Maltose, a natural, efficient and economical catalyst for the one-pot synthesis of highly substituted dihydropyrrol-2-ones

Article abstract of DOI:10.3184/174751913X13739000149898

Maltose is a natural, economical and very effective catalyst for promotion of the four-component domino reaction between amines, dialkyl acetylenedicarboxylates and formaldehyde to afford substituted dihydropyrrol-2-ones at room temperature. The advantages of this protocol are good yields, short reaction times, low cost, environmentally friendly, simple work-up and lack of need for column chromatography. Website

Full text of DOI:10.3184/174751913X13739000149898

5
50 RESEARCH PAPER
SEPTEMBER, 550–552
JOURNAL OF CHEMICAL RESEARCH 2013
Maltose, a natural, efficient and economical catalyst for the one-pot
synthesis of highly substituted dihydropyrrol-2-ones
Nourallah Hazeri*, Seyed Sajad Sajadikhah, Malek Taher Maghsoodlou, Mahmoud Norouzi,
Maryam Moein and Sajad Mohamadian-Souri
Department of Chemistry, Faculty of Sciences, University of Sistan and Baluchestan, PO Box 98135-674, Zahedan, Iran
Maltose is a natural, economical and very effective catalyst for promotion of the four-component domino reaction
between amines, dialkyl acetylenedicarboxylates and formaldehyde to afford substituted dihydropyrrol-2-ones at
room temperature. The advantages of this protocol are good yields, short reaction times, low cost, environmentally
friendly, simple work-up and lack of need for column chromatography.
Keywords: dihydropyrrol-2-one, maltose, dialkyl acetylenedicarboxylate, four-component reaction
Nitrogen containing heterocyclic compounds are the key
building blocks of many natural products, fine chemicals and
biologically active pharmaceuticals essential for enhancing
1
the quality of life. Amongst them, dihydropyrrol-2-ones
(
dihydro-2-oxopyrroles) are very interesting compounds due
to their biological as well as their pharmaceutical activity such
as anti-HIV, anti-influenza, anti cancer, antibiotics, noot-
ropic agents, pesticides, and herbicidal. Dihydropyrrol-2-
one derivatives were also reported as potential inhibitors of
Trypanosoma brucei leucyl-tRNA synthetase which represents
a promising new approach to treatment of Human African
2
3
4
5
6
7
8
Fig. 2 Chemical structure of maltose.
9
trypanosomiasis (sleeping sickness). Furthermore, these het-
erocycles are the core structure of many bioactive natural
1
0
11
products such as jatropham, 13holomycin and thiolutin,
In continuation of our interest in developing efficient syn-
1
2
(
Z)-pulchellalactam, and EBPC (Fig. 1).
Recently, efforts have been made towards the synthesis of
thetic methodologies for the synthesis of dihydropyrrol-2-one
19–21
derivatives,
we now report that commercially available
dihydropyrrol-2-one derivatives by the reaction of amines,
dialkyl acetylenedicarboxylates and aldehydes using catalytic
maltose, acts as a bio-resource homogeneous catalyst for the
one-pot synthesis of highly substituted dihydropyrrol-2-ones
via a four-component domino reaction of amines, dialkyl acet-
ylenedicarboxylates and formaldehyde at room temperature
1
4
15
systems such as acetic acid, molecular iodine, benzoic
16
17
acid, and TiO nanopowder. However, the development
2
of novel methods for the synthesis of dihydropyrrol-2-ones is
of great importance because of their potential biological and
pharmaceutical activity.
(
Scheme 1).
Results and discussion
The use of organocatalysts has received considerable atten-
tion in organic chemistry because their properties provides the
possibility to perform reactions for acid-sensitive substrates,
In preliminary experiments, the model reaction of aniline,
dimethyl acetylenedicarboxylate (DMAD) and formaldehyde
in MeOH was studied to establish the optimal conditions. The
results are summarised in Table 1. In the absence of catalyst,
only trace amount of the desired product 5a was obtained, even
after long reaction time (Table 1, entry 1). To determine the
appropriate amount of catalyst, the model reaction was inves-
tigated with different quantities of maltose, such as 5, 10, 15,
1
8
under milder reaction conditions and better selectivity.
