Synthesis of 3-(benzylideneamino)-2-phenyl-5H-imidazo[1,2-b]pyrazole-7- carbonitriles via a four-component condensation reaction

Article abstract of DOI:10.1016/j.tet.2013.03.103

A direct and efficient approach for the synthesis of a new series of 3-(benzylideneamino)-2-phenyl-5H-imidazo[1,2-b]pyrazole-7-carbonitriles has been developed through a sequential one-pot, four-component condensation reaction of easily available aromatic aldehydes, toluene-4-sulfonylmethyl isocyanide (TsCH₂NC), and 5-amino-1H-pyrazole-4-carbonitrile. The reaction was performed in the presence of p-toluenesulfonic acid as a catalyst at room temperature in acetonitrile as a solvent. Products were obtained in moderate to high yields.

Full text of DOI:10.1016/j.tet.2013.03.103

Tetrahedron 69 (2013) 4199e4204
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of 3-(benzylideneamino)-2-phenyl-5H-imidazo[1,2-b]
pyrazole-7-carbonitriles via a four-component condensation
reaction
*
Abbas Rahmati , Miranda Eskandari-Vashareh, Meysam Alizadeh-Kouzehrash
Department of Chemistry, University of Isfahan, PO Box 81746-73441, Isfahan, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
A direct and efficient approach for the synthesis of a new series of 3-(benzylideneamino)-2-phenyl-5H-
imidazo[1,2-b]pyrazole-7-carbonitriles has been developed through a sequential one-pot, four-compo-
nent condensation reaction of easily available aromatic aldehydes, toluene-4-sulfonylmethyl isocyanide
(TsCH2NC), and 5-amino-1H-pyrazole-4-carbonitrile. The reaction was performed in the presence of p-
toluenesulfonic acid as a catalyst at room temperature in acetonitrile as a solvent. Products were ob-
tained in moderate to high yields.
Received 5 November 2012
Received in revised form 14 March 2013
Accepted 26 March 2013
Available online 1 April 2013
Keywords:
Ó 2013 Elsevier Ltd. All rights reserved.
Multi-component reactions
Tosylmethyl isocyanide
Imidazopyrazole
Isocyanide
1. Introduction
of these methods are based on multi-step syntheses, and the range
of compounds that can be prepared is limited.
Imidazopyrazoles, as one of the most important fused hetero-
cyclic compounds, are attractive for ‘drug discovery’; since many
compounds incorporating these scaffolds exhibit a wide range of
biological, medicinal, and pharmaceutical activities, such as anti-
tumor,1 anti-inflammatory,2 antiviral in Herpes Simplex Virus type-
1,3 and anti-neoplastic with L1210 leukemia-cells.4 In addition,
some of these compounds have shown inhibitor effects, such as
deoxyribonucleic acid synthesis,5 MAP kinase,2 L1220 tumor-de-
rived ribonucleotide reductase6 and ribonucleoside diphosphate
reductase,7 synchronization of human lymphoid cells, and HeLa
cells.8,9 Additionally, some others, which are nonsteroidal agonists
and antagonists of androgen receptor modulators have been shown
to be useful in the treatment of a variety of diseases.10
Very recently, a new series of anti-inflammatory agents, with all
imidazopyrazole structure, have been synthesized and accordingly,
biological evaluation showed dual inhibition activity in both fMLP-
OMe and IL8-induced chemotaxis.11 Therefore, providing good
synthetic methods, as well as new derivatives with this structure, is
important in organic synthesis. Although several methods have
been reported for the synthesis of imidazo[1,2-b]pyrazoles,12 many
Multi-component reactions (MCRs), are chemical trans-
formations in which three or more different starting materials are
combined together in a single reaction flask and generate a final
complex product.13 These reactions, because of their productivity,
simplicity, convergence, facile execution, environmental concerns,
atom economy, and ability to generate large libraries of compounds
are one of the most powerful synthetic tools in medicinal chemistry,
combinatorial chemistry, drug discovery, organic synthesis, and
materials science.13 Therefore, the use of MCRs has raised great at-
tention from research groups working in these areas. Isocyanides
are valuable synthons with interesting chemical properties,14 and
have been used widely in MCRs.15 A subclass of MCR with an iso-
cyanide base is known as the isocyanide multi-component reaction
(IMCRs).15 One IMCR, which was used to produce imidazo[1,2-b]
azines using isocyanides, aldehydes, and 2-aminoazines and/or
aminoazoles in the presence of acid catalysts was first reported by
the Groebke, Blackburn, and Bienayme groups simultaneously in
1998.16 The methodologies for this reaction have been developed by
various groups, using different Bronsted and Lewis acid catalysts.17
Also, various aminoazole rings, such as 2-aminobenzimidazole,
2-aminobenzthiazole, 2-aminothiadiazole, 2-aminothiadiazole,
3-aminotriazole, and 3-aminopyrazoles have been utilized for pro-
duction of a wide range of products.16c,18 Mikhail Krasavin, who has
worked carefully on this reaction, proved that products of the re-
action between of benzyl isocyanides, with 3-amino-1,2,4-triazole
* Corresponding author. Tel.: þ98 311 7932730; e-mail address: a.rahmati@
sci.ui.ac.ir (A. Rahmati).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.03.103

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A. Rahmati et al. / Tetrahedron 69 (2013) 4199e4204
and aromatic aldehydes is different from others due to the oxidation
of the product.19 In addition, in another report he has showed that in
the presence of trifluoroacetic acid (TFA), N-alkyl imidazo[1,2-b]
azines are produced instead of N-acyl imidazo[1,2-b]azines.20
Recently, we have reported the synthesis of a new series of 5H-
imidazo[1,2-b]pyrazoles using various aminopyrazoles, aromatic
aldehydes, and isocyanides by the GroebkeeBlackburneBienayme
three-component reaction.21 Our efforts in the continuation of this
work, led to superior results, and we synthesized a novel series of
these fused ring systems. By this method, we have developed an
efficient method for the synthesis of 3-(benzylideneamino)-2-aryl-
5H-imidazo[1,2-b]pyrazole-7-carbonitriles (4ael). In our work,
a one-pot four-component condensation reaction was performed
between 5-amino-1H-pyrazole-4-carbonitrile (1), 2 equiv of an
aldehyde (2) and toluene-4-sulfonylmethyl isocyanide 3 using
acetonitrile as solvent and p-toluenesulfonic acid as catalyst at
room temperature (Scheme 1).
