Coupling of amines, dialkyl acetylenedicarboxylates and formaldehyde promoted by [n-Bu4N][HSO4]: An efficient synthesis of highly functionalized dihydro-2-oxopyrroles and bis-dihydro-2-oxopyrroles

Article abstract of DOI:10.1007/s11164-012-0998-7

Tetrabutylammonium hydrogen sulfate [n-Bu₄N][HSO₄] is used as an efficient catalyst for the one-pot, multi-component synthesis of highly substituted dihydro-2-oxopyrroles and bis-dihydro-2-oxopyrroles by means of reaction between amines, dialkyl acetylenedicarboxylates and formaldehyde in methanol at ambient temperature. This homogeneous catalyst procedure includes some important aspects like the easy work-up, no need to column chromatography, simple and readily available precursors, relatively short reaction time, and high yields. Graphical abstract: [Figure not available: see fulltext.]

Full text of DOI:10.1007/s11164-012-0998-7

Res Chem Intermed
DOI 10.1007/s11164-012-0998-7
Coupling of amines, dialkyl acetylenedicarboxylates
and formaldehyde promoted by [n-Bu4N][HSO4]:
an efficient synthesis of highly functionalized dihydro-2-
oxopyrroles and bis-dihydro-2-oxopyrroles
•
Seyed Sajad Sajadikhah Nourallah Hazeri
Received: 17 November 2012 / Accepted: 19 December 2012
Ó Springer Science+Business Media Dordrecht 2013
Abstract Tetrabutylammonium hydrogen sulfate [n-Bu4N][HSO4] is used as an effi-
cient catalyst for the one-pot, multi-component synthesis of highly substituted dihydro-
2-oxopyrroles and bis-dihydro-2-oxopyrroles by means of reaction between amines,
dialkyl acetylenedicarboxylates and formaldehyde in methanol at ambient temperature.
This homogeneous catalyst procedure includes some important aspects like the easy
work-up, no need to column chromatography, simple and readily available precursors,
relatively short reaction time, and high yields.
Keywords Dihydro-2-oxopyrrole ꢀ Dialkyl acetylenedicarboxylate ꢀ Amine ꢀ
Formaldehyde ꢀ [n-Bu4N][HSO4] ꢀ Multi-component reaction
Introduction
Synthesis of five-membered heterocycles such as pyrrole and its derivatives is very
important because of their synthetic conditions and pharmacological and biological
properties. The dihydro-2-oxopyrroles exhibit diverse biological activity such as
inhibitors of the annexin A2-S100A10 protein interaction [1], human cytomega-
lovirus (HCMV) protease [2], CD45 protein tyrosine phosphatase [3], cardiac
cAMP phosphodiesterase [4], protoporphyrinogen oxidase [5], Trypanosoma brucei
leucyl-tRNA synthetase [6], DNA polymerase [7], and human cytosolic carbonic
anhydrase isozymes [8]. In addition, these important compounds have been used as
HIV integrase [9], vascular endothelial growth factor receptors [10], modulators of
GABAA receptors [11], cytotoxic, anti-tumor and anticancer agents [12], mitomycin
S. S. Sajadikhah ꢀ N. Hazeri (&)
Department of Chemistry, Faculty of Science, University of Sistan and Baluchestan,
P.O. Box 98135–674, Zahedan, Iran
e-mail: n_hazeri@yahoo.com
123