Maltose (malt sugar) is an important part of malt and occurs
in many plants. Chemically, maltose is a disaccharide that con-
sists of two glucose units (Fig. 2). This small natural product
contains many hydroxyl groups and therefore it can act as a
mild catalytic system.
2
0 and 30 mol%. The results indicate that 20 mol% of maltose
is enough to carry out the reaction efficiently (Table 1, entry
). The efficiency of other catalysts including lactose and
5
dextrin were tested. However, they did not affect the yield of
product. The reaction was also examined in solvents such as
EtOH and H O, in which the reaction was sluggish and the
2
product was obtained in a low yield.
Fig. 1 Bioactive natural products containing dihydropyrrol-2-
one skeleton.
Scheme 1 Synthesis of highly substituted
*
Correspondent. E-mail: nhazeri@chem.usb.ac.ir
dihydropyrrol-2-ones.

JOURNAL OF CHEMICAL RESEARCH 2013 551
Table
1
Optimisation of the reaction conditions on the
In conclusion, we have developed a simple and efficient
method for the preparation of highly substituted dihydropyr-
rol-2-ones using maltose as catalyst in MeOH at room tem-
perature. The present protocol has several advantages such as
natural, biodegradable and inexpensive catalyst, mild reaction
conditions, good product yields, short reaction times, simple
work-up procedure and an easy isolation of products.
formation of 5a
Yield/%a
Entry
Catalyst/mol%
Solvent
Time/h
1
2
3
4
5
6
7
8
9
―
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
EtOH
24
4
Trace
55
Maltose/5
Maltose/10
Maltose/15
Maltose/20
Maltose/30
Lactose/20
Dextrin/20
Maltose/20
Maltose/20
3
63
3
75
3
82
3
81
Experimental
5
65
All the chemicals were purchased from Merck (Darmastadt,
Germany), Acros (Geel, Belgium) and Fluka (Buchs, Switzerland),
and used without further purification. Melting points were determined
on an Electrothermal 9100 apparatus. IR spectra were obtained on a
4
30
2
51
10
H
2
O
24
10
a
1
13
Isolated yield.
JASCO FT/IR-460 plus spectrophotometer. The H and C NMR
spectra were recorded on a Bruker DRX-400 Avance instrument with
CDCl as solvent at 400 and 100 MHz, respectively; chemical shifts
3
are given in δ ppm, relative to TMS as internal standard.
The scope and limitations of this domino four-component
reaction under optimised conditions were explored using
a variety of amines and acetylenic esters, as summarised in
Table 2. Anilines containing either electron-withdrawing or
electron-donating substituents successfully react with dimethyl
and/or diethyl acetylenedicarboxylate and formaldehyde,
affording good yields of products 5a–j. Next, two different
amines were examined to study the generality and scope of the
present protocol. Various aliphatic amines such as benzyl-
amine, cyclohexylamine and n-butylamine were treated with
varying anilines, dialkyl acetylenedicarboxylates and formal-
dehyde under indicated reaction conditions. All reactions
proceeded smoothly to provide the corresponding dihydropyr-
rol-2-one derivatives in moderate to good yields (Table 2,
products 5k–r). The reactions displayed high functional group
tolerance and provided the desired products with great
efficiency.
Synthesis of highly substituted dihydropyrrol-2-one 5; general
procedure
A mixture of amine 1 (1 mmol) and dialkyl acetylenedicarboxylate 2
(
(
(
1 mmol) in MeOH (3 mL) was stirred for 30 min. The amine 3
1 mmol), formaldehyde 4 (37% solution, 1.5 mmol) and maltose
20 mol %) were then added successively. The progress of the reaction
was monitored by TLC. After completion of the reaction, the solid
product 5 was obtained through simple filtration, and washed with
EtOH to afford pure products. Physical and spectroscopic data for
selected examples are shown below.
