Efficient synthesis of 3-arylaminopyrroline-2-ones by the tandem reaction of anilines and β,γ-unsaturated α-ketoesters

Article abstract of DOI:10.1002/jhet.5570430421

A concise and efficient synthetic approach to 3-arylaminopyrroline-2-ones from anilines and β,γ-unsaturated α-ketoesters in boiling dichloromethane has been developed. This protocol possesses many advantages such as short reaction time, high isolated yiel

Full text of DOI:10.1002/jhet.5570430421

Jul-Aug 2006
949
Efficient Synthesis of 3-Arylaminopyrroline-2-ones by the Tandem
Reaction of Anilines and ꢀ,ꢁ-Unsaturated ꢂ-Ketoesters
Yan-Chao Wu,[a],[b] Li Liu,[a] Dong Wang,[a] Yong-Jun Chen,[a]*
[a] Center for Molecular Science, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100080, China.
Tel.: +86 10 62554614; Fax: +86 10 62554449; Email: yjchen@iccas.ac.cn.
[b] Graduate School of Chinese Academy of Sciences, Beijing 100080, China.
Received September 24, 2005
O
H
N
O
Ar
CH2Cl2
2
ArNH2
reflux
4-12 h
O
O
N
Ar
X
X
1
2
3
A concise and efficient synthetic approach to 3-arylaminopyrroline-2-ones from anilines and ꢀ,ꢁ-
unsaturated ꢂ-ketoesters in boiling dichloromethane has been developed. This protocol possesses many
advantages such as short reaction time, high isolated yields, and expanding substrate scopes. According to
the isolated intermediates and controlled reactions, the reaction was tentatively proposed to involve the
Michael addition/condensation and subsequent intramolecular cyclization. The structures of the title
compounds were unambiguously confirmed by various spectral data such as X-ray crystallographic
analysis.
J. Heterocyclic Chem., 43, 949 (2006).
crystallographic technologies. In this case, we discussed
here the NMR data and the X-ray crystallographic
analysis, and elucidated them as 3-arylaminopyrroline-
2-ones (not 3-aryliminopyrrolidin-2-ones).
Introduction.
The development of synthetic methods for
constructing pyrroles and their analogues has been of
great interest to organic chemists for many years due to
the presence of these structural units in a variety of
biologically active natural products, medicinally
relevant compounds, and functional materials [1-14].
It’s worth mentioning that 3-arylaminopyrroline-2-ones
had been reported to exhibit anti-inflammatory,
analgesic [15], antiphlogistic, and analgetic activities
[16]. Some strategies have been developed for the
synthesis of these molecules. One is the condensation of
pyruvic acid derivatives, anilines and aldehydes, in
which imines or ꢀ,ꢁ-unsaturated ꢂ-ketoesters sometimes
were preformed [15-18]. Another is the condensation
of anilines with pyrrolidine-2,3-diones or furan-2(5H)-
ones [19]. These established strategies can synthesize 3-
arylaminopyrroline-2-ones, but they have some
shortcomings such as only low to moderate yields, long
reaction time, and substrate limitation. Therefore it is
still demand for efficient synthetic strategy to provide
these compounds. Herein we would like to report our
recent results on the convenient preparation of 3-
arylaminopyrroline-2-ones (3) from anilines (1) and
ꢀ,ꢁ-unsaturated ꢂ-ketoesters (2), in which two
molecules 1 are coupled in one pot with one molecule 2
in boiling dichloromethane (Scheme 1). On the other
hand, this kind of compounds had been incorrectly
identified as 3-aryliminopyrrolidin-2-ones (4, Scheme
2) [20] due to the historical difficulties in properly
characterizing them without NMR and X-ray
Scheme 1
O
H
N
O
Ar
CH2Cl2
2
ArNH2
reflux
4-12 h
O
O
N
Ar
X
X
1
2
3
Scheme 2
Ar
N
O
N
Ar
X
4
Results and Discussion.
The new strategy for the synthesis of 3-arylamino-
pyrroline-2-ones came from our attempts to construct
quinolines without catalyst. It is well known that many
methods for the synthesis of quinolines needed various
catalysts or promoters [21-25]. Therefore it was our
interest to develop a simple synthetic method for
quinolines. In this regard, p-toluidine (1a) and (E)-methyl
2-oxo-4-phenylbut-3-enoate (2a) were chosen to screen
the reaction conditions (Scheme 3).

950
Y.-C. Wu, L. Liu, D. Wang, Y.-J. Chen
Vol 43
Scheme 3
detected in these reaction conditions. At room
temperature in dichloromethane or dioxane, the isolated
yield of 3a decreased dramatically (entries 7-8). When the
reaction is heated to the same temperature as entry 6 in
dioxane or chloroform, 3a was still obtained in lower
yields than that in dichloromethane (entries 6, 9 and 10).
Dichloromethane seems to be the most suitable reaction
solvent in all screened media in terms of reaction
temperature and isolated yields. Although the solvent
effects on the reaction pathway were not fully
investigated, it appears that an efficient synthetic process
for 3-arylaminopyrroline-2-ones such as 3a could be
realized under the reaction conditions of entry 6.
O
O
NH2
O
O
solvent
O
N
1a
2a
5
O
O
O
H
N
N
O
O
N
N
Table 2
3a
6
Synthesis of 3-arylaminopyrroline-2-ones (3, Scheme 1).
Table 1
Time
(hours)
Yielda
(%)
Entry
1
2
3
Selected results on the solvent effects (Scheme 3).
