, it was found that 2e is also valuable
in the Michael reaction.
On the other hand, anodic fluorination of N-methylpyrrole
devoid of an electron-withdrawing group did not take place at
all and a polymeric product was formed at the anode surface.
The reaction pathway greatly depended on the reactivity of
cation radical intermediates derived from one-electron oxidation
Conclusion
We have successfully carried out the anodic fluorination of
pyrroles having electron-withdrawing groups at 1- and/or
2-positions to provide some corresponding fluorinated products.
J. Org. Chem, Vol. 71, No. 4, 2006 1439

Tajima et al.
(dd, J ) 18.7, 6.7 Hz), 129.8, 128.3, 112.0 (d, J ) 58.7 Hz), 99.7
(d, J ) 210.2 Hz), 95.1 (d, J ) 210.7 Hz), 21.8; 19F NMR (254
MHz, CDCl3) δ -23.1 (dd, J ) 42.5, 7.4 Hz), -60.3 (dd, J )
66.6, 42.5 Hz); MS (m/z) 284 (M+), 155, 109, 91, 65, 51; HRMS
calcd for C12H10F2N2O2S 284.0431, found 284.0435. trans-4b: 1H
NMR (270 MHz, CDCl3) δ 7.90 (d, J ) 8.1 Hz, 2H), 7.34 (d, J )
8.1 Hz, 2H), 6.48 (d, J ) 5.8 Hz, 1H), 6.47 (dd, J ) 64.6, 18.0
Hz, 1H), 6.34 (d, J ) 5.8 Hz, 1H), 2.45 (s, 3H); 13C NMR (67.8
MHz, CDCl3) δ 145.4, 136.0, 133.4 (dd, J ) 17.9, 6.7 Hz), 131.4
(dd, J ) 22.4, 8.4 Hz), 129.7, 128.0, 112.0 (dd, J ) 58.1, 11.7
Hz), 99.0 (dd, J ) 213.5, 6.1 Hz), 94.7 (dd, J ) 215.2, 6.1 Hz),
21.7; 19F NMR (254 MHz, CDCl3) δ -20.3 (dd, J ) 42.5, 18.0
Hz), -55.1 (dd, J ) 64.6, 42.5 Hz); MS (m/z) 284 (M+), 155,
109, 91, 65, 51; HRMS calcd for C12H10F2N2O2S 284.0431, found
284.0428.
of N-substituted pyrroles. Anodic fluorination of 2-cyano-1-
methylpyrrole (2a) in Et3N-5HF/MeCN gave 5,5-difluoro-1-
methyl-3-pyrrolin-2-one (2e) having a biologically interesting
gem-difluoromethylene unit and an activated olefin in the
heterocyclic ring in moderate yield. The Diels-Alder reaction
of 2e with various dienes proceeded smoothly to provide the
corresponding cycloaddition products in excellent yields. Fur-
thermore, the Michael reaction of 2e with various nucleophiles
also took place to provide the corresponding Michael addition
products in good to excellent yields. Therefore, it was found
that 2e derived from anodic fluorination of 2a is a highly useful
building block having a gem-difluoromethylene unit in the
Diels-Alder reaction and Michael reaction.
General Procedure for the Diels-Alder Reaction. The Diels-
Alder reaction of 2e (0.1 mmol) with a diene (1 mmol) was carried
out in toluene (5 mL). The reaction mixture was stirred for 0.5-
1.5 d under reflux. After the reaction was complete, the reaction
mixture was passed through a short column of silica gel eluting
with CHCl3. The eluent was evaporated under vacuum. Then, the
yields of the cycloaddition products 5b, 5c, 6b, 7b, 8b, and 9b
were calculated by means of 19F NMR by using a known amount
of monofluorobenzene as an internal standard. After that, 5b, 5c,
6b, 7b, 8b, and 9b were isolated by liquid chromatography eluting
with MeCN to give the pure cycloaddition products.
Experimental Section
General Procedure for Anodic Fluorination. Anodic fluorina-
tion of 1a, 2a, 3a, 4a, and 2c (1 mmol) was carried out with
platinum plate electrodes (2 × 2 cm2) in MeCN (10 mL) containing
a fluoride salt (1 M), using an undivided cell at room temperature.
Constant current (10 mA cm-2) was applied. The conversion of a
starting material was monitored by TLC. After the charge was
passed (4 F mol-1) until the starting material was consumed, the
electrolytic solution was passed through a short column of silica
gel eluting with CHCl3 to remove the fluoride salt. The eluent was
evaporated under vacuum. Then, the yields of the fluorinated
products 2c-e, 3b, and 4b were calculated by means of 19F NMR
by using a known amount of monofluorobenzene as an internal
standard. After that, 2c, 2e, 3b, and 4b were isolated by liquid
chromatography eluting with MeCN to give the pure fluorinated
products.
