Synthesis of N-alkyl-2-aryl-5 H-imidazo[1,2-b]pyrazol-3-amines by a three-component condensation reaction

Article abstract of DOI:10.1055/s-0030-1260154

An efficient method has been developed for the synthesis of a novel series of N-alkyl-2-aryl-5H-imidazo[1,2-b]pyrazol-3-amines in good-to-high yields by the three-component condensation of an aromatic aldehyde, an aminopyrazole, and an isocyanide in acetonitrile with 4-toluenesulfonic acid as a catalyst at room temperature. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1260154

PAPER
2913
Synthesis of N-Alkyl-2-aryl-5H-imidazo[1,2-b]pyrazol-3-amines by a Three-
Component Condensation Reaction
Synthesis of
5
H
-Im
b
idazo[1,2-
b
b
pyrazol-3-am
a
ines s Rahmati,* Meysam Alizadeh Kouzehrash
Department of Chemistry, University of Isfahan, P. O. Box 81746-73441, Isfahan, Iran
Fax 0098(311)6689732; E-mail: a.rahmati@sci.ui.ac.ir
Received 12 May 2011; revised 25 June 2011
of diseases.13 Additionally, some imidazopyrazoles have
Abstract: An efficient method has been developed for the synthesis
of a novel series of N-alkyl-2-aryl-5H-imidazo[1,2-b]pyrazol-3-
amines in good-to-high yields by the three-component condensa-
tion of an aromatic aldehyde, an aminopyrazole, and an isocyanide
been used as central nervous system agents.14 The devel-
opment of simple and rapid synthetic methods for these
derivatives is therefore an important aim in organic syn-
in acetonitrile with 4-toluenesulfonic acid as a catalyst at room tem- thesis.
perature.
A literature survey reveals that several methods have been
reported for the synthesis of imidazo[1,2-b]pyrazoles.13–15
These methods are based on multistep synthesis, and the
range of compounds that can be prepared is limited. Re-
cently, Groebke et al.16a and Blackburn et al.16b reported a
new three-component reaction in which various 2-ami-
noazines and aminoazoles were used to synthesize imida-
zole fused ring systems.17 Here, we report a multi-
component procedure for the synthesis of N-alkyl-2-aryl-
5H-imidazo[1,2-b]pyrazol-3-amines.
Key words: multicomponent reactions, condensation, heterocy-
cles, aldehydes, amines, polycycles
The discovery and design of new and simple methods for
generating useful organic compounds from available
chemicals lie at the heart of organic synthesis.1 One such
method involves the use of multicomponent reactions
(MCRs),2 which occupy an advantageous position be-
cause of their high atom economy, convergent character-
istics, and simple procedures.2 A particular subclass of
MCRs is that of isocyanide-based MCRs,3 and their de-
velopment is of particular interest to organic chemists.
In continuation of our investigations on MCRs of amino-
azoles,18 we have developed an efficient method for the
synthesis of N-alkyl-2-aryl-5H-imidazo[1,2-b]pyrazol-3-
amines 4 by a one-pot, three-component condensation re-
action of an aldehyde 1 and a pyrazole-3-amine 2 with an
isocyanide 3 in acetonitrile in the presence of 4-toluene-
sulfonic acid as a catalyst at room temperature
(Scheme 1).
Imidazopyrazoles, as unusual fused heterocyclic com-
pounds, are attractive compounds for drug discovery be-
cause many compounds incorporating these scaffolds
exhibit a wide range of biological, medicinal, and pharma-
ceutical activities, including antitumor activities,4 anti-in-
flammatory activities,5 antiviral activity against herpes
simplex virus type 1,6 and antineoplastic activity against
L1210 leukemia cells.7 In addition, some compounds of
this class show inhibitory effects on deoxyribonucleic
acid synthesis,8 MAP kinase,5 L1220 tumor-derived ribo-
nucleotide reductase,9 and ribonucleoside diphosphate re-
ductase,10 as well as synchronization of human lymphoid
cells and HeLa cells.11–12 Recently, other members of this
group of compounds have been shown to be useful as non-
steroidal agonists and antagonists of the androgen recep-
tor modulators that are useful in the treatment of a variety
To optimize the reaction conditions, we selected the reac-
tion of 4-chlorobenzaldehyde with 5-methylpyrazole-3-
amine and cyclohexyl isocyanide as a model reaction. The
aim of the first trial was to identify a suitable solvent for
the transformation, so we examined a series of solvents in-
cluding water (Table 1, entry 1), ethanol (entry 2), metha-
nol (entry 3), ethyl acetate (entry 4), dichloromethane
(entry 5), and acetonitrile (entry 6). Acetonitrile was iden-
tified as the optimal solvent for conducting the reaction at
room temperature. Moreover, we found that the presence
of an acidic catalyst was essential to obtain a high yield.