showed that the best yields of reaction were obtained at room
temperature.
To find out the scope and limitations of the reaction, we ex-
tended the procedure to use various substituted benzaldehydes in
the presence of 3-amino-4-pyrazolecarbonitrile and toluene-4-
sulfonylmethyl isocyanide (Table 3). The reactions proceeded
with electron-withdrawing and electron-donating substituents in
the ortho, meta, and para positions of the benzaldehydes.
It’s worthy to note, when 2-hydroxybenzaldehyde was used, it
was expected that a seven membered ring is formed. But, 1H NMR
and 13C NMR spectra demonstrate that no seven membered ring has
been produced. Both phenolic OH groups have been appeared in H
NMR spectra while the formation of a seven membered ring product
results in the appearance of one of them. Furthermore, not obser-
vation of the signal of amine group protons in H NMR and signal of
a sp3 carbon atom, which linked to oxygen and nitrogen in 13C NMR
are strong evidences for no formation of seven membered ring.
Scheme 1. Synthesis of 3-(arylideneamino)-2-aryl-5H-imidazo[1,2-b]pyrazole-7-carbonitriles 4ael.
2. Results and discussions
Table 1
Optimization of solvent type and effect of catalyst in synthesis of 3-(benzylide-
Firstly, 5-amino-1H-pyrazole-4-carbonitrile (1 equiv) was
treated with benzaldehyde (1 equiv) in acetonitrile in the presence
of p-toluenesulfonic acid catalyst (10 mol %) at room temperature
for 24 h. Then, 1 equiv of TsCH2NC (3) was added. After 48 h,
monitoring of the reaction showed that a new product had been
generated. Separation was performed by column chromatography
and the yield of reaction was 23%. Spectroscopic data indicated
that 3-(benzylideneamino)-2-phenyl-5H-imidazo[1,2-b]pyrazole-
7-carbonitrile 4a was synthesized in a four-component reaction. In
another reaction (in one-pot form) it was found that a good yield
(54%) was obtained after 48 h. Next, various experiments were
designed to optimize the reaction conditions.
To optimize the conditions for this four-component reaction, 5-
amino-1H-pyrazole-4-carbonitrile (1), benzaldehyde (2a), and
TsCH2NC (3) were selected as model reactants. Initially, different
solvents in the presence and absence of p-TsOH at room tempera-
ture were utilized for investigation of solvent and catalytic effects
(Table 1). The reactions were also performed under solvent free
conditions (Table 1, entry 14). The results indicated that in solvent
free conditions no yield was obtained, and among the different
solvents acetonitrile was found to be the best solvent at room
temperature (Table 1). The presence of the catalyst for this trans-
formation was also found to be necessary (column 4, Table 1).
Next, in order to determine the best catalyst, a number of Lewis
and Bronsted acids (10 mol %) were screened. The employed cata-
lysts are listed in Table 2. The experiments showed that the highest
yields were obtained using p-TsOH as catalyst. The optimum cata-
lyst amount was next investigated by studying the reaction with
different amounts of p-TsOH at room temperature. The best results
were obtained in the presence of 20 mol % of p-TsOH. Results show
that by reducing the amount of catalyst from 20 mol %, yields were
decreased, while increasing the amount of p-TsOH did not have any
effect on the yield of the reaction. The reaction was then repeated at
various temperatures (entry 6, Table 2) in acetonitrile. The results
neamino)-2-phenyl-5H-imidazo[1,2-b]pyrazole-7-carbonitrilea
Entry
Solvent
Yieldb,c (%)
Yieldb,c,d (%)
1
2
3
4
5
6
7
8
Water
Methanol
Ethanol
DMSO
DMF
Dioxane
THF
Acetonitrile
Ethyl acetate
Chloroform
Toluene
[bmim]Br
[bmim]BF4
Solvent-free
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
20
20
18
21
50
51
54
18
10
Trace
30
30
0
9
10
11
12
13
14
a
Benzaldehyde (2 mmol), TsCH2NC (1 mmol), 5-amino-1H-pyrazole-4-
carbonitrile (1 mmol) in solvent (5 mL), 48 h.
b
Isolated yield.
