Microwave-assisted synthesis of ethyl 1,3-disubstituted-1,6- dihydropyrrolo[2,3-c]pyrazole-5-carboxylates

Article abstract of DOI:10.1002/jhet.1115

A novel series of ethyl 1,3-disubstituted-1,6-dihydropyrrolo[2,3-c] pyrazole-5-carboxylates can be rapidly and efficiently synthesized in excellent yields by condensing a variety of 1,3-substituted-4-formyl-5-chloropyrazole with ethyl isocyanoacetate in the presence of 1-methyl-3-butylimidazolium hydroxide under microwave irradiation. The simple experimental procedure, DMSO-free condition, short period of conversion, and excellent yields are the advantages of the present method. The structures of the novel compounds are confirmed by IR, ¹H NMR, ¹³C NMR, MALDI-TOF MS, and elemental analysis.

Full text of DOI:10.1002/jhet.1115

Month 2013
Microwave-Assisted Synthesis of Ethyl 1,3-Disubstituted-1,6-
dihydropyrrolo[2,3-c]pyrazole-5-carboxylates
a
b
*
Lijun Gu and Xiangguang Li
aKey Laboratory of Chemistry in Ethnic Medicinal Resources, State Ethnic Affairs Commission & Ministry of Education,
Yunnan University of Nationalities, Kunming, Yunnan, China, 650500
bDepartment of Chemistry, Northwest University, Xi’an, China
*
E-mail: gulijun2005@126.com
Received June 5, 2011
DOI 10.1002/jhet.1115
Published online 00 Month 2013 in Wiley Online Library (wileyonlinelibrary.com).
CHO
R2
R2
CO2Et
CuI, [bmIm]OH
DMSO-free, MW
+
N
CNCH2CO2Et
Cl
N
NH
N
N
R1
2
R1
1
A novel series of ethyl 1,3-disubstituted-1,6-dihydropyrrolo[2,3-c]pyrazole-5-carboxylates can be rapidly and
efficiently synthesized in excellent yields by condensing a variety of 1,3-substituted-4-formyl-5-chloropyrazole
with ethyl isocyanoacetate in the presence of 1-methyl-3-butylimidazolium hydroxide under microwave irradiation.
The simple experimental procedure, DMSO-free condition, short period of conversion, and excellent yields are
the advantages of the present method. The structures of the novel compounds are confirmed by IR, 1H NMR,
13C NMR, MALDI-TOF MS, and elemental analysis.
J. Heterocyclic Chem., 00, 00 (2013).
INTRODUCTION
low yield and the long reaction time make it less attractive
synthetically. Herein, we report a simple and efficient
reaction of ethyl isocyanoacetate with 1,3-substituted-4-
formyl- 5-chloropyrazole via microwave irradiation in
the presence of 1-methyl-3-butylimidazolium hydroxide
([bmIm]OH). The synthetic sequence is depicted in Scheme 1.
Nitrogen-containing heteroaromatic molecules and their
analogs are pharmaceutically significant scaffolds, widely
present in naturally occurring and synthetic biologically
active molecules [1]. Among these heterocycles, pyrazole
and its derivatives are important heterocyclic compounds,
which show a broad spectrum of biological activities such
as antimicrobial [2], herbicidal [3], antitumor [4], and anti-
inflammatory activities [5]. In our design of new inhibi-
tors of aspartyl protease [6], we were interested in differently
substituted ethyl 1,3-disubstituted-1,6-dihydropyrrolo[2,3-c]
pyrazole-5-carboxylates. To the best of our knowledge, only
one method exists for the synthesis of these compounds. The
method involves the condensation between an arylaldehyde
and an azidoacetate to provide a-azidocinnamates, which
upon heating give ethyl 1,3-disubstituted-1,6-dihydropyrrolo
[2,3-c]pyrazole-5-carboxylates [7]. One problem is associated
with employing high boiling solvent. In addition, the yield
of the reaction is low. Therefore, it is necessary to further
develop a practical method for the synthesis of such a
significant scaffold.
