One-pot sequential double annulations cascade reaction for imidazo[1,2-b]pyrazoles synthesis

Article abstract of DOI:10.1007/s13738-018-1467-z

Abstract: We have developed efficient and green methods for the synthesis of imidazo[1,2-b]pyrazole derivatives by Groebke–Blackburn–Bienaymé (GBB) reaction of 5-aminopyrazole, aldehyde and trimethylsilyl cyanid under thermal condition in 1-n-butyl-3-methylimidazolium tetrafluoroborate [Bmim]BF₄ ionic liquid. A one-pot sequential double annulation cascade reaction has also been demonstrated for imidazo[1,2-b]pyrazoles synthesis.

Full text of DOI:10.1007/s13738-018-1467-z

Journal of the Iranian Chemical Society
https://doi.org/10.1007/s13738-018-1467-z
ORIGINAL PAPER
One-pot sequential double annulations cascade reaction
for imidazo[1,2-b]pyrazoles synthesis
1
1
1
Shokoufe Goli · Peiman Mirzaei · Ayoob Bazgir
Received: 24 May 2018 / Accepted: 7 August 2018
©
Iranian Chemical Society 2018
Abstract
We have developed efficient and green methods for the synthesis of imidazo[1,2-b]pyrazole derivatives by Groebke–Black-
burn–Bienaymé (GBB) reaction of 5-aminopyrazole, aldehyde and trimethylsilyl cyanid under thermal condition in 1-n-butyl-
3
-methylimidazolium tetrafluoroborate [Bmim]BF ionic liquid. A one-pot sequential double annulation cascade reaction
4
has also been demonstrated for imidazo[1,2-b]pyrazoles synthesis.
Graphical abstract
Keywords Imidazo[1,2-b]pyrazoles · GBB reaction · [Bmim]BF · Sequential reaction · One-pot synthesis
4
Introduction
therapeutically-relevant N-fused heterocycles [9, 13–16].
Recently, to avoid the use of isocyanide, a new GBB method
has been developed using trimethylsilyl cyanide (TMSCN)
as a functional isonitrile equivalent [9, 17–23].
One-pot sequential isocyanide-based multi-component reac-
tions, which consist of several simultaneous bond-forming
reactions in a one-pot manner, are an attractive and powerful
synthetic method for the synthesis of diverse complex mol-
ecules from simple precursors [1]. Due to savings in time,
chemicals and effort, sequential reactions can increase syn-
thetic efficiency and provide a positive environmental impact
by reducing chemical use [1–8]. Among sequential isocya-
nide-based multi-component reactions, the Groebke–Black-
burn–Bienaymé (GBB)-based sequential reactions for het-
erocycles synthesis are one of the best examples [9–12].
GBB reaction of isocyanides, heterocyclic amidines, and
aldehydes via imine formation/ [4+1] cycloaddition reac-
tion is an applicable and wide platform for the synthesis of
Improvement of simple and effective methods for the syn-
thesis of imidazopyrazole frameworks has attracted attention
in the area of synthetic and medicinal chemistry because of
their outstanding biological activities [24, 25]. They have
been reported as anti-inflammatory [26], antifungal [24], and
anticancer [27]. Furthermore, some imidazopyrazoles play
an important role in the neurodegenerative disorders treat-
ment [28], or the hepatitis C virus [29]. Also, imidazo[1,2-b]
pyrazole nucleus have been described as photographic dye-
forming couplers comprise, useful in photographic materials
and processes [30, 31].
