A one-pot multi-component synthesis of N-aryl-3-aminodihydropyrrol-2-one-4- carboxylates catalysed by oxalic acid dihydrate

Article abstract of DOI:10.3184/174751912X13547952669204

A simple synthesis of N-aryl-3-aminodihydropyrrol-2-one-4-carboxylates via one-pot multi-component reaction of amines, dialkyl acetylenedicarboxylates and formaldehyde in the presence of oxalic acid dihydrate (20 mol%) as catalyst in methanol is described

Full text of DOI:10.3184/174751912X13547952669204

40 RESEARCH PAPER
JANUARY, 40–42
JOURNAL OF CHEMICAL RESEARCH 2013
A one-pot multi-component synthesis of N-aryl-3-aminodihydropyrrol-2-
one-4-carboxylates catalysed by oxalic acid dihydrate
Seyed Sajad Sajadikhaha, Nourallah Hazeria*, Malek Taher Maghsoodloua, Sayyed Mostafa
Habibi-Khorassania and Khatereh Khandan-Baranib
aDepartment of Chemistry, Faculty of Science, University of Sistan and Baluchestan, PO Box 98135-674, Zahedan, Iran
bDepartment of Chemistry, Zahedan Branch, Islamic Azad University, PO Box 98135-978, Zahedan, Iran
A simple synthesis of N-aryl-3-aminodihydropyrrol-2-one-4-carboxylates via one-pot multi-component reaction of
amines, dialkyl acetylenedicarboxylates and formaldehyde in the presence of oxalic acid dihydrate (20 mol%) as
catalyst in methanol is described. This homogeneous catalytic procedure offers advantages including mild reaction
conditions, good to high yields, short reaction time, simple and readily available starting materials, easy work-up and
there is no need for column chromatography.
Keywords: heterocycle, dihydropyrrol-2-one, oxalic acid dihydrate, dialkyl acetylenedicarboxylate, multi-component reaction
A number of biologically-active compounds and natural prod-
ucts contain the dihydropyrrol-2-one ring.1–6 For example,
dihydropyrrol-2-one derivatives act as HIV integrase,7 anti-
tumor and anticancer agents,8 antibiotics,9 vascular endothelial
growth factor inhibitors,10 modulators of GABAA receptors,11
and nootropic agents.12 Moreover, these heterocycles have
been demonstrated as inhibitors for the protoporphyrinogen
oxidase,13 human cytomegalovirus (HCMV) protease,14
annexin A2-S100A10 protein interaction,15 human cytosolic
carbonic anhydrase isozymes,16 CD45 protein tyrosine
phosphatase,17 and DNA polymerase.18
Recently, two methods have been reported for the pre-
paration of dihydropyrrol-2-ones involving one-pot multi-
component reaction using catalysts, such as acetic acid19
and molecular iodine.20 Owing to the wide applications and
significance of dihydropyrrol-2-one derivatives in organic
synthesis, pharmacology and industry, there is still the need
to develop an efficient, mild and environmentally benign
protocol for the synthesis of these important compounds.
In continuation of our work on multi-component reac-
tions,21–24 we report here a simple and efficient synthesis of
N-aryl-3-aminodihydropyrrol-2-one-4-carboxylates by means
of one-pot, multi-component reaction between amines, dialkyl
acetylenedicarboxylates and formaldehyde in the present of
oxalic acid dihydrate (20 mol%) as a catalyst in methanol at
ambient temperature (Scheme 1).
dihydrate (20 mol %) were added successively. While the all
four reactants were added at once, the corresponding product
was obtained in lower yield and required a longer reaction
time. When the reaction was carried out in the absence of a
catalyst, the product 5a was obtained in trace amounts after
24 h.
Using these optimised experimental conditions, different
aromatic amines were allowed to undergo a one-pot reaction
with dimethyl and/or diethyl acetylenedicarboxylate and form-
aldehyde, to afford a series of N-aryl-3-aminodihydropyrrol-
2-one-4-carboxylates in good to high yields (Table 2, entries
1–8). Anilines with various substituents such as, OMe, Me, F,
Cl and Br were examined. The products were obtained in good
yields. In order to explore the scope of this procedure, different
functionalised dihydropyrrol-2-ones 5i–q were synthesised via
a one-pot four-component domino reaction using two different
amines, dialkyl acetylenedicarboxylates and formaldehyde
using optimum conditions (Table 2, entries 9–17). Aliphatic
amines such as benzyl amine, n-propyl amine and n-butyl
amine were employed in the reaction, affording the products in
high yields.
The structures of products were characterised by IR, 1H and
13C NMR and elemental analysis. For example, the mass spec-
trum of 5c displayed a molecular ion (M+) at m/z = 344, which
is consistent with the proposed structure. In the IR spectrum of
5c the NH absorption band at 3284 cm−1 and two absorption
bands at 1676 and 1649 cm−1, which are related to two C=O
stretching frequencies, revealed the significant functional
groups in the product. The 1H NMR spectrum of compound 5c
exhibited two singlets at δ 3.79 and 4.52 ppm for a methoxy
group and CH2 of the dihydropyrrol-2-one ring, respectively.
The aromatic protons of 5c were observed at δ 7.01–7.76 ppm
as two multiplets and the NH proton was shown as a broad
singlet at δ 8.05 ppm. The 13C NMR spectrum of 5c showed
13 distinct resonances consistent with the functionalised
dihydropyrrol-2-one structure. A partial assignment of these
resonances is given in the experimental section.
Results and discussion
First, we examined the feasibility of the reaction of aniline,
dimethyl acetylenedicarboxylate (DMAD) and formaldehyde
as a model in the presence of oxalic acid dihydrate as a catalyst
for the preparation of desired dihydropyrrol-2-one 5a. We
screened the amount of catalyst and solvents to develop
standard reaction conditions. As shown in Table 1, the use of
20 mol% of oxalic acid dihydrate resulted in the maximum
yield (89%) in methanol at ambient temperature in 2h (Table 1,
entry 7). In this reaction, a mixture of aniline (1 mmol) and
DMAD (1 mmol) in MeOH was first stirred for 30 min. Then
aniline (1 mmol), formaldehyde (1.5 mmol) and oxalic acid
On the basis of above experimental results together with the
related reports, a reasonable mechanism for the synthesis of
functionalised dihydropyrrol-2-one 5 is depicted in Scheme 2.
Scheme 1 Synthesis of N-aryl-3-aminodihydropyrrol-2-one-4-carboxylate 5.
* Correspondent. E-mail: n_hazeri@yahoo.com