S. S. Sajadikhah, N. Hazeri
Fig. 1 Biologically active
compounds containing dihydro-
2-oxopyrrole framework
O
H
O
HO
R3
R2
N
N R1
R2
N R1
O
S
S
O
Inhibitors of the annexin
A2-S100A10 protein interaction
Anticancer agents
O
R1
O
N H
N
Ar
R2
N
R1
N
N
R2
Modulators of
GABAA receptors
Inhibitors of cardiac
cAMP phosphodiesterase
antibiotics [13], nootropic agents [14], herbicides [5], and pesticides [15], while
several other uses of these compounds have also been reported [16–19] (Fig. 1).
On the other hand, in the past two decades, a broad range of bioactive natural
products containing dihydro-2-oxopyrrole moiety have been isolated. For example,
thiomarinol A4 and pyrrocidine A are two potent antibiotics which have been
isolated from marine bacteria Alteromonas rava and fermentation broth of a fungus
(LL-Cyan426), respectively [20, 21]. Some other such natural products include
oteromycin [22], talaroconvolutin A [23], and UCS1025A [24, 25] (Fig. 2). As a
result, considerable efforts have been made for the synthesis of this important class
of compounds due to their medicinal properties [25–36].
Recently, multi-component reactions (MCRs) have received great attention from
research groups in medicinal chemistry, drug discovery, and materials science due
to their significant advantages over conventional linear-type syntheses, including
simple procedures, eco-friendliness, atom economy, and the ability to generate
architecturally complex molecules in one synthetic step [37]. Nevertheless, few
methods have been reported for the preparation of dihydro-2-oxopyrroles by one-pot
MCR using catalysts, such as acetic acid [38] and molecular iodine [39]. Owing to
the wide applications and significance of dihydro-2-oxopyrrole 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 MCRs [40–44], here we report a simple and efficient
synthesis of highly substituted dihydro-2-oxopyrroles and bis-dihydro-2-oxopyrroles
by means of a one-pot, four-component reaction between amines, dialkyl acetylen-
edicarboxylates, and formaldehyde in the presence of [n-Bu4N][HSO4] (10 mol%) as
a catalyst in methanol at ambient temperature.
123

Coupling of amines, dialkyl acetylenedicarboxylates and formaldehyde
H
O
H
H
NH
OH
O
H
O
O
NH
O
OH
Pyrrocidine A
Talaroconvolutin A
O
O
N
H
H
O
OH
O
HO
H
OH
NH
O
Oteromycin
UCS1025A
Fig. 2 Bioactive natural products containing dihydro-2-oxopyrrole unit
Results and discussion
At the outset, the one-pot three-component reaction of aniline (2 mmol), dimethyl
acetylenedicarboxylate (DMAD) (1 mmol), and formaldehyde (1.5 mmol) in the
presence of [n-Bu4N][HSO4] (5 mol%) was tested in ethanol at ambient temper-
ature. The reaction proceeded smoothly to afford the corresponding highly
substituted dihydro-2-oxopyrrole 4a in 62 % after 7 h. Encouraged by this result;
this reaction was chosen as a model for the study of the optimum conditions.
As shown in Table 1, the best result was obtained in the presence of 10 mol%
[n-Bu4N][HSO4] (Table 1, entry 4). Lower amounts of catalyst gave a low yield
even after long reaction times, and larger amounts of it did not affect the efficiency
of this conversion. Note that, in the absence of a catalyst, the product was obtained
in very low yield after 24 h. Furthermore , the effect of different solvents such as
CH3CN, CHCl3, CH2Cl2, AcOEt, and methanol was also investigated, from which it
was found that methanol is the best solvent for this conversion.
Thus, a variety of other anilines containingan electron-withdrawing or -donating
group were reacted with dimethyl and/or diethyl acetylenedicarboxylate and
formaldehyde under the optimized conditions (Scheme 1). The results are
summarized in Table 2. The substituents on the benzene ring such as OMe, Me,
F, Cl, and Br were tolerated during the reaction. In all cases, the reaction proceeded
smoothly to generate the corresponding functionalized dihydro-2-oxopyrrole in high
yield.
Next, to explore the scope and generality of this procedure, different function-
alized dihydro-2-oxopyrroles 7 were synthesized by means of a one-pot four-
component reaction between two different amines, dialkyl acetylenedicarboxylates
123