1
1a: Ar = 4-MeC6H4
1b: Ar = 4-MeOC6H4
1c: Ar = 4-FC6H4
1d: Ar = 4-ClC6H4
1e: Ar = 3-ClC6H4
1f: Ar = 2-naphthyl
1g: Ar = 4-NO2C6H4
1h: Ar = C6H5
3a
3b
3c
3d
3e
3f
6
4
88
92
78
81
70
64
0
2a: X = H
2a: X = H
2a: X = H
2a: X = H
2a: X = H
2a: X = H
2a: X = H
2b: X = OMe
2c: X = Me
2c: X = Me
Time
(hours)
5a
(%)
3aa
(%)
6a
(%)
Entry
Solvent
T (°C)
1a: 2a
2
3
7
1
2
3
4
5
6
Toluene
THF
110
67
78
62
40
40
2
4
3
5
6
6
1:1
1:1
1:1
1:1
1:1
2:1
2
1
2
1
2
0
22
19
12
21
23
88
8
8
6
6
9
0
4
7
5
8
EtOH
6
9
HCCl3
CH Cl
2
2
2
2
7
--
12
6
CH Cl
2
8
3g
3h
3i
80
83
84
86
87
84
CH Cl
2
7
8
25
25
40
40
24
24
6
2:1
2:1
2:1
2:1
0
0
0
0
29
27
69
64
0
0
0
0
9
1h: Ar = C6H5
6
Dioxane
Dioxane
HCCl3
10
11
12
13
1a: Ar = 4-MeC6H4
5
9
1b: Ar = 4-MeOC6H4 2c: X = Me
3j
4
10
6
1h: Ar = C6H5
2d: X = Cl
2d: X = Cl
3k
3l
6
a isolated yields
1d: Ar = 4-ClC6H4
7
a isolated yields
Representative results are listed in Table 1. It was
found that when a solution of (1a, 0.2 mmol) and (2a,
0.2 mmol) in 2 mL toluene under atmospheric N2 was
refluxed for 2 hours, the expected methyl 6-methyl-2-
phenylquinoline-4-carboxylate (5) was isolated only in
extremely low isolated yield (2%, entry 1). However, we
were surprised to find that 3-(p-tolylamino)-5-phenyl-1-
(p-tolyl)-1H-pyrrol-2(5H)-one (3a, 22%) and methyl 4-
(N-(2,5-dihydro-2-oxo-5-phenyl-1-(p-tolyl)-1H-pyrrol-
3-yl)-N-(4-methylcyclohexa-2,4-dienyl)amino)-2-oxo-
4-phenylbutanoate (6, 8%) were also obtained in this
reaction mixture (entry 1). This finding promoted us to
investigate the solvent effect on the reaction. So the
reaction in other solvents such as tetrahydrofuran, ethanol,
chloroform and dichloromethane, gave similar results
(entries 2-5). Markedly, when the ratio of 1a to 2a was
changed from 1:1 to 2:1, only 3a was obtained in high
isolated yield (88%, entry 6). The side product 6 was not
With the view to understanding the generality of the
reaction, we carried out the reaction with various anilines
(1) and ꢀ,ꢁ-unsaturated ꢂ-ketoesters (2) under identical
reaction conditions as outlined above and representative
results as listed in Table 2. It is evident that a wide range
of 1 and 2, which were subjected to this procedure, could
afford the corresponding 3-arylaminopyrroline-2-ones (3)
in high isolated yields. In most cases, the electron-
donating group or electron-withdrawing group on 1 or 2
has no significant impact on yields (entries 1-4, 8-13).
However, there was a decrease in the yield when using 3-
substituted aniline in comparison with its 4-substituted
analogue (entries 4-5), or using bulky aromatic amine
(entry 6). This process did not work, however, with
aniline bearing strong electron-withdrawing groups such
as a nitro one (entry 7).

Jul-Aug 2006
Efficient Synthesis of 3-Arylaminopyrroline-2-ones
951
1
The H NMR diagram of three non-aryl hydrogen
atoms in compound 3d was elucidated in Figure 1. If 3d
were 3-(4-chlorophenylamino)-1-(4-chlorophenyl)-5-
phenyl-1H-pyrrol-2(5H)-one (upper structure), the three
non-aryl hydrogen atoms should be one single-peak (N-
H) and two double-peaks (AB system). If 3d were 3-(4-
chlorocyclohexa-2,4-dienylimino)-1-(4-chlorophenyl)-
5-phenylpyrrolidin-2-one (nether structure), the three
non-aryl hydrogen atoms should be three quadruple-
peaks (ABX system) because C-2 is a chiral carbon
center. Three groups of peaks can be easily observed
in Figure 1, one single-peak (N-H, Ha) and two double-
peaks (Hb and Hc). These results confirmed that 3d
belongs to 3-arylaminopyrroline-2-ones (not 3-aryl-
iminopyrrolidin-2-ones).
Figure 2. The X-ray structure of 3d.
(7c, 0.21%) along with the title product of 3-(4-fluoro-
phenylamino)-1-(4-fluorophenyl)-5-phenyl-1H-
pyrrol-2(5H)-one (3c, 63%) were produced when a
solution of 4-fluorobenzenamine (1c) and (E)-2-oxo-4-
phenylbut-3-enoic acid methyl ester (2a) in
dichloromethane under atmospheric N2 was refluxed
for 4 hours.
Scheme 4
Figure 1. The 1H NMR of 3d.
NH2
O
O
CH2Cl2, reflux
4 h
The structure of compound 3d was further determined
by X-ray crystallographic analysis [26] (Figure 2). On one
hand, the bond lengths of C(7)-C(8), C(8)-C(9) and C(9)-
C(10) are 1.509 Å, 1.317 Å and 1.487 Å, respectively.