Recently, it was reported that the reaction 2-halo aryl
aldehydes or ketones with ethyl isocyanoacetate under the
catalysis of CuI afforded indole-2-carboxylic acid esters
[8]. According to the structure of ethyl 1,3-disubstituted-1,
6-dihydropyrrolo[2,3-c]pyrazole-5-carboxylates, we envi-
sioned that 1,3-substituted-4-formyl-5- chloropyrazole
may be used to react with isocyanoacetate under the
catalysis of CuI to synthesize such products. Although Cai
[8] developed a copper-catalyzed cascade process from
2-chloro heteroaryl ketones with ethyl isocyanoacetate, the
RESULTS AND DISCUSSION
Initial studies were carried out using 1-phenyl-3-methyl-
4-formyl-5-chloro-pyrazole as the substrate and isocyanoa-
cetate as the nitrogen source in DMSO/NaOH under the
catalysis of CuI (12 mol%) at 120ꢀC for 12 h, the desired
product ethyl 1-phenyl-3-methyl-1,6-dihydropyrrolo[2,3-c]
pyrazole-5-carboxylate was obtained in a low yield (34%).
Microwave-assisted organic synthesis has shown to be a
valuable tool for reducing reaction times, improving yields,
and is proving quite successful in the formation of a variety
of carbon–heteroatom and carbon–carbon bonds [9]. In view
of this, when the reaction under microwave irradiation is per-
formed, high yield was reached. Encouraged by the result,
we replaced DMSO/NaOH with [bmIm]OH. To our delight,
substrate 1a also successfully rendered the corresponding
product in high yield (entries 2 and 3 of Table 1). Further
investigations were aimed at determining the optimal condi-
tions by changing the reaction time, as well as altering the
reaction temperature. Increasing or decreasing the reaction
time did not improve the yield of the desired product. It
was found that 60ꢀC was the optimal reaction temperature.
Finally, the optimal condition was determined to be 12 mol
% CuI at 60ꢀC for 10 min in [bmIm]OH under microwave
© 2013 HeteroCorporation

L. Gu and X. Li
Vol 000
Scheme 1
CHO
Cl
R2
R2
CO2Et
CuI, [bmIm]OH
+
N
CNCH2CO2Et
N
NH
DMSO-free, MW
N
N
R1
2
R1
1
2a R1= Ph, R2 = Me; 2b R1 = p-Cl-Ph, R2 = Me;
2c R1= p-MeO-Ph, R2 = Me; 2d R1 = p-NO2-Ph, R2 = Me;
2e R1= p-Me-Ph, R2 = Me; 2f R1 = Me, R2 = Me;
2g R1= Me, R2 = p-Me-Ph; 2h R1= Me, R2 = p-Cl-Ph
General procedure for the preparation of 2.
An oven-
irradiation. Having these optimized reaction conditions in
hand, other Cu reagents, such as CuBr or CuCl, were inves-
tigated. The results showed that replacement of CuI with
CuBr slightly affected the outcome of this reaction. CuCl
was less active (entries 4 and 5, Table 1). When other copper
sources such as Cu2O and Cu(OAc)2 were used, no desired
product was detected.
The substitution variations of substrates were then
investigated. To our satisfaction, the reaction shows a wide
scope for the structural variation of R1 and R2 groups
under the optimized reaction conditions. Both electron-
donating and electron-withdrawing groups allowed smooth
transformation of 1,3-substituted-4-formyl-5-chloropyrazole
into the corresponding products with high yields.
In conclusion, in this study, we have developed a conve-
nient and efficient method for the synthesis of ethyl
1,3-disubstituted-1,6-dihydropyrrolo[2,3-c]pyrazole-5- car-
boxylates by condensation of ethyl isocyanoacetate with
1,3-substituted-4-formyl-5-chloropyrazole in the presence
of [bmIm]OH under microwave irradiation. The simple
experimental procedure, DMSO-free reaction conditions,
and high yields are the advantages of the present method.
dried 10-mL microwave vial was charged with CuI
(0.24 mmol), [bmIm]OH (2 mL), 1,3-substituted-4-formyl-5-
chloropyrazole (1 mmol) 1, and ethyl isocyanoacetate
(1.1 mmol), with an addition of a stirrer bar. The reaction vessel
was sealed, evacuated, and flushed with argon three times. The
mixture was irradiated by 100-W microwave at 60ꢀC for
10 min. The reaction mixture was partitioned between ethyl
acetate and water. The organic layers were washed with water
and brine, dried over anhydrous MgSO4, and concentrated
under vacuum to yield the crude product. The crude product
was purified by flash chromatography with ethyl acetate/
petroleum ether as eluent on silica gel to afford the desired
products.
