Green and facile synthesis of dihydropyrrol-2-ones and highly substituted piperidines using ethylenediammonium diformate (EDDF) as a reusable catalyst

Article abstract of DOI:10.1007/s11164-016-2512-0

Abstract: Extremely facile and efficient procedures have been developed for the synthesis of dihydropyrrol-2-ones and highly substituted piperidines. One-pot four-component reaction of amines, dialkyl acetylenedicarboxylates, and formaldehyde in the presence of ethylenediammonium diformate in ethanol under reflux conditions provides N-aryl-3-amino dihydropyrrol-2-one-4-carboxylates in good to high yields. The same conditions were found useful for the synthesis of highly substituted piperidines via a three (pseudo five)-component reaction of amines, aldehydes, and β-ketoesters. It is found that the catalyst is reusable and can be used up to five times without significant loss of its activity. Graphical Abstract: [Figure not available: see fulltext.]

Full text of DOI:10.1007/s11164-016-2512-0

Res Chem Intermed
DOI 10.1007/s11164-016-2512-0
Green and facile synthesis of dihydropyrrol-2-ones
and highly substituted piperidines using
ethylenediammonium diformate (EDDF) as a reusable
catalyst
Mahboobeh Zarei1 Seyed Sajad Sajadikhah1
•
Received: 4 November 2015 / Accepted: 7 March 2016
Ó Springer Science+Business Media Dordrecht 2016
Abstract Extremely facile and efficient procedures have been developed for the
synthesis of dihydropyrrol-2-ones and highly substituted piperidines. One-pot four-
component reaction of amines, dialkyl acetylenedicarboxylates, and formaldehyde in the
presence of ethylenediammonium diformate in ethanol under reflux conditions provides
N-aryl-3-amino dihydropyrrol-2-one-4-carboxylates in good to high yields. The same
conditions were found useful for the synthesis of highly substituted piperidines via a
three (pseudo five)-component reaction of amines, aldehydes, and b-ketoesters. It is
found that the catalyst is reusable and can be used up to five times without significant
loss of its activity.
Graphical Abstract
CO2R2
O
H
N
R1 NH2
Ar NH2
R1
N
Ar
CO2R2
CH2O
R2O2C
Green solvent
Recyclable catalyst
Simple work-up
EDDF
EtOH, reflux
No column chromatography
Good to high yields
Ar'
Ar' NH2
NH
O
O
O
OR'
Ar''
OR'
Ar''
N
Ar'
Ar'' CHO
&
Seyed Sajad Sajadikhah
sssajadi@pnu.ac.ir
1
Department of Chemistry, Payame Noor University (PNU), P. O. Box 19395-3697, Tehran, Iran
123

M. Zarei, S. S. Sajadikhah
Keywords N-heterocycle Á Dihydropyrrol-2-one Á Piperidine Á Multi-component
reaction Á EDDF Á Reusable catalyst
Introduction
Development of novel methodologies that reduce pollution in chemical synthesis
has received considerable attention due to increasing environmental concerns. In
this context, one active area is the use of an eco-friendly recyclable catalyst instead
¨
of conventional, toxic, and polluting Bronsted acid catalyst [1, 2]. Ethylenedi-
ammonium diformate (EDDF) is a salt (m.p. 132 °C), and recently it was used as a
homogeneous catalyst for the synthesis of 4H-pyrans [3], 3-indolochromenes, and
3-indoloxanthenes [4]. Some advantages of EDDF are reusability, low cost,
operational simplicity, ease of preparation, and handling. Among the several aspects
of green chemistry, the replacement of volatile organic solvents with green solvents
such as water and ethanol is of greatest concern [5, 6].
Polyfunctionalized heterocyclic compounds play important roles in drug
discovery processes and in the analysis of drugs. In this context, the ubiquity of
pyrrol-2-ones in pharmaceuticals and natural products makes them attractive targets
for organic synthesis. Dihydropyrrol-2-one and its derivatives are key compounds
for the synthesis of bioactive molecules such as Chaetoglobosin A and C [7] and
Clausenamide [8]. Moreover, dihydropyrrol-2-ones have been successfully used as
HIV integrase [9], herbicidal [10], pesticides [11], anti-tumor and anticancer agents
[12], mitomycin antibiotics [13], and also inhibitors of DNA polymerase [14].
