A simple and efficient approach to one-pot synthesis of mono- and bis-N-aryl-3-aminodihydropyrrol-2-one-4-carboxylates catalyzed by InCl 3

Article abstract of DOI:10.1016/j.cclet.2013.10.010

An efficient and straightforward procedure has been developed for the synthesis of highly substituted mono- and bis-N-aryl-3-aminodihydropyrrol-2-one- 4-carboxylates via a one-pot, four-component domino reaction of amines, dialkyl acetylenedicarboxylates and formaldehyde in the presence of InCl₃ (20 mol%) in MeOH at ambient temperature. The salient advantages of this method are mild reaction conditions, environmentally benign, high to excellent yields, shorter reaction times, easy operation and no column chromatographic separation.

Full text of DOI:10.1016/j.cclet.2013.10.010

Chinese Chemical Letters 25 (2014) 58–60
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Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
Original article
A simple and efficient approach to one-pot synthesis of mono- and
bis-N-aryl-3-aminodihydropyrrol-2-one-4-carboxylates catalyzed
by InCl3
b
b
Seyed Sajad Sajadikhah a, , Malek Taher Maghsoodlou , Nourallah Hazeri
*
a Department of Chemistry, Payame Noor University, Iran
b Department of Chemistry, Faculty of Sciences, University of Sistan and Baluchestan, Zahedan 98135-674, Iran
A R T I C L E I N F O
A B S T R A C T
Article history:
An efficient and straightforward procedure has been developed for the synthesis of highly substituted
mono- and bis-N-aryl-3-aminodihydropyrrol-2-one-4-carboxylates via a one-pot, four-component
domino reaction of amines, dialkyl acetylenedicarboxylates and formaldehyde in the presence of InCl3
(20 mol%) in MeOH at ambient temperature. The salient advantages of this method are mild reaction
conditions, environmentally benign, high to excellent yields, shorter reaction times, easy operation and
no column chromatographic separation.
Received 21 May 2013
Received in revised form 3 September 2013
Accepted 12 September 2013
Available online 7 November 2013
Keywords:
ß 2013 Seyed Sajad Sajadikhah. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All
rights reserved.
Dihydropyrrol-2-one
Heterocycle
InCl3
Four-component reaction
1. Introduction
of these methods have drawbacks, such as high temperature and
utilize a chlorinated solvent. Therefore, the development of a
In recent years, growing attention has been paid to the
synthesis of N-heterocycles due to diverse biological and
pharmaceutical applications [1–3]. In this respect, the presence
milder and more efficient route for one-pot synthesis of these
important heterocycles is still in demand.
In continuation of our ongoing studies for the preparation of
heterocyclic compounds, in particular, highly substituted dihy-
dropyrrol-2-ones [26–31], herein we report a simple and efficient
procedure for the synthesis of mono- and bis-N-aryl-3-aminodi-
hydropyrrol-2-one-4-carboxylates 5 and 6 via one-pot, four-
component domino reaction of amines, dialkyl acetylenedicarbox-
ylates and formaldehyde. The reaction was performed in the
presence of catalytic amounts of InCl3 (20 mol%) in MeOH at room
temperature (Scheme 1).
of pyrrol-2-ones (5-lactams or g-lactams) in pharmaceuticals and
natural products has continued to stimulate a great deal of
interest in the development of new methodologies for their
synthesis [4–6]. There are several bioactive natural molecules
with a pyrrol-2-one moiety, such as holomycin and thiolutin [7],
thiomarinol A4 [8], oteromycin [9], pyrrocidine A [10], quino-
lactacin
C [11], and ypaoamide [12]. On the other hand,
dihydropyrrol-2-ones have been successfully used as peptido-
mimetic [13], HIV integrase [14], herbicidals [15], DNA polymer-
ase inhibitors [16], caspase-3 inhibitors [17] cytotoxic and anti-
tumor agents [18], antibiotics [19], and also inhibitors of the
annexin A2-S100A10 protein interaction [20]. Recently, a few
methods have been reported for the synthesis of highly
substituted dihydropyrrol-2-ones using one-pot, four-compo-
nent reactions in the presence of catalyst, such as AcOH, I2, benzoic
acid, TiO2 nanopowder or Cu(OAc)2ꢀH2O [21–25]. However, some
2. Experimental
Melting points were taken on an Electrothermal 9100 appara-
tus. IR spectra were obtained on
a JASCO FT/IR-460 plus
spectrometer. The 1H NMR and 13C NMR spectra were recorded
on a Bruker DRX-400 Avanve instrument with CDCl3 as solvent and
using TMS as internal reference at 400 MHz and 100 MHz,
respectively. Chemicals were purchased from Merck (Darmastadt,
Germany), Acros (Geel, Belgium) and Fluka (Buchs, Switzerland),
and used without further purification.
*
Corresponding author.
E-mail address: sssajadi@yahoo.com (S.S. Sajadikhah).
1001-8417/$ – see front matter ß 2013 Seyed Sajad Sajadikhah. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
http://dx.doi.org/10.1016/j.cclet.2013.10.010