O
H
R1
NH2
N
TsOH
R2
R2
+
R3
NC
+
N
N
N
MeCN, r.t.
3–7 h
N
H
R1
H
NH
R3
4a–k
62–97%
1
2
3
Scheme 1 Synthesis of N-alkyl-2-aryl-5H-imidazo[1,2-b]pyrazol-3-amines 4
SYNTHESIS 2011, No. 18, pp 2913–2920
x
x.
x
x
.
2
0
1
1
Advanced online publication: 05.08.2011
DOI: 10.1055/s-0030-1260154; Art ID: N49511SS
© Georg Thieme Verlag Stuttgart · New York

2914
A. Rahmati, M. A. Kouzehrash
PAPER
Table 1 Synthesis of 2-(4-Chlorophenyl)-N-cyclohexyl-6-methyl-
5H-imidazo[1,2-b]pyrazol-3-amine in Various Solvents
Table 2 Effects of Various Catalysts on the Synthesis of 2-(4-Chlo-
rophenyl)-N-cyclohexyl-6-methyl-5H-imidazo[1,2-b]pyrazol-3-
amine
Entrya
Solvent
Temp (°C)
Yield (%)b
Entrya
Catalyst
MnCl2
Temp (°C)
Yield (%)b
r.t.
50
0
0
0
0
r.t.
50
28
28
1
H2O
1
75
(r.t.)c
r.t.
50
19
18
2
3
MgCl2
Sc(OTf)3
ZrCl4
r.t.
50
12
10
10
20
2
3
4
EtOH
r.t.
50
36
33
reflux
(r.t.)c
r.t.
50
30
32
r.t.
50
8
4
trace
trace
12
MeOH
MeCN
reflux
r.t.
50
21
19
(r.t.)c
5
HClO4
r.t.
50
35
32
30
73
montmorillonite
K-10
r.t.
50
24
22
6
reflux
(r.t.)c
r.t.
50
24
22
7
ZnCl2
r.t.
50
trace
trace
9
r.t.
50
26
25
5
6
EtOAc
CH2Cl2
8
AlCl3
reflux
(r.t.)c
35
r.t.
50
34
31
9
NH4Cl
r.t.
23
23
48
reflux
(r.t.)c
r.t.
50
27
38
10
11
12
[bmim]Brc
NH2SO3H
TsOH
a 4-Chlorobenzaldehyde (1 mmol), 5-methylpyrazole-3-amine (1
mmol), cyclohexyl isocyanide (1 mmol), solvent (5 mL), 8 h.
b Isolated yield.
r.t.
50
32
34
c 4-Chlorobenzaldehyde (1 mmol), 5-methylpyrazole-3-amine (1
mmol), cyclohexyl isocyanide (1 mmol), TsOH (0.3 mmol), solvent
(5 mL), 8 h.
r.t.
50
45
36
a 4-Chlorobenzaldehyde (1 mmol), 5-methylpyrazole-3-amine (1
mmol), cyclohexyl isocyanide (1 mmol), catalyst (0.1 mmol), MeCN
(5 mL), 8 h.
Furthermore, when high temperatures were used, the
yields decreased.
b Isolated yield.
Next, we attempted to identify the optimal catalyst by
screening 0.1 mmol quantities of a number of Lewis or
Brønsted acids (Table 2, entries 1–12). The experiments
showed that the highest yields were obtained with 4-tolu-
enesulfonic acid.
c 1-Butyl-3-methylimidazolium bromide.
withdrawing and electron-releasing substituted benzalde-
hydes, but did not do so with aliphatic aldehydes. Some
moderate increases in reaction yields were observed on in-
creasing the electron-withdrawing effect of substituents
on the benzaldehyde (Table 1, entries 1–4, 6, and 7),
whereas the presence of ortho-substituents decreased the
yield, probably as a result of greater steric hindrance (en-
tries 6 and 8). In a similar manner to the aldehydes, the
yield increased on increasing the electron-withdrawing
effect of substituents on the pyrazole ring (entries 4–6), al-
though this effect was more pronounced than that ob-
served with the substituted aldehydes. A different trend
was observed for the isocyanides, and the reaction did not
proceed with isocyanides 3c and 3d, and only the imine
was generated. The effect of the structure of the isocya-
nide was greater than that observed with the aldehyde or
pyrazole. Whereas the yields obtained by using the tertia-
ry isocyanide 3a were excellent, lower yields were ob-
tained with the secondary isocyanide 3b (Figure 1).
We then examined the efficiency of 4-toluenesulfonic
acid as a catalyst by studying the reaction in the presence
of various amounts of 4-toluenesulfonic acid in acetoni-
trile over a range of temperatures for various times
(Table 3). The best results were obtained in the presence
of 0.3 mmol of 4-toluenesulfonic acid at room tempera-
ture (entry 3). It is interesting to note that the yield of the
reaction was not significantly affected by increasing the
amount of 4-toluenesulfonic acid. The effects of the tem-
perature and the reaction time on the reaction yield were
also investigated, and the best results were obtained at
room temperature after five hours.