Recently, multi-component reactions have been used for one-pot synthesis of
dihydropyrrol-2-ones using catalysts such as AcOH, I2 benzoic acid, TiO2
nanopowder, and Cu(OAc)2ÁH2O [15–20]. However, some of these methods
displayed drawbacks, such as performing the reaction in the presence of 200 mol%
catalyst at 70 °C and purification of products by preparative TLC [15], long reaction
times [17], and environmental pollution caused by use of chlorinated solvent under
reflux conditions [18].
On the other side, piperidines and their analogues have been receiving attention
owing to their biological activities such as antimalarial [21], antihypertensive [22],
antibacterial [23], anticonvulsant, and anti-inflammatory agents [24]. Additionally,
substituted piperidines have been also established as therapeutic agents such as
clebopride, cisapride, bamipine, fentanyl, a-methylfentanyl, and indoramine [25].
To date, methods for the synthesis of functionalized piperidines have been reported
using multi-component reactions in the presence of L-proline/TFA, InCl3,
bromodimethylsulfonium bromide (BDMS), tetrabutylammonium tribromide
(TBATB), I2, cerium ammonium nitrate (CAN), ZrOCl2Á8H2O, picric acid, and
BF3ÁSiO2 [21, 26–34]. However, owing to the importance of dihydropyrrol-2-ones
and piperidines from pharmaceutical and biological view points, there is still the
need to develop green, efficient, and environmentally benign protocols for the
synthesis of these heterocycles in the presence of recyclable catalyst. Therefore, in
this work EDDF was used as reusable catalyst for the synthesis N-aryl-3-amino
123

Green and facile synthesis of dihydropyrrol-2-ones and…
dihydropyrrol-2-one-4-carboxylates and highly functionalized piperidines in ethanol
under reflux conditions.
Results and discussion
In continuation of our work on heterocycles synthesis, especially synthesis of
dihydropyrrol-2-ones [35–39], herein EDDF was employed as an efficient catalyst
for the one-pot four-component synthesis of N-aryl-3-amino dihydropyrrol-2-one-4-
carboxylates in ethanol under reflux conditions (Scheme 1).
Initially, a mixture of aniline, dimethyl acetylendicarboxylate (DMAD), and
formaldehyde in ethanol (5 mL) was treated with 10 mol% of EDDF at ambient
temperature. The corresponding dihydropyrrol-2-one 5a was obtained in 52 % yield
after 10 h. To optimize the reaction conditions, the above reaction was carried out
under different conditions and the results are summarized in Table 1. The best result
was obtained in the presence 20 mol% of catalyst under reflux conditions. Note that
control experiments showed that product 5a was obtained only in trace and low
yields when the reaction was examined in the absence of catalyst at ambient
temperature and reflux conditions, respectively (Table 1, entries 10 and 11).
Under the optimized reaction conditions, various anilines and dimethyl and/or
diethyl acetylenedicarboxylates were used to test the versatility of this reaction, and
the results are presented in Table 2. This protocol efficiently coupled anilines with
electron donating groups such as Me and OMe, as well as electron withdrawing
groups including F, Cl, and Br to produce the expected products 5a–h in good to
high yields (Table 2, entries 1–8). Additionally, two different amines were used for
the one-pot four-component synthesis of different highly functionalized dihydropy-
rrol-2-ones 5i–q (Table 2, entries 9–17). Aliphatic amines such as benzyl amine,
1-(pyridin-2-yl)methanamine, cyclohexyl amine, n-propyl amine, and n-buthyl
amine reacted smoothly with dialkyl acetylenedicarboxylates, aromatic amines, and
formaldehyde to generate the desired products in high yields. All known compounds
have been reported previously in the literature and were characterized by
comparison of melting points, IR, and NMR spectra with authentic samples.