S.S. Sajadikhah et al. / Chinese Chemical Letters 25 (2014) 58–60
59
O
Table 1
H
N
Optimization of the reaction conditions for the synthesis of 5a.a
1
2
2
1
NH
R
CO R
2
R
2
N
Ar
Yield (%)b
1
Entry
Catalyst (mol%)
Solvent
Time (h)
2
or
R O C
2
5
1
2
InCl3 (10)
InCl3 (10)
InCl3 (10)
InCl3 (5)
EtOH
4
3.5
6
63
75
21
59
81
85
85
39
33
61
57
Trace
H N
2
CO R
2
NH
MeOH
H2O
2
InCl (20 mol%)
3
or
O
3
1'
2
2
R O C
2
+
4
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
5
MeOH, r.t.
5
InCl3 (15)
InCl3 (20)
InCl3 (25)
ZnO (20)
Zn(OAc)2ꢀ2H2O (20)
NiCl2 (20)
ZnCl2 (20)
–
3
H
N
N
Ar
O
6
3
N
H
7
3
Ar NH
Ar
N
2
O
H
H
8
8
3
2
4
CO R
2
9
10
7
10
11
12
6
7
24
Scheme 1. Synthesis of mono- and bis-N-aryl-3-aminodihydropyrrol-2-one-4-
a
carboxylates.
Amounts of material in all reactions: aniline (2 mmol), DMAD (1 mmol), and
formaldehyde (1.5 mmol).
b
Isolated yield.
General procedure for the synthesis of mono- and bis-N-aryl-3-
aminodihydropyrrol-2-one-4-carboxylates 5 and 6: A mixture of
amine 1 or 10 (1 mmol) and dialkyl acetylenedicarboxylate 2
(1 mmol for product 5, 2 mmol for product 6) in MeOH (3 mL) was
stirred for 25 min. Next, amine 3 (1 mmol for product 5, 2 mmol for
product 6), formaldehyde 4 (37% solution, 1.5 mmol for product 5,
3 mmol for product 6) and InCl3 (20 mol%) were added succes-
sively. The reaction mixture was allowed to stir at ambient
temperature for appropriate time. After completion of the reaction
(monitored by TLC), the solid precipitate was filtered off and
washed with ethanol (3ꢁ 2 mL) to give the pure product 5 or 6. The
structures of the synthesized compounds were characterized by
their IR, 1H NMR and 13C NMR spectra and were found to be
identical with data described in the literature [21,22,28–31]. The
physical and spectral data of the products are given as Supporting
information.
(Table 1, entry 6). Notably, when the reaction was examined in the
absence of the catalyst only a trace amount of the target product
was obtained.
To demonstrate the utility and generality of this method, the
various substituted anilines, dimethyl and/or diethyl acetylene-
dicarboxylates and formaldehyde were employed successfully to
generate the desired N-aryl-3-aminodihydropyrrol-2-one-4-car-
boxylates 5a–h (Table 2). Encouraged by these results, different
polyfunctionalized dihydropyrrol-2-ones 5i–q were synthesized
using two different amines. Aliphatic amines, such as benzyl
amine, 1-(pyridin-2-yl)methanamine and n-butyl amine, were
reacted with dialkyl acetylenedicarboxylates, anilines and formal-
dehyde to produce the corresponding products in good to high
yields. We next explored the scope of this procedure in the four-
component (pseudo seven-component) synthesis of bis-N-aryl-3-
aminodihydropyrrol-2-one-4-carboxylates 6, via the condensation
of ethane-1,2-diamine 10 (1 equiv.), dialkyl acetylenedicarboxy-
lates 2 (2 equiv.), aromatic amine 3 (2 equiv.) and formaldehyde 4
(2 equiv.). In all cases, the reaction proceeded smoothly and the
desired products were obtained in good yields.