To explore the scope and limitations of the reaction, we
extended it to various substituted benzaldehydes and
pyrazole-3-amines in the presence of a range of isocya-
nides (Table 4). Both aromatic and aliphatic aldehydes
were examined. The reaction proceeded with electron-
Synthesis 2011, No. 18, 2913–2920 © Thieme Stuttgart · New York

PAPER
Synthesis of 5H-Imidazo[1,2-b]pyrazol-3-amines
2915
Another interesting feature of this reaction was observed
when 3-amino-1H-pyrazole-4-carbonitrile (1a; 2 equiv)
and cyclohexyl isocyanide (2a; 2 equiv) were added si-
multaneously to isophthalaldehyde; in this case, the reac-
tion proceeded as a pseudo five-component reaction to
give a good yield of 2,2¢-(1,3-phenylene)bis[3-(cyclohex-
ylamino)-5H-imidazo[1,2-b]pyrazole-7-carbonitrile] (5).
1H NMR and 13C NMR spectroscopic data showed that the
product 5 is not symmetric. It is possible that one of pyra-
zoloimidazole ring adopts an alternative tautomeric form
Table 3 Effects of the Reaction Time and the Amount of 4-Tolu-
enesulfonic Acid on the Yield of 4d
Entrya
[TsOH] (mmol) Temp (°C) Time (h) Yield (%)b
1.0
0.5
0.3
0.2
0.1
73
73
73
60
45
1
r.t.
8
8
reflux
50
r.t.
38
45
73
2
3
0.3
as
a result of intramolecular hydrogen bonding
(Scheme 2).
8
6
5
4
2
1
0.5
73
73
73
65
50
20
10
Reports on the Groebke–Blackburn three-component re-
action show that perchloric acid17c or zirconium(IV)
chloride17a,b can be used in syntheses of imidazo[1,2-
b]pyrazoles; however, yields from pyrazoles were low,
long reaction times were needed, and only one imida-
zo[1,2-b]pyrazole was synthesized. In addition, active
isocyanides, such as tert-butyl isocyanide, were needed to
produce imidazo[1,2-b]pyrazoles. When we used cyclo-
hexyl isocyanide in the presence of perchloric acid or zir-
conium(IV) chloride as the catalyst, the reactions showed
low yields (21 and 30%, respectively), confirming the ad-
vantages of our current method.
0.3
r.t.
a 4-Chlorobenzaldehyde (1 mmol), 5-methylpyrazol-3-amine (1
mmol), cyclohexyl isocyanide (1 mmol), MeCN (5 mL).
b Isolated yield.
O
O
NC
S
NC
NC
NC
>
>>
,
3a
3b
3c
3d
Figure 1 Structures of isocyanides
Table 4 Synthesis of N-Alkyl-2-aryl-5H-imidazo[1,2-b]pyrazol-3-amines 4
Entrya Aminopyrazole
Isocyanide
Aldehyde
Product
Time (h) Yield (%)b
N
N
N
N
NH2
NC
CHO
HN
N
1
6
65
62
67
73
N
N
NH
H
4a
CHO
NH2
NC
NC
NC
HN
N
2
7
5
6
N
N
NH
H
4b
CHO
NH2
HN
N
3
N
N
NH
Ph
H
Ph
4c
CHO
NH2
HN
N
4
N
N
NH
Cl
H
Cl
4d
Synthesis 2011, No. 18, 2913–2920 © Thieme Stuttgart · New York

2916
A. Rahmati, M. A. Kouzehrash
PAPER
Table 4 Synthesis of N-Alkyl-2-aryl-5H-imidazo[1,2-b]pyrazol-3-amines 4 (continued)
Entrya Aminopyrazole
Isocyanide
Aldehyde
Product
HN
Time (h) Yield (%)b
CHO
NH2
NC
N
N
5
5
70
N
N
NH
H
Cl
Cl
4e
CN
CHO
NC
NC
NC
NC
NH2
NC
NC
NC
N
HN
HN
HN
HN
N
6
7
8
9
5
5
6
3
84
86
79
94
N
N
H
NH
Cl
Cl
4f
CN
CHO
NH2
N
N
N
N
H
NH
O2N
NO2
4g
4h
CN
N
CHO
Cl
NH2
N
Cl
N
N
H
NH
Cl
Cl
CN
N
CHO
CHO
CHO
NH2
N
N
NC
NC
NC
N
H
NH
Br
Cl
Cl
Ph
4i
CN
N
NC
NH2
N
HN
10
11
3
4
97
90
N
N
H
NH
Cl
4j
CN
N
NC
NH2
N
HN
N
N
H
NH
Ph
4k
a Benzaldehyde (1 mmol), 3-aminopyrazole (1 mmol), isocyanide (1 mmol), solvent (5 mL), TsOH (0.3 mmol).
b Isolated yield.