There are several methods for the synthesis of
imidazo[1,2-b]pyrazoles such as intermolecular aza-
Wittig reaction of 5-(triphenylphosphoranylideneamino)-
3-phenylpyrazole, [32] reaction of 5-amino-pyrazole-
4-carbonitriles with α-bromoacetophenones, followed
by the cyclocondensation of the resulting intermediates
*
Ayoob Bazgir
a_bazgir@sbu.ac.ir
1
Department of Chemistry, Shahid Beheshti University,
General Campus, Tehran 1983963113, Iran
[
33], condensation reaction of aldehydes, isocyanide, and
Vol.:(0
1
123456789)
3

Journal of the Iranian Chemical Society
amino-pyrazole [34, 35], three-steps method from N-aryl
3‑(benzylideneamino)‑6‑(methylthio)‑2‑phe‑
nyl‑1H‑imidazo[1,2‑b]pyrazole‑7‑carbonitrile (6a)
2
-oxoethanehydrazonoyl bromide [36], and a two-steps
method starting from ethyl cyanopyruvate sodium salt and
hydrazinoacetaldehyde doethylacetal in the presence of a
stoichiometric amount of H SO [37]. In spite of potential
−
1
Yellow powder. Mp 277–279 °C. IR (KBr) (ν /cm ):
max
1
3167, 2919, 2222, 1621, 1474. H NMR (300 MHz, DMSO-
2
4
utility, many of these methods involve expensive reagents in
multi-steps manner, strongly acidic conditions, long reaction
times and the range of compounds that can be prepared is
limited. Therefore, the development of new methods for the
preparation of imidazo[1,2-b]pyrazole frameworks is still
of much interest. According to the above reports and as a
continuation of our interest in synthesis of heterocycles [38,
d ): δ 2.70 (3H, s, SCH ), 7.47–8.14 (10H, m, H-Ar),
6
H
3
9.66 (1H, s, CH), 13.19 (1H, brs, NH). MS (EI): m/z 357
+
(M , 56), 310 (100), 267 (76), 91 (95). Anal. Calcd for
C H N S: C, 67.21; H, 4.23; N, 19.59. Found: C, 67.13 ;
2
0
15
5
H, 4.31; N, 19.47.
3
‑((4‑methylbenzylidene)amino)‑6‑(methylthio)‑2‑
3
9], herein, we wish to report synthesis of imidazo[1,2-b]
(
(
p‑tolyl)‑1H‑imidazo[1,2‑b]pyrazole‑7‑carbonitrile
6b)
pyrazoles by TMSCN-based GBB reaction.
−
1
Yellow powder. Mp 273–275 °C. IR (KBr) (ν /cm ):
max
1
3
244, 3183, 2220, 1619, 1460. H NMR (300 MHz, DMSO-
Experimental
d ): δ (ppm) 2.39 (6H, s, 2CH ), 2.68 (3H, s, SCH ),
6
H
3
3
3
7
.34–7.39 (4H, m, H-Ar), 7.82 (2H, d, J = 7.5 Hz, H-Ar),
HH
Melting points were determined on a melting point appa-
ratus and are uncorrected. IR spectra were taken with a
Bomem FT-IR MB spectrometer. The NMR spectra were
recorded on a BRUKERDRX-300AVANCE spectrometer.
Mass spectra were recorded on an Agilent 5975C VL MSD
with Tripe-Axis Detector operating at an ionization poten-
tial of 70 eV. Elemental analyses were performed using a
Heraeus CHN–O–Rapid analyzer. All chemicals were pur-
chased from Merck or Aldrich and were used without further
purification.
3
8
.00 (2H, d, J = 7.5 Hz, H-Ar), 9.60 (1H, s, CH), 13.09
HH
+
(
1H, brs, NH). MS (EI): m/z 385 (M ), 357 (100), 106. Anal.
Calcd for C H N S: C, 68.55; H, 4.97; N, 18.17. Found:
2
2
19
5
C, 68.68 ; H, 4.88; N, 18.10.
3
‑((2‑bromobenzylidene)amino)‑2‑(2‑bromopheny
l)‑6‑(methylthio)‑1H‑imidazo[1,2‑b]pyrazole‑7‑car‑
bonitrile (6c)
−
1
Yellow powder. Mp 289–291 °C. IR (KBr) (ν /cm ):
max
1
3
462, 3156, 2925, 2228, 1617, 1447. H NMR (300 MHz,
DMSO-d ): δ (ppm) 2.70 (3H, s, SCH ), 7.33–7.61 (4H, m,
General procedure for the synthesis
of imidazo[1,2‑b]pyrazole (6)
6
H
3
H-Ar), 7.69–7.75 (2H, m, H-Ar), 7.85–7.95 (2H, m, H-Ar),
1
0.01 (1H, s, CH), 13.36 (1H, brs, NH). MS (EI): m/z 515
+
(
M , 90), 468 (100), 387 (65), 102 (50).
A mixture of amino-1H-pyrazole (1 mmol), aldehyde
(
2 mmol), TMSCN (1.2 mmol) in [Bmim]BF (0.5 g) was
4
ͦ
heated at 120 C for 24 h. After cooling, the reaction mixture
was washed with water (5 mL) and the residue washed with
MeOH to afford pure product.