S. S. Sajadikhah, N. Hazeri
Table 1 Optimization of the reaction conditions
NH2
CO2Me
O
O
HN
+
+
H
H
N
CO2Me
MeO2C
Entry
Catalyst (mol%)
Solvent
Time (h)
Yielda (%)
1
5
EtOH
7
4
62
2
5
MeOH
MeOH
MeOH
MeOH
MeOH
EtOH
69
3
7.5
10
12.5
15
10
10
10
10
10
–
4
76
4
4
88
5
4
88
6
4
86
7
8
81
8
CH3CN
CHCl3
CH2Cl2
AcOEt
MeOH
10
10
10
10
24
64
9
47
10
11
12
44
40
Trace
Amount of materials in all reactions: aniline (2 mmol), DMAD (1 mmol), and formaldehyde (1 mmol).
The best result is shown in bold
a
Isolated yield
R1
NH2
CO2R2
O
O
N
[n-Bu4N][HSO4] (10 mol%)
R1
H
+
+
H
H
N
MeOH, rt
CO2R2
R2O2C
R1
1
4
2
3
Scheme 1 Synthesis of highly functionalized dihydro-2-oxopyrrole 4
and formaldehyde, in the presence of [n-Bu4N][HSO4] (10 mol%) in methanol at
room temperature (Scheme 2).
As shown in Table 3, the various aromatic and aliphatic amines, such as benzyl
amine, 1-(pyridin-2-yl)methanamine, and n-buthyl and/or n-propyl amine, were
applicable to the reaction, affording the products in good to high yields. The
versatility of this MCR was also studied with respect to ethane-1,2-diamine 50
instead of amine 5, under the same reaction conditions. Using this approach gave a
new class of bis-dihydro-2-oxopyrroles 8 in excellent yields (Scheme 3). Aromatic
amines with substituents such as Me, F, and Cl reacted with ethane-1,2-diamine 50,
alkyl acetylenedicarboxylates 2, and formaldehyde 3 to generate the corresponding
highly functionalized bis-dihydro-2-oxopyrroles 8, and the results are summarized
in Table 4.
123

Coupling of amines, dialkyl acetylenedicarboxylates and formaldehyde
Table 2 Synthesis of highly functionalized dihydro-2-oxopyrrole 4a–j
Me
OMe
Me
O
O
O
O
O
N
C
N
N
C
N
C
N
H
H
H
H
H
N
N
N
Me
N
OMe
N
Me
EtO2
MeO2C
Cl
MeO2
MeO2
EtO2C
4a
4b
4c
Br
4e
4d
F
Cl
Br
N
O
O
O
O
O
N
N
C
N
C
N
H
H
H
H
H
N
F
N
Cl
N
Br
N
Cl
N
Br
EtO2C
MeO2
MeO2
EtO2
C
EtO2C
4g
4j
4h
4i
4f
Entry
R1
R2
Product
Time (h)
Yielda (%)
1
2
3
4
5
6
7
8
9
10
a
H
Me
Et
4a
4b
4c
4d
4e
4f
4
88
86
83
87
77
85
86
87
82
84
H
4
4-Me
4-Me
Me
Et
4
4.5
5
4-OMe
4-Cl
4-Cl
4-Br
4-Br
4-F
Me
Et
5
Me
Me
Et
4g
4h
4i
4
4
4
Et
4j
5
Isolated yield
CO2R''
H
O
H
O
H
N
[n-Bu4N][HSO4] (10 mol%)
N
+
R'
R''O2C
+
+
N
R'
H
H
H
N Ar
Ar
H
MeOH, rt
CO2R''
5
2
7
6
3
Scheme 2 Synthesis of different functionalized dihydro-2-oxopyrroles 7
The structures of all the compounds were deduced from their IR, NMR, and mass
spectra as well as elemental analysis. For instance, the mass spectrum of 8a displayed a
molecular ion peak (M?) at m/z = 526, which is consistent with the proposed
structure. In the IR spectrum of 8a, the NH absorption band at 3,310 cm-1 and two
absorption bands at 1,696 and 1,637 cm-1, which are related to stretching frequencies
of two C=O groups, clearly indicated the most significant functional groups of the
product. The 1H NMR spectrum of product 8a exhibited a singlet at d 3.68 ppm for two
methoxy groups. The methylene protons of ethane-1,2-diamine moiety appeared at d
4.15–4.16 ppm as a multiplet, and the methylene protons of dihydro-2-oxopyrrole
rings were observed at d 4.30 ppm as a singlet. The NH protons were shown as a broad
singlet at d 6.75 ppm, as well as 8 aromatic protons which appeared as a triplet at d 7.08
(J = 8.4 Hz) and a multiplet at d 7.67–7.71 ppm, respectively. The 13C NMR
123