Ethyl 1-phenyl-3-methyl-1,6-dihydropyrrolo[2,3-c]pyrazole-
5-carboxylate (2a). White powder, mp 102–103ꢀC; IR (KBr) n:
3331, 3018, 2973, 1715, 1501, 1194, 813cmÀ1 1H NMR
;
(CDCl3, 400MHz): d 9.87 (br s, 1H), 7.37–7.41 (m, 5H), 6.46
(dd, J = 2.4 Hz, 1H), 4.43 (q, J = 4.8Hz, 2H), 2.43 (s, 3H), 1.43 (t,
J = 4.8 Hz, 3H); 13C NMR (CDCl3, 100 MHz): d 162.7, 142.3,
141.7, 134.3, 130.7, 129.2, 127.1, 126.6, 109.5, 61.0, 14.9, 13.8;
MALDI-TOF MS: m/z = 269 (M+). Anal. Calcd for C15H15N3O2:
C 66.90, H 5.61, N 15.60. Found: C 66.88, H 5.63, N 15.51.
Ethyl 1-(4-chloro-phenyl)-3-methyl-1,6-dihydropyrrolo[2,3-
c]pyrazole-5-carboxylate (2b). White powder, mp 117–119ꢀC; IR
(KBr) n: 3329, 3021, 2929, 1710, 1499, 1241, 827cmÀ1 1H
;
NMR (CDCl3, 400MHz): d 9.81 (br s, 1H), 7.33 (d, J = 1.6Hz,
2H), 7.11 (d, J = 1.6 Hz, 2H), 6.41 (dd, J =2.8 Hz, 1H), 4.47 (q,
J = 4.8 Hz, 2H), 2.49 (s, 3H), 1.39 (t, J = 4.8Hz, 3H); 13C NMR
(CDCl3, 100 MHz): d 162.1, 142.5, 141.2, 135.7, 133.8, 129.3,
128.9, 128.0, 127.3, 108.4, 61.5, 14.7, 13.6; MALDI-TOF MS: m/
z = 303 (M+); Anal. Calcd for C15H14ClN3O2: C 59.31, H 4.65, N
13.83. Found: C 59.33, H 4.62, N 13.86.
EXPERIMENTAL
Reagents were obtained commercially and used as received.
Solvents were purified and dried by standard methods. [bmIm]OH
was synthesized according to the method described in the literature
[10]. 1,3-Substituted-4-formyl-5-chloropyrazole was synthesized
according to Du et al. [11]. Microwave reactions were performed
on a CEM Explorer Hybrid 12/Discover (Pynn, USA), with built
in temperature/pressure probes and associated software. The
melting points were determined on an XT-4 (Beijing Tech, China)
micro melting point apparatus and were uncorrected. IR spectra
were recorded on an EQUINOX-55 (Bruker, Germany) spectrometer
on a KBr matrix. NMR spectra were recorded on an INOVA-400
(Varian, USA) NMR instrument at room temperature using TMS as
internal standard. Coupling constants (J) were measured in Hz.
Chemical shift values (d) are given in ppm. Elemental analyses were
performed on a Vario EL III (Germany) CHNS analyzer. Electrospray
mass spectra were obtained with an MALDI-TOF (Kratos, UK) mass
spectrometer. For column chromatography, 200–300 mesh silica gel
was used.
Ethyl 1-(4-methoxy-Phenyl)-3-methyl-1,6-dihydropyrrolo[2,3-
c]pyrazole-5-carboxylate (2c). White powder, mp 121–122ꢀC; IR
(KBr) n: 3343, 3055, 2925, 1707, 1492, 1225, 823cmÀ1 1H
;
NMR (CDCl3, 400MHz): d 9.81 (br s, 1H), 7.01 (d, J = 8.8Hz,
2H), 6.91 (d, J = 8.8 Hz, 2H), 6.49 (dd, J = 2.8Hz, 1H), 4.39 (q,
J = 4.8 Hz, 2H), 3.83 (s, 3H), 2.51 (s, 3H), 1.40 (t, J = 4.8 Hz, 3H);
13C NMR (CDCl3, 100 MHz): d 161.8, 141.9, 141.0, 135.3,
133.7, 129.3 128.6, 128.1, 127.4, 109.3, 60.7, 55.1, 14.9, 13.9;
MALDI-TOF MS: m/z = 299 (M+); Anal. Calcd for C16H17N3O3:
C 64.20, H 5.72, N 14.04. Found: C 64.23, H 5.69, N 14.05.