Methyl 2,5-dihydro-2-oxo-1-phenyl-3-(phenylamino)-1H-pyrrole-
−1
4
(
-carboxylate (5a): White solid; IR (KBr, cm ): ν 3264 (NH), 1692
1
C=O), 1641 (C=O); H NMR (400 MHz, CDCl ): δ 3.76 (3H,
3 H
s, OCH ), 4.57 (2H, s, CH -N), 7.16–7.23 (4H, m, ArH), 7.35 (2H,
3
2
t, J = 7.8 Hz, ArH), 7.42 (2H, t, J = 7.8 Hz, ArH), 7.81 (2H, d, J =
.0 Hz, ArH), 8.05 (1H, br s, NH).
Ethyl 4-(4-methylphenylamino)-2,5-dihydro-2-oxo-1-(4-methyl-
phenylamino)-1H-pyrrole-4-carboxylate (5h): Yellow solid; IR (KBr,
8
−1
1
cm ): ν 3286 (NH), 1691 (C=O), 1646 (C=O); H NMR (400 MHz,
CDCl ): δ 1.25 (3H, t, J = 7.2 Hz, OCH CH ), 2.36 (3H, s, CH ), 2.37
3
H
2
3
3
In general, at the beginning of the reaction, the substrates
were completely soluble in reaction medium to form a homo-
geneous mixture. But, at the end of the reaction, the system
became a suspension and finally the product precipitated. The
products were obtained through simple filtration and washed
with EtOH to afford pure products. The structure of the
(
7
3H, s, CH ), 4.24 (2H, t, J = 7.2 Hz, OCH CH ), 4.52 (2H, s, CH ),
.06 (2H, d, J = 8.4 Hz, ArH), 7.14 (2H, d, J = 8.0 Hz, ArH), 7.21 (2H,
3
2
3
2
d, J = 8.4 Hz, ArH), 7.69 (2H, d, J = 8.8 Hz, ArH), 8.01 (1H, br s, NH):
13
C NMR (100 MHz, CDCl ): δ 14.2, 20.9, 21.0, 48.3, 60.2, 102.4,
3
c
119.1, 122.9, 128.9, 129.6, 134.2, 134.6, 136.2, 136.3, 143.1, 163.7
(
C=O), 164.7 (C=O).
Methyl 4-(benzylamino)-1-(4-bromophenyl)-2,5-dihydro-2-oxo-
H-pyrrole-4-carboxylate (5l): Yellow solid; IR (KBr, cm ): ν 3309
1
13
products 5a–r was characterised by their IR, H and C NMR
spectra and comparison of their melting points with those
of authentic samples.
−1
1
1
(
NH), 1698 (C=O), 1644 (C=O); H NMR (400 MHz, CDCl ): δ
3 H
3
.77 (3H, s, OCH ), 4.41 (2H, s, CH -N), 5.11 (2H, d, J = 6.4 Hz,
3 2
A plausible mechanism for the generation of highly substi-
tuted dihydropyrrol-2-ones 5 is shown in Scheme 2.
CH -NH), 6.85 (1H, br, NH), 7.28–7.37 (5H, m, ArH), 7.52 (2H, d,
2
J = 8.4 Hz, ArH), 7.69 (2H, d, J = 8.8 Hz, ArH).