Room temperature.
In the presence of p-TsOH catalyst (10 mol %).
c
d
The structures of 4ael were deduced from their IR, 1H NMR, 13
C
NMR, Mass spectra, and elemental analyses. For example, the IR
spectrum of 4g showed absorptions at 3298 (NH), 2939 (CH3), 2217
(CN), 1606 (C]N), 1509 (C]C), 1430 (bending CH3), 1289 (CeN),
1269, and 1269 (CeN) cmꢀ1, indicating the presence of these
functional groups in the proposed structure. The 1H NMR spectrum
of 4g exhibited three singlets for the CH of imine group, the NH, and
the CH on the pyrazole ring at
spectively. Four doublets corresponding to the four aromatic hy-
drogen atoms appeared at
¼6.63 and 7.78 with J 8.8 Hz and at
d¼9.87, 12.45, and 8.24 ppm, re-
d
d
¼6.73 and 7.86 with J 8.4 Hz as well as two singlets at ¼6.66 and
d
6.74 for the aromatic hydrogens. Four singlets at 3.91, 3.88, 3.86,
and 3.84 ppm were identified as the methoxy groups in the aro-
matic rings. The 1H decoupled 13C NMR spectrum of 4g showed 23

A. Rahmati et al. / Tetrahedron 69 (2013) 4199e4204
4201
Table 2
A proposed mechanism for the formation of the product 4 is
provided in Scheme 3. It is reasonable to assume that the pro-
tonated Schiff base 5 is formed by adding benzaldehyde to the
aminopyrazole solution in the presence of p-toluenesulfonic acid.
Then, compound 6 is produced by a nonconcerted [4þ1] cycload-
dition reaction between protonated Schiff base 5 and isocyanide 3,
followed by tautomerization.16 After that, intermediate 7 was ob-
tained via oxidation of 6.19 After this stage, it is likely that imine
group in intermediate 7 was protonated by p-toluenesulfonic acid
and consequently intermediate 8 was generated. Following, by
quenching with water, hemiaminal 9 was produced. Then, second
hemiaminal 10 was generated via hydrolysis of hemiaminal 9.
Subsequently, by elimination of formaldehyde from hemiaminal 10,
3-amino-2-phenyl-1H-imidazo[1,2-b]pyrazole-7-carbonitrile 11 is
generated. Finally, the other benzaldehyde reacts with the amine
group and generates the final product 3-(4-nitrobenzylidene
amino)-2-(4-nitrophenyl)-5H-imidazo[1,2-b]pyrazole-7-
Effects of catalyst types and catalyst amount in synthesis of 3-(benzylideneamino)-
2-phenyl-5H-imidazo[1,2-b]pyrazole-7-carbonitrilea
Entry
Catalyst
Amount (%)
Time (h)
Yieldb (%)
1
2
3
4
5
AcOH
10 mol
10 mol
10 mol
10 mol
40 mol
20 mol
20 mol
20 mol
20 mol
20 mol
10 mol
5 mol
48
48
48
48
72
48
24
18
12
6
48
48
48
48
48
38
44
29
39
65
65
48
21
CF3CO2H
H3PO4 85%
H2SO4 88%
p-TsOH
10
d
54
20
<5
<5c
Traced
3 mol
20 mol
20 mol
6
p-TsOH
a
Benzaldehyde (2 mmol), TsCH2NC (1 mmol), 5-amino-1H-pyrazole-4-
carbonitrile 4. We could not detect compound 10, because this
compound was converted to p-toluenesulfonic acid via an un-
known mechanism; this subject was confirmed by an increase in
the amount of catalyst at the end of reaction.
carbonitrile (1 mmol) in acetonitrile (5 mL), rt.
b
Isolated yield.
c
Isolated yield 50 ꢁC.
d
Isolated yield reflux.
Table 3
Synthesis of 3-(benzylideneamino)-2-phenyl-5H-imidazo[1,2-b]pyrazole-7-carbonitriles
Entry
X
Y
Product
Yielda
Mp (ꢁC)
1
2
3
4
5
6
7
8
eH
eH
eH
eH
eH
eH
eH
4-OCH3
4-OCH3
eH
4a
4b
4c
4d
4e
4f
4g
4h
4i
65
67
34
76
65
60
61
54
68
76
78
69
195e196
202e203
232e233
220e221
223e224
209e210
251e252
254e255
225e226
266e267
236e237
254e255
4-CH3
4-iso-Pr
4-OCH3
3-OCH3
2-OH
2-OCH3
3-OCH3
4-Cl
9
10
11
12
3-Br
3-NO2
2-Cl
eH
eH
4-Cl
4j
4k
4l
a
Isolated yield.
distinct resonances, in agreement with the suggested structures.
Mass spectrum of 4g showed the expected molecular-ion peak.
Elemental analysis faithfully confirmed the amounts of C, H, and N
in the final product. The spectral data for 4g and other compounds
are given in the Experimental section.