There is no established mechanism for the formation of zo[1,2-b]pyrazol-3-amine. The reaction may proceed by
N-alkyl-2-aryl-5H-imidazo[1,2-b]pyrazol-3-amines; one the initial reaction of aldehyde 1 with the 3-aminopyra-
plausible mechanism is shown in Scheme 3 for the case zole 2 in the presence of 4-toluenesulfonic acid to give the
of 2-(4-chlorophenyl)-N-cyclohexyl-6-methyl-5H-imida- imine 6, which reacts with 4-toluenesulfonic acid to give
Synthesis 2011, No. 18, 2913–2920 © Thieme Stuttgart · New York

PAPER
Synthesis of 5H-Imidazo[1,2-b]pyrazol-3-amines
2917
3383, 3245 (NH), 2949 (CH2), 2226 (CN), 1620 (C=N),
1486 (bending CH2), 1208, and 1181 (C–N) cm–1, indicat-
ing the presence of these functional groups in the pro-
posed structure. The mass spectrum of 4i displayed
molecular ion peaks at m/z = 415 (81Br) and 413 (79Br),
which were consistent with a 1:1:1 adduct of the starting
materials with loss of water. The 1H NMR spectrum of 4i
exhibited a singlet for a C(CH3)3 group at d = 0.99 ppm
and two other singlets at d = 1.02 and 1.57 ppm for
C(CH3)2 and CH2 groups, respectively. The signal for the
NH proton appeared as a singlet at d = 4.30 ppm. A dou-
blet of doublets corresponding to the aromatic hydrogen
atoms appeared at d = 7.66 and 7.88 ppm with 3JHH = 8.80
Hz. Two singlet lines at d = 8.05 and 12.43 ppm could be
readily identified as arising from the CH and NH moieties
O
H
O
NH2
NC
NC
TsOH
H
+
+
2
2
N
MeCN, r.t.
24 h
N
H
2a
1a
3b
NC
N
H
N
N
N
H
NH
N
N
N
H
NC
5
Scheme 2 Pseudo five-component reaction
1
in the pyrazole ring. The H decoupled 13C NMR spec-
trum of 4i showed 15 distinct resonances, in agreement
with the suggested structures. The 1H and 13C NMR spec-
tra of the related compounds 4 are similar to those of 4i,
except for the R1, R2, and R3 groups, which exhibit char-
acteristic signals with appropriate chemical shifts. As a re-
sult of proton exchange, the NH signal from the pyrazole
ring was not observed in the 1H NMR spectra of some of
the products.
the iminopyrazolium salt 7. This, in turn, is converted into
the intermediate 8 by a [4 + 1] cycloaddition of isocyanide
3. Intermediate 8 undergoes proton elimination to form
imine 9. Finally, a 1,3-prototropic shift of compound 9
gives the imidazopyrazolamines 4 (Scheme 3).
Cl
CHO
To summarize, we have developed an efficient three-com-
ponent condensation reaction of typical aldehydes, 3-ami-
nopyrazoles, and isocyanides for the synthesis of N-alkyl-
2-aryl-5H-imidazo[1,2-b]pyrazol-3-amines. The simple
one-pot nature of the reaction makes it an interesting alter-
native to other multistep approaches. Among the advan-
tages of the method compared with previous methods are
the excellent yield of products and the short reaction
times.
NH2
N
TsOH
– H2O
+
N
N
N
H
N
H
Cl
1
2
6
Cl
Cl
–C N+
N
N
TsOH
N+
3
C
NH
N
+
H
••
N
H
N
H
Melting points were determined on an Electrothermal 9100 appara-
tus. IR spectra were recorded on a Shimadzu IR-470 spectropho-
7
7
–
tometer. H NMR and 13C NMR spectra were recorded with a
–
1
TsO
TsO
Bruker DRX-400 Avance (topspin) spectrometer at 400 MHz and
100 MHz, respectively. Mass spectra were recorded on a Shimadzu
QP1100 EX mass spectrometer operating at an ionization potential
of 70 eV. Elemental analyses were performed using a Heraeus
CHNS Rapid Analyzer.
Cl
Cl
N
N
N
TsOH
+
N
N
H
N
N
N
N-Alkyl-2-aryl-5 H-imidazo[1,2-b]pyrazol-3-amines (4a–k);
General Procedure
H
H
–
8
9
TsO
A soln of the isocyanide (1 mmol), the aldehyde (1 mmol), the 3-
aminopyrazole (1 mmol), and TsOH (0.3 mmol) in MeCN (5 mL)
was stirred for 3–8 h at r.t. When the reaction was complete [TLC,
EtOAc–hexane (1:2)], the solvent was removed by evaporation in
vacuum. The residue was washed with water and crystallized
(MeOH).