Table 2 The synthesis of dihydropyrrol-2-ones 5a–r
Product
R1
R2
Ar
Time/h
Yield/%a
M.p./°C
Lit. m.p./°CRef, b
1
1
1
1
1
1
1
1
2
1
1
1
1
1
1
5
5
5
5
4
9
4
4
0
4
4
5
5
4
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
r
Ph
Me
Me
Me
Me
Me
Me
Et
Ph
3
5
5
3
4
4
6
6
5
6
4
3
3
4
6
4
3
4
82
78
79
79
81
80
73
74
67
72
80
80
83
76
82
73
71
79
153–155
175–177
176–178
170–172
165–167
163–165
136–138
129–131
152–154
170–172
140–143
121–123
143–145
128–130
124–126
59–61
155–156
177–178
176–177
173–174
169–171
163–165
138–140
131–132
152–154
172–173
140–141
120–121
147–148
130–132
123–124
4-Me-C
6
H
6
4
4-Me-C
6
H
6
4
4-OMe-C
4-Cl-C
4-Br-C
H
4
4-OMe-C
H
4
6
H
4
4-Cl-C
6 4
H
6 4
6
H
4
4-Br-C H
4-F-C
6
H
4
6 4
4-F-C H
Ph
Ph
4-Me-C
6
H
4
Et
4-Me-C
6
H
4
4-OMe-C
6
H
4
Et
Et
4-OMe-C
6
H
4
4-F-C
6
H
4
6 4
4-F-C H
Ph-CH
Ph-CH
Ph-CH
Ph-CH
2
Me
Me
Me
Et
Me
Me
Me
Et
Ph
2
2
2
6 4
4-Br-C H
4-Cl-C
Ph
4-Br-C
Ph
4-Br-C
4-Br-C
6 4
H
Cyclohexyl
6
H
4
15
n-C
n-C
n-C
4
4
4
H
H
H
9
9
9
60
108–109
1
5
6
H
H
4
4
108–110
94–96
2
0
6
94–96
a
Isolated yield.
b
References refer to known products as mentioned in the literature.

5
52 JOURNAL OF CHEMICAL RESEARCH 2013
Scheme 2 Plausible mechanism for the synthesis of substituted dihydropyrrol-2-ones 5.
Methyl 4-(butylamino)-2,5-dihydro-2-oxo-1-phenyl-1H-pyrrole-4-
5
6
7
A.S. Demir, F. Aydigan and I.M. Akhmedov, Tetrahedron: Asymm., 2002,
13, 601.
−
1
carboxylate (5p): White solid; IR (KBr, cm ): ν 3345 (NH), 1688
1
Z. Feng, X. Li, G. Zheng and L. Huang, Bioorg. Med. Chem.Lett., 2009, 19,
(
C=O), 1634 (C=O); H NMR (400 MHz, CDCl ): δ 0.97 (3H, t,
3 H
2
112.
J = 7.2 Hz, CH ), 1.42 (2H, sextet, J = 7.2 Hz, CH ), 1.64 (2H, quintet,
3
2
R. Fischer, S. Lehr, M.W. Drewes, D. Feucht, O. Malsam, G. Bojack, C.
Arnold, T.Auler, M. Hills and H. Kehne, German Patent DE 102004053191,
2006.
L. Zhang, Y. Tan, N.–X. Wang, Q.–Y. Wu, Z. Xi and G.–F. Yang, Bioorg.
Med. Chem., 2010, 18, 7948.
Y. Zhao, Q. Wang, Q. Meng, D. Ding, H. Yang, G. Gao, D. Li, W. Zhu and
H. Zhou, Bioorg. Med. Chem., 2012, 20, 1240.
J.P. Dittami, F. Xu, H. Qi and M.W. Martin, Tetrahedron Lett., 1995, 36,
4201.
J = 7.2 Hz, CH ), 3.82 (3H, s, OCH ), 3.85 (2H, t, J = 7.2 Hz, CH -
2
3
2
NH), 4.45 (2H, s, CH -N), 6.85 (1H, br, NH), 7.18 (1H, d, J = 7.6 Hz,
2
13
ArH), 7.40 (2H, d, J = 7.6 Hz, ArH), 7.73 (2H, d, J = 7.6 Hz, ArH);
NMR (100 MHz, CDCl ): δ 13.8, 20.0, 33.4, 42.6, 47.9, 51.0, 96.1,
C
8
9
0
1
2
3
C
1
19.2, 125.5, 128.9, 138.6, 164.4 (C=O), 165.5 (C=O).
1
1
1
The authors gratefully acknowledge financial support from the
Research Council of the University of Sistan and Baluchestan.
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L. Neipp, V. Prelog and H. Zähner, Helv. Chim. Acta, 1959, 42, 563.
K.A. Alvi, A. Casey, B.G. Nair, J. Antibiot., 1997, 51, 515.
Received 21 May 2013; accepted 24 June 2013
Paper 1301959 doi: 10.3184/174751913X13739000149898
Published online: 6 September 2013
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