This work was done in continuation of the Groebkee
BlackburneBienayme and Krasavin three-component reactions,
and the products were similar to those reported by Krasavin
(Scheme 2). This new isocyanide-based four-component strategy
provides an efficient, simple, convenient, and applicable way for
the synthesis of different types of 3-(benzylideneamino)-2-phenyl-
5H-imidazo[1,2-b]pyrazoles. In this synthetic method, readily
available starting materials were used. Also inexpensive and un-
pleasant benzyl isocyanides have been replaced with TsCH2NC that
is a solid isocyanide. Additionally, an imine group was generated,
which could be important for other transformations.
In conclusion, a convenient and efficient one-pot four-compo-
nent synthesis of 3-(benzylideneamino)-2-phenyl-5H-imidazo[1,2-
b]pyrazole-7-carbonitriles is reported from readily available and
inexpensive starting materials, such as aldehydes, 3-amino-4-
pyrazolecarbonitrile, and tosmic isocyanide. The 3-(benzylide-
neamino)-2-phenyl-5H-imidazo[1,2-b]pyrazole-7-carbonitriles ob-
tained in this study could also serve as valuable synthons for further
elaboration into more complex compounds.
3. Experimental
3.1. General procedure
All chemicals were purchased from Acros and/or Alfa-Aesar
companies and used without any further purification. Melting
points were determined on an Electrothermal 9100 apparatus. IR

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A. Rahmati et al. / Tetrahedron 69 (2013) 4199e4204
Scheme 2. Comparing this reaction with previous similar reports.
Scheme 3. Mechanism of the four-component reaction.

A. Rahmati et al. / Tetrahedron 69 (2013) 4199e4204
4203
spectra were recorded on a FT Infrared Spectroscope instrument
JASCO, FT/IR-6300 model as KBr discs. The 1H NMR and 13C NMR
spectra were recorded on a Bruker-AVANCE 400 MHz NMR in-
strument using DMSO-d6 as solvent. Mass spectra were recorded on
a Shimadzu QP 1100 EX mass-Spectrometer operating at an ioni-
zation potential of 70 eV. Elemental analyses were performed using
a Heraeus CHNS Rapid analyzer.
3J 7.6 Hz, 2CHarom), 8.08 (2H, d, 3J 7.6 Hz, 2CHarom), 8.24 (1H, s,
CHpyrazole), 9.58 (1H, s, CHimine), 12.93 (1H, s, NHpyrazole) ppm; dC
(100 MHz, DMSO-d6) 55.26, 55.38, 66.20, 114.31, 114.53, 114.76,
121.44, 124.47, 126.04, 128.41, 129.50, 129.79, 139.10, 146.12, 154.41,
159.31, 161.70 ppm; m/z (EI, 70 eV) 371 (Mþ, 74%); Anal. Found: C,
67.80; H, 4.59; N, 18.92. C21H17N5O2 requires C, 67.91; H, 4.61; N,
18.86.
3.2. General procedure for the synthesis of 3-(benzylidenea-
mino)-2-phenyl-5H-imidazo[1,2-b]pyrazoles (4ael)
3.3.5. 3-(3-Methoxybenzylideneamino)-2-(3-methoxyphenyl)-5H-
imidazo[1,2-b]pyrazole-7-carbonitrile (4e). Yellow powder (0.241 g,
65%); mp 223e224 ꢁC; Rf (20% petroleum ether/EtOAc) 0.53; nmax
(KBr) 3253, 3170, 2938, 2230, 1630, 1569, 1489, 1468, 1280, 1241,
A solution of aldehyde (2 mmol), 3-aminopyrazole (1 mmol),
and p-toluenesulfonic acid catalyst (20 mol %) in MeCN (5 mL) was
magnetically stirred for 24 h in room temperature. Next TsCH2NC
(1 mmol) was added and the reaction mixture was stirred for 24 h
in room temperature. After completion of the reaction, which was
followed by TLC EtOAc/petroleum ether 4:1, the reaction mixture
was filtered, and the precipitate washed with methanol. Finally
pure solid product was obtained by column chromatography.
1207, 1040, 778 cmꢀ1
; dH (400 MHz, DMSO-d6) 3.83 (3H, s, OMe),
3.86 (3H, s, OMe), 6.98e7.77 (8H, m, CHarom), 8.27 (1H, s, CHpyrazole),
9.60 (1H, s, CHimine), 13.13 (1H, s, NHpyrazole) ppm; dC (100 MHz,
DMSO-d6) 55.08, 55.20, 66.45, 111.88, 112.20, 114.53, 114.57, 117.52,
119.35, 120.94, 125.02, 126.73, 129.88, 129.99, 130.13, 138.01, 139.44,
146.54, 155.46, 159.35, 159.64 ppm; m/z (EI, 70 eV) 371 (Mþ, 90%);
Anal. Found: C, 67.79; H, 4.58; N, 18.88. C21H17N5O2 requires C,
67.91; H, 4.61; N, 18.86.