Cl
N
N
HN
N
N-Cyclohexyl-6-methyl-2-phenyl-5 H-imidazo[1,2-b]pyrazol-3-
amine (4a)
Yellow powder; yield: 65%; mp 185–188 °C.
H
4
Scheme 3 Mechanism of the three-component reaction
IR (KBr): 3437, 3064, 2928, 2853, 1673, 1596, 1444, 1335, 1274
cm–1.
1H NMR (400 MHz, CDCl3): d = 1.28–1.92 (m, 10 H, 5CH2), 2.14
(s, 3 H, CH3), 4.71 (m, 1 H, CH), 5.50 (br s, 1 H, NH), 7.28–7.50
(m, 4 H, 1CHpyrazole and 3CHarom), 8.43 (br s, 2 H, 2CHarom).
The structures of products 4a–k and 5 were deduced from
their IR, 1H NMR, 13C NMR, mass spectra and by elemen-
tal analysis. The IR spectrum of 4i showed absorptions at
Synthesis 2011, No. 18, 2913–2920 © Thieme Stuttgart · New York

2918
A. Rahmati, M. A. Kouzehrash
PAPER
13C NMR (100 MHz, CDCl3): d = 14.16, 24.13, 25.84, 33.06, 58.62,
111.16, 126.82, 128.23, 128.37, 128.44, 128.65, 129.71, 131.22,
156.92.
6-tert-Butyl-2-(4-chlorophenyl)-N-cyclohexyl-5H-imidazo[1,2-
b]pyrazol-3-amine (4e)
Yellow powder; yield: 70%; mp 196–198 °C.
MS (EI, 70 eV): m/z (%) = 294 (4.58) [M+], 292 (9.30), 263 (13.50),
209 (11.33), 184 (30.50), 115 (23.83), 105 (32.67), 83 (30.17), 77
(88.67), 67 (40.33), 55 (100).
IR (KBr): 3316, 2929, 2853, 2735, 1605, 1499, 1467, 1233, 1153
cm–1.
1H NMR (400 MHz, DMSO-d6), d = 1.16–1.21 (m, 6 H, 3CH2), 1.37
(s, 9 H, 3CH3), 1.50–1.75 (m, 4 H, 2CH2), 3.07 (m, 1 H, CH), 6.10
(br s, 1 H, NH), 7.12 (s, 1 H, CHpyrazole), 7.57 (d, 3J = 8.8 Hz, 2 H,
Anal. Calcd for C18H22N4: C, 73.44; H, 7.53; N, 19.03. Found: C,
73.65; H, 7.47; N, 19.15.
3
2CHarom), 7.90 (d, J = 8.8 Hz, 2 H, 2CHarom), 12.43 (br s, 1 H,
N-Cyclohexyl-6-methyl-2-(4-methylphenyl)-5H-imidazo[1,2-
b]pyrazol-3-amine (4b)
Yellow powder; yield: 62%; mp 190–192 °C.
IR (KBr): 3430, 2927, 2853, 1666, 1513, 1437, 1336, 1273 cm–1.
NHpyrazole).
13C NMR (75 MHz, DMSO-d6): d = 24.92, 25.37, 29.56, 32.61,
33.25, 57.19, 84.63, 122.04, 123.96, 127.15, 127.39, 128.76,
133.42, 138.06, 160.75.
1H NMR (400 MHz, CDCl3): d = 1.34–1.90 (m, 10 H, 5CH2), 2.13
MS (EI, 70 eV): m/z (%) = 372 (20.13) [M + 2]+, 370 (65.41) [M+],
368 (40.25), 314 (21.54), 313 (37.26), 312 (40.88), 311 (65.41), 262
(17.30), 260 (29.87), 246 (15.09), 244 (31.92), 138 (15.41), 93
(15.88), 79 (32.39), 77 (76.73), 67 (83.02), 55 (100).
(s, 3 H, CH3), 2.39 (s, 3 H, CH3), 4.68 (m, 1 H, CH), 5.51 (s, 1 H,
3
NH), 7.14 (s, 1 H, CHpyrazole), 7.19 (d, J = 8.0 Hz, 2 H, 2CHarom),
8.33 (d, 3J = 8.0 Hz, 2 H, 2CHarom).
13C NMR (100 MHz, CDCl3): d = 14.29, 21.71, 24.14, 25.88, 33.09,
58.50, 111.02, 128.50, 129.05, 129.20, 129.71, 137.11, 142.05,
157.07, 165.17.
Anal. Calcd for C21H27ClN4: C, 68.00; H, 7.34; N, 15.10. Found: C,
67.84; H, 7.42; N, 14.99.