CO2R2
O
H
N
R1
EDDF (20 mol%)
EtOH, reflux
R1 NH2
Ar NH2
+
+
CH2O
+
N Ar
R2O2C
CO2R2
1
3
5
2
4
O
H
O
EDDF:
H3N
NH3
O
O
H
Scheme 1 Synthesis of N-aryl-3-amino dihydropyrrol-2-one-4-carboxylate 5
123

M. Zarei, S. S. Sajadikhah
Table 1 Optimization of the reaction conditions for the synthesis 5a
O
H
N
CO2Me
Ph
EDDF
+
Ph NH2
+
CH2O
Ph NH2
+
N Ph
MeO2C
CO2Me
Entry
Solvent
Temperature (°C)
Catalyst (mol%)
Time (h)
Yield (%)a
1
EtOH
MeOH
MeCN
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
rt
10
10
10
15
14
10
9
52
2
rt
10
50
3
rt
10
39
4
rt
5
41
5
rt
15
59
6
rt
20
64
7
rt
25
9
61
8
Reflux
Reflux
rt
20
3
89
9
25
3
87
10
11
a
No catalyst
No catalyst
24
9
Trace
19
Reflux
Isolated yield
A reasonable mechanism for the synthesis of N-aryl-3-amino dihydropyrrol-2-one-
4-carboxylate 5 was proposed in Scheme 2. The reaction between amine 1 and dialkyl
acetylenedicarboxylate 2 gives intermediate A. Next, the reaction of amine 3 with
formaldehyde 4 produces imine B. Attack of A on B leads to intermediate C, which
converts to intermediate D by intramolecular cyclization. In the final step,
tautomerization of intermediate D produces the corresponding dihydropyrrol-2-one 5.
Recently, we have reported the effective and efficient synthesis of piperidine
derivatives using multi-component reactions [40–44]. Motivated from the efficient
catalytic activity of EDDF for the synthesis of N-aryl-3-amino dihydropyrrol-2-one-
4-carboxylates, its catalytic activity was examined for the synthesis of highly
substituted piperidines 9 via one-pot three (pseudo five)-component reaction of
amines, aldehydes and b-ketoesters in ethanol under reflux conditions (Scheme 3).
At the outset, the reaction between benzaldehyde (2 mmol), aniline (2 mmol), and
methyl acetoacetate (1 mmol) was carried out in the presence of EDDF (10 mol%) in
ethanol at room temperature. The reaction proceeds smoothly to generate the
corresponding highly substituted piperidine 9a in 48 % yield after 12 h. In order to
optimize the reaction conditions, this reaction was considered as the model (Table 3).
The best result was achieved in the presence of 25 mol% EDDF in ethanol under reflux
conditions (Table 3, entry 11). To illustrate the need for catalytic amounts of EDDF in
these reactions, the model reaction was also studied in the absence of the catalyst in
ethanol, where no product was obtained at room temperature and under reflux
conditions, even after 24 and 10 h, respectively (Table 3, entries 12 and 13).