3,3-Difluoro-2,5-dimethyl-2,3,3a,4,7,7a-hexahydroisoindol-1-
1
one (5b): H NMR (270 MHz, CDCl3) δ 5.48 (br s, 1H), 3.01-
2.83 (m, 2H), 2.87 (s, 3H), 2.39-2.14 (m, 4H), 1.72 (br s, 3H);
13C NMR (67.8 MHz, CDCl3) δ 174.6, 134.3, 126.8 (dd, J ) 250.4,
247.6 Hz), 118.8, 39.8, 38.5 (dd, J ) 26.3, 20.7 Hz), 29.8, 27.4,
23.4, 21.3 (dd, J ) 6.7, 2.2 Hz); 19F NMR (254 MHz, CDCl3) δ
-1.0 (dd, J ) 185.0, 12.9 Hz), -17.5 (d, J ) 185.0 Hz); MS (m/
z) 201(M+), 186, 181, 152; HRMS calcd for C10H13F2NO 201.0965,
found 201.0962.
1
2-Cyano-5-fluoro-1-methylpyrrole (2c): H NMR (270 MHz,
CDCl3) δ 6.66 (m, 1H), 5.60 (m, 1H), 3.62 (s, 3H); 13C NMR (67.8
MHz, CDCl3) δ 148.2 (d, J ) 267.2 Hz), 129.3 (d, J ) 4.5 Hz),
117.9 (d, J ) 3.9 Hz), 113.3, 88.3 (d, J ) 11.7 Hz), 30.1 (d, J )
1.7 Hz); 19F NMR (254 MHz, CDCl3) δ -54.5 (m); MS (m/z) 124
(M+), 109, 84; HRMS calcd for C6H5N2F 124.0437, found
124.0443.
3,3-Difluoro-2,6-dimethyl-2,3,3a,4,7,7a-hexahydroisoindol-1-
1
one (5c): H NMR (270 MHz, CDCl3) δ 5.48 (br s, 1H), 3.01-
2.83 (m, 2H), 2.87 (s, 3H), 2.39-2.14 (m, 4H), 1.72 (br s, 3H);
13C NMR (67.8 MHz, CDCl3) δ 174.8, 134.2, 126.8 (dd, J ) 250.4,
247.6 Hz), 119.6, 39.4 (dd, J ) 25.7, 20.7 Hz), 39.3 (d, J ) 1.7
Hz), 25.9 (dd, J ) 6.7, 1.7 Hz), 23.8, 23.4, 23.2; 19F NMR (254
MHz, CDCl3) δ -1.3 (dd, J ) 185.0, 14.8 Hz), -15.7 (d, J )
185.0 Hz); MS (m/z) 201(M+), 186, 170, 152; HRMS calcd for
C10H13F2NO 201.0965, found 201.0961.
2,5,5-Trifluoro-1-methyl-3-pyrrolin-2-carbonitrile (2d): 19F
NMR (254 MHz, CDCl3) δ -2.5 (dd, J ) 205.3, 18.5 Hz), -11.3
(dd, J ) 205.3, 27.7 Hz), -30.4 (dd, 27.7, 18.5 Hz); MS (m/z)
162 (M+).
5,5-Difluoro-1-methyl-3-pyrrolin-2-one (2e): FTIR (KBr) νmax
3,3-Difluoro-2,5,6-trimethyl-2,3,3a,4,7,7a-hexahydroisoindol-
3445 (br), 3096, 1705, 1441, 1389, 1256, 1107, 1053, 941, 831,
1
1
698 cm-1; H NMR (270 MHz, CDCl3) δ 6.92 (d, J ) 5.8 Hz,
1-one (6b): H NMR (270 MHz, CDCl3) δ 2.94 (m, 2H), 2.85 (s,
3H), 2.38-2.11 (m, 4H), 1.67 (s, 6H); 13C NMR (67.8 MHz,
CDCl3) δ 174.5, 126.9 (dd, J ) 249.8, 247.0 Hz), 126.0, 125.3,
40.5, 39.7 (dd, J ) 25.7, 20.1 Hz), 29.5, 27.9 (dd, J ) 6.7, 1.7
Hz), 23.8, 19.2, 18.8; 19F NMR (254 MHz, CDCl3) δ 1.0 (dd, J )
186.8, 14.8 Hz), -15.6 (d, J ) 186.8 Hz); MS (m/z) 215(M+),
200, 195, 152; HRMS calcd for C11H15F2NO 215.1122, found
215.1117.