3‑((2‑chlorobenzylidene)amino)‑2‑(2‑chloropheny
l)‑6‑(methylthio)‑1H‑imidazo[1,2‑b]pyrazole‑7‑car‑
bonitrile (6d)
−
1
Yellow powder. Mp 292–294 °C. IR (KBr) (ν /cm ):
max
1
General sequential procedure for the synthesis
of imidazo[1,2‑b]pyrazole (6)
3496, 3416, 3145, 2919, 2231, 1620, 1474. H NMR
(300 MHz, DMSO-d ): δ (ppm) 2.69 (3H, s, SCH ),
6
H
3
7
.44–7.97 (8H, m, H-Ar), 10.06 (1H, s, CH), 13.36 (1H, s,
+
A mixture of 2-(bis(methylthio)methylene)malononitrile
NH). MS (EI): m/z 425 (M , 50), 378 (100), 240 (74).
(
1 mmol) and hydrazine hydrate (1 mmol) in [Bmim]
4
ͦ
BF (0.5 g) was heated at 70 C for 0.5 h. Then, aldehyde
3‑((4‑bromobenzylidene)amino)‑2‑(4‑bromopheny
l)‑6‑(methylthio)‑1H‑imidazo[1,2‑b]pyrazole‑7‑car‑
bonitrile (6e)
(
2 mmol) and TMSCN (1.2 mmol) were added and heated
ͦ
at 120 C for 24 h. After cooling, the reaction mixture was
washed with water (5 mL) and the residue washed with
MeOH to afford pure product.
−1
Yellow powder. Mp 300–302 °C. IR (KBr) (ν /cm ): 3181,
max
The products have low solubility and the 13C NMR data
have not been reported.
1
2
912, 2220, 1616, 1472. H NMR (300 MHz, DMSO-d ): δ
6
H
1
3

Journal of the Iranian Chemical Society
(
ppm) 2.66 (3H, s, SCH ), 7.67–7.80 (6H, m, H-Ar), 7.94 (2H,
5‑((4‑methylbenzylidene)
amino)‑3‑(methylthio)‑1H‑pyrazole‑4‑carbonitrile
(7b)
3
3
d, J = 6.1 Hz, H-Ar), 9.42 (1H, s, CH), 13.13 (1H, brs,
HH
+
NH). MS (EI): m/z 515 (M , 25), 512 (45), 487 (100). Anal.
Calcd for C H Br N S: C, 46.62; H, 2.54; N, 13.59. Found:
20
13
2
5
C, 46.48 ; H, 2.45; N, 13.47.
Light-yellow powder. Mp 165–167 °C. IR (KBr) (ν
/
max
−
1
cm ): 3469, 3135, 2992, 2925, 2214, 1597, 1545, 1489.
1
3
‑((4‑chlorobenzylidene)amino)‑2‑(4‑chloropheny
H NMR (300 MHz, CDCl ): δ (ppm) 2.46 (3H, s, CH ),
3
H
3
3
l)‑6‑(methylthio)‑1H‑imidazo[1,2‑b]pyrazole‑7‑car‑
2.64 (3H, s, SCH ), 7.32 (2H, d, J = 7.5 Hz, H-Ar), 7.85
3
HH
3
bonitrile (6f)
(2H, d, J = 7.5 Hz, H-Ar), 9.08 (2H, s, CH), 10.48 (1H,
HH
+
brs, NH). MS (EI): m/z 256 (M , 80), 238 (50), 130 (100).
−1
Yellow powder. Mp 301–303 °C. IR (KBr) (ν /cm ): 3184,
max
1
2
221, 1617, 1473. H NMR (300 MHz, DMSO-d ): δ (ppm)
5‑((4‑bromobenzylidene)
amino)‑3‑(methylthio)‑1H‑pyrazole‑4‑carbonitrile
(7c)
6
H
2
.66 (3H, s, SCH ), 7.53–8.03 (8H, m, H-Ar), 9.45 (1H, s,
3
+
CH), 13.15 (1H, s, NH). MS (EI): m/z 425 (M , 70), 378 (93),
3
52 (100).