Using the optimized reaction conditions, a series of highly substituted piperidines
were prepared in good to high yields from the reaction between aromatic anilines,
methyl/ethyl acetoacetate, and different aromatic aldehydes. As indicated in Table 4,
123

Green and facile synthesis of dihydropyrrol-2-ones and…
Table 2 Synthesis of N-aryl-3-amino dihydropyrrol-2-one-4-carboxylates 5a–q
Entry R1
R2
Ar
Product Time Yield Mp (°C) (Lit. mp)b
(h)
(%)a
1
Ph
Me Ph
5a
5b
5c
5d
5e
5f
3
89
88
91
87
84
86
80
79
85
90
70
72
89
88
87
85
86
150–152 (155–156) [16]
163–165 (163–165) [35]
170–172 (173–174) [16]
163–175 (168–170) [16]
137–139 (138–140) [15]
168–170 (168–170) [37]
164–166 (169–171) [15]
152–154 (152–154) [36]
135–137 (140–141) [15]
144–146 (144–146) [38]
160–162 (159–161) [39]
106–108 (106–108) [37]
103–105 (107–108) [15]
76–78 (78–79) [15]
2
4-F-C6H4
4-Cl-C6H4
4-Me-C6H4
Ph
Me 4-F-C6H4
Me 4-Cl-C6H4
Me 4-Me-C6H4
3
3
2.5
3
4
5
Et
Et
Et
Et
Ph
3.5
3
6
4-Cl-C6H4
4-Br-C6H4
4-OMe-C6H4
PhCH2
4-Cl-C6H4
4-Br-C6H4
4-OMe-C6H4
7
5g
5h
5i
2.5
3.5
2.5
2.5
3
8
9
Me Ph
10
11
12
13
14
15
16
17
a
PhCH2
Me 4-Me-C6H3
5j
C5H4N-2-CH2 Me 4-Br-C6H4
C5H4N-2-CH2 Me 4-Me-C6H3
5k
5l
3
Cyclohexyl
n-C3H7
Et
Et
Ph
Ph
5m
5n
5o
5p
5q
3
3
n-C4H9
Me 4-F-C6H4
Me 4-Cl-C6H4
2.5
3
81–83 (81–83) [38]
n-C4H9
91–93 (92–94) [39]
n-C4H9
Et
4-Br-C6H4
3
95–97 (94–96) [35]
Isolated yield
b
Literature references for known compounds
aniline and its derivatives containing electron withdrawing and/or electron donating
groups reacted efficiently with benzaldehyde and substituted benzaldehydes to give
the corresponding products 9 in good to high yields. However, p-nitro benzaldehyde
gives the corresponding product in low yield (Table 4, entry 8), which is caused by
the formation of more stable imine due to extra conjugation in the presence of a nitro
group, which is less reactive [30]. The relative stereochemistry of this class of
compounds has been confirmed by single X-ray crystallographic analysis in authentic
literature [26–30, 36, 40, 43], and stereochemistry of our products was proved by
comparison of spectroscopic data of some products with authentic samples.
On the basis of the previous literature [28–31], the proposed mechanism for the
formation of piperidine 9 is illustrated in Scheme 4. First, aniline 6 reacts with b-
ketoester 7 and aldehyde 8 in the presence of EDDF to give enamine E and imine F,
respectively. Next, the reaction between enamine E and activated imine F leads to
intermediate G through intermolecular Mannich-type reaction. The intermediate
G reacts with aldehyde 8 to generate intermediate H. Then, tautomerization of
HgeneratesintermediateI, whichimmediatelyundergoesintramolecularMannich-type
reaction to produce intermediate J. Eventually, tautomerization of the intermediate
J generates the desired piperidine 9 due to conjugation with the ester group.
In general, at the beginning of both reactions for the synthesis of N-aryl-3-amino
dihydropyrrol-2-one-4-carboxylates 5 and piperidines 9, the reagents were com-
pletely soluble in reaction medium to form a homogeneous mixture. But, at the end
of the reactions, the products were precipitated and separated by simple filtration.
123

M. Zarei, S. S. Sajadikhah
O
O
H
H3N
O
H
H
O
H
N
H2N Ar
H
O
H
H
O
H
H
4
O
H
H3N
O
O
H
H
N
H
H
H
O
H
O
O
N
O
Ar
H3N
H
O
O
H
NH3
O
O
H
N
H2O
R
Ar
N
O
CO2R
H
O
5
H
NH3
O
O
H
H
H
H
N
O
H
N
O
OR2
O
H
N
H
O
H
NH3
R2O
R1
O
O
O
H2N R1
1
N
N
R
Ar
O
H
OR2
Ar
N
H
B
R2O
CO2R2
A
2
D
O
N
H
H3N
O
O
H
R
H
N
H
ROH
O
H
O
RO
H
N
CO2R2
Ar
C
Scheme 2 Suggested mechanism for the synthesis of N-aryl-3-amino dihydropyrrol-2-one-4-
carboxylates 5
Ar'
NH
O
4
O
O
3
OR'
5
EDDF (25 mol%)
EtOH, reflux
2 Ar'' CHO
+
+
2
OR'
2
Ar' NH2
6
Ar''
N1 Ar''
Ar'
6
7
8
9
Scheme 3 Synthesis of highly substituted piperidine 9
No column chromatography technique was used for products purification. This
avoids use of large amounts of volatile organic solvents, as the solvent is generally
the main source of waste as well as environmental pollutions.