S. S. Sajadikhah, N. Hazeri
Table 3 Synthesis of different functionalized dihydro-2-oxopyrroles 7a–i
H
N
H
N
H
O
N
O
O
N
N
N
OMe
Me
EtO2C
MeO2C
MeO2C
N
7a
7b
7c
H
N
H
H
N
O
O
O
N
N
Cl
N
N
Br
MeO2C
MeO2C
MeO2C
7f
7e
7d
H
N
H
N
H
O
O
O
N
N
N
Br
N
MeO2C
MeO2C
EtO2C
7g
7h
7i
Entry
R0
R00
Ar
Product
Time (h)
Yielda (%)
1
2
3
4
5
6
7
8
9
a
Ph–CH2
Me
Et
Ph
Ph
7a
7b
7c
7d
7e
7f
4
4
89
85
82
85
88
73
84
76
88
Ph–CH2
Ph–CH2
Ph–CH2
Ph–CH2
C5H4N–CH2
n-C4H9
Me
Me
Me
Me
Me
Me
Et
4-OMe–C6H4
4-Cl–C6H4
4-Br–C6H4
4-Me–C6H4
4-Br–C6H4
Ph
7
5
4
10
6
7g
7h
7i
n-C4H9
6
n-C3H7
Ph
5
Isolated yield
RO2C
CO2R
O
H
H
N
H
N
O
[n-Bu4N][HSO4] (10 mol%)
N
Ar'
N
H
H
+
+
+
N
H
H
H
Ar'
H
N
H
MeOH, rt
Ar'
N
CO2R
O
CO2R
5'
2
6'
3
8
Scheme 3 Synthesis of highly functionalized bis-dihydro-2-oxopyrroles 8
spectrum of 8a showed 10 distinct resonances in agreement with the structure of the
product.
As reported in the literature [38, 39], a possible mechanism for the formation of
these heterocycles is outlined in Scheme 4. The reaction occurs via initial formation of
intermediate A and imine B by reactions of amine 1, 5, or 50 with dialkyl
acetylenedicarboxylate 2 and amine 1, 6, or 60 with formaldehyde 3, respectively. In
the next step, the intermolecular Mannich-type reaction between A and B in the
presence of [n-Bu4N][HSO4] produced intermediate C. The cyclization of interme-
diate C accompanying intramolecular nucleophilic reaction affords intermediate
123

Coupling of amines, dialkyl acetylenedicarboxylates and formaldehyde
Table 4 Synthesis of highly functionalized bis-dihydro-2-oxopyrroles 8a–d
Cl
MeO2C
EtO2C
H
N
O
H
N
O
N
F
N
Cl
N
H
N
H
F
N
Cl
N
O
O
CO2Me
CO2Et
8b
Cl
8a
MeO2C
EtO2C
H
H
N
O
O
N
N
Me
N
N
H
N
H
N
Me
N
O
O
CO2Me
CO2Et
8d
8c
Entry
R
Ar0
Product
Time (h)
Yielda (%)
1
2
3
4
a
Me
Et
4-F–C6H4
3,4-Cl2–C6H3
Ph
8a
8b
8c
8d
6
8
6
7
84
81
84
79
Me
Et
4-Me–C6H4
Isolated yield
OR2
H
R1
O
O
O
O
N
H
N
OR2
hydroamination
R2
O
R1
N
+
H
O
N
R1
R1
O
A
intramolecular
cyclization
N
OR2
R2
O
Mannich reaction
N
Ar
R2O
4 / 7 / 8
H
R2
O
O
O
Ar
H
[n-Bu4N]
H
O
[n-Bu4N][HSO4
]
+
N
N
C
D
Ar
H
H
H
Ar
B
Scheme 4 Possible mechanism for the formation of dihydro-2-oxopyrroles 4, 7 and bis-dihydro-2-
oxopyrroles 8
D. The final step involves imine–enamine tautomerization of intermediate D to form
the desired products 4/7/8.
Experimental
Melting points and IR spectra were obtained on an Electrothermal 9100 apparatus and
a JASCO FT/IR-460 plus spectrometer, respectively. The 1H 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 recorded on an Agilent Technology (HP) mass spectrometer, operating at
an ionization potential of 70 eV. Elemental analyses for C, H and N were performed
using a Heraeus CHN-O-Rapid analyzer. All reagents were purchased from Merck
123