2-(4-Chlorophenyl)-3-(cyclohexylamino)-5H-imidazo[1,2-
b]pyrazole-7-carbonitrile (4f)
Yellow powder; yield: 84%; mp 263–265 °C.
IR (KBr): 3210, 2928, 2853, 2224, 1619, 1487, 1447, 1170 cm–1.
1H NMR (400 MHz, DMSO-d6), d = 1.12–1.77 (m, 10 H, 5CH2),
3.35 (m, 1 H, CH), 4.86 (d, 3J = 5.20 Hz, NHamine), 7.53 (d, 3J = 8.0
Hz, 2 H, 2CHarom), 7.92 (d, 3J = 7.6 Hz, 2 H, 2CHarom), 8.06 (s, 1 H,
CHpyrazole), 12.34 (br s, 1 H, NHpyrazole).
MS (EI, 70 eV): m/z (%) = 308 (2.12) [M+], 306 (10.32), 223
(29.36), 198 (63.76), 118 (16.78), 91 (23.49), 83 (43.62), 77
(24.33), 67 (44.30), 55 (100).
Anal. Calcd for C19H24N4: C, 73.99; H, 7.84; N, 18.17. Found: C,
74.18; H, 7.97; N, 18.33.
2-Biphenyl-4-yl-N-cyclohexyl-6-methyl-5H-imidazo[1,2-
b]pyrazol-3-amine (4c)
Yellow powder; yield: 67%; mp 186–188 °C.
IR (KBr): 3437, 3029, 2928, 2853, 1672, 1560, 1484, 1274 cm–1.
13C NMR (100 MHz, DMSO-d6): d = 24.67, 25.86, 33.55, 54.77,
65.85, 115.63, 120.01, 125.13, 127.48, 129.13, 129.37, 131.96,
138.84, 146.33.
MS (EI, 70 eV): m/z (%) = 341 (12.71) [M + 2]+, 339 (38.02) [M+],
259 (20.25), 257 (58.68), 232 (27.69), 230 (81.82), 195 (39.67), 140
(8.06), 138 (21.90), 67 (34.09), 55 (100).
1H NMR (400 MHz, CDCl3): d = 1.29–1.97 (m, 10 H, 5CH2), 2.24
(s, 3 H, CH3), 4.76 (m, 1 H, CH), 5.51 (s, 1 H, NH), 7.38–7.70 (m,
8 H, 7CHarom and 1CHpyrazole), 8.33 (d, 3J = 8.0 Hz, 2 H, 2CHarom).
13C NMR (100 MHz, CDCl3): d = 14.26, 24.18, 25.88, 33.14, 58.69,
111.13, 126.95, 127.24, 127.93, 128.98, 129.12, 130.20, 130.79,
140.30, 141.33, 144.04, 156.96, 164.81.
Anal. Calcd for C18H18ClN5: C, 63.62; H, 5.34; N, 20.61. Found: C,
63.78; H, 5.45; N, 20.56.
MS (EI, 70 eV): m/z (%) = 370 (3.32) [M+], 327 (6.17), 291 (2.47),
263 (5.17), 217 (7.56), 177 (11.34), 115 (14.58), 103 (16.51), 97
(17.60), 91 (11.42), 79 (16.67), 77 (50.31), 67 (44.14), 55 (100).
3-(Cyclohexylamino)-2-(4-nitrophenyl)-5H-imidazo[1,2-
b]pyrazole-7-carbonitrile (4g)
Orange powder; yield: 86%; mp 289–292 °C.
Anal. Calcd for C24H26N4: C, 77.80; H, 7.07; N, 15.12. Found: C,
77.58; H, 6.91; N, 15.34.
IR (KBr): 3329, 3196, 2930, 2858, 2220, 1625, 1469, 1411, 1336,
1112 cm–1.
2-(4-Chlorophenyl)-N-cyclohexyl-6-methyl-5H-imidazo[1,2-
b]pyrazol-3-amine (4d)
Yellow powder; yield: 73%; mp 208–210 °C.
IR (KBr): 3437, 2928, 2854, 1664, 1482, 1241, 1154 cm–1.
1H NMR (400 MHz, DMSO-d6), d = 1.26–1.82 (m, 10 H, 5CH2),
3
3.49–3.53 (m, 1 H, CH), 5.28 (d, J = 6.4 Hz, NHamine), 8.08 (d,
3J = 11.6 Hz, 2 H, 2CHarom), 8.10 (s, 1 H, CHpyrazole), 8.27 (d,
3J = 11.6 Hz, 2 H, 2CHarom), 12.50 (br s, 1 H, NHpyrazole).
13C NMR (100 MHz, DMSO-d6): d = 24.80, 25.87, 33.71, 54.72,
65.92, 115.39, 117.50, 124.45, 125.56, 127.86, 137.05, 139.82,
145.39, 147.19.