1H), 6.30 (d, J ) 5.8 Hz, 1H), 2.94 (s, 3H); 13C NMR (67.8 MHz,
CDCl3) δ 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 (254 MHz, CDCl3) δ -23.6
(s); MS (m/z) 133 (M+), 106, 84; HRMS calcd for C5H5F2NO
133.0339, found 133.0335.
2,5-Difluoro-1-p-tosyl-3-pyrroline (3b): cis-3b: 1H NMR (270
MHz, CDCl3) δ 7.88 (d, J ) 8.1 Hz, 2H), 7.33 (d, J ) 8.1 Hz,
2H), 6.48 (dd, J ) 50.0, 24.0 Hz, 2H), 6.24 (s, 2H), 2.44 (s, 3H);
19F NMR (254 MHz, CDCl3) δ -57.1 (dd, J ) 50.0, 24.0 Hz);
MS (m/z) 259 (M+), 155, 109, 91, 65, 51; HRMS calcd for
C11H11F2NO2S 259.0479, found 259.0477. trans-3b: 1H NMR (270
MHz, CDCl3) δ 7.85 (d, J ) 8.1 Hz, 2H), 7.33 (d, J ) 8.1 Hz,
2H), 6.50 (dd, J ) 50.8, 32.3 Hz, 2H), 6.28 (s, 2H), 2.43 (s, 3H);
13C NMR (67.8 MHz, CDCl3) δ 144.4, 137.2, 131.6 (dd, J ) 14.0,
13.4 Hz), 129.6, 127.1, 98.8 (dd, J ) 224.1, 8.4 Hz), 21.7; 19F
NMR (254 MHz, CDCl3) δ -51.1 (dd, J ) 50.8, 32.3 Hz); MS
(m/z) 259 (M+), 155, 109, 91, 65, 51; HRMS calcd for C11H11F2-
NO2S 259.0479, found 259.0484.
5,5-Difluoro-4-methyl-4-aza-tricyclo[5.2.1.02,6]dec-8-en-3-
one (7b): endo-7b: 1H NMR (270 MHz, CDCl3) δ 6.09 (s, 2H),
3.34-3.10 (m, 4H), 2.73 (s, 3H), 1.66 (d, J ) 8.7 Hz), 1.46 (d, J
) 8.7 Hz); 13C NMR (67.8 MHz, CDCl3) δ 172.8, 134.3, 134.1,
125.3 (dd, J ) 248.7, 244.8 Hz), 51.4, 48.8 (t, J ) 2.2 Hz), 45.8
(dd, J ) 26.3, 20.7 Hz), 44.5, 43.9 (t, J ) 2.8 Hz), 23.3; 19F NMR
(254 MHz, CDCl3) δ 7.7 (dd, J ) 190.5, 16.6 Hz), -13.4 (d, J )
190.5 Hz); MS (m/z) 199(M+), 172, 156, 149; HRMS calcd for
C10H11F2NO 199.0809, found 199.0815.
5,5-Difluoro-4-methyl-4-aza-tricyclo[5.2.2.02,6]undec-8-en-3-
one (8b): endo-8b: 1H NMR (270 MHz, CDCl3) δ 6.13 (m, 2H),
3.09 (m, 1H), 2.99 (m. 1H), 2.85-2.71 (m, 2H), 2.79 (s, 3H), 1.53
(m, 2H), 1.34 (m, 2H); 13C NMR (67.8 MHz, CDCl3) δ 173.7,
132.4, 131.3, 126.5 (dd, J ) 248.2, 245.4 Hz), 46.6 (t, J ) 1.7
Hz), 44.4 (dd, J ) 25.7, 20.1 Hz), 31.0, 29.4 (dd, J ) 5.0, 2.2 Hz),
23.8, 23.5, 23.0; 19F NMR (254 MHz, CDCl3) δ 7.5 (dd, J ) 186.8,
2,5-Difluoro-1-p-tosyl-3-pyrrolin-2-carbonitrile (4b): cis-4b:
1H NMR (270 MHz, CDCl3) δ 7.96 (d, J ) 8.1 Hz, 2H), 7.34 (d,
J ) 8.1 Hz, 2H), 6.58 (dd, J ) 66.6, 7.4 Hz, 1H), 6.46 (d, J ) 5.8
Hz, 1H), 6.31 (d, J ) 5.8 Hz, 1H), 2.45 (s, 3H); 13C NMR (67.8
MHz, CDCl3) δ 145.6, 135.3, 133.7 (dd, J ) 15.9, 6.7 Hz), 130.9
1440 J. Org. Chem., Vol. 71, No. 4, 2006

Electrolytic Partial Fluorination of Organic Compounds
16.6 Hz), -11.7 (d, J ) 186.8 Hz); MS (m/z) 213(M+), 185, 170,
155; HRMS calcd for C11H13F2NO 213.0965, found 213.0970.