Obviously, C(8)-C(9) is a double bond that is shorter than
C(7)-C(8) (or C(9)-C(10), single bond). On the other
hand, the bond length of C(9)-N(2) is 1.371Å that belongs
to C-N single bond. A packing diagram of the crystal
structure shows that the crystal of this compound is
formed with aromatic ꢀ-ꢀ interactions and the intermo-
lecular hydrogen bonds of N-H···O. These results also
confirmed that 3d belongs to 3-arylaminopyrroline-2-ones
(not 3-aryliminopyrrolidin-2-ones).
2
O
F
1c
2a
F
H
N
NH
O
F
O
N
F
O
HN
3c
7c
F
As Scheme 5 showed, intermediate 7c was isolated and
found to convert into 3c in high yield (92%) by refluxing
it in dichloromethane under atmospheric N2 for 2 hours.
Based on above results, the title reaction mechanism
was tentatively proposed to take a two-step route as
After screening various reaction conditions, it was found
that the reaction intermediate could be obtained under
certain reaction conditions. As Scheme 4 showed, methyl
2,4-bis(4-fluorophenylamino)-4-phenylbut-2-enoate

952
Y.-C. Wu, L. Liu, D. Wang, Y.-J. Chen
Vol 43
XL-300 (1H, 300 MHz and 13C, 75 MHz). Data for 1H are
reported as follows: chemical shift (ꢃ, ppm), multiplicity (s =
singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br =
broad), integration, coupling constant (Hz) and number. Data for
13C NMR are reported in terms of chemical shift (ꢃ, ppm).
Infrared (IR) spectra were recorded on a Perkin Elmer 500 FT-
IR spectrophotometer and are reported in terms of frequency of
absorption (cm-1). Mass spectra were obtained from the Bruker
APEX-2 FT-ICRMS spectrometer. Elemental analyses were
performed on Calro-Mod 1102 instrument. Melting points were
measured on a Beijing-Tike X-4 apparatus and were not
corrected. The crystal X-ray structures were measured on
Rigaku R-axis RAPID IP.
Scheme 5
F
H
N
NH
O
CH2Cl2, reflux
2 h, 92%
F
O
N
F
O
HN
F
7c
3c
shown in Scheme 6: Two molecules of anilines (1) might
react with one molecule ꢀ,ꢁ-unsaturated ꢂ-ketoesters (2)
via aza-Michael addition/condensation to afford
intermediates 7, and the intramolecular cyclization of 7 to
give 3-arylamino-pyrroline-2-ones (3).
ꢀ,ꢁ-Unsaturated ꢂ-ketoesters (2) were all reported compounds
that were synthesized according to the reported procedure. [27-
28]
(E)-2-Oxo-4-phenylbut-3-enoic acid methyl ester (2a).
This compound was obtained from methanol as yellow
crystals in 37% yield for two steps; mp 68-70° (literature [27].
70-71°); H nmr (300 MHz, deuteriochloroform): ꢃ 7.84 (d, J =
Scheme 6
1
O
O
16.14 Hz, 1H), 7.60 (dd, J = 9.45, 1.86 Hz, 2H), 7.43-7.31 (m,
4H), 3.91 (s, 3H, OCH3); 13C nmr (75 MHz, deuterio-
chloroform): ꢃ 182.40 (CO), 162.53, 148.59, 133.97, 131.70,
129.10, 129.07, 120.46, 53.01 (OCH3).
ArNH2
2
O
X
1
2
(E)-4-(4-Methoxyphenyl)-2-oxobut-3-enoic acid methyl ester
(2b).
Ar
NH
H
N
O
This compound was obtained from methanol as yellow
crystals in 44% yield for two steps; mp 99-100° (literature [29].
Ar
O
HN
Ar
O
N
Ar
1
109°); H nmr (300 MHz, deuteriochloroform): ꢃ 7.83 (d, J =
X
16.00 Hz, 1H), 7.58 (d, J = 8.38 Hz, 2H), 7.23 (d, J = 16.00 Hz,
1H), 6.92 (d, J = 8.38 Hz, 2H), 3.92 (s, 3H), 3.84 (s, 3H, OCH3);
13C nmr (75 MHz, deuteriochloroform): ꢃ 182.20 (CO), 162.68,
148.53, 131.12, 126.76, 118.03, 114.61, 55.48 (OCH3), 52.97
(OCH3).
X
7
3
Tentatively proposed reaction mechanism.
Conclusion.
(E)-4-(4-Methylphenyl)-2-oxobut-3-enoic acid methyl ester (2c)
In summary, the synthetic protocol reported here
represents an efficient synthesis of 3-arylaminopyrroline-
2-ones that is confirmed with X-ray crystallographic
analysis. This discovery might trigger others to revisit the
other established molecules to obtain constructive results.
Applications of this synthetically useful reaction are now
in progress in our laboratory.
This compound was obtained from methanol as yellow
crystals in 41% yield for two steps; mp 81-83° (literature [19].
81°); 1H nmr (300MHz, deuteriochloroform): ꢃ 7.76 (d, J =
16.09 Hz, 1H), 7.44 (d, J = 8.06 Hz, 2H), 7.24 (d, J = 16.09 Hz,
1H), 7.14 (d, J = 8.06 Hz, 2H), 3.86 (s, 3H, OCH3), 2.31 (s, 3H,
Ar-CH3); 13C nmr (75MHz, deuteriochloroform): ꢃ 182.38 (CO),
162.63, 148.68, 142.54, 131.24, 129.84, 129.14, 119.39, 52.95
(OCH3), 21.60 (Ar-CH3).
(E)-4-(4-Chlorophenyl)-2-oxobut-3-enoic acid methyl ester (2d).
EXPERIMENTAL
General Methods.