The reusability of the catalyst is an important factor from an economical and
environmental point of views and has attracted much attention in recent years. Thus, the
reusability of EDDF was examined in the synthesis of dihydropyrrol-2-one 5a and
highly functionalized piperidine 9f as two examples. After completion of the reaction,
solid product was separated and the filtrated ethanol containing catalyst was evaporated
under reduced pressure and catalyst was recovered and reused. The results show that
EDDF can be used up to five times without significant loss of its activity (Table 5).
In conclusion, we have developed simple and green methods for the one-pot
multi-component synthesis of N-aryl-3-amino dihydropyrrol-2-one-4-carboxylates
123

Green and facile synthesis of dihydropyrrol-2-ones and…
Table 3 Optimization of the reaction conditions for the synthesis 9a
Ph
NH
O
2
2
Ph NH2
Ph CHO
O
O
EDDF
OMe
+
OMe
Ph
N
Ph
Ph
Entry
Solvent
Temperature (°C)
Catalyst (mol%)
Time (h)
Yield (%)a
1
EtOH
MeOH
MeCN
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
rt
10
12
12
16
15
12
12
10
10
6
48
49
36
37
57
64
69
69
81
–
2
rt
10
3
rt
10
6
rt
5
7
rt
15
8
rt
20
9
rt
25
10
11
12
13
a
rt
30
Reflux
rt
25
No catalyst
No catalyst
24
10
Reflux
–
Isolated yield
and highly substituted piperidines using EDDF as a homogeneous catalyst in
ethanol under reflux conditions. The noteworthy aspects of these procedures are
green solvent, high atom economy, good to high yields, readily available starting
material, recyclable catalyst, and operational simplicity. Moreover, all products
were obtained through simple filtration and no need to column chromatography,
which reduces the waste as well as environmental pollutions.
Experimental
Preparation of the catalyst EDDF
Ethylenediamine (10 mL, 0.15 mol) was diluted with acetone (15 mL) and was
added dropwise to a previously cooled and stirred mixture of 90 % formic acid (aq.)
(12.5 mL, 0.30 mol) and acetone (15 mL). The reaction mixture was maintained at
0 °C under continuous stirring for 2 h. The precipitated EDDF as a white solid was
filtered, washed with acetone, and dried at 50 °C under vacuum [3].
General procedure for synthesis of N-aryl-3-amino dihydropyrrol-2-one-4-
carboxylates 5
A mixture of amine 1 (1 mmol) and dialkyl acetylenedicarboxylate 2 (1 mmol) in
ethanol (5 mL) was stirred for 30 min at room temperature. Next, aromatic amine 3
123

M. Zarei, S. S. Sajadikhah
Table 4 Synthesis of substituted piperidines 9a–s
Entry
Ar0
R0
Ar00
Product
Time
(h)
Yield
(%)a
Mp (°C) (Lit. mp)b
1
Ph
Me
Me
Et
Ph
9a
9b
9c
9d
9e
9f
6
5.5
6
81
89
82
84
87
88
80
47
77
76
88
83
89
90
82
85
88
84
87
182–184 (185–186) [30]
214–217 (215–217) [30]
150–152 (149–151) [44]
164–166 (164–167) [44]
190–192 (193–195) [30]
219–222 (225–227) [30]
182–184 (186–188) [30]
234–236 (239–241) [30]
197–199 (198–200) [36]
174–176 (173–175) [41]
233–235 (234–236) [43]