5,5-Difluoro-4-methyl-10-oxa-4-aza-tricyclo[5.2.1.02,6]dec-8-
en-3-one (9b): endo-9b: 1H NMR (270 MHz, CDCl3) δ 6.45-
6.36 (m, 2H), 5.25-5.19 (m, 2H), 3.60-3.52 (m, 1H), 3.41-3.30
(m, 1H), 2.73 (s, 3H); 13C NMR (67.8 MHz, CDCl3) δ 170.4, 134.6,
134.4, 123.5 (dd, J ) 247.0, 246.0 Hz), 79.4, 78.5 (dd, J ) 4.5,
2.2 Hz), 49.2 (t, J ) 2.2 Hz), 45.4 (dd, J ) 28.5, 21.2 Hz), 23.6;
19F NMR (254 MHz, CDCl3) δ 5.5 (dd, J ) 194.2, 14.8 Hz), -13.7
(dt, J ) 194.2, 7.4 Hz); MS (m/z) 201 (M+), 172, 132, 114, 95;
HRMS calcd for C9H9F2NO2 201.0601, found 201.0588. exo-9b:
1H NMR (270 MHz, CDCl3) δ 6.53-6.45 (m, 2H), 5.33 (s, 1H),
5.25 (s, 1H), 2.89 (s, 3H), 2.89-2.86 (m, 1H), 2.77-2.72 (m, 1H);
13C NMR (67.8 MHz, CDCl3) δ 170.9, 137.2, 135.9, 124.4 (dd, J
) 249.3, 246.0 Hz), 80.3, 78.6 (dd, J ) 7.3, 3.4 Hz), 49.4, 46.7
(dd, J ) 27.9, 22.9 Hz), 24.0; 19F NMR (254 MHz, CDCl3) δ 5.1
(dd, J ) 188.7, 14.8 Hz), -14.9 (d, J ) 188.7 Hz); MS (m/z) 201-
(M+), 132, 114, 95; HRMS calcd for C9H9F2NO2 201.0601, found
201.0601.
General Procedure for the Michael Reaction. Michael reaction
of 2e (0.1 mmol) with a nucleophile (1 mmol) was carried out in
CH2Cl2 (5 mL) in the presence of Bu4NF (0.2 mmol). The reaction
mixture was stirred for 0.25-2 d at room temperature. After the
reaction was complete, the reaction mixture was passed through a
short column of silica gel eluting with CHCl3. The eluent was
evaporated under vacuum. Then, the yields of the Michael addition
products 10b, 11b, 12b, 13b, and 14b were calculated by means
of 19F NMR by using a known amount of monofluorobenzene as
an internal standard. After that, 10b, 11b, 12b, 13b, and 14b were
isolated by liquid chromatography eluting with MeCN to give the
pure Michael addition products.
248.7, 240.9 Hz), 114.7, 55.4, 47.9 (dd, J ) 26.3, 24.6 Hz), 36.1
(d, J ) 2.2 Hz), 24.0; 19F NMR (254 MHz, CDCl3) δ -3.3 (ddd,
J ) 183.1, 12.9, 3.7 Hz), -8.9 (ddd, J ) 183.1, 7.4, 1.9 Hz); MS
(m/z) 253 (M+ - HF), 251, 151, 139; HRMS calcd for C12H13F2-
NO2S 273.0635, found 273.0634.
4-(4-Ethoxyphenylamino)-5,5-difluoro-1-methylpyrrolidin-2-
1
one (12b): H NMR (270 MHz, CDCl3) δ 6.82-6.78 (m, 2H),
6.68-6.65 (m, 2H), 4.39-4.27 (m, 1H), 3.97 (q, J ) 7.1 Hz, 2H),
3.69 (br s, 1H), 3.12-3.02 (m, 1H), 2.93 (s, 3H), 2.44-2.34 (m,
1H), 1.38 (t, J ) 7.1 Hz, 3H); 13C NMR (67.8 MHz, CDCl3) δ
169.6, 152.5, 139.3, 124.7 (dd, J ) 254.3, 252.1 Hz), 115.6, 115.3,
64.0, 54.5 (dd, J ) 26.8, 21.8 Hz), 37.2, 23.8, 15.0; 19F NMR (254
MHz, CDCl3) δ -7.6 (dd, J ) 185.0, 11.1 Hz), -17.3 (dd, J )
185.0, 5.5 Hz); MS (m/z) 270 (M+), 250 (M+ - HF), 221, 207;
HRMS calcd for C13H16F2N2O2 270.1180, found 270.1172.