This compound was obtained from methanol as yellow
crystals in 31% yield for two steps; mp 112-114° (literature [30].
116-117°); 1H nmr (300 MHz, deuteriochloroform): ꢃ 7.70 (d, J
= 16.13 Hz, 1H), 7.47 (d, J = 8.48 Hz, 2H), 7.31-7.22 (m, 3H),
3.86 (s, 3H, OCH3); 13C nmr (75MHz, deuteriochloroform): ꢃ
182.05 (CO), 162.31, 146.74, 137.57, 132.45, 130.13, 129.35,
120.85, 53.00 (OCH3).
All reactions were performed using oven-dried glassware
under a positive atmosphere of dry nitrogen with magnetic
stirring unless otherwise indicated. Common reagents and
materials were purchased from commercial sources and purified
by recrystallization or distillation. Flash chromatography was
performed with column chromatography silica gel (Kiesselgel
60, 200-300 mesh). Analytical thin layer chromatography was
performed with 0.2 mm coated commercial silica gel plates
(Kiesselgel 60 GF254). NMR spectra were measured on a Bruker
Methyl 6-methyl-2-phenylquinoline-4-carboxylate (5).
p-Toluidine (1a, 21.43 mg, 0.2 mmol) and (E)-methyl 2-oxo-
4-phenylbut-3-enoate (2a, 38.04 mg, 0.2 mmol) was mixed

Jul-Aug 2006
Efficient Synthesis of 3-Arylaminopyrroline-2-ones
953
was cooled to room temperature, and 3-arylaminopyrroline-2-
ones (3) was isolated by flash chromatography (ethyl
acetate:petroleum ether = 1:2, v/v) on silica gel (200-300 mesh)
column.
together, flushed with atmospheric N2, and then refluxed in 2
mL dichloromethane for 2 hours. Then the mixture was cooled
to room temperature, and the products were isolated by flash
chromatography (ethyl acetate: petroleum ether = 1:2, v/v) on
silica gel (200-300 mesh) column to give methyl 6-methyl-2-
phenylquinoline-4-carboxylate (5, 1.11 mg, 2%), 3-(p-tolyl-
amino)-5-phenyl-1-p-(tolyl)-1H-pyrrol-2(5H)-one (3a, 7.80 mg,
22%) and methyl 4-(N-(2,5-dihydro-2-oxo-5-phenyl-1-(p-tolyl)-
1H-pyrrol-3-yl)-N-p-tolylamino)-2-oxo-4-phenylbutanoate (6,
4.36 mg, 8%).
3-(p-Tolylamino)-5-phenyl-1-(p-tolyl)-1H-pyrrol-2(5H)-one
(3a).
This compound was obtained from ethyl acetate/petroleum as
white solids in 88% yield; mp 215-217° (literature [19]. 214.5-
215.5°); ir (potassium bromide): ꢀ 3312, 1677 (CO), 1648, 1516,
1401, 822 cm-1; 1H nmr (300 MHz, deuteriochloroform): ꢁ 7.47
(d, J = 8.29 Hz, 2H), 7.33-7.13 (m, 10H), 7.04 (d, J = 8.24 Hz,
1H), 6.71 (s, 1H), 6.07 (d, J = 2.14 Hz, 1H), 5.68 (d, J = 2.14
Hz, 1H), 2.35 (s, 3H), 2,32 (s, 3H); 13C nmr (75 MHz,
deuteriochloroform): ꢁ 167.28 (CO), 138.93, 137.74, 134.74,
134.65, 132.41, 130.64, 129.86, 129.51, 128.96, 128.10, 126.85,
121.76, 116.84, 107.38, 64.35, 20.91, 20.71.
This compound 5 was obtained from ethyl acetate/petroleum
as white solids in 2% yield; mp 101-103°; ir (potassium
bromide): ꢀ 2923, 2853, 1727 (CO), 1346, 1251, 1185, 1149,
1
1029, 826, 755, 695 cm-1; H nmr (300 MHz, deuteriochloro-
form): ꢁ 8.25 (d, J = 8.66 Hz, 1H), 8.11 (s, 1H), 7.71 (s, 1H),
7.58 (d, J = 8.84 Hz, 1H), 7.50-7.54 (m, 5H), 4.07 (s, 3H,
OCH3), 2.48 (s, 3H, Ar-CH3)); 13C nmr (75 MHz, deuterio-
chloroform): ꢁ 166.15 (CO), 149.04, 146.76, 146.52, 139.11,
137.67, 132.46, 130.81, 129.54, 128.68, 128.64, 127.87, 124.44,
121.46, 53.19 (OCH3), 22.05 (Ar-CH3).
Anal. Calcd for C24H22N2O: C, 81.33; H, 6.26; N, 7.90. Found:
C, 81.49; H, 6.38; N, 7.75.
3-(4-Methoxyphenylamino)-1-(4-methoxyphenyl)-5-phenyl-1H-
pyrrol-2(5H)-one (3b).
Anal. Calcd for C18H15NO2: C, 77.96; H, 5.45; N, 5.05. Found:
C, 77.92; H, 5.47; N, 4.91.
This compound was obtained from ethyl acetate/petroleum
ether as white solids in 92% yield; mp 197-199° (literature [19].