JOURNAL OF CHEMICAL RESEARCH 2013 41
Table 1 Optimisation of the reaction conditions for the
synthesis of 5aa
recorded on an Agilent Technology (HP) mass spectrometer, operat-
ing at an ionisation potential of 70 eV. Elemental analyses for C, H
and N were performed using a Heraeus CHN–O-Rapid analyser.
Chemicals were purchased from Merck (Darmastadt, Germany),
Acros (Geel, Belgium) and Fluka (Buchs, Switzerland), and used
without further purification.
Entry
Catalyst/mol%
Solvent
Time/h
Yield/%b
1
2
10
MeOH
EtOH
MeCN
CH2Cl2
THF
MeOH
MeOH
MeOH
MeOH
MeOH
3
4
73
66
10
3
10
7
60
Synthesis of dihydropyrrol-2-one 5; general procedure
4
10
8
39
A mixture of amine 1 (1 mmol) and dialkyl acetylenedicarboxylate 2
(1 mmol) in MeOH (3 mL) was stirred for 30 min. Next, amine 3
(1 mmol), formaldehyde 4 (1.5 mmol) and oxalic acid dihydrate
(20 mol %) were added in succession. The reaction mixture was stirred
at ambient temperature for the appropriate time (see Table 2). After
completion of the reaction (monitored by TLC), the solid precipitate
was filtered off and washed with ethanol (3 × 2 mL) to give the pure
product 5.
5
10
7
43
6
15
2
82
7
20
25
2
89
8
2
87
9
30
2
88
10
No catalyst
24
Trace
a Amount of materials in all reactions: aniline (2 mmol), DMAD
(1 mmol), and formaldehyde (1.5 mmol).
b Isolated yield.
Methyl 3-(4-fluorophenylamino)-1-(4-fluorophenyl)-2,5-dihydro-2-
oxo-1H-pyrrole-4-carboxylate (5c): White solid, m.p. 163–165 °C. IR
1
(KBr) (λmax, cm−1): 3284 (NH), 1676, 1649; H NMR (400 MHz,
CDCl3): δH 3.79 (3H, s, OCH3), 4.52 (2H, s, CH2), 7.01–7.16 (6H,
m, ArH), 7.73–7.76 (2H, m, ArH), 8.05 (1H, br s, NH); 13C NMR
(100 MHz, CDCl3): δC 48.3, 51.4, 115.1 (d, JCF = 23.0 Hz), 115.9 (d,
JCF = 22.0 Hz), 121.0 (d, JCF = 7.0 Hz), 125.1 (d, JCF = 8.0 Hz), 134.4
(d, JCF = 3.0 Hz), 134.7 (d, JCF = 2.0 Hz), 143.4, 153.7 (d, JCF = 33.0 Hz),
161.2 (d, JCF = 32.0 Hz), 163.5, 164.8; MS, (m/z, %): 345 (M+1, 10),
344 (M+, 70), 313 (7), 285 (100), 257 (25), 163 (27), 137 (12), 123
(30), 109 (10), 95 (50), 69 (33), 57 (30);Anal. Calcd for C18H14F2N2O3:
C, 62.79; H, 4.10; N, 8.14. Found: C, 63.13; H, 4.23; N, 8.29%.
Ethyl 1-(4-bromophenyl)-3-(butylamino)-2,5-dihydro-2-oxo-1H-
pyrrole-4-carboxylate (5q): White solid, m.p. 94–96 °C. IR (KBr)
In summary, we have developed a facile and efficient one-
pot multi-component synthesis of substituted dihydropyrrol-2-
ones by coupling amines, dialkyl acetylenedicarboxylates
and formaldehyde promoted by oxalic acid dihydrate as a
homogeneous catalyst. This protocol is endowed with several
advantages such as mild reaction conditions, clean reaction,
simplicity in operation, no need to column chromatography,
short reaction times and good to high yields.
1
(λmax, cm−1): 3323 (NH), 2955, 2934, 2870, 1698, 1647; H NMR