Diethyl 2-(2,2-difluoro-1-methyl-5-oxo-pyrrolidin-3-yl)ma-
1
lonate (13b): H NMR (270 MHz, CDCl3) δ 4.30-4.19 (m, 4H),
3.69 (d, J ) 9.1 Hz), 3.53-3.36 (m, 1H), 2.92-2.81 (m, 1H), 2.89
(s, 3H), 2.66-2.55 (m, 1H), 1.32-1.25 (m, 6H); 13C NMR (67.8
MHz, CDCl3) δ 170.3, 166.6, 166.5, 125.7 (dd, J ) 251.0, 249.3
Hz), 62.3, 62.2, 51.2, 39.9 (dd, J ) 25.7, 21.8 Hz), 33.4, 23.8,
14.0; 19F NMR (254 MHz, CDCl3) δ -1.5 (ddd, J ) 186.8, 12.9,
3.7 Hz), -19.5 (dd, J ) 186.8, 7.4 Hz); MS (m/z) 273 (M+
-
HF), 248, 220, 200, 172, 152, 128; HRMS calcd for C12H17F2NO5
293.1075, found 293.1080.
Diethyl 2-(2,2-difluoro-1-methyl-5-oxo-pyrrolidin-3-yl)-2-me-
1
thylmalonate (14b): H NMR (270 MHz, CDCl3) δ 4.29-4.15
(m, 4H), 3.49-3.34 (m, 1H), 2.97-2.77 (m, 2H), 2.88 (s, 3H),
1.61 (s, 3H), 1.30-1.22 (m, 6H); 13C NMR (67.8 MHz, CDCl3) δ
171.0, 170.0, 169.4, 126.2 (dd, J ) 252.2, 248.7 Hz), 62.2, 61.9,
54.1, 45.4 (dd, J ) 25.7, 20.1 Hz), 33.3, 23.7, 19.3, 14.0; 19F NMR
(254 MHz, CDCl3) δ 6.2 (ddd, J ) 190.5, 15.0, 1.9 Hz), -11.5
(ddd, J ) 190.5, 7.4, 1.9 Hz); MS (m/z) 287 (M+ - HF), 262,
214, 186, 166, 142, 128; HRMS calcd for C13H19F2NO5 307.1231,
found 307.1234.
5,5-Difluoro-1-methyl-4-(phenylthio)pyrrolidin-2-one (10b):
1H NMR (270 MHz, CDCl3) δ 7.53-7.50 (m, 2H), 7.35-7.33 (m,
3H), 4.06-3.93 (m, 1H), 3.07-2.96 (m, 1H), 2.90 (s, 3H), 2.60-
2.49 (m, 1H); 13C NMR (67.8 MHz, CDCl3) δ 169.4, 132.8, 131.7,
129.2, 128.5, 124.8 (dd, J ) 251.5, 248.7 Hz), 47.1 (dd, J ) 27.4,
24.6 Hz), 36.4 (t, J ) 1.1 Hz), 24.1; 19F NMR (254 MHz, CDCl3)
δ -3.0 (ddd, J ) 183.1, 11.1, 3.7 Hz), -8.7 (ddd, J ) 183.1, 7.4,
1.9 Hz); MS (m/z) 223 (M+ - HF), 221, 136, 135, 109; HRMS
calcd for C11H11F2NOS 243.0529, found 243.0522.
Acknowledgment. This research was supported by a Grant-
in-Aid for Scientific Research on Priority Areas (A) “Exploita-
tion of Multi-Element Cyclic Molecules” from the Ministry of
Education, Culture, Sports, Science and Technology, Japan.
5,5-Difluoro-1-methyl-4-(4-methoxyphenylthio)pyrrolidin-2-
one (11b): H NMR (270 MHz, CDCl3) δ 7.49 (d, J ) 8.6 Hz,
2H), 6.87 (d, J ) 8.6 Hz, 2H), 3.90-3.81 (m, 1H), 3.81 (s, 3H),
2.99-2.88 (m, 1H), 2.88 (s, 3H), 2.56-2.46 (m, 1H); 13C NMR
(67.8 MHz, CDCl3) δ 169.3, 160.4, 136.4, 128.5, 121.2 (dd, J )
Supporting Information Available: General experimental
details and spectroscopy data. This material is available free of
charge via the Internet at http://pubs.acs.org.
1
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J. Org. Chem, Vol. 71, No. 4, 2006 1441