186–188 (190–192) [36]
200–202 (200–202) [41]
171–173 (169–171) [40]
164–166 (160–163) [21]
194–196 (196–198) [40]
198–201 (199–201) [43]
204–206 (204–206) [44]
182–184 (183–185) [31]
2
Ph
4-Me-C6H4
3-Me-C6H4
3-Br-C6H4
4-F-C6H4
4-Cl
3
Ph
4
Ph
Et
6.5
6
5
Ph
Me
Me
Me
Me
Et
6
Ph
6
7
Ph
4-OMe-C6H4
4-NO2-C6H4
3-Br-C6H4
4-Me-C6H4
4-Me-C6H4
Ph
9g
9h
9i
8
8
Ph
10
7
9
4-OMe-C6H4
3,4-Cl2-C6H3
4-Br-C6H4
4-Me-C6H4
4-Me-C6H4
4-Me-C6H4
4-Cl-C6H4
4-Br-C6H4
4-F-C6H4
4-Cl-C6H4
4-F-C6H4
10
11
12
13
14
15
16
17
18
19
a
Et
9j
6
Et
9k
9l
6.5
6
Me
Me
Et
4-F-C6H4
4-Me-C6H4
4-Br-C6H4
Ph
9m
9n
9o
9p
9q
9r
9s
6
6
Me
Et
6
7
Me
Me
Et
4-Me-C6H4
4-Me-C6H4
4-Me-C6H4
6
6.5
6
Isolated yield
b
Literature references for known compounds
(1 mmol), formaldehyde 4 (37 % solution, 1.5 mmol), and EDDF (20 mol%) were
added successively. The reaction mixture was allowed to stir under reflux conditions
for the appropriate time. The progress of the reaction was monitored by TLC. After
completion, the reaction mixture was cooled to ambient temperature. The solid
precipitate was filtered off and washed with ethanol to afford the pure products 5. In
order to recover the catalyst, filtrated solution was evaporated under reduced
pressure, and the resulting catalyst was washed with diethyl ether, and dried. The
recovered catalyst was reused five times.
General procedure for synthesis of highly functionalized piperidine 9
First, a solution of aromatic amine 6 (2 mmol) and b-ketoester 7 (1 mmol) in
ethanol (5 mL) was stirred for 30 min in the presence of EDDF (25 mol%) at
ambient temperature. Next, the aromatic aldehyde 8 (2 mmol) was added and the
reaction mixture was allowed to stir for appropriate time under reflux conditions.
After completion of the reaction (monitored by TLC), the reaction mixture was
cooled to ambient temperature. The tick precipitate was filtered off and washed with
123

Green and facile synthesis of dihydropyrrol-2-ones and…
O
O
H3N
O
H
H
O
H
N
H
H
Ar'
H
N
O
inter-molecular
Ar''
6 + 7
6 + 8
Mannich reaction
N
OR'
Ar'
E
-2 H2O
F
O
Ar'
O
O
N
O
H3N
H
O
O
H
NH3
O
H
OR'
Ar''
Ar'
H3N
O
H
H
NH
O
N
O
HN
Ar'
H
OR'
Ar''
H
O
Ar''
N
G
Ar''
Ar'
9
O
H
O
H
N
O
O
H3N
H
O
O
H
H
H3N
H
N
H
H
O
H
Ar'
N
H
O
Ar'
N
N
O
OR'
Ar''
H
O
H
OR'
Ar''
Ar''
N
Ar'
Ar''
J
O
Ar'
H
O
H
Ar'
H
N
O
NH3
intra-molecular
Mannich reaction
OR'
Ar''
H3N
Ar''
N
Ar'
O
H
O
I
Scheme 4 Proposed mechanism for the synthesis of highly substituted piperidine 9
Table 5 Recyclability of
EDDF in the synthesis of
compounds 5a and 9f
Run no.
Compound 5a
Compound 9f
Time (h)
Yield (%)a
Time (h)
Yield (%)a
1
2
3
4
5
3
89
89
87
84
85
6
6
6
7
7
88
85
87
86
82
3
3.5
3.5
4
a
Isolated yield
ethanol to give the pure product 9. In order to recover the catalyst, filtrated ethanol
was evaporated under reduced pressure, and the resulting catalyst was washed with
diethyl ether, and dried. The recovered catalyst was reused next times.