196.5-197°); ir (potassium bromide): ꢀ 3313, 1676 (CO), 1646,
1513, 1250, 1033, 830, 816 cm-1; 1H nmr (300 MHz,
dimethylsulfoxide-d6): ꢁ 7.88 (s, 1H), 7.47 (d, J = 8.94 Hz, 2H),
7.24 -7.19 (m, 7H), 6.86 –6.81 (m, 4H), 6.10 (d, J =2.43 Hz,
1H), 5.90 (d, J = 2.43 Hz, 1H), 3.66(s, 6H); 13C nmr (75 MHz,
dimethylsulfoxide-d6): ꢁ 166.84 (CO), 156.66, 153.84, 138.76,
136.00, 133.13, 130.67, 129.15, 128.14, 127.31, 123.99, 118.76,
114.77, 114.35, 107.71, 63.31, 55.63, 55.56.
3-(p-Tolylamino)-5-phenyl-1-(p-tolyl)-1H-pyrrol-2(5H)-one (3a).
This compound was obtained from ethyl acetate/petroleum as
white solids in 22% yield; mp 215-217° (literature [22]. 214.5-
215.5°); ir (potassium bromide): ꢀ 3312, 1677 (CO), 1648, 1516,
1401, 822 cm-1; 1H nmr (300 MHz, deuteriochloroform): ꢁ 7.47 (d,
J = 8.29 Hz, 2H), 7.33 -7.13 (m, 10H), 7.04 (d, J = 8.24 Hz, 1H),
6.71 (s, 1H), 6.07 (d, J = 2.14 Hz, 1H), 5.68 (d, J = 2.14 Hz, 1H),
2.35 (s, 3H, Ar-CH3), 2,32 (s, 3H, Ar-CH3); 13C nmr (75 MHz,
deuteriochloroform): ꢁ 167.28 (CO), 138.93, 137.74, 134.74,
134.65, 132.41, 130.64, 129.86, 129.51, 128.96, 128.10, 126.85,
121.76, 116.84, 107.38, 64.35, 20.91 (Ar-CH3), 20.71 (Ar-CH3).
Anal. Calcd for C24H22N2O: C, 81.33; H, 6.26; N, 7.90. Found:
C, 81.49; H, 6.38; N, 7.75.
Anal. Calcd for C24H22N2O3: C, 74.59; H, 5.74; N, 7.25.
Found: C, 74.44; H, 5.87; N, 7.24.
3-(4-Fluorophenylamino)-1-(4-fluorophenyl)-5-phenyl-1H-
pyrrol-2(5H)-one (3c).
Methyl 4-(N-(2,5-dihydro-2-oxo-5-phenyl-1-(p-tolyl)-1H-
pyrrol-3-yl)-N-p-tolylamino)-2-oxo-4-phenylbutanoate (6).
This compound was obtained from ethyl acetate/petroleum as
white solids in 78% yield; mp = 240-242°; ir (potassium
1
bromide): ꢀ 3333, 1676 (CO), 1653, 1509, 1391, 836 cm-1; H
This compound was obtained from ethyl acetate/petroleum as
white solids in 8% yield; mp 167-168°; ir (potassium bromide):
ꢀ 3028, 2923, 2854, 1727 (CO), 1692 (CO), 1681 (CO), 1514,
1454, 1359, 1291, 1253, 1224, 1179, 1143, 815, 755, 695 cm-1;
1H nmr (300 MHz, deuteriochloroform): ꢁ 7.47 (d, J = 8.07 Hz,
2H), 7.26 (s, 1H), 7.20 (d, J = 7.95 Hz, 4H), 6.93-6.91 (m, 7H),
6.79 (s, m, 5H), 5.86 (d, J = 4.67 Hz, 1H), 5.38 (s, 1H), 5.30 (s,
1H), 4.63 (d, J = 4.67 Hz, 1H), 3.50 (s, 3H), 2.37 (s, 3H), 2.15
(s, 3H); 13C nmr (75 MHz, deuteriochloroform): ꢁ 182.31 (CO),
164.09 (CO), 164.06 (CO), 139.54, 137.15, 136.10, 135.23,
134.36, 134.12, 133.46, 129.48, 129.11, 128.98, 128.57, 128.15,
128.13, 128.06, 127.66, 127.37, 126.49, 122.03, 116.44, 64.94,
52.01, 41.51, 21.31, 20.78.
nmr (300 MHz, deuteriochloroform): ꢁ 7.47-6.97 (m, 13H),
6.58 (s, 1H), 6.00 (d, J = 2.60 Hz, 1H), 5.61 (d, J = 2.60 Hz,
1H); 13C nmr (75 MHz, deuteriochloroform): ꢁ 167.08 (CO),
1
1
162.11 (d, JC-F = 243.45 Hz), 159.87 (d, JC-F = 243.45 Hz),
137.39, 137.05, 133.21, 132.42, 129.09, 128.38, 126.78, 123.54
3
3
4
(d, JC-F = 7.95 Hz), 118.23 (d, JC-F = 7.73 Hz), 115.88 (d, JC-F
= 2.78 Hz), 115.88 (d, 2JC-F = 42.23 Hz), 107.34, 64.55.
Anal. Calcd for C22H16F2N2O: C, 72.92; H, 4.45; N, 7.73.
Found: C, 72.64; H, 4.71; N, 7.62.
3-(4-Chlorophenylamino)-1-(4-chlorophenyl)-5-phenyl-1H-
pyrrol-2(5H)-one (3d)
Anal. Calcd for C35H32N2O4: C, 77.18; H, 5.92; N, 5.14.
Found: C, 77.31; H, 5.96; N, 5.03.
This compound was obtained from ethyl acetate/petroleum as
white solids in 81% yield; mp 217-219°; ir (potassium bromide):
1
ꢀ 3328, 1674 (CO), 1654, 1493, 1386, 824 cm-1; H nmr (300
Preparation of 3-Arylaminopyrroline-2-ones (3).