Ethyl 1-(4-nitrol-phenyl)-3-methyl-1,6-dihydropyrrolo[2,3-c]
pyrazole-5-carboxylate (2d). Pale yellow powder, mp 127–
129ꢀC; IR (KBr) n: 3347, 3041, 2927, 1710, 1502, 1497,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet.1115

Month 2013
Microwave-Assisted Synthesis of Ethyl 1,3-Disubstituted-1,6-dihydropyrrolo
[2,3-c]pyrazole-5-carboxylates
Table 1
Reactions of 1,3-substituted-4-formyl-5-chloropyrazole with ethyl isocyanoacetate.
Entry
1b
Substrate
Product
Yield (%)a
34
2c
89
90
85
79
91
3
4d
5 e
6
7
87
8
92
(Continued)
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet.1115

L. Gu and X. Li
Vol 000
Table 1
(Continued)
Entry
Substrate
Product
Yield (%)a
9
89
10
89
89
11
12
91
Reaction conditions: CuI (0.24 mmol), [bmIm]OH (2 mL), 4-formyl-5-chloropyrazole (1 mmol), ethyl isocyanoacetate (1.1 mmol), Ar atmosphere,
microwave irradiation, 60ꢀC, 10 min.
aIsolated yields.
bCuI (0.24 mmol), DMSO (1 mL), NaOH (3.0 mmol), 4-formyl-5-chloropyrazole (1 mmol), ethyl isocyanoacetate (1.1 mmol), 100ꢀC, 12 h, Ar
atmosphere.
cCuI (0.24 mmol), DMSO (1 mL), NaOH (3.0 mmol), 4-formyl-5-chloropyrazole (1 mmol), ethyl isocyanoacetate (1.1 mmol), microwave irradiation,
60ꢀC, 10 min, Ar atmosphere.
dCuBr as catalyst.
eCuCl as catalyst.
1341, 1229, 831 cmÀ1
;
1H NMR (CDCl3, 400 MHz): d 9.93
Ethyl 1-(4-methyl-phenyl)-3-methyl-1,6-dihydropyrrolo[2,3-
(br s, 1H), 7.91 (d, J = 7.2 Hz, 2H), 7.03 (d, J = 7.2 Hz, 2H),
6.54 (dd, J = 2.8 Hz, 1H), 4.41 (q, J = 4.0 Hz, 2H), 2.37 (s,
3H), 1.44 (t, J = 4.0 Hz, 3H); 13C NMR (CDCl3, 100 MHz):
d 162.5, 143.6, 141.7, 141.4, 134.1, 130.2, 129.4, 129.1,
127.8, 109.5, 60.9, 15.1, 14.0; MALDI-TOF MS: m/z = 314
(M+); Anal. Calcd for C15H14N4O4: C 57.32, H 4.49, N
17.83. Found: C 57.34, H 4.46, N 17.81.
c]pyrazole-5-carboxylate (2e). White powder, mp 107–109ꢀC; IR
(KBr) n: 3347, 3031, 2927, 1711, 1497, 1223, 829cmÀ1 1H
;
NMR (CDCl3, 400 MHz):
d 9.89 (br s, 1H), 7.19 (d,
J = 7.2 Hz, 2H), 6.96 (d, J = 7.2 Hz, 2H), 6.44 (dd, J = 2.0 Hz,
1H), 4.45 (q, J = 4.8 Hz, 2H), 2.39 (s, 3H), 2.17 (s, 3H),1.40
(t, J = 4.8 Hz, 3H); 13C NMR (CDCl3, 100 MHz): d 161.4,
141.5, 141.1, 135.3, 133.3, 130.7, 129.6, 128.9, 127.5,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet.1115

Month 2013
Microwave-Assisted Synthesis of Ethyl 1,3-Disubstituted-1,6-dihydropyrrolo
[2,3-c]pyrazole-5-carboxylates
108.7, 60.3, 20.9, 15.3, 14.1; MALDI-TOF MS: m/z = 283
(M+); Anal. Calcd for C16H17N3O2: C 67.83, H 6.05, N
14.83. Found: C 67.77, H 6.11, N 14.81.
130.6, 129.1, 127.8, 126.9, 60.4, 40.8, 14.0; MALDI-TOF MS:
m/z = 303 (M+); Anal. Calcd for C15H14ClN3O2: C 59.31, H
4.65, N 13.83. Found: C 59.29, H 4.67, N 13.80.