Light-yellow powder. Mp 174–176 °C. IR (KBr) (ν
/
max
−
1
3
‑((4‑methoxybenzylidene)amino)‑2‑(4‑methox
cm ): 3283, 3131, 3065, 3000, 2927, 2839, 2219, 1609,
1
yphenyl)‑6‑(methylthio)‑1H‑imidazo[1,2‑b]pyra‑
1589, 1557, 1483. H NMR (300 MHz, DMSO-d ): δ
6
H
zole‑7‑carbonitrile (6g)
(ppm) 2.60 (3H, s, SCH ), 7.77–7.91 (4H, m, H-Ar), 8.97
3
+
(
1H, s, CH), 13.93 (1H, brs, NH). MS (EI): m/z 321 (M +
−
1
+
Yellow powder. Mp 270–272 °C. IR (KBr) (ν /cm ):
2, 60), 319 (M , 60), 287 (20), 194 (25), 89 (100).
max
1
3
416, 3171, 2925, 2826, 2219, 1611, 1514, 1460. H NMR
(
(
300 MHz, DMSO-d ): δ (ppm) 2.69 (3H, s, SCH ), 3.86
General procedure for the synthesis
of imidazo[1,2‑b]pyrazole (8)
6
H
3
6H, s, 2OCH ), 7.13–8.08 (8H, m, H-Ar), 9.57 (1H, s, CH),
3
+
1
2.98 (1H, brs, NH). MS (EI): m/z 417 (M , 40), 370 (100),
2
50 (65).
A mixture of pyrazole-imines 7 (1 mmol), aldehyde
(
1 mmol), TMSCN (1.2 mmol) in [Bmim]BF (0.5 g) was
4
ͦ
General procedure for the synthesis of pyra‑
zole‑imines (7)
heated at 120 C for 24 h. After cooling, the reaction mixture
was washed with water (5 mL) and the residue washed with
MeOH to afford pure product 8.
A mixture of 5-amino-1H-pyrazole (1 mmol), aldehyde
ͦ
(
1 mmol) in [Bmim]BF (0.5 g) was heated at 60 C for 30 min.
3‑(benzylideneamino)‑2‑(4‑chlorophenyl)‑6‑(methyl
thio)‑1H‑imidazo[1,2‑b]pyrazole‑7‑carbonitrile (8a)
4
After cooling, the reaction mixture was washed with water
(5 mL) and the residue was washed with CHCl to afford pure
3
−
1
product 7.
Yellow powder. Mp 284–286 °C. IR (KBr) (ν /cm ):
max
1
3
462, 3157, 2922, 2222, 1625 1475. H NMR (300 MHz,
5
‑((4‑chlorobenzylidene)
amino)‑3‑(methylthio)‑1H‑pyrazole‑4‑carbonitrile
7a)
DMSO-d ): δ (ppm) 2.68 (3H, s, SCH ), 7.46–8.11 (9H,
6 H 3
m, H-Ar), 9.62 (1H, s, CH), 13.22 (1H, brs, NH). MS (EI):
+
(
m/z 391 (M , 50), 344 (90), 91 (100). Anal. Calcd for
C H ClN S: C, 61.30; H, 3.60; N, 17.87. Found: C, 61.15;
20
14
5
−
1
Light-yellow powder. Mp 168–170 °C. IR (KBr) (ν /cm ):
H, 3.52; N, 17.99.
max
1
3
284, 3140, 3058, 2921, 2216, 1601, 1549, 1482. H NMR
(
(
300 MHz, DMSO-d ): δ (ppm) 2.61 (3H, s, SCH ), 7.64
2‑(4‑chlorophenyl)‑3‑((4‑methoxybenzylidene)
amino)‑6‑(methylthio)‑1H‑imidazo[1,2‑b]pyra‑
zole‑7‑carbonitrile(8b)
6
H
3
3
3
2H, d, J = 9.0 Hz, H-Ar), 8.01 (2H, d, J = 9.0 Hz,
HH
HH
H-Ar), 9.00 (1H, s, CH), 13.95 (1H, brs, NH). MS (EI):
+
m/z 276 (M , 100), 243 (30), 150 (50). Anal. Calcd for
−
1
C H ClN S: C, 52.08; H, 3.28; N, 20.25. Found: C, 52.15;
Yellow powder. Mp 287–289 °C. IR (KBr) (ν /cm ):
12
9
4
max
1
H, 3.23; N, 20.31.