MS (EI, 70 eV): m/z (%) = 350 (16.52) [M+], 348 (23.60) [M – 2]+,
318 (13.95), 268 (23.83), 240 (27.34), 210 (28.67), 83 (30.33), 67
(39.92), 55 (100).
1H NMR (400 MHz, CDCl3): d = 1.26–1.89 (m, 10 H, 5CH2), 2.14
(s, 3 H, CH3), 4.67 (m, 1 H, CH), 5.43 (s, 1 H, NH), 7.32 (s, 1 H,
CHpyrazole), 7.36 (d, 3J = 8.4 Hz, 2 H, 2CHarom), 8.37 (d, 3J = 8.4 Hz,
2 H, 2CHarom).
13C NMR (100 MHz, CDCl3): d = 14.13, 24.13, 25.79, 33.07, 58.80,
110.87, 128.64, 130.94, 138.11, 138.52, 140.96, 155.24, 156.73,
164.09.
MS (EI, 70 eV): m/z (%) = 328 (3.30) [M+], 326 (3.30) [M – 2]+, 220
(3.38), 218 (8.37), 207 (14.95), 193 (4.70), 191 (8.63), 85 (13.66),
83 (27.36), 67 (37.87), 57 (63.54), 55 (100).
Anal. Calcd for C18H18N6O2: C, 61.70; H, 5.18; N, 23.99. Found: C,
61.95; H, 5.06; N, 24.08.
3-(Cyclohexylamino)-2-(2,4-dichlorophenyl)-5H-imidazo[1,2-
b]pyrazole-7-carbonitrile (4h)
White powder; yield: 79%; mp 283–285 °C.
Anal. Calcd for C18H21ClN4: C, 65.74; H, 6.44; N, 17.04. Found: C,
65.92; H, 6.53; N, 16.58.
IR (KBr): 3374, 3246, 2930, 2854, 2236, 1685, 1638, 1530, 1212,
1125 cm–1.
Synthesis 2011, No. 18, 2913–2920 © Thieme Stuttgart · New York

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Synthesis of 5H-Imidazo[1,2-b]pyrazol-3-amines
2919
1H NMR (400 MHz, DMSO-d6), d = 1.09–1.75 (m, 10 H, 5CH2),
3.57–3.63 (m, 1 H, CH), 5.49 (d, 3J = 4.4 Hz, 1 H, NHamine), 7.11 (d,
3J = 7.6 Hz, 1 H, CHarom), 7.49 (s, 1 H, CHarom), 7.99 (d, 3J = 7.6 Hz,
1 H, CHarom), 8.11 (s, 1 H, CHpyrazole).
13C NMR (100 MHz, DMSO-d6): d = 24.88, 25.62, 32.50, 48.35,
58.24, 115.22, 125.96, 127.62, 128.50, 129.04, 130.86, 133.16,
134.85, 136.66, 146.11, 168.45.
MS (EI, 70 eV): m/z (%) = 411 (5.25) [M+], 340 (2.17), 299 (34.30),
272 (13.62), 180 (26.34), 77 (9.13), 69 (25.64), 57 (100).
Anal. Calcd for C26H29N5: C, 75.88; H, 7.10; N, 17.02; Found: C,
75.96; H, 7.21; N, 17.08.
2,2¢-(1,3-Phenylene)bis[3-(cyclohexylamino)-5H-imidazo[1,2-
b]pyrazole-7-carbonitrile] (5)
Yellow powder; yield: 68%; mp 372–375 °C.
MS (EI, 70 eV): m/z (%) = 377 (4.34) [M + 4]+, 375 (9.95) [M + 2]+,
373 (9.49) [M+], 360 (17.77), 268 (19.84), 267 (36.69), 266 (73.61),
265 (57.40), 264 (81.37), 232 (36.83), 230 (78.59), 228 (65.12), 120
(40.83), 118 (68.05), 94 (29.59), 82 (51.48), 67 (31.07), 63 (41.42),
55 (100).
IR (KBr): 3260, 3227, 2929, 2855, 2215, 1646, 1564, 1448, 1332,
1207 cm–1.
1H NMR (400 MHz, DMSO-d6), d = 1.24–1.178 (m, 20 H, 10CH2),
3.34–3.53 (m, 2 H, 2CH), 4.77 (d, 3J = 6.4 Hz, 1 H, NHamine), 5.23
3
Anal. Calcd for C18H17Cl2N5: C, 57.76; H, 4.58; N, 18.71; Found:
C, 57.49; H, 4.45; N, 18.56.
(d, J = 6.3 Hz, 1 H, NHamine), 7.42 (m, 1 H, CHarom), 7.73 (d,
3J = 6.8 Hz, 2 H, 2CHarom), 8.00 (s, 1 H, CHpyrazole), 8.05 (s, 1 H,
CHpyrazole), 8.21 (s, 1 H, CHarom), 12.26 (s, 1 H, NHpyrazole), 12.53 (s,
1 H, NHpyrazole).
2-(4-Bromophenyl)-3-[(1,1,3,3-tetramethylbutyl)amino]-5H-
imidazo[1,2-b]pyrazole-7-carbonitrile (4i)
Yellow powder; yield: 94%; mp 216–219 °C.