Ethyl 1,3-dimethyl-1,6-dihydropyrrolo[2,3-c]pyrazole-5-
carboxylate (2f). White powder, mp 95–97ꢀC; IR (KBr) n: 3340,
2925, 1707, 1223, 925cmÀ1; 1H NMR (CDCl3, 400 MHz): d 9.77
(br s, 1H), 6.37 (dd, J = 2.8 Hz, 1H), 4.36 (q, J = 5.6 Hz, 2H), 2.91
(s, 3H), 2.21 (s, 3H),1.33 (t, J = 5.6Hz, 3H); 13C NMR (CDCl3,
100 MHz): d 161.1, 140.7, 140.2, 128.8, 127.3, 108.1, 60.4, 40.5,
14.8, 13.9; MALDI-TOF MS: m/z = 207 (M+); Anal. Calcd for
C10H13N3O2: C 57.96, H 6.32, N 20.28. Found: C 57.93, H 6.29,
N 20.24.
Acknowledgment. The authors thank the Youth Fund of Yunnan
University of Nationalities (no. 09QN04) for the financial support.
REFERENCES AND NOTES
[1] Fan, H.; Peng, J.; Hamann, M. T.; Hu, J. F. Chem Rev 2008,
108, 264.
Ethyl 1-methyl-3-(4-methyl-phenyl)-1,6-dihydropyrrolo[2,3-c]
[2] Velaparthi, S.; Brunsteiner, M.; Uddin, R.; Wan, B.;
Franzblau,S. G.; Petukhov, P. A. J Med Chem 2008, 51, 1999.
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[5] Rovnyak, G. C.; Millonig, R. C.; Schwartz, J.; Shu, V. J Med
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Soc 2010, 21, 58.
[7] El-Saied, A. A.; El-Borai, M. A.; Barren, M. A. Chem Abstr
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[8] Cai, Q.; Li, Z. Q.; Wei, J. J.; Ha, C. Y.; Pei, D. Q.; Ding, K.
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pyrazole-5-carboxylate (2g). White powder, mp 114–116ꢀC; IR
(KBr) n: 3353, 3039, 2931, 1703, 1503, 1227, 834 cmÀ1 1H
;
NMR (CDCl3, 400 MHz): d 9.85 (br s, 1H), 7.32 (d, J = 9.0 Hz,
2H), 7.08 (d, J = 9.0 Hz, 2H), 6.53 (dd, J = 3.0 Hz, 1H), 4.42
(q, J = 7.2 Hz, 2H), 2.93 (s, 3H), 2.10 (s, 3H),1.36 (t, J = 7.2 Hz,
3H); 13C NMR (CDCl3, 100MHz): d 160.3, 142.9, 141.7, 136.4,
135.2, 131.1, 130.9, 129.6, 128.4, 127.3, 60.1, 40.3, 20.2, 13.9;
MALDI-TOF MS: m/z = 306 [M+ Na]+; Anal. Calcd for
C16H17N3O2: C 67.83, H 6.05, N 14.83. Found: C 67.89, H 6.03,
N 14.79.
Ethyl 1-methyl-3-(4-chloro-phenyl)-1,6-dihydropyrrolo[2,3-c]
pyrazole-5-carboxylate (2h). White powder, mp 111–113ꢀC; IR
(KBr) n: 3353, 3047, 2931, 1713, 1503, 1227, 834 cmÀ1 1H
;
NMR (CDCl3, 400 MHz): d 9.78 (br s, 1H), 7.36 (d, J = 2.4 Hz,
2H), 7.17 (d, J = 2.4 Hz, 2H), 6.58 (dd, J = 2.8 Hz, 1H), 4.33 (q,
J = 4.8 Hz, 2H), 3.03 (s, 3H), 1.42 (t, J = 4.8 Hz, 3H); 13C NMR
(CDCl3, 100 MHz): d 161.5, 142.3, 141.4, 135.8, 134.6, 131.3,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet.1115