S. S. Sajadikhah, N. Hazeri
(Darmstadt, Germany), Acros (Geel, Belgium), and Fluka (Buchs, Switzerland), and
used without further purification.
General procedure for the synthesis of dihydro-2-oxopyrrole 4
A mixture of aromatic amine 1 (1 mmol) and dialkyl acetylenedicarboxylate 2
(1 mmol) in methanol (3 mL) was stirred for 15 min. Next, aromatic amine 1
(1 mmol), formaldehyde 3 (1.5 mmol), and [n-Bu4N][HSO4] (10 mol%) were added
successively. The reaction mixture was stirred at ambient temperature for the
appropriate time. The progress of the reaction was monitored by TLC. After
completion, the solid precipitate was filtered off and washed with ethanol (3 9 2 mL)
to give the pure product 4.
Methyl 2,5-dihydro-5-oxo-1-phenyl-4-(phenylamino)-1H-pyrrole-3-carboxylate
(4a)
White solid, mp: 152–154 °C (lit. 155–156 °C[39]);1HNMR(400 MHz, CDCl3):d3.76
(3H, s, OCH3), 4.57 (2H, s, CH2), 7.16–7.23 (4H, m, ArH), 7.34 (2H, t, J = 8.0 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).
Ethyl 4-(p-tolylamino)-2,5-dihydro-5-oxo-1-p-tolyl-1H-pyrrole-3-carboxylate (4d)
Yellow solid, mp: 129–132 °C (lit. 131–132 °C [38]); 1H NMR (400 MHz, CDCl3):
d 1.25 (3H, t, J = 7.2 Hz, OCH2CH3), 2.36 (3H, s, CH3), 2.37 (3H, s, CH3), 4.23
(2H, q, J = 7.2 Hz, OCH2CH3), 4.52 (2H, s, CH2), 7.06 (2H, d, J = 8.4 Hz, ArH),
7.14 (2H, d, J = 8.0 Hz, ArH), 7.21 (2H, d, J = 8.4 Hz, ArH), 7.69 (2H, d,
J = 8.8 Hz, ArH), 8.01 (1H, br s, NH).
Ethyl 4-(4-chlorophenylamino)-1-(4-chlorophenyl)-2,5-dihydro-5-oxo-1H-pyrrole-
3-carboxylate (4f)
White solid, mp 168–170 °C. IR (KBr) (kmax, cm-1): 3,320 (NH), 2,991, 1,698, 1,640;
1H NMR (400 MHz, CDCl3): d 1.29 (3H, t, J = 7.2 Hz, OCH2CH3), 4.27 (2H, q,
J = 7.2 Hz, OCH2CH3), 4.52 (2H, s, CH2), 7.09 (2H, d, J = 8.8 Hz, ArH), 7.29 (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); 13C NMR (100 MHz, CDCl3): d 14.2, 48.1, 60.6, 104.2, 120.2, 123.9,
128.4, 129.2, 129.9, 130.2, 137.1, 137.2, 142.6, 163.6, 164.4; MS, (m/z, %): 394 (M? 4,
7), 392 (M? 2, 37), 390 (M?, 56), 346 (9), 344 (13), 319 (64), 317 (100), 289 (11), 208
(12), 179 (18), 163 (16), 139 (34), 111 (42), 75 (25), 55 (13). Anal. Calcd for
C19H16Cl2N2O3 (391.25): C, 58.33; H, 4.12; N, 7.16. Found: C, 58.65; H, 4.21; N, 7.29.
General procedure for the synthesis of dihydro-2-oxopyrrole 7
and bis-dihydro-2-oxopyrrole 8
A mixture of amine (5; 1 mmol for 7 and 50; 1 mmol for 8) and dialkyl
acetylenedicarboxylate (2; 1 mmol for 7 and 2 mmol for 8) in methanol (3 mL) was
123