3242, 3159, 2924, 2221, 1622, 1465. H NMR (300 MHz,
DMSO-d ): δ (ppm) 2.67 (3H, s, SCH ), 3.86 (3H, s,
6
H
3
3
3
OCH ), 7.06 (2H, d, J = 8.4 Hz, H-Ar), 7.58 (2H, d, J
3
HH
HH
3
=
8.4 Hz, H-Ar), 7.86 (2H, d, J = 8.4 Hz, H-Ar), 8.08
HH
3
(
2H, d, J = 8.4 Hz, H-Ar), 9.53 (1H, s, CH), 13.07 (1H,
HH
+
brs, NH). MS (EI): m/z 421 (M , 90), 348 (60), 287 (100).
1
3

Journal of the Iranian Chemical Society
3
‑(benzylideneamino)‑6‑(methylthio)‑2‑(p‑tolyl)‑1H
‑
imidazo[1,2‑b]pyrazole‑7‑carbonitrile (8c)
−
1
Yellow powder. Mp 292–294 °C. IR (KBr) (ν /cm ):
max
1
3
236, 3172, 2924, 2222, 1620, 1465. H NMR (300 MHz,
DMSO-d ): δ (ppm) 2.38 (3H, s, CH ), 2.68 (3H, s,
6
H
3
SCH ), 7.35–8.12 (9H, m, H-Ar), 9.61 (1H, brs, CH),
3
Scheme 1 Synthesis of 5-amino-1H-pyrazole 3
+
1
3.07 (1H, brs, NH). MS (EI): m/z 371 (M , 95), 324
(
100), 91 (85).
Table 1 Optimization of the reaction conditions
o
Yield (%)a
Entry
Solvent
Catalyst
Temperature ( C)
3‑((4‑chlorobenzylidene)amino)‑6‑(methylthio)‑2‑
(
(
p‑tolyl)‑1H‑imidazo[1,2‑b]pyrazole‑7‑carbonitrile
8d)
1
2
3
4
5
6
7
8
9
EtOH
MeOH
MeCN
H2O
[Bmim]BF4
[Bmim]BF4
[Bmim]BF4
[Bmim]BF4
[Bmim]BF4
[Bmim]BF4
[Bmim]BF4
[Bmim]BF4
–
–
–
–
–
80
Reflux
80
80
80
80
80
80
60
100
120
140
120
<10
<10
<10
Trace
20
18
21
16
Trace
46
63
59
−
1
Yellow powder. Mp 287–288 °C. IR (KBr) (ν /cm ):
max
1
3
469, 3171, 2925, 2220, 1613, 1473 H NMR (300 MHz,
–
I2
P-TSA
HCl
–
–
–
–
–
DMSO-d ): δ (ppm) 2.38 (3H, s, CH ), 2.67 (3H, s, SCH ),
6
H
3
3
7
.33–8.07 (8H, m, H-Ar), 9.53 (1H, s, CH), 13.07 (1H, brs,
+
NH). MS (EI): m/z 405 (M , 74), 358 (80), 332 (35), 137
(
100).
1
1
1
1
0
1
2
3
2
)
‑(4‑bromophenyl)‑3‑((4‑chlorobenzylidene)amino
‑6‑(methylthio)‑1H‑imidazo[1,2‑b]pyrazole‑7‑car‑
bonitrile (8e)
37
5
-amino-1H-pyrazole (1 mmol), 4-methylbenzaldehyde (2 mmol),
−
1
TMSCN (1.2 mmol)
Yellow powder. Mp 295–297 °C. IR (KBr) (ν /cm ):
max
1
a
Isolated yields
3
433, 3178, 2919, 2221, 1618, 1540, 1473. H NMR
(
300 MHz, DMSO-d ): δ (ppm) 2.67 (3H, s, SCH ),
6 H 3
7
.56–8.04 (8H, m, H-Ar), 9.50 (1H, s, CH), 13.20 (1H,
+
+
+
CH), 12.98 (1H, brs, NH). MS (EI): m/z 401 (M , 95), 328
100), 152 (55).
brs, NH). MS (EI): m/z 471 (M +2, 60), 469 (M , 60), 421
(
(
100).
3
‑((2‑chlorobenzylidene)amino)‑6‑(methylthio)‑2‑(p
Results and discussion
‑
tolyl)‑1H‑imidazo[1,2‑b]pyrazole‑7‑carbonitrile (8f)
First, the 5-amino-1H-pyrazole 3 was synthesized by the
reaction of 2-(bis(methylthio)methylene)malononitrile 1 and
hydrazine hydrate 2 (Scheme 1) [40].