3.3. Compounds characterization data
3.3.6. 3-(2-Hydroxybenzylideneamino)-2-(2-hydroxyphenyl)-5H-
imidazo[1,2-b]pyrazple-7-carbonitrile (4f). Cream powder (0.206 g,
60%); mp 209e210 ꢁC; Rf (20% petroleum ether/EtOAc) 0.45; nmax
3.3.1. 3-(Benzylideneamino)-2-phenyl-1H-imidazo[1,2-b]pyrazole-7-
carbonitrile (4a). Yellow powder (0.202 g, 65%); mp 195e196 ꢁC; Rf
(20% petroleum ether/EtOAc) 0.55; nmax (KBr) 3242, 3197, 3057,
(KBr) 3270, 3099, 2224, 1622, 1596, 1485, 1457, 1193, 746 cmꢀ1
; dH
2224, 1623, 1483, 1197 cmꢀ1
;
dH (400 MHz, DMSO-d6) 7.12e8.16
(400 MHz, DMSO-d6) 6.91e7.66 (8H, m, CHarom), 8.31 (1H, s,
CHpyrazole), 9.77 (1H, s, CHimine), 10.50 (1H, s, OH), 11.67 (1H, s, OH),
12.96 (1H, s, NHpyrazole) ppm; dC (100 MHz, DMSO-d6) 66.35, 114.71,
115.09, 116.42, 116.55, 117.17, 119.26, 119.46, 119.57, 120.67, 129.18,
130.13, 130.77, 132.73, 136.41, 146.42, 154.98, 155.18, 158.72 ppm;
m/z (EI, 70 eV) 343 (Mþ, 91%); Anal. Found: C, 66.53; H, 3.80; N,
20.29. C19H13N5O2 requires C, 66.47; H, 3.82; N, 20.40.
(10H, m, 10CHarom), 8.31 (1H, s, CHpyrazole), 9.71 (1H, s, CHimine),
13.19 (1H, s, NHpyrazole) ppm; dC (100 MHz, DMSO-d6) 66.48, 114.58,
125.47, 126.77, 127.18, 128.82, 129.05, 129.41, 129.55, 131.27, 135.20,
136.54, 139.49, 146.52, 155.76 ppm; m/z (EI, 70 eV) 311 (Mþ, 87%);
Anal. Found: C, 73.09; H, 4.09; N, 22.38. C19H13N5 requires C, 73.30;
H, 4.21; N, 22.49.
3.3.2. 3-(4-Methylbenzylideneamino)-2-p-tolyl-5H-imidazo[1,2-b]
pyrazole-7-carbonitrile (4b). Cream powder (0.220 g, 65%); mp
202e203 ꢁC; Rf (20% petroleum ether/EtOAc) 0.60; nmax (KBr) 3242,
3.3.7. 3-(2,4-Dimethoxybenzylideamino)-2-(2,4-dimethoxyphenyl)-
5H-imidazo[1,2-b]pyrazole-7-carbonitrile
(4g). Yellow powder
(0.263 g, 61%); mp 251e252 ꢁC; Rf (20% petroleum ether/EtOAc)
0.50; nmax (KBr) 3414, 3298, 2939, 2835, 2217,1606,1508,1267,1211,
3171, 3055, 2918, 2223, 1620, 1480, 1196, 818 cmꢀ1
; dH (400 MHz,
DMSO-d6) 2.37 (6H, s, 2CH3), 7.31 (2H, d, 3J 8.0 Hz, 2CHarom), 7.35
(2H, d, 3J 8.0 Hz, 2CHarom), 7.77 (2H, d, 3J 8.0 Hz, 2CHarom), 8.00 (2H,
d, 3J 8.0 Hz, 2CHarom), 8.31 (1H, s, CHpyrazole), 9.70 (1H, s, CHimine),
13.03 (1H, s, NHpyrazole) ppm; dC (100 MHz, DMSO-d6) 20.85, 21.17,
66.33, 114.62, 124.80, 126.06, 126.69, 126.99, 128.02, 129.35, 129.61,
134.02, 138.08, 139.29, 141.29, 146.26, 155.24 ppm; m/z (EI, 70 eV)
339 (Mþ, 44%). Anal. Found: C, 74.49; H, 5.09; N, 20.80. C21H17N5
requires C, 74.32; H, 5.05; N, 20.63.
1030 cmꢀ1
; dH (400 MHz, DMSO-d6) 3.84 (3H, s, OMe), 3.86 (3H, s,
OMe), 3.88 (3H, s, OMe), 3.91 (3H, s, OMe), 6.63e6.74 (4H, m,
4CHarom), 7.78 (1H, d, 3J 8.4 Hz, 1CHarom), 7.86 (1H, d, 3J 8.8 Hz,
1CHarom), 8.24 (1H, s, CHpyrazole), 9.87 (1H, s, CHimine), 12.45 (1H, s,
NHpyrazole) ppm; dC (100 MHz, DMSO-d6) 55.42, 55.48, 55.71, 55.83,
65.87, 97.95, 98.50, 105.32, 106.77, 109.70, 115.02, 118.03, 123.89,
125.68, 127.21, 132.96, 138.25, 146.17, 149.84, 157.95, 160.38, 161.27,
163.26 ppm; m/z (EI, 70 eV) 431 (Mþ, 100%); Anal. Found: C, 64.16;
H, 4.96; N, 16.31. C23H21N5O4 requires C, 64.03; H, 4.91; N, 16.23.