Coupling of amines, dialkyl acetylenedicarboxylates and formaldehyde
stirred for 15 min. Next, aromatic amine (6; 1 mmol for 7 and 60; 2 mmol for 8),
formaldehyde (3; 1.5 mmol for 7 and 3 mmol for 8) and [n-Bu4N][HSO4]
(10 mol%) were added successively. The reaction mixture was stirred at ambient
temperature for the appropriate time. The progress of the reaction was monitored by
TLC. After completion, the solid precipitate was separated and washed with ethanol
(3 9 2 mL) to give the pure product 7/8.
Methyl 4-(benzylamino)-2,5-dihydro-5-oxo-1-phenyl-1H-pyrrole-3-carboxylate (7a)
White solid, mp: 137–139 °C (lit. 139–140 °C [38, 39]); 1H NMR (400 MHz,
CDCl3): d 3.80 (3H, s, OCH3), 4.48 (2H, s, CH2–N), 5.10 (2H, d, J = 6.4 Hz, CH2–
NH), 6.95 (1H, br, NH), 7.18–7.41 (8H, m, ArH), 7.73 (2H, d, J = 8.0 Hz, ArH).
Methyl 4-((pyridin-2-yl) methylamino)-2,5-dihydro-5-oxo-1-p-tolyl-1H-pyrrole-3-
carboxylate (7f)
White solid, mp 106–108 °C. IR (KBr) (kmax, cm-1): 3,306 (NH), 2,946, 2,860,
1,693, 1,628; 1H NMR (400 MHz, CDCl3): d 2.36 (3H, s, CH3), 3.82 (3H, s, OCH3),
4.44 (2H, s, CH2–N), 5.25 (2H, d, J = 5.6 Hz, CH2–NH), 7.21 (3H, d, J = 8.8 Hz,
ArH), 7.33 (1H, d, J = 7.6 Hz, ArH), 7.65–7.70 (4H, m, NH and ArH), 8.63 (1H, d,
J = 4.4 Hz, ArH); 13C NMR (100 MHz, CDCl3): d 20.9, 47.5, 48.1, 51.1, 119.4,
121.7, 122.2, 129.6, 134.8, 136.2, 136.7, 149.1, 154.4, 164.5, 165.5; MS, (m/z, %):
337 (M?, 90), 305 (42), 277 (10), 213 (10), 190 (25), 172 (30), 158 (80), 144 (73),
118 (25), 108 (25), 93 (100), 81 (39), 69 (82), 65 (54), 55 (56). Anal. Calcd for
C19H19N3O3 (337.37): C, 67.64; H, 5.68; N, 12.46. Found: C, 67.51; H, 5.77; N,
12.57.
Methyl 1-(4-bromophenyl)-4-(butylamino)-2,5-dihydro-5-oxo-1H-pyrrole-
3-carboxylate (7g)
1
Pale yellow solid, mp: 105–107 °C (lit. 108–109 °C [39]); H NMR (400 MHz,
CDCl3): d 0.96 (3H, t, J = 7.2 Hz, CH3), 1.41 (2H, sextet, J = 7.2 Hz, CH2), 1.61
(2H, quintet, J = 7.2 Hz, CH2), 3.80 (3H, s, OCH3), 3.86 (2H, t, J = 7.2 Hz, CH2–
NH), 4.41 (2H, s, CH2–N), 6.77 (1H, br, NH), 7.50 (2H, d, J = 8.4 Hz, ArH), 7.73
(2H, d, J = 8.4 Hz, ArH).
Bis-(methyl 1-(4-fluorophenyl)-2,5-dihydro-4-(methyleneamino)-5-oxo-1H-
pyrrole-3-carboxylate) (8a)
White solid, mp 199–201 °C. IR (KBr) (kmax, cm-1): 3,310 (NH), 2,949, 1,696,
1
1,637; H NMR (400 MHz, CDCl3): d 3.68 (6H, s, 2OCH3), 4.15–4.16 (4H, m,
2CH2–NH), 4.30 (4H, s, 2CH2–N), 6.75 (2H, br s, 2NH), 7.08 (4H, t, J = 8.4 Hz,
ArH), 7.67–7.71 (4H, m, ArH); 13C NMR (100 MHz, CDCl3): d 43.7, 48.2, 51.0,
98.0, 115.7 (d, J = 22.0 Hz), 120.9 (d, J = 7.0 Hz), 134.7 (d, J = 2.0 Hz), 159.7
(d, J = 243.0 Hz), 164.3, 165.2; MS, (m/z, %): 526 (M?, 3), 494 (2), 435 (5), 403
(5), 344 (5), 276 (98), 263 (45), 231 (100), 217 (45), 205 (53), 185 (41), 140 (31),
123