−
1
Yellow powder. Mp 275–277 °C. IR (KBr) (ν /cm ):
max
1
3
416, 3173, 2912, 2219, 1614, 1454. H NMR (300 MHz,
DMSO-d ): δ (ppm) 2.39 (3H, s, CH ), 2.70 (3H, s, SCH ),
Then, a three-component reaction of 5-amino-1H-pyra-
zole 3, 4-methylbenzaldehyde 4b and TMSCN 5 was inves-
tigated in different solvents such as EtOH, MeOH, MeCN,
H O and in [Bmim]BF ionic liquid at 80 °C (Table 1,
6
H
3
3
7
.35–8.01 (8H, m, H-Ar), 9.56 (1H, s, CH), 13.19 (1H, brs,
+
NH). MS (EI): m/z 405 (M , 90), 358 (30), 281 (80), 125
(
100).
2
4
entries 1–4). The [Bmim]BF ionic liquid was found to be
4
the most suitable reaction media, providing 1H-imidazo[1,2-
3
‑((4‑methoxybenzylidene)amino)‑6‑(methylthio)‑2
(p‑tolyl)‑1H‑imidazo[1,2‑b]pyrazole‑7‑carbonitrile
b]pyrazole 6b in 20% yield (Entry 5). When the model reac-
‑
(
tion was performed in the presence of I , P-TSA and HCl as
2
8 g)
catalyst (entry 2), no improvement in the yield was detected
(
Entries 6–8). To optimize the reaction temperature, we also
−
1
Yellow powder. Mp 290–292 °C. IR (KBr) (ν /cm ):
max
performed some experiments at 60, 100, 120 and 140 °C
1
3
235, 3170, 2924, 2220, 1614, 1454. H NMR (300 MHz,
(
entries 8–12) in [Bmim]BF in the absence of catalyst. As
4
DMSO-d ): δ (ppm) 2.37 (3H, s, CH ), 2.67 (3H, s, SCH ),
6
H
3
3
can be seen from Table 1, the most suitable reaction temper-
3
.84 (3H, s, OCH ), 7.05–8.06 (8H, m, H-Ar), 9.53 (1H, s,
3
ature was 120 °C and the desired product 6b was obtained
1
3

Journal of the Iranian Chemical Society
Scheme 2 Synthesis of imidazo[1,2-b]pyrazole 6
Table 2 Synthesis of imidazo[1,2-b]pyrazole 6
Product 6
Ar
Yield (%)a
Yield (%)b
a
b
c
d
e
f
C H
4-Me–C H
2-Br–C H
2-Cl–C H
4-Br–C H
4-Cl–C H
4-OMe–C H
58
63
64
57
72
60
55
46
50
52
43
51
40
41
6
5
Scheme 4 Synthesis of imidazopyrazole 8
6
4
6
4
4
6
Table 3 Sequential two-step imination/GBB reaction
6
4
Yield (%)a
Product 8
Solvent
Catalyst
6
4
g
a
b
c
d
e
f
4-Cl–C H
C H
4-OMe–C H
C H
6 5
4-Cl–C H
4-Cl–C H
2-Cl–C H
4-OMe–C H
6
40
54
59
57
64
50
42
6
4
6
4
6
5
4-Cl–C H
a
6
4
6
4
Isolated yields for three-component reaction
4-Me–C H
b
6
4
4
Isolated yields for sequential double annulation reaction
4-Me–C H
6
6
4
4
4
4-Br–C H
6
4
6
4-Me–C H
6
4
4
6
g
4-Me–C H
6
4
aIsolated yields
the same isolated yields. Due to savings in time, solvent and
effort, sequential reactions can increase synthetic efficiency
and provide a positive environmental impact by reducing
chemical use.