3. Results and discussion
To find the optimal conditions, the reaction between aniline,
dimethyl acetylendicarboxylate (DMAD) and formaldehyde was
chosen as a model. This reaction was performed under different
conditions and the results are summarized in Table 1. The best
result was obtained in the presence of 20 mol% of InCl3 in MeOH
On the basis of the above experimental results, together with
the related reports, a plausible reaction mechanism for this one-
pot, four-component heteroannulation is illustrated in Scheme 2.
Table 2
Synthesis of mono- and bis-N-aryl-3-aminodihydropyrrol-2-one-4-carboxylates 5 and 6.
Product
R1
R2
Ar
Time (h)
Yield (%)a
Mp (8C)
Lit. mp (8C) [Ref.]b
5a
5b
5c
5d
5e
5f
Ph
Me
Et
Ph
3
85
85
86
81
73
81
79
84
80
81
84
86
80
68
79
83
76
79
82
80
78
154–155
136–138
177–179
128–130
152–154
163–165
167–170
167–169
136–138
127–129
166–168
119–121
144–146
104–106
60–62
155–156 [22]
138–140 [21]
177–178 [22]
131–132 [21]
152–154 [28]
163–165 [31]
168–170 [29]
169–171 [21]
140–141 [21]
130–132 [21]
166–168 [28]
120–121 [22]
144–146 [30]
106–108 [29]
60 [22]
Ph
Ph
3
4-Me-C6H4
4-Me-C6H4
4-OMe-C6H4
4-F-C6H4
4-Cl-C6H4
4-Br-C6H4
PhCH2
Me
Et
4-Me-C6H4
4-Me-C6H4
4-OMe-C6H4
4-F-C6H4
4-Cl-C6H4
4-Br-C6H4
Ph
3.5
3
Et
5
Me
Et
3.5
3
5g
5h
5i
Et
3
Me
Et
3
5j
PhCH2
Ph
3.5
3
5k
5l
PhCH2
Me
Me
Me
Me
Me
Et
4-F-C6H4
4-Br-C6H4
4-Me-C6H4
4-Me-C6H4
Ph
PhCH2
3.5
3.5
5
5m
5n
5o
5p
5q
6a
6b
6c
6d
PhCH2
C5H4N-2-CH2
n-C4H9
3.5
3
n-C4H9
4-Br-C6H4
3,4-Cl2-C6H3
Ph
94–97
94–96 [31]
n-C4H9
Me
Me
Me
Et
4.5
5
97–99
97–99 [28]
H2NCH2CH2
H2NCH2CH2
H2NCH2CH2
H2NCH2CH2
148–150
200–202
210–212
204–207
149–151 [29]
199–201 [29]
210–212 [29]
206–208 [29]
4-F-C6H4
4-Me-C6H4
3,4-Cl2-C6H3
5
4.5
6
Et
a
Isolated yield.
b
References refer to known products as mentioned in the literature.

60
S.S. Sajadikhah et al. / Chinese Chemical Letters 25 (2014) 58–60
2
2
O
CO R
2
H
N
1
2
2
1
R
OR
O
R
NH
2
+
O
O
H
N
N
N
2
1
2
R O C
1
2
OR
1
2
6
1 or 1'
CO R
2
2
R
R
R
N
Ar
N
Ar
H
R O C
InCl
2
R O C
3
2
2
R O C
2
InCl
NH
3
N
Ar NH
CH O
2
+
2
5 or 6
Ar
Ar
7
8
9
3
4
Scheme 2. Proposed mechanism for the synthesis of N-aryl-3-aminodihydropyrrol-2-one-4-carboxylates 5 and 6.
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4. Conclusion
In summary, we have developed an efficient one-pot, four-
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3-aminodihydropyrrol-2-one-4-carboxylates using InCl3 as
a
Lewis acid catalyst. This methodology has advantages including
mild reaction conditions, available starting materials, easy
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Acknowledgment
We gratefully acknowledge financial support from the Research
Council of University of Sistan and Baluchestan and Payame Noor
University.
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Appendix A. Supplementary data
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Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.cclet.2013.10.010.
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