S. S. Sajadikhah, N. Hazeri
122 (44), 95 (37), 66 (52). Anal. Calcd for C26H24F2N4O6 (526.49): C, 59.31; H,
4.59; N, 10.64. Found: C, 59.65; H, 4.63; N, 10.73.
Bis-(ethyl 1-(3,4-dichlorophenyl)-2,5-dihydro-4-(methyleneamino)-5-oxo-1H-
pyrrole-3-carboxylate) (8b)
White solid, mp 206–208 °C. IR (KBr) (kmax, cm-1): 3,324 (NH), 3,049, 1,705,
1,642; 1H NMR (400 MHz, CDCl3): d 1.29 (6H, t, J = 7.0 Hz, 2OCH2CH3),
4.12–4.20 (8H, br s, 2OCH2CH3 and 2CH2–NH), 4.30 (4H, s, 2CH2–N), 6.74 (2H,
br s, 2NH), 7.43 (2H, d, J = 8.8 Hz, ArH), 7.59 (2H, dd, J = 8.8, 2.4 Hz, ArH),
7.97 (2H, d, J = 2.4 Hz, ArH); 13C NMR (100 MHz, CDCl3): d 14.4, 43.8, 47.6,
60.0, 98.5, 117.8, 120.5, 128.2, 130.5, 133.0, 138.1, 164.5, 165.1; MS, (m/z, %): 656
(M? 2, 2), 654 (M?, 2), 457 (6), 342 (38), 342 (38), 340 (52), 314 (33), 283 (46),
281 (68), 257 (61), 255 (100), 241 (15), 173 (42), 145 (25), 136 (29), 111 (26), 91
(34), 66 (52), 55 (44). Anal. Calcd for C28H26Cl4N4O6 (656.34): C, 51.24; H, 3.99;
N, 8.54. Found: C, 51.55; H, 4.12; N, 8.66.
Bis-(methyl 2,5-dihydro-4-(methyleneamino)-5-oxo-1-phenyl-1H-pyrrole-3-
carboxylate) (8c)
White solid, mp 149–151 °C. IR (KBr) (kmax, cm-1): 3,308 (NH), 2,947, 1,698,
1
1,637; H NMR (400 MHz, CDCl3): d 3.67 (6H, s, 2OCH3), 4.16–4.18 (4H, m,
2CH2–NH), 4.34 (4H, s, 2CH2–N), 6.71–6.78 (2H, br m, 2NH), 7.19 (2H, t,
J = 7.6 Hz, ArH), 7.39 (4H, t, J = 7.6 Hz, ArH), 7.74 (4H, d, J = 7.6 Hz, ArH);
13C NMR (100 MHz, CDCl3): d 43.7, 47.9, 51.0, 115.1, 119.3, 125.0, 129.1, 138.6,
164.4, 165.3. Anal. Calcd for C26H26N4O6 (490.51): C, 63.66; H, 5.34; N, 11.42.
Found: C, 63.92; H, 5.47; N, 11.57.
Bis-(ethyl 2,5-dihydro-4-(methyleneamino)-5-oxo-1-p-tolyl-1H-pyrrole-3-
carboxylate) (8d)
White solid, mp 210–212 °C. IR (KBr) (kmax, cm-1): 3,308 (NH), 2,946, 1,698,
1
1,636; H NMR (400 MHz, CDCl3): d 1.28 (6H, t, J = 7.2 Hz, 2OCH2CH3), 2.36
(6H, s, 2OCH3), 4.13–4.18 (8H, m, 2OCH2CH3 and 2CH2–NH), 4.33 (4H, s, 2CH2–N),
6.73 (2H, br s, 2NH), 7.19 (4H, d, J = 8.4 Hz, ArH), 7.62 (4H, d, J = 8.4 Hz, ArH);
13C NMR (100 MHz, CDCl3): d 14.4, 20.9, 30.9, 43.8, 48.0, 59.8, 98.5, 119.4, 129.5,
134.6, 136.2, 164.3, 165.1; MS, (m/z, %): 546 (M?, 3), 454 (4), 368 (5), 286 (40), 260
(14), 227 (34), 213 (28), 201 (29), 187 (12), 171 (8), 111 (28), 97 (46), 83 (56), 69 (76),
57 (100), 55 (88). Anal. Calcd for C30H34N4O6 (546.61): C, 65.92; H, 6.27; N, 10.25.
Found: C, 66.26; H, 6.39; N, 10.40.
Conclusion
In summary, a simple and efficient protocol has been described for the one-pot
multi-component synthesis of dihydro-2-oxopyrrole and bis-dihydro-2-oxopyrrole
123

Coupling of amines, dialkyl acetylenedicarboxylates and formaldehyde
derivatives catalyzed by [n-Bu4N][HSO4] under mild conditions using inexpensive
starting materials. This method offers several advantages, such as easy purification,
no need for column chromatography, short reaction times, simple and readily
available precursors, and high yields, as well as the ability to tolerate a wide variety
of substitutions in the compounds.
Acknowledgments We gratefully acknowledge financial support from the Research Council of the
University of Sistan and Baluchestan.
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