An efficient one-pot access to substituted dihydropyrrol-2-one derivatives using sucrose as natural, biodegradable and inexpensive catalyst

Article abstract of DOI:10.1002/jccs.201300311

An efficient and simple procedure for the synthesis of highly substituted dihydropyrrol-2-ones has been developed via one-pot four-component condensation of amines, dialkyl acetylenedicarboxyaltes and formaldehyde in the presence of sucrose as an organocatalyst. The salient advantages of this method are using a natural, biodegradable and commercial available catalyst, good yields, short reaction times, simple work-up and lack of need for column chromatography. An efficient and simple procedure for the synthesis of highly substituted dihydropyrrol-2-ones has been developed via one-pot four-component condensation of amines, dialkyl acetylenedicarboxyaltes and formaldehyde in the presence of sucrose as an organocatalyst. The salient advantages of this method are using a natural, biodegradable and commercial available catalyst, good yields, short reaction times, simple work-up and lack of need for column chromatography. Copyright

Full text of DOI:10.1002/jccs.201300311

JOURNAL OF THE CHINESE
CHEMICAL SOCIETY
Article
An Efficient One-pot Access to Substituted Dihydropyrrol-2-one Derivatives Using
Sucrose as Natural, Biodegradable and Inexpensive Catalyst
a
Nourallah Hazeri, * Seyed Sajad Sajadikhah, Malek Taher Maghsoodlou,
b
a
a
Sajad Mohamadian-Souri, Mahmoud Norouzi and Maryam Moein
a
a
a
Department of Chemistry, University of Sistan and Baluchestan, P.O. Box 98135-674, Zahedan, Iran
Department of Chemistry, Payame Noor University, Iran
b
(Received: Jun. 23, 2013; Accepted: Sept. 22, 2013; Published Online: Nov. 8, 2013; DOI: 10.1002/jccs.201300311)
An efficient and simple procedure for the synthesis of highly substituted dihydropyrrol-2-ones has been
developed via one-pot four-component condensation of amines, dialkyl acetylenedicarboxyaltes and
formaldehyde in the presence of sucrose as an organocatalyst. The salient advantages of this method are
using a natural, biodegradable and commercial available catalyst, good yields, short reaction times, simple
work-up and lack of need for column chromatography.
Keywords: Dihydropyrrol-2-one; Heterocycle; Sucrose; Organocatalyst; Multi-component reaction.
INTRODUCTION
Nitrogen containing heterocycles play key roles in
pharmaceutical scenes and exhibit a wide range of biologi-
In recent years, the use of organocatalysts has re-
ceived considerable attention in organic chemistry due to
their properties such as lack of sensitivity to moisture and
oxygen, ready availability, low cost, low toxicity and re-
1
-4
cal activities. Amongst them, dihydropyrrol-2-ones (di-
hydro-2-oxopyrroles) are very interesting compounds due
to their biological and pharmaceutical activity such as anti-
2
3-25
duced waste formation.
Sucrose is a carbohydrate mol-
ecule commonly known as table sugar. Chemically, sucrose
is a disaccharide composed of the monosaccharides glu-
5
6
7
8
HIV, anti-influenza, anti cancer, antibiotics, nootropic
9
agents, pesticides, and herbicidal. Furthermore, these
10
11
22
cose and fructose with molecular formula C12H O11. This
heterocycles are the core structure of many bioactive natu-
small natural molecule contains three primary and five sec-
ondary hydroxyl groups and therefore it can acts as mild
catalytic system (Fig. 1).
1
ral compounds such as quinolactacins, ypaoamide, otero-
2
13
1
mycin, jatropham, EBPC, and (Z)-pulchellalactam.
4
15
16
17
Recently, Jiang et al. have reported the synthesis of di-
hydropyrrol-2-ones by means of the reaction between
amines, dialkyl acetylenedicarboxylates and aldehydes in
In continuation of our research work on the synthesis
2
6-29
of dihydropyrrol-2-ones,
herein we wish to report com-
mercially available sucrose as bio-resource homogeneous
catalyst, for the one-pot synthesis of highly substituted
dihydropyrrol-2-ones by means of four-component dom-
ino reaction of amines, dialkyl acetylenedicarboxylates
and formaldehyde (Scheme I).