13C NMR (100 MHz, DMSO-d6): d = 24.87, 24.91, 25.60, 25.76,
32.62, 33.57, 48.14, 54.97, 60.71, 65.76, 115.45, 115.75, 120.38,
124.23, 124.80, 125.00, 126.59, 128.90, 128.92, 130.15, 135.81,
138.66, 140.73, 146.18, 156.46, 169.88.
IR (KBr): 3383, 3245, 2949, 2226, 1620, 1486, 1365, 1208, 1181
cm–1.
1H NMR (400 MHz, DMSO-d6): d = 0.99 (s, 9 H, 3CH3), 1.02 (s, 6
MS (EI, 70 eV): m/z (%) = 532 (3.67) [M+], 357 (2.06), 206 (2.08),
191 (4.55), 127 (11.27), 119 (11.93), 105 (23.39), 91 (27.27), 85
(11.74), 83 (18.94), 69 (43.94), 57 (93.56), 55 (100).
H, 2CH3), 1.57 (s, 2 H, CH2), 4.30 (s, 1 H, NHamine), 7.66 (d,
3
3J = 8.80 Hz, 2 H, 2CHarom), 7.88 (d, J = 8.80 Hz, 2 H, 2CHarom),
8.05 (s, 1 H, CHpyrazole), 12.43 (s, 1 H, NHpyrazole).
Anal. Calcd for C30H32N10: C, 67.65; H, 6.06; N, 26.30; Found: C,
67.84; H, 5.99; N, 26.44.
13C NMR (100 MHz, DMSO-d6): d = 29.44, 31.75, 32.04, 55.85,
59.35, 65.77, 115.63, 121.20, 123.27, 124.49, 129.10, 129.84,
131.83, 138.85, 145.81.
MS (EI, 70 eV): m/z (%) = 415 (2.62) [M + 2]+, 413 (3.43) [M+],
301 (16.61), 303 (3.20), 184 (10.20), 182 (10.34), 159 (3.56), 157
(3.32), 57 (100).
Acknowledgment
We gratefully acknowledge financial support from the Research
Council of the University of Isfahan.
Anal. Calcd for C20H24BrN5: C, 57.97; H, 5.84; N, 16.90. Found: C,
58.11; H, 5.92; N, 17.06.
References
2-(4-Chlorophenyl)-3-[(1,1,3,3-tetramethylbutyl)amino]-5H-
imidazo[1,2-b]pyrazole-7-carbonitrile (4j)
Yellow powder; yield: 97%; mp 207–209 °C.
IR (KBr): 3330, 3163, 2952, 2219, 1629, 1498, 1368, 1189 cm–1.
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1H NMR (400 MHz, DMSO-d6): d = 0.99 (s, 9 H, 3CH3), 1.02 (s, 6
H, 2CH3), 1.58 (s, 2 H, CH2), 4.31 (s, 1 H, NHamine), 7.52 (d,
3
3J = 8.80 Hz, 2 H, 2CHarom), 7.95 (d, J = 8.80 Hz, 2 H, 2CHarom),
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59.33, 65.76, 115.64, 123.25, 124.47, 128.86, 128.92, 129.47,
132.62, 138.84, 145.79.
MS (EI, 70 eV): m/z (%) = 371 (2.37) [M + 2]+, 369 (7.10) [M+],
259 (26.58), 257 (74.27), 232 (24.03), 230 (73.30), 195 (26.82), 140
(8.47), 138 (22.09), 97 (41.26), 57 (100).
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65.03; H, 6.69; N, 19.08.
2-Biphenyl-4-yl-3-[(1,1,3,3-tetramethylbutyl)amino]-5H-imida-
zo[1,2-b]pyrazole-7-carbonitrile (4k)
Yellow powder; yield: 90%; mp 228–230 °C.
IR (KBr): 3420, 3107, 2952, 2214, 1610, 1487, 1199, 1179 cm–1.
1H NMR (300 MHz, DMSO-d6), d = 1.01 (s, 9 H, 3CH3), 1.06 (s, 6
H, 2CH3), 1.62 (s, 2 H, CH2), 4.33 (s, 1 H, NHamine), 7.37–8.03 (m,
9 H, 9CHarom), 8.06 (s, 1 H, CHpyrazole), 12.42 (br s, 1 H, NHpyrazole).
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66.25, 115.69, 122.72, 124.87, 126.91, 126.92, 127.27, 127.53,
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Synthesis 2011, No. 18, 2913–2920 © Thieme Stuttgart · New York