Experimental
Melting points were recorded on an Electrothermal 9100 apparatus.
IR spectra were obtained on a JASCO FT/IR-460 plus spectrometer.
(400 MHz, CDCl3): δH 0.97 (3H, t, J = 7.2 Hz, CH3), 1.35 (3H, t,
J = 7.2 Hz, OCH2CH3), 1.43 (2H, sextet, J = 7.6 Hz, CH2), 1.61 (2H,
quintet, J = 7.6 Hz, CH2), 3.87 (2H, t, J = 7.2 Hz, CH2–NH), 4.28 (2H,
t, J = 7.2 Hz, OCH2CH3), 4.40 (2H, s, CH2–N), 6.72 (1H, br, NH),
7.52 (2H, d, J = 8.8 Hz, ArH), 7.71 (2H, d, J = 8.8 Hz, ArH); 13C NMR
1
The H and 13C NMR spectra were recorded on a Bruker DRX-400
Avance instrument with CDCl3 as solvent and using TMS as internal
reference at 400 and 100 MHz, respectively. The mass spectra were
Table 2 The synthesis of N-aryl-3-aminodihydropyrrol-2-one-4-carboxylate 5
Entry
R1
R2
Ar
Product
Time/h
Yield/%a
M.p./°C
Lit. m.p./°CRef,b
1
2
Ph
Ph
Me
Et
Me
Me
Et
Me
Me
Et
Me
Et
Me
Me
Me
Et
Me
Me
Et
Ph
Ph
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
5q
2
89
87
85
88
89
77
88
85
82
84
85
85
73
88
84
85
87
154–156
136–138
163–165
170–172
168–170
172–174
178–180
129–131
142–144
126–128
119–121
147–149
124–126
76–78
155–15620
138–14019
This work
173–17420
169–17119
176–17720
177–17820
131–13219
140–14119
130–13219
120–12120
147–14820
129–13020
78–7919
2
3
4-F–C6H4
4-Cl–C6H4
4-Br–C6H4
4-OMe–C6H4
4-Me–C6H4
4-Me–C6H4
Ph–CH2
Ph–CH2
Ph–CH2
Ph–CH2
Ph–CH2
n-C3H7
4-F–C6H4
4-Cl–C6H4
4-Br–C6H4
4-OMe–C6H4
4-Me–C6H4
4-Me–C6H4
Ph
2
4
2
5
2
6
3
7
2
8
2.5
2
9
10
11
12
13
14
15
16
17
Ph
2.5
2
3
5
2.5
3
3
2
4-Br–C6H4
4-Cl–C6H4
4-OMe–C6H4
Ph
n-C4H9
4-Br–C6H4
Ph
4-Br–C6H4
110–112
60–62
94–96
108–10920
6020
n-C4H9
n-C4H9
This work
a Isolated yield.
b All known products have been reported previously in the literature and were characterised by comparison of IR and NMR spectra
with those of authentic samples.
Scheme 2 Proposed mechanism for preparation of N-aryl-3-aminodihydropyrrol-2-one-4-carboxylates 5.

42 JOURNAL OF CHEMICAL RESEARCH 2013
9
A.S. Demir, F. Aydigan and I.M. Akhmedov, Tetrahedron: Asymm., 2002,
13, 601.
(100 MHz, CDCl3): δC 13.8, 14.5, 19.8, 33.4, 42.8, 47.8, 59.8, 98.1,
117.7, 120.6, 132.0, 137.9, 164.6, 165.5; MS, (m/z, %): 382 (M+2,
38), 380 (M+, 38), 353 (16), 351 (16), 337 (44), 307 (100), 293 (41),
291 (42), 184 (20), 182 (20), 157 (16), 98 (18), 80 (17), 66 (29), 55
(33);Anal. Calcd for C17H21BrN2O3: C, 53.55; H, 5.55; N, 7.35. Found:
C, 53.88; H, 5.71; N, 7.54%.
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We gratefully acknowledge financial support from the Research
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Received 2 October 2012; accepted 16 November 2012
Paper 1201549 doi: 10.3184/174751912X13547952669204
Published online: 15 January 2013
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