Scheme 3 Sequential synthesis of imidazopyrazole 6
in 63% isolated yield (entry 10). When this reaction was
carried out without [Bmim]BF in neat conditions at 120 °C,
During the reaction optimization, it was found, when the
reaction of the 5-amino-1H-pyrazole 3, 4-methylbenzalde-
hyde 4b and TMSCN 5 was carried out at 60 °C, the prod-
uct 6b was not observed, while 1H-pyrazole-imine 7b was
obtained in 62% isolated yield (Scheme 4). To illustrate the
synthetic viability of our methodology, several 1H-pyrazole-
imines 7 were synthesized in 62–75% isolated yield at 60 °C
after 0.5 h (Scheme 4). The synthesized pyrazole-imines 7
could be a suitable substrate for the synthesis of imidazo-
pyrazole 8 with two different aryl groups. Therefore, the
synthetic utility of pyrazole-imines 7 was tested by employ-
ing in GBB reaction with aldehydes 4 and TMSCN 5 to
provide interesting imidazopyrazole with two different aryl
scaffolds 8 in good yields (Scheme 4). This pyrazole-imina-
tion reaction and GBB reaction approach can be systemati-
cally used for the synthesis of library of imidazopyrazoles 8
in a sequential three-step imination/GBB/imination reaction
(Table 3).
4
the yield of the product was 37% (entry 13).
Then, the scope of the three-component reaction was
examined using several substituted aldehydes containing
both electron-withdrawing and electron-donating group 4
(
Scheme 2 and Table 2) under the optimized reaction condi-
tions and the expected products 6 were obtained in 55–72%
isolated yields (Table 2).
After having successfully developed the methodology, a
sequential double annulation cascade protocol was examined
for the synthesis of imidazo[1,2-b]pyrazole 6 directly from
2
-(bis(methylthio)methylene)malononitrile 1 and hydrazine
hydrate 2 involving nuclephilic substitution/cyclization of
1
and TMSCN-based GBB reaction (Scheme 3). To our
delight, the one-pot sequential reaction afforded the desired
product 6 in 40–52% isolated yield (Table 2).
The comparison between the yield of three-component
reaction ([80× (55–72)]= 44–57%) with the total yield of
sequential double annulation reaction (40–52%) for imida-
zopyrazole 6 synthesis shows that both methods have almost
The imidazopyrazole 6 apparently results from the for-
mation of pyrazole-imine 7 (formed in situ by reaction of
1
3

Journal of the Iranian Chemical Society
Scheme 5 Proposed mechanism
5
-amino-1H-pyrazole 3 and aldehyde 4). Subsequent nucleo-
11. T. Kaur, D. Saha, N. Singh, U.P. Singh, A. Sharma, Chem.
Select. 3, 434 (2016)
philic reaction of TMSCN 5 and imine 7, intramolecular
1
2. T. Kaur, R.N. Gautam, A. Sharma, Chem. Asian J. 11, 2938
cyclization and prototropic shift afforded the intermediate
(
2016)
9
. Finally, the product was produced by the imine forma-
13. S. Shaaban, B.F. Abdel-Wahab, Mol. Divers. 20, 233 (2016)
14. S.K. Guchhait, C. Madaan, Tetrahedron Lett. 52, 56 (2011)
tion of intermediate 9 and second molecule of aldehyde 4
Scheme 5) [9, 17–23, 41, 42].
1
5. I. Akritopoulou-Zanze, B.D. Wakefield, A. Gasiecki, D. Kalvin,
E.F. Johnson, P. Kovar, S.W. Djuric, Bioorg. Med. Chem. Lett.
(
2
1, 1480 (2011)
1
6. A.T. Baviskar, C. Madaan, R. Preet, P. Mohapatra, V. Jain,
A. Agarwal, S.K. Guchhait, C.N. Kundu, U.C. Banerjee, P.V.
Bharatam, J. Med. Chem. 54, 5013 (2011)
Conclusions
1
1
7. J. Schwerkoske, T. Masquelin, T. Perun, C. Hulme, Tetrahedron
Lett. 46, 8355 (2005)
In this article, new and efficient GBB-based sequential cas-
cade reactions for the synthesis of imidazo[1,2-b]pyrazole
derivatives are developed from readily available starting
materials.
8. T. Masquelin, H. Bui, B. Brickley, G. Stephenson, J. Schwerko-
ske, C. Hulme, Tetrahedron Lett. 47, 2989 (2006)
19. E. Bell, A.Y. Shaw, F. De Moliner, C. Hulme, Tetrahedron 70,
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2
0. A.I. Polyakov, V.A. Eryomina, L.A. Medvedeva, N.I. Tihonova,
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Acknowledgements We gratefully acknowledge the financial support
from the Research Council of Shahid Beheshti University and the Iran
National Science Foundation (INSF) for the financial support of this
work.
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