3.3.3. 3-(4-Isopropylbenzylideneamino)-2-(4-isopropylphenyl)-5H-
imidazo[1,2-b]pyrazole-7-carbonitrile (4c). Orange powder (0.134 g,
34%); mp 232e233 ꢁC; Rf (20% petroleum ether/EtOAc) 0.60; nmax
3.3.8. 3-(3,4-Dimethoxybenzylideamino)-2-(3,4-dimethoxyphenyl)-
5H-imidazo[1,2-b]pyrazole-7-carbonitrile (4h). Yellow powder
(0.233 g, 54%); mp 254e255 ꢁC; Rf (20% petroleum ether/EtOAc)
0.50; nmax (KBr) 3253, 3202, 2939, 2833, 2226, 1630, 1507, 1483,
(KBr) 3269, 3214, 2981, 2223, 1628, 1597, 1509, 1480, 1339 cmꢀ1
; dH
(400 MHz, DMSO-d6) 1.27 (6H, d, 3J 7.2 Hz, 2CH3), 1.31 (6H, d, 3J
7.2 Hz, 2CH3), 2.93e3.02 (2H, m, 2CH), 7.41 (2H, d, 3J 8.2 Hz,
2CHarom), 7.45 (2H, d, 3J 8.2 Hz, 2CHarom), 7.88 (2H, d, 3J 8.2 Hz,
2CHarom), 8.07 (2H, d, 3J 8.2 Hz, 2CHarom), 8.27 (1H, s, 1CHpyrazole),
9.65 (1H, s, CHimine), 13.08 (1H, br s, NHpyrazole) ppm; dC (100 MHz,
DMSO-d6) 23.58, 23.68, 33.27, 33.47, 66.32, 114.76, 124.87, 126.66,
126.74, 127.04, 127.12, 128.17, 134.54, 139.53, 146.32, 148.85, 151.95,
154.97; m/z (EI, 70 eV) 395 (Mþ, 100%); Anal. Found: C, 76.05; H,
6.29; N, 17.80. C25H25N5 requires C, 75.92; H, 6.37; N, 17.71.
1264, 1232, 1023 cmꢀ1
; dH (400 MHz, DMSO-d6) 3.84 (6H, s, 2OMe),
3.89 (3H, s, OMe), 3.89 (3H, s, OMe), 7.10 (1H, d, 3J 8.4 Hz, CHarom),
7.14 (1H, d, 3J 8.5 Hz, CHarom), 7.46 (1H, dd, 3J 8.4 Hz, 4J 1.4 Hz,
CHarom), 7.49 (1H, d, 4J 1.4 Hz, CHarom), 7.70 (1H, dd, 3J 8.5 Hz, 4J
1.8 Hz, CHarom), 7.83 (1H, d, 4J 1.8 Hz, CHarom), 8.25 (1H, s, CHpyrazole),
9.60 (1H, s, CHimine), 12.95 (1H, s, NHpyrazole) ppm; dC (100 MHz,
DMSO-d6) 55.32, 55.48, 55.55, 55.63, 66.16, 109.13, 110.34, 111.63,
111.84, 114.77, 119.66, 121.54, 122.88, 124.61, 129.58, 139.10, 146.12,
148.65, 149.03, 149.12, 151.66, 154.87 ppm; m/z (EI, 70 eV) 431 (Mþ,
3%); Anal. Found: C, 64.19; H, 4.93; N, 16.19. C23H21N5O4 requires C,
64.03; H, 4.91; N, 16.23.
3.3.4. 3-(4-Methoxybenzylideneamino)-2-(4-methoxyphenyl)-5H-
imidazo[1,2-b]pyrazole-7-carbonitrile (4d). Yellow powder (0.282 g,
76%); mp 221e221 ꢁC; Rf (20% petroleum ether/EtOAc) 0.53; nmax
(KBr) 3243, 3173, 2932, 2223, 1612, 1507, 1253, 1181, 1166, 1035,
3.3.9. 3-(4-Chlorobenzylideneamino)-2-(4-chlorophenyl)-5H-imi-
dazo[1,2-b]pyrazole-7-carbonitrile (4i). Yellow powder (0.254 g,
67%); mp 225e226 ꢁC; Rf (20% petroleum ether/EtOAc) 0.55; nmax
837 cmꢀ1
;
dH (400 MHz, DMSO-d6) 3.84 (6H, s, 2OMe), 7.07 (2H, d,
3J 7.6 Hz, 2CHarom), 7.13 (2H, d, 3J 7.6 Hz, 2CHarom), 7.86 (2H, d,

4204
A. Rahmati et al. / Tetrahedron 69 (2013) 4199e4204
(KBr) 3271, 3221, 3051, 2224, 1623, 1501, 1486, 1268, 1132,
815 cmꢀ1 dH (400 MHz, DMSO-d6) 7.43 (2H, d, 3J 7.3 Hz, 2CHarom),
References and notes
;
7.47 (2H, d, 3J 7.3 Hz, 2CHarom), 7.72 (2H, d, 3J 7.2 Hz, 2CHarom),
7.98 (2H, d, 3J 7.3 Hz, 2CHarom), 8.15 (1H, s, CHpyrazole), 9.40 (1H,
s, CHimine), 13.05 (1H, s, NHpyrazole) ppm; dC (100 MHz, DMSO-d6)
67.02, 114.85, 125.37, 126.31, 127.93, 128.96, 129.11, 129.34,
129.93, 133.55, 135.57, 136.18, 139.85, 146.84, 154.79 ppm; m/z
(EI, 70 eV) 383 (Mþþ4, 1), 381 (Mþþ2, 4), 379 (Mþ, 7%); Anal.