MHz, deuteriochloroform): ꢁ 7.51 (d, J = 8.98 Hz, 2H), 7.28 -
7.20 (m, 9H), 7.00 (d, J = 8.89 Hz, 2H), 6.80(s, 1H), 6.04 (d, J =
2.60 Hz, 1H), 5.63 (d, J = 2.60 Hz, 1H); 13C nmr (75 MHz,
deuteriochloroform): ꢁ 167.04 (CO), 139.80, 136.83, 135.73,
131.81, 130.25, 129.32, 129.21, 129.04, 128.48, 126.66, 126.11,
122.55, 117.94, 108.65, 64.20.
Anilines (1) (0.4 mmol) and ꢂ,ꢃ-unsaturated ꢄ-ketoesters (2)
(0.2 mmol) were mixed together, flushed with atmospheric N2,
and then refluxed in 2 mL dichloromethane for 4-12 hours
according to Table 2 that came from the results monitored by
TLC (ethyl acetate:petroleum ether = 1:2, v/v). Then the mixture

954
Y.-C. Wu, L. Liu, D. Wang, Y.-J. Chen
Vol 43
Anal. Calcd for C22H16Cl2N2O: C, 66.85; H, 4.08; N, 7.09.
Found: C, 66.61; H, 4.29; N, 7.01.
MHz, deuteriochloroform): ꢁ 7.39 (d, J = 8.48 Hz, 2H), 7.26 -
7.06 (m, 6H), 6.97 (d, J = 8.48 Hz, 2H), 6.55 (s, 1H), 5.99 (d, J
= 2.60 Hz, 1H), 5.60 (d, J = 2.60 Hz, 1H), 2.29 (s, 3H), 2,27 (s,
3H), 2,26 (s, 3H); 13C nmr (75 MHz, deuteriochloroform): ꢁ
167.22 (CO), 138.89, 137.84, 134.72, 134.58, 134.55, 132.25,
130.59, 129.82, 129.62, 129.46, 126.73, 121.74, 116.74, 107.56,
64.09, 21.14, 20.88, 20.65.
3-(3-Chlorophenylamino)-1-(3-chlorophenyl)-5-phenyl-1H-
pyrrol-2(5H)-one (3e).
This compound was obtained from ethyl acetate/petroleum as
white solids in 70% yield; mp 207-209°; ir (potassium bromide):
1
ꢀ 3321, 1680 (CO), 1651, 1596, 1482, 1396, 780 cm-1; H nmr
Anal. Calcd for C25H24N2O: C, 81.49; H, 6.57; N, 7.60.
Found: C, 81.48; H, 6.70; N, 7.49.
(300 MHz, deuteriochloroform): ꢁ 7.71 (s, 1H), 7.39-7.07 (m,
10H), 6.93 (d, J = 7.95 Hz, 2H), 6.75 (s, 1H), 6.10 (d, J = 1.86
Hz, 1H), 5.66 (d, J = 1.86 Hz, 1H); 13C nmr (75 MHz,
deuteriochloroform): ꢁ 166.93 (CO), 143.69, 138.80, 137.46,
134.24, 133.89, 131.92, 130.53, 130.18, 129.16, 128.28, 126.95,
124.43, 121.11, 120.44, 119.39, 116.88, 115.35, 110.99, 63.14.
Anal. Calcd for C22H16Cl2N2O: C, 66.85; H, 4.08; N, 7.09.
Found: C, 66.59; H, 4.32; N, 7.16.
3-(4-Methoxyphenylamino)-1-(4-methoxyphenyl)-5-p-tolyl-1H-
pyrrol-2(5H)-one (3j)
This compound was obtained from ethyl acetate/petroleum as
white solids in 86% yield; mp 218-220°; ir (potassium bromide):
1
ꢀ 3313, 1674 (CO), 1648, 1514, 1249, 813 cm-1; H nmr (300
MHz, deuteriochloroform): ꢁ 7.37 (dd, J = 9.06, 2.15 Hz, 2H),
7.26(s, 1H), 7.03 (dd, J = 8.96, 2,18 Hz, 2H), 6.86-6.79 (m, 4H),
6.44 (s, 1H), 5.92 (d, J = 2.56 Hz, 1H), 5.54 (d, J = 2.56 Hz,
1H), 3.77 (s, 3H), 3.74 (s, 3H), 2.28 (s, 3H); 13C nmr (75 MHz,
deuteriochloroform): ꢁ 167.18 (CO), 156.89, 154.35, 137.89,
134.91, 134.54, 132.86, 130.32, 129.59, 126.85, 123.77, 118.39,
114.66, 114.12, 106.40, 64.50, 55.61, 55.35, 21.15.
1-(Naphthalen-3-yl)-3-(naphthalen-3-ylamino)-5-phenyl-1H-
pyrrol-2(5H)-one (3f).
This compound was obtained from ethyl acetate/petroleum as
white solids in 64% yield; mp 280-282°; ir (potassium bromide): ꢀ
1
3305, 1683 (CO), 1621, 1597, 1401, 819, 748, 697 cm-1; H nmr
(300 MHz, dimethylsulfoxide-d6): ꢁ 8.41 (s, 1H), 8.11 (s, 1H),
7.86-7.15 (m, 19H), 6.74 (s, 1H), 6.27 (s, 1H); 13C nmr (75 MHz,
dimethylsulfoxide-d6): ꢁ 166.61 (CO), 137.85, 134.73, 134.24,
131,51, 130.16, 128.74, 128.48, 128.20, 127.82, 127.39, 127.28,
127.02, 126.51, 126.18, 121.35, 119.98, 118.90, 109.54, 62.81.
Anal. Calcd for C30H22N2O: C, 84.48; H, 5.20; N, 6.57.
Found: C, 84.25; H, 5.41; N, 6.63.