1
8
the presence of acetic acid, and Khan et al. documented
the iodine catalyzed synthesis of dihydropyrrol-2-one de-
1
rivatives. Additionally, a few efforts have been also paid
9
to the synthesis of highly substituted dihydropyrrol-2-ones
21
2
using catalysts such as benzoic acid, TiO
0
2
nanopowder,
2
O. Therefore, the development of novel
2
and Cu(OAc)
2
·H
2
Scheme I Synthesis of dihydropyrrol-2-ones 5
methods for the synthesis of dihydropyrrol-2-ones is of
great importance because of their potential biological and
pharmaceutical activities.
RESULTS AND DISCUSSION
First, we looked for the optimum reaction conditions.
The screening was performed with aniline, dimethyl ace-
Fig. 1. Chemical structure of sucrose.
*
Corresponding author. Tel: +98-541-2416586; Fax: +98-541-2416586; Email: nhazeri@chem.usb.ac.ir
J. Chin. Chem. Soc. 2014, 61, 217-220
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217

Article
Hazeri et al.
tylenedicarboxylate (DMAD) and formaldehyde as a
model system, and the results are summarized in Table 1.
The first experiment was carried out in the presence of su-
crose (20 mol%) in methanol at ambient temperature, and
the corresponding functionalized dihydropyrrol-2-one 5a
was obtained in 39% yield (Table 1, entry 1). In the absence
of catalyst, only a trace yield of product was obtained even
after prolonged reaction time. Next, the effect of the cata-
lyst was investigated in various conditions. The best result
was obtained in the presence of 20 mol% of the catalyst at
Table 1. Optimization of the reaction conditions
CO Me
H
N
O
2
Ph
Ph NH2
+
+
Ph NH2 + CH2O
N Ph
CO2Me
MeO2C
Catalyst
(mol%)
Temperature Time
Yield
a
(%)
Entry
Solvent
(°C)
(h)
1
2
3
4
5
6
7
8
9
20
-
MeOH
MeOH
EtOH
25
25
25
40
50
60
60
60
60
60
60
5.5
24
7
39
Trace
31
20
20
20
20
5
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
5
50
4
78
6
0 °C (Table 1, entry 6).
4
89
The scope and limitations of this domino four-com-
5
63
10
15
25
30
4.5
4
85
ponent reaction were explored under optimized conditions
using a variety of amines and acetylenic esters, as summa-
rized in Table 2. Anilines containing either electron-donat-
ing or electron-withdrawing substituents successfully react
with dialkyl acetylenedicarboxylates and formaldehyde,
affording good yields of products 5a-l. Next, two different
amines were examined to study the generality and scope of
the present protocol. Aliphatic amines such as benzyl amine
and n-butyl amine were treated with varying anilines, di-
methyl and/or diethyl acetylenedicarboxylate and formal-
dehyde under indicated reaction conditions. All reactions
underwent smoothly to provide the corresponding dihydro-
pyrrol-2-one derivatives 5m-s in good to high yields (Table
86
1
1
a
0
1
4
83
5
78
Isolated Yield.
functional group tolerance and provided the desired prod-
ucts with great efficiency. The structure of the products was
1
13
characterized by IR, H and C NMR spectral data and
comparison of their melting points with those of authentic
samples.
A plausible mechanism for the synthesis of highly
substituted dihydropyrrol-2-ones 5 is illustrated in Scheme
II.