Found: C, 60.21; H, 2.96; N, 18.38. C19H11Cl2N5 requires C, 60.02;
H, 2.92; N, 18.42.
1. Ennis, H. L.; Moller, L.; Wang, J. J.; Selawry, O. S. Biochem. Pharmacol. 1971, 20,
2539e2546.
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3. Pelling, J. C.; Shipman, C., Jr. Biochem. Pharmacol. 1976, 25, 2377e2382.
4. Matsumoto, M.; Weckbecker, G.; Cory, J. G. Cancer Commun. 1990, 2, 1e6.
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2639e2646.
6. (a) Goddard, A. J.; Orr, R. M.; Stock, J. A.; Wilman, D. E. Anti-Cancer Drug Des.
1987, 2, 235e245; (b) Ahmet, M. T.; Douglas, K. T.; Silver, J.; Goddard, A. J.;
Wilman, D. E. Anti-Cancer Drug Des. 1986, 1, 189e195.
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10. Zhang, X.; Sui, Z. U.S. Patent 7,655,683 B2, 2010.
3.3.10. 3-(3-Bromobenzylideamino)-2-(3-bromophenyl)-5H-imidazo
[1,2-b]pyrazole-7-carbonitrile (4j). Yellow powder (0.356 g, 76%);
mp 266e267 ꢁC; Rf (20% petroleum ether/EtOAc) 0.55; nmax (KBr)
11. Brullo, C.; Spisani, S.; Selvatic, R.; Bruno, O. Eur. J. Med. Chem. 2012, 47, 573e579.
12. (a) Zhang, X.; Li, X.; Allan, G. F.; Sbriscia, T.; Linton, O.; Lundeen, S. G.; Sui, Z. J.
Med. Chem. 2007, 50, 3857e3869; (b) Zhang, X.; Li, X.; Allan, G. F.; Sbriscia, T.;
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Shawali, A. S.; Mosselhi, M. A.; Altablawy, F. M. A.; Farghaly, T. A.; Tawfik, N. M.
Tetrahedron 2008, 64, 5524e5530; (e) Bruno, O.; Brullo, C.; Bondavalli, F.;
Ranise, A.; Schenone, S.; Falzarano, M. S.; Varani, K.; Spisani, S. Bioorg. Med.
Chem. Lett. 2007, 17, 3696e3701; (f) Blass, B. E.; Srivastava, A.; Coburn, K. R.;
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45, 619e621; (g) Shawali, A. S.; Abdelkader, M. H.; Eltalbawy, F. M. A. Tetra-
hedron 2002, 58, 2875e2880; (h) Farag, A. M.; Dawood, K. M. Heteroat. Chem.
1997, 8, 129e133; (i) Sherif, S. M.; Hussein, A. M.; El-Kholy, Y. M. Arch. Pharm.
Res. 1994, 17, 298e303; (j) Elagamey, A. G. A.; Sowellim, S. Z. A.; Khodeir, M. N.
Arch. Pharm. Res. 1987, 10, 14e17; (k) Wood, S. G.; Dalley, N. K.; George, R. D.;
Robins, R. K.; Revankar, G. R. J. Org. Chem. 1984, 49, 3534e3540; (l) Schweizer,
E. E.; Lee, K.-J. J. Org. Chem. 1984, 49, 4848e4853; (m) Schweizer, E. E.; Lee, K.-J.
J. Org. Chem. 1984, 49, 1964e1969.
3236, 3183, 3057, 2226, 1619, 1449, 1194, 774, 672 cmꢀ1
; dH
(400 MHz, DMSO-d6) 7.44e8.26 (8H, m, 3CHarom), 8.37 (1H, s,
CHpyrazole), 9.49 (1H, s, CHimine), 13.30 (1H, br s, NHpyrazole) ppm. dC
(100 MHz, DMSO-d6) 66.66, 114.38, 122.01, 122.45, 125.04, 125.65,
125.89, 127.49, 129.63, 129.76, 130.81, 130.85, 131.01, 131.10, 133.73,
138.65, 139.73, 146.70, 154.13 ppm; m/z (EI, 70 eV) 471 (Mþþ4, 1),
469 (Mþþ2, 2), 467 (Mþ, 1%); Anal. Found: C, 48.41; H, 2.35; N,
14.87. C19H11Br2N5 requires C, 48.64; H, 2.36; N, 14.93.
3.3.11. 3-(3-Nitrobenzylideamino)-2-(3-nitrophenyl)-5H-imidazo
[1,2-b]pyrazole-7-carbonitrile (4k). Yellow powder (0.313 g, 78%);
mp 236e237 ꢁC; Rf (20% petroleum ether/EtOAc) 0.48; nmax (KBr)
3236, 3109, 2239, 1622, 1529, 1354, 1182, 808, 678 cmꢀ1
; dH
13. (a) Zhu, J.; Bienayme, H. Multicomponent Reactions; Wiley-VCH: Weinheim,
Germany, 2005; (b) Terrett, N. K. Combinatorial Chemistry; Oxford University:
New York, NY, 1998.