123

M. Zarei, S. S. Sajadikhah
Physical and spectral data for selected products
Ethyl 4-(4-chlorophenylamino)-1-(4-chlorophenyl)-2,5-dihydro-2-oxo-1H-pyrrole-
4-carboxylate (5f)
1
White solid; IR (KBr, cm-1): m 3320 (NH), 1693 (C=O), 1640 (C=O); H NMR
(400 MHz, CDCl3): d 1.29 (3H, t, J = 7.0 Hz, OCH2CH3), 4.27 (2H, q,
J = 7.0 Hz, OCH2CH3), 4.52 (2H, s, CH2), 7.08 (2H, d, J = 8.2 Hz, ArH), 7.27
(2H, d, J = 8.4 Hz, ArH), 7.38 (2H, d, J = 8.8 Hz, ArH), 7.76 (2H, d, J = 8.8 Hz,
ArH), 8.05 (1H, br s, NH); 13C NMR (100 MHz, CDCl3): d 14.2, 48.1, 60.6, 104.3,
120.2, 124.0, 128.5, 129.2, 129.9, 130.2, 137.2, 137.2, 142.6, 163.6, 164.5.
Methyl 4-(benzylamino)-1-(4-methylphenyl)-2,5-dihydro-2-oxo-1H-pyrrole-4-
carboxylate (5j)
1
White solid; IR (KBr, cm-1): m 3311 (NH), 1682 (C=O), 1646 (C=O); H NMR
(400 MHz, CDCl3): d 1.34 (3H, t, J = 7.2 Hz, OCH2CH3), 4.28 (2H, t, J = 7.2 Hz,
OCH2CH3), 4.41 (2H, s, CH2-N), 5.12 (2H, d, J = 6.4 Hz, CH2-NH), 6.89 (1H, br s,
NH), 7.28–7.37 (5H, m, ArH), 7.53 (2H, d, J = 8.4 Hz, ArH), 7.71 (2H, d,
J = 8.8 Hz, ArH); 13C NMR (100 MHz, CDCl3): d 20.9, 46.6, 48.1, 51.1, 97.1,
119.4, 127.3, 127.5, 128.7, 129.6, 134.8, 136.2, 139.5, 164.3, 165.6.
Methyl 3-(butylamino)-1-(4-chlorophenyl)-2,5-dihydro-2-oxo-1H-pyrrole-4-
carboxylate (5p)
1
White solid; IR (KBr, cm-1): m 3358 (NH), 1699 (C=O), 1635 (C=O); H NMR
(400 MHz, CDCl3): d 0.97 (3H, t, J = 7.6 Hz, CH3), 1.42 (2H, sextet, J = 7.5 Hz,
CH2), 1.62 (2H, quintet, J = 7.6 Hz, CH2), 3.80 (3H, s, OCH3), 3.87 (2H, t,
J = 6.4 Hz, CH2-NH), 4.39 (2H, s, CH2-N), 6.75 (1H, br s, NH), 7.37 (2H, d,
J = 8.8 Hz, ArH), 7.75 (2H, d, J = 8.8 Hz, ArH); 13C NMR (100 MHz, CDCl3): d
13.8, 19.8, 33.3, 42.5, 47.8, 51.1, 96.0, 120.2, 129.1, 130.0, 137.3, 164.5, 165.6.
Ethyl 2,6-bis(3-bromophenyl)-1-phenyl-4-(phenylamino)-1,2,5,6-
tetrahydropyridine-3-carboxylate (9d)
1
White solid; IR (KBr, cm-1): m 3223 (NH), 1656 (C=O); H NMR (400 MHz,
CDCl3): d 1.51 (3H, t, J = 7.2 Hz, OCH2CH3), 2.79 (1H, d, J = 15.1 Hz, H0-5),
2.88 (1H, dd, J = 15.2, 5.2 Hz, H00-5), 4.38 (1H, dq, J = 10.8, 7.2 Hz, OCHaHb),
4.54 (1H, dq, J = 10.8, 7.0 Hz, OCHaHb), 5.14 (1H, br, H-6), 6.41 (2H, d,
J = 8.2 Hz, ArH), 6.42 (1H, s, H-2), 6.51 (2H, d, J = 8.0 Hz, ArH), 6.70 (1H, t,
J = 7.2 Hz, ArH), 7.09–7 .27 (9H, m, ArH), 7.30 (1H, s, ArH), 7.39 (1H, d,
J = 7.6 Hz, ArH), 7.44 (1H, d, J = 7.6 Hz, ArH), 7.60 (1H, s, ArH), 10.34 (1H, s,
NH); 13C NMR (100 MHz, CDCl3): d 14.9, 33.6, 55.0, 57.5, 59.9, 97.3, 113.1,
116.9, 1 22.7, 123.9, 1 25.1, 125.2, 126.1, 126.2, 129.1, 129.4, 129.6, 129.7, 129.8,
130.3, 130.4, 137.6, 145.1, 146.3, 146.6, 155.8, 167.9.