Anal. Calcd for C25H24N2O3: C, 74.98; H, 6.04; N, 7.00.
Found: C, 75.01; H, 5.98; N, 6.89.
5-(4-Chlorophenyl)-1-phenyl-3-(phenylamino)-1H-pyrrol-
2(5H)-one (3k) [18].
This compound was obtained from ethyl acetate/petroleum as
white solids in 87% yield; mp 222-224°; ir (potassium bromide):
1
ꢀ 3321, 1674 (CO), 1651, 1501, 1394, 840 cm-1; H nmr (300
5-(4-Methoxyphenyl)-1-phenyl-3-(phenylamino)-1H-pyrrol-2(5H)-
one (3g).
MHz, deuteriochloroform): ꢁ 7.37 (d, J = 7.89 Hz, 2H), 7.33-
7.06 (m, 12H), 6.96 (t, J = 7.29 Hz, 1H), 6.67 (s, 1H), 6.05 (d, J
= 2.39 Hz, 1H), 5.66 (d, J = 2.39 Hz, 1H); 13C nmr (75 MHz,
deuteriochloroform): ꢁ 167.07 (CO), 141.13, 136.93, 136.06,
133.92, 132.28, 129.42, 129.24, 129.02, 128.15, 125.19, 121.63,
121.43, 116.74, 107.49, 63.54.
This compound was obtained from ethyl acetate/petroleum as
white solids in 80% yield; mp 171-173°; ir (potassium bromide):
ꢀ 3315, 1676 (CO), 1651, 1601, 1502, 751 cm-1; 1H nmr
(300MHz, deuteriochloroform): ꢁ 7.52 (dd, J = 8.66, 1.04 Hz,
2H), 7.31 –6.94 (m, 10H), 6.80 (d, J = 8.73 Hz, 2H), 6.64(s,
1H), 6.07 (d, J = 2.60 Hz, 1H), 5.64 (d, J = 2.60 Hz, 1H), 3,74(s,
3H); 13C nmr (75MHz, deuteriochloroform): ꢁ 167.17 (CO),
159.40, 141.32, 137.17, 131.86, 129.38, 129.08, 128.89, 128.04,
124.98, 121.80, 121.18, 116.61, 114.36, 108.45, 63.75, 55.24.
Anal. Calcd for C23H20N2O2: C, 77.51; H, 5.66; N, 7.86.
Found: C, 77.37; H, 5.49; N, 7.70.
Anal. Calcd for C22H17ClN2O: C, 73.23; H, 4.75; N, 7.76.
Found: C, 73.41; H, 4.82; N, 7.60.
3-(4-Chlorophenylamino)-1,5-bis(4-chlorophenyl)-1H-pyrrol-
2(5H)-one (3l).
This compound was obtained from ethyl acetate/petroleum as
white solids in 84% yield; mp 258-260°; ir (potassium bromide): ꢀ
3325, 1669 (CO), 1652, 1538, 1516, 1392, 813 cm-1; 1H nmr (300
MHz, deuteriochloroform): ꢁ 7.46 (dd, J = 8.92, 1.97 Hz, 2H),
7.29-7.24 (m, 6H), 7.12 (d, J = 8.41 Hz, 2H), 6.99 (d, J = 8.81 Hz,
2H), 6.64 (s, 1H), 6.00 (d, J = 2.48 Hz, 1H), 5.61 (d, J = 2.48 Hz,
1H); 13C nmr (75 MHz, deuteriochloroform): ꢁ 166.80 (CO),
139.57, 135.43, 134.29, 132.07, 130.55, 129.43, 129.41, 129.15,
128.03, 126.43, 122.57, 117.97, 107.87, 77.21, 63.53.
1-Phenyl-3-(phenylamino)-5-(p-tolyl)-1H-pyrrol-2(5H)-one (3h).
This compound was obtained from ethyl acetate/petroleum as
white solids in 83% yield; mp 234-236°; ir (potassium bromide):
1
ꢀ 3318, 1684 (CO), 1597, 1265, 1093 cm-1; H nmr (300 MHz,
deuteriochloroform): ꢁ 7.55 (dd, J = 8.58, 0.94 Hz, 2H), 7.32 -
7.06 (m, 12H), 6.65 (s, 1H), 6.07 (d, J = 2.59 Hz, 1H), 5.66 (d, J
= 2.59 Hz, 1H), 2.28 (s, 3H); 13C nmr (75 MHz, deuterio-
chloroform): ꢁ 162.71 (CO), 142.61, 137.95, 134.31, 129.90,
129.36, 129.19, 126.66, 124.88, 121.56, 121.18, 119.46, 116.63,
108.47, 63.99, 53.0, 21.68.
Anal. Calcd for C22H15Cl3N2O: C, 61.49; H, 3.52; N, 6.52.
Found: C, 61.38; H, 3.75; N, 6.47.
Procedure for the Reaction Mechanism.
Anal. Calcd for C23H20N2O: C, 81.15; H, 5.92; N, 8.23.
Found: C, 80.97; H, 6.00; N, 8.34.
4-Fluorobenzenamine (1c, 4.45 g, 40 mmol) and (E)-2-oxo-4-
phenyl-but-3-enoic acid methyl ester (2a, 3.80 g, 20 mmol) was
mixed together, flushed with atmospheric N2, and then refluxed in
2 mL dichloromethane for 4 hours. Then the mixture was cooled
to room temperature, and methyl 2,4-bis(4-fluorophenylamino)-4-
phenylbut-2-enoate (7c, 16.56 mg, 0.21%) and 3-(4-fluoro-
3-(p-Tolylamino)-1,5-(dip-tolyl)-1H-pyrrol-2(5H)-one (3i).