2
, entries 13-19). Satisfactory, the reactions displayed high
Table 2. The synthesis of substituted dihydropyrrol-2-ones 5
1
2
a
Product Time (h) Yield (%) m.p. (lit. reported)
Ref., b
Entry
R
R
Ar
Ph
1
1
1
2
1
1
1
1
2
1
2
1
1
1
1
9
9
9
6
9
9
8
8
7
8
8
8
8
9
9
1
2
3
4
5
6
7
8
9
Ph
Me
Me
Me
Me
Me
Me
Et
5a
5b
5c
5d
5e
5f
4
4
89
81
77
89
84
90
84
71
72
85
84
83
83
83
88
83
78
88
85
153-155 (155-156)
173-175 (177-178)
170-173 (176-177)
163-165 (163-165)
168-170 (173-174)
175-178 (179-180)
137-139 (138-140)
126-128 (131-132)
152-154 (152-154)
172-174 (172-173)
167-169 (168-170)
170-172 (169-171)
141-143 (140-141)
144-147 (147-148)
123-125 (120-121)
4-Me-C H4
6
4-Me-C H4
6
4-OMe-C H4
6
4-OMe-C H4
6
4.5
4
4-F-C H4
6
4-F-C H4
6
4-Cl-C H4
6
4-Cl-C H4
6
4.5
4
4-Br-C H4
6
4-Br-C H4
6
Ph
Ph
5g
5h
5i
4
4-Me-C H4
6
Et
4-Me-C H4
6
5
4-OMe-C H4
6
Et
4-OMe-C H4
6
4.5
4
1
1
1
1
1
1
1
1
1
1
a
0
1
2
3
4
5
6
7
8
9
4-F-C H4
6
Et
4-F-C H4
6
5j
4-Cl-C H4
6
Et
4-Cl-C H4
6
5k
5l
4.5
4
4-Br-C H4
6
Et
4-Br-C H4
6
PhCH2
PhCH2
PhCH2
Me
Me
Me
Me
Me
Me
Et
Ph
5m
5n
5o
5p
5q
5r
5s
4
4-Cl-C H4
6
6
4-Br-C H4
6
3.5
5
1
9
n-C H9
4
Ph
60-62 (60)
2
9
n-C H9
4
4-F-C H4
6
6
81-83 (81-83)
1
9
n-C H9
4
4-Br-C H4
6
5
109-111 (108-109)
26
n-C H9
4
4-Br-C H4
6
5
94-96 (94-96)
Isolated yield.
b
The references of known products in the literature.
218
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J. Chin. Chem. Soc. 2014, 61, 217-220

JOURNAL OF THE CHINESE
CHEMICAL SOCIETY
Synthesis of Dihydropyrrol-2-one Derivatives
Scheme II Suggested mechanism for the synthesis of
dihydropyrrol-2-ones 5
1H-pyrrole-3-carboxylate (5a): White solid, IR (KBr) (nmax,
-
cm ): 3266 (NH), 1676 (C=O), 1645 (C=O); H NMR (400 MHz,
1
1
CDCl ): d 3.76 (3H, s, OCH ), 4.57 (2H, s, CH ), 7.16-7.23 (4H,
2
3
3
m, ArH), 7.35 (2H, t, J = 7.8 Hz, ArH), 7.42 (2H, t, J = 8.0 Hz,
ArH), 7.81 (2H, d, J = 8.0 Hz, ArH), 8.05 (1H, br s, NH).
Methyl 3-(4-fluorophenylamino)-1-(4-fluorophenyl)-
2
,5-dihydro-2-oxo-1H-pyrrole-4-carboxylate (5d): White solid,
-
1
1
IR (KBr) (nmax, cm ): 3286 (NH), 1676 (C=O), 1646 (C=O); H
NMR (400 MHz, CDCl ): d 3.78 (3H, s, OCH ), 4.53 (2H, s,
CH ), 7.01-7.16 (6H, m, ArH), 7.73-7.76 (2H, m, ArH), 8.05 (1H,
br s, NH); C NMR (100 MHz, CDCl
23.0 Hz), 115.9 (d, JCF = 22.1 Hz), 121.0 (d, JCF = 7.0 Hz), 125.1
d, JCF = 8.1 Hz), 134.4 (d, JCF = 3.0 Hz), 134.7 (d, JCF = 2.0 Hz),
43.4, 159.8 (d, JCF = 243.0 Hz), 160.1 (d, JCF = 242.0 Hz), 163.5
C=O), 164.8 (C=O).