123

Green and facile synthesis of dihydropyrrol-2-ones and…
Methyl 4-(4-methylphenylamino)-1-(4-methylphenyl)-2,6-diphenyl-1,2,5,6-
tetrahydropyridine-3-carboxylate (9l)
1
White solid; IR (KBr, cm-1): m 3308 (NH), 1652 (C=O); H NMR (400 MHz,
CDCl3): d 2.20 (3H, s, CH3), 2.30 (3H, s, CH3), 2.78 (1H, dd, J = 15.2, 2.4 Hz,
H0-5), 2.89 (1H, dd, J = 15.2, 5.8 Hz, H00-5), 3.96 (3H, s, OCH3), 5.16 (1H, d,
J = 3.6 Hz, H-6), 6.21 (2H, d, J = 8.8 Hz, ArH), 6.46 (1H, s, H-2), 6.49 (2H, d,
J = 8.8 Hz, ArH), 6.92 (4H, t, J = 8.4 Hz, ArH), 7.20–7.33 (10H, m, ArH), 10.22
(1H, s, NH); 13C NMR (100 MHz, CDCl3): d 20.1, 20.9, 33.6, 50.9, 55.2, 58.2, 97.5,
112.9, 125.1, 126.0, 126.2, 126.4, 126.7, 127.1, 128.2, 128.6, 129.4, 135.2, 135.6,
143.1, 144.3, 144.8, 156.6, 168.6.
Ethyl 4-(4-fluorophenylamino)-1-(4-fluorophenyl)-2,6-bis(4-methylphenyl)-1,2,5,6-
tetrahydropyridine-3-carboxylate (9s)
1
White solid; IR (KBr, cm-1): m 3298 (NH), 1655 (C=O); H NMR (400 MHz,
CDCl3): d 1.49 (3H, t, J = 7.2 Hz, OCH2CH3), 2.36 (3H, s, CH3), 2.39 (3H, s,
CH3), 2.67 (1H, dd, J = 15.2, 2.4 Hz, H0-5), 2.86 (1H, dd, J = 15.2, 5.8 Hz, H00-5),
4.36 (1H, dq, J = 10.5, 7.2 Hz, OCHaHb), 4.49 (1H, dq, J = 10.5, 6.8 Hz,
OCHaHb), 5.08 (1H, d, J = 3.6 Hz, H-6), 6.24–6.29 (2H, m, ArH), 6.35 (1H, s,
H-2), 6.44–6.49 (2H, m, ArH), 6.77–6.86 (4H, m, ArH), 7.05–7.23 (8H, m, ArH),
10.22 (1H, s, NH); 13C NMR (100 MHz, CDCl3): d 14.8, 21.0, 21.1, 33.6, 55.4,
58.1, 59.7, 98.3, 113.5 (d, J = 7.0 Hz), 115.3 (d, J = 22.2 Hz), 115.6 (d,
J = 23.0 Hz), 127.0 (d, J = 23.0 Hz), 127.9 (d, J = 9.1 Hz), 129.0, 129.4, 134.1
1
(d, J = 3.0 Hz), 135.9, 136.9, 139.7, 140.7, 143.6, 155.1 (d, JCF = 234.0 Hz),
1
156.0, 160.6 (d, JCF = 245.0 Hz), 168.2.
Acknowledgments Financial support from the Research Council of the Payame Noor University (PNU)
is gratefully acknowledged.
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