This compound was obtained from ethyl acetate/petroleum as
white solids in 84% yield; mp 249-251°; ir (potassium bromide):
1
ꢀ 3325, 1669 (CO), 1652, 1516, 1392, 813 cm-1; H nmr (300

Jul-Aug 2006
Efficient Synthesis of 3-Arylaminopyrroline-2-ones
955
[11] A. I. Khalaf, R. D. Waigh, A. J. Drummond, B. Pringle, I. McGroarty,
G. G. Skellern and C. J. Suckling, J. Med. Chem., 47, 2133 (2004).
[12] M. Baumgarten and N. Tyutyulkov, Chem. Eur. J., 4, 987
(1998).
phenylamino)-1-(4-fluorophenyl)-5-phenyl-1H-pyrro (3c, 4.57 g,
63%) were isolated by flash chromatography (ethyl acetate:
petroleum ether = 1:5, v/v) on silica gel (200-300 mesh) column.
[13] D. E. Wemmer, Biopolymers, 52, 197 (1999).
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(2004).
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D. Potemkin, Pharm. Chem. J., 27, 343 (1993).
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Pharmazie, 48, 107 (1993).
[17] S. T. Kocharyan, N. P. Churkina, T. L. Razina, V. E.
Karapetyan, S. M. Ogandzhanyan, V. S. Voskanyan and A. T. Babayan,
Khim. Geterotsikl+., 1345 (1994).
[18] Y. S. Andreichikov, V. L. Gein, O. I. Ivanenko and A. N.
Maslivets, J. Org. Chem. USSR (Engl. Transl)., 22, 1983 (1986).
[19] W. R.Vaughan and R. C. Tripp, J. Am. Chem. Soc., 82, 4370
(1960).
[20] R. E. Lutz, P. S. Bailey, M. T. Clark, J. F. Codington, A. J.
Deinet, J. A. Freek, G. H. Harnest, N. H. Leake, T. A. Martin, R. J. Rowlett,
J. M. Salsbury, N. H. Shearer, J. D. Smith and J. W. Wilson, J. Am. Chem.
Soc., 68, 1813 (1946).
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Lett., 6, 2361 (2004).
(E)-Methyl 2,4-bis(4-fluorophenylamino)-4-phenylbut-2-enoate (7c).
This compound was obtained from ethyl acetate/petroleum as
white solids in 0.21% yield; mp 157-160°; ir (potassium
bromide): ꢀ 3444, 3333, 2964, 1677 (CO), 1652, 1508, 1438,
1262, 1221, 1096, 1022, 803 cm-1; 1H nmr (300 MHz,
deuteriochloroform): ꢁ 7.86-6.97 (m, 14H), 6.58 (s, 1H), 6.00
(d, J = 2.60 Hz, 1H), 5.60 (d, J = 2.60 Hz, 1H), 3.94 (s, 3H); 13
C
nmr (75 MHz, deuteriochloroform): ꢁ 182.43 (CO), 167.07,
162.57, 158.24, 148.67, 137.39, 137.07, 134.00, 132.44, 131.71,
129.12, 129.08, 128.37, 126.77, 123.58, 123.47, 120.48, 118.29,
118.19, 116.16, 115.88, 115.86, 115.59, 107.35, 64.55, 53.04.
Anal. Calcd for C23H20F2N2O2: C, 70.04; H, 5.11; N, 7.10.
Found: C, 69.82; H, 5.37; N, 6.85.
7c (7.89 mg, 0.02 mmol) was flushed with atmospheric N2,
and then refluxed in 2 mL dichloromethane for 2 hours. Then
the mixture was cooled to room temperature, and 3c (6.67 mg,
92%) was isolated by flash chromatography (ethyl acetate:
petroleum ether = 1:2, v/v) on silica gel (200-300 mesh) column.
Acknowledgement.
[22] R. Y. Lai, X. Kong, S. A. Jenekhe and A. J. Bard, J. Am.
Chem. Soc., 125, 12631 (2003).
[23] A. Fayol and J. Zhu, Angew. Chem. Int. Ed., 41, 3633 (2002).
[24] X. Zhang, M. A. Campo, T. Yao and R. C. Larock, Org.
Lett., 7, 763 (2005).
We thank the National Natural Science Foundation of China
(No. 20232010, 20332030), Ministry of Science and Technology
of China (No. 2002CCA03100), and the Chinese Academy of
Sciences for financial support. We appreciate the suggestions
and corrections from the reviewers.
[25] B. R. McNaughton and B. L. Miller, Org. Lett., 5, 4257
(2003).
[26] Singlecrystal X-ray analysis of 3-(4-chlorophenylamino)-1-
(4- chlorophenyl)-5-phenyl-1H-pyrrol-2 (5H)-one (3d): C22H16Cl2N2O,
Mr = 395.27, Triclinic, P-1. a = 6.3462 (13), b = 12.223(2), c =
13.077(3) Å, V = 962.5(3) Å3, Z = 2, Dx = 1.364 Mg/m3. T = 293(2) K,
reflections collected 6347, unique 3489 (Rint = 0.0582) which were used
in all calculations. Data collection: Rapid Auto. Cell refinement: Rapid
Auto. Data reduction: Rapid Auto. Program(s) used to solve structure:
SHELXS-97. Program(s) used to refine structure: SHELXL-97. The data
have been deposit with the Cambridge Crystallographic Data Center (Nr
CCDC 270001). Selected bond lengths (Å): C(7)-C(8) = 1.509(5), C(8)-
C(9) = 1.317(5), C(9)-C(10) = 1.487(5), N(2)-C(9) = 1.371(5), N(2)-
C(17) = 1.392(5).
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