(400 MHz, DMSO-d6) 7.51e8.18 (8H, m, 8CHarom), 8.24 (1H, s,
CHpyrazole), 9.20 (1H, s, CHimine), 13.08 (1H, br s, NHpyrazole) ppm; dC
(100 MHz, DMSO-d6) 66.70, 113.97, 120.93, 121.48, 122.30, 124.93,
125.16, 129.77, 129.86, 130.26, 131.57, 133.71, 137.34, 139.54, 146.63,
147.48, 147.94, 153.38 ppm; m/z (EI, 70 eV) 371 (Mþꢀ30, 1%); Anal.
Found: C, 56.99; H, 2.78; N, 24.34. C19H11N7O4 requires C, 56.86; H,
2.76; N, 24.43.
14. Ugi, I. Isonitrile Chemistry; Academic: New York, NY, 1968.
€
€
15. (a) Domling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168e3210; (b) Domling,
€
A. Curr. Opin. Chem. Biol. 2002, 6, 306e313; (c) Domling, A. Chem. Rev. 2006, 106,
17e89.
16. (a) Groebke, K.; Weber, L.; Mehlin, F. Synlett 1998, 661e664; (b) Blackburn, C.
Tetrahedron Lett. 1998, 39, 5469e5472; (c) Bienayme, H.; Bouzid, K. Angew.
Chem., Int. Ed. 1998, 37, 2234e2237.
17. (a) Khan, A. T.; Basha, R. S.; Lal, M. Tetrahedron Lett. 2012, 53, 2211e2217; (b)
€
ꢀ
Hieke, M.; Rodl, C. B.; Wisniewska, J. M.; la Buscato, E.; Stark, H.; Schubert-
Zsilavecz, M.; Steinhilber, D.; Hofmann, B.; Proschak, E. Bioorg. Med. Chem. Lett.
2012, 22, 1969e1975; (c) Odell, L. R.; Nilsson, M. T.; Gising, J.; Lagerlund, O.;
Muthas, D.; Nordqvist, A.; Karlen, A.; Larhed, M. Bioorg. Med. Chem. Lett. 2009,
19, 4790e4793; (d) Sandulenko, Y.; Komarov, A.; Rufanov, K.; Krasavin, M.
Tetrahedron Lett. 2008, 49, 5990e5993; (e) Rousseau, A. L.; Matlaba, P.;
Parkinson, C. J. Tetrahedron Lett. 2007, 48, 4079e4082; (f) Adib, M.; Mahdavi, M.;
Alizadeh Noghani, M.; Mirzaei, P. Tetrahedron Lett. 2007, 48, 7263e7265; (g)
3.3.12. 3-(2,4-Dichlorobenzylideamino)-2-(2,4-dichlorophenyl)-5H-
imidazo[1,2-b]pyrazole-7-carbonitrile (4l). Yellow powder (0.310 g,
69%); mp 254e255 ꢁC; Rf (20% petroleum ether/EtOAc) 0.58; nmax
(KBr) 3219, 3172, 3099, 2234, 1617, 1589, 1436, 1102, 864 cmꢀ1
; dH
(400 MHz, DMSO-d6) 7.52 (1H, dd, 3J 8.6 Hz, 4J 1.8 Hz, CHarom), 7.66
(1H, dd, 3J 8.4 Hz, 4J 2.0 Hz, CHarom), 7.76 (1H, d, 4J 2.0 Hz, CHarom),
7.77 (1H, d, 3J 8.4 Hz, CHarom), 7.90 (1H, d, 4J 1.8 Hz, CHarom), 7.65
(1H, d, 3J 8.6 Hz, CHarom), 8.37 (1H, s, CHpyrazole), 9.93 (1H, s,
CHimine), 13.50 (1H, br s, NHpyrazole) ppm; dC (100 MHz, DMSO-d6)
66.75, 114.33, 126.18, 127.57, 128.15, 128.37, 129.59, 129.63, 132.23,
134.09, 134.79, 135.29, 135.35, 136.33, 138.80, 139.60, 146.89,
150.58 ppm; m/z (EI, 70 eV) 455 (Mþþ8, 1), 453 (Mþþ6, 19),
451 (Mþþ4, 79) 449 (Mþþ2, 97), 447 (Mþ, 90%); Anal. Found: C,
50.63; H, 2.00; N, 15.64. C19H9Cl4N5 requires C, 50.81; H, 2.02;
N, 15.59.
€
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Acknowledgements
20. Parchinsky, V. Z.; Koleda, V. V.; Shuvalova, O.; Kravchenko, D. V.; Krasavin, M.
Tetrahedron Lett. 2006, 47, 6891e6894.
We gratefully acknowledge financial support from the Research
Council of the University of Isfahan.
21. Rahmati, A.; Alizadeh-Kouzehrash, M. Synthesis 2011, 2913e2920.