Ethyl 4-(4-chlorophenylamino)-1-(4-chlorophenyl)-2,5-
dihydro-5-oxo-1H-pyrrole-3-carboxylate (5k): White solid, IR
3
3
2
1
3
3
): d 48.3, 51.4, 115.1 (d, JCF
=
(
1
(
In conclusion, we have developed a very simple and
efficient method for the synthesis substituted dihydropyr-
rol-2-one derivatives using sucrose as natural, biodegrad-
able and inexpensive catalyst via condensation of amines,
dialkyl acetylenedicarboxylates and formaldehyde in
methanol. This method offers several advantages such as
easy purification and lack of need for column chromatogra-
phy, high yields, short reaction times, simple and readily
available precursors.
-
1
1
(KBr) (nmax, cm ): 3320 (NH), 1696 (C=O), 1640 (C=O); H
NMR (400 MHz, CDCl ): d 1.29 (3H, t, J = 7.0 Hz, OCH CH ),
4.27 (2H, q, J = 7.2 Hz, OCH CH ), 4.52 (2H, s, CH ), 7.09 (2H,
3
2
3
2
3
2
d, J = 8.4 Hz, ArH), 7.28 (2H, d, J = 8.4 Hz, ArH), 7.37 (2H, d, J =
8.8 Hz, ArH), 7.76 (2H, d, J = 8.8 Hz, ArH), 8.07 (1H, br s, NH).
Ethyl 1-(4-bromophenyl)-3-(butylamino)-2,5-dihydro-
2-oxo-1H-pyrrole-4-carboxylate (5s): White solid, IR (KBr)
-
1
1
(nmax, cm ): 3320 (NH), 1698 (C=O), 1646 (C=O); H NMR (400
MHz, CDCl ): d 0.98 (3H, t, J = 7.2 Hz, CH ), 1.35 (3H, t, J = 7.2
Hz, OCH CH ), 1.44 (2H, sextet, J = 7.4 Hz, CH ), 1.62 (2H,
quintet, J = 7.4 Hz, CH ), 3.87 (2H, t, J = 7.2 Hz, CH -NH), 4.28
(2H, t, J = 7.2 Hz, OCH CH ), 4.40 (2H, s, CH -N), 6.72 (1H, br,
NH), 7.52 (2H, d, J = 8.8 Hz, ArH), 7.71 (2H, d, J = 8.8 Hz, ArH);
3
3
EXPERIMENTAL
2
3
2
General: All the chemicals were purchased from Merck
2
2
(
(
Darmastadt, Germany), Acros (Geel, Belgium) and Fluka
Buchs, Switzerland), and used without further purification.
2
3
2
1
3
Melting points were determined on an Electrothermal 9100 appa-
3
C NMR (100 MHz, CDCl ): d 13.8, 14.5, 19.8, 33.4, 42.8, 47.8,
ratus. IR spectra were obtained on a JASCO FT/IR-460 plus
1 13
spectrophotometer. The H and C NMR spectra were recorded
59.8, 98.1, 117.7, 120.6, 132.0, 137.9, 164.6 (C=O), 165.5 (C=O).
on a Bruker DRX-400 Avanve instrument with CDCl as solvent
3
ACKNOWLEDGEMENTS
at 400 and 100 MHz, respectively; chemical shifts are given in d
ppm, relative to TMS as internal standard.
We gratefully acknowledge financial support from
the Research Council of the University of Sistan and
Baluchestan.
General procedure for the synthesis of dihydropyrrol-2-
one 5: A mixture of amine 1 (1 mmol) and dialkyl acetylene-
dicarboxylate 2 (1 mmol) in methanol (3 mL) was stirred for 30
min. Next, amine 3 (1 mmol), formaldehyde 4 (1.5 mmol) and su-
crose (20 mol %) were added successively. The reaction mixture
was allowed to stir at 60 °C for appropriate time. The progress of
the reaction was monitored by TLC. After completion of the reac-
tion, the solid precipitate was obtained through simple filtering,
and washed with methanol to give the pure product 5. Physical
and spectral data for selected products are represented below.
Methyl 2,5-dihydro-5-oxo-1-phenyl-4-(phenylamino)-
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