A novel synthesis of new 2-aryl-6-(arylamino)-1H-imidazo[1,2-b]pyrazole-7-carbonitrile derivatives

Article abstract of DOI:10.1016/j.tetlet.2014.10.061

New 2-aryl-6-(arylamino)-1H-imidazo[1,2-b]pyrazole-7-carbonitriles are synthesized in good yields, via cyclocondensation of 5-amino-1-(2-oxo-2-arylethyl)-3-(arylamino)-1H-pyrazole-4-carbonitriles, which are prepared by the reaction of 5-amino-3-arylamino-

Full text of DOI:10.1016/j.tetlet.2014.10.061

Accepted Manuscript
A novel synthesis of new 2-aryl-6-(arylamino)-1H-imidazo[1,2-b]pyrazole-7-
carbonitrile derivatives
Jabbar Khalafy, Ahmad Poursattar Marjani, Fatemeh Salami
PII:
S0040-4039(14)01744-4
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.10.061
TETL 45290
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
13 August 2014
1 October 2014
9 October 2014
Please cite this article as: Khalafy, J., Marjani, A.P., Salami, F., A novel synthesis of new 2-aryl-6-
(
arylamino)-1H-imidazo[1,2-b]pyrazole-7-carbonitrile derivatives, Tetrahedron Letters (2014), doi: http://
dx.doi.org/10.1016/j.tetlet.2014.10.061
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Graphical Abstract
A novel synthesis of new 2-aryl-6-(arylamino)-1H-imidazo[1,2-b]pyrazole-7-carbonitrile
derivatives
Jabbar Khalafy, Ahmad Poursattar Marjani, Fatemeh Salami

Tetrahedron Letters
journal homepage: www.elsevier.com
A novel synthesis of new 2-aryl-6-(arylamino)-1H-imidazo[1,2-b]pyrazole-7-
carbonitrile derivatives
Jabbar Khalafy*, Ahmad Poursattar Marjani, Fatemeh Salami
Departement of Chemistry, Faculty of Science, Urmia University, Urmia 57154, Iran
*
Email: jkhalafi@yahoo.com; j.khalafi@urmia.ac.ir
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
New 2-aryl-6-(arylamino)-1H-imidazo[1,2-b]pyrazole-7-carbonitriles are synthesized in good
yields, via cyclocondensation of 5-amino-1-(2-oxo-2-arylethyl)-3-(arylamino)-1H-pyrazole-4-
carbonitriles, which are prepared by the reaction of 5-amino-3-arylamino-1H-pyrazole-4-
2 3
carbonitriles and α-bromoacetophenone derivatives in the presence of K CO using acetone as
Available online
the solvent.
2
014 Elsevier Ltd. All rights reserved.
Keywords:
1
H-imidazo[1,2-b]pyrazole
Cyclocondensation,
-Amino-1H-Pyrazoles
5
α-Bromoacetophenones
The development of new methods for the synthesis of
nitrogen-containing heterocycles is very important in organic
chemistry. Among various biheterocyclic compounds, bicyclic
imidazo[1,2-b]pyrazoles exhibit a wide range of biological and
1
-3
4
pharmaceutical activities such as antitumor, herbicidal, anti-
5
6
7
inflammatory, antiviral and antineoplastic activities.
Despite there being many literature reports on the synthesis of
fused pyrazole derivatives, imidazopyrazoles have rarely been
reported. However, there are a variety of methods for the
8
-21
synthesis of imidazo[1,2-b]pyrazoles,
among which, many
involve tedious and time-consuming multi-step procedures.
As part of our studies on the synthesis of tri- and tetracyclic
2
2-25
heterocycles,
herein we report a facile method for the
synthesis of new derivatives of 1H-imidazo[1,2-b]pyrazole (5a-
h) with possible pharmaceutical applications. The synthetic
procedure involves the cyclocondensation of 5-amino-1-(2-oxo-
2
-arylethyl)-3-(arylamino)-1H-pyrazole-4-carbonitriles
which were prepared by the reaction of 5-amino-3-arylamino-1H-
pyrazole-4-carbonitriles 3a-f and α-bromoacetophenone
derivative 2a,b in the presence of K CO using acetone as the
4a-h,
Scheme 1. Synthesis of 2-aryl-6-(arylamino)-1H- imidazo[1,2-
b]pyrazole-7-carbonitiles 5a-h
2
3
Eight examples of the conversion of α-bromoacetophenones
solvent.
2
a,b into the corresponding substituted 5-amino-1-(2-oxo-2-
arylethyl)-3-(arylamino)-1H-pyrazole-4-carbonitriles 4a-h and 2-
aryl-6-(arylamino)-1H-imidazo[1,2-b]pyrazole-7-carbonitiles 5a-
h along with reaction conditions, reaction times, melting points
and yields are listed in Tables 1 and 2, respectively.
Bromination of acetophenones 1a,b in Br /AcOH gave the
2
2
6
corresponding α-bromoacetophenones 2a,b.
Although the
synthesis of 5-amino-3-arylamino-1H-pyrazole-4-carbonitriles
2
7
3
a-f derivaties have been reported, we prepared these by a
28
different method. Reaction of α-bromoacetophenones 2a,b with
pyrazole derivatives 3a-f gave the corresponding pyrazole
intermediates (4a-h). Finally, cyclocondensation of compounds
4
a-h by refluxing in ethanol in the presence of hydrochloric acid
gave the desired products 5a-h in 78-93% yields (Scheme 1).

2
Tetrahedron Letters
Table 1. The physical properties and reaction conditions for
the synthesis of compounds 4a-h
Table 2. The physical properties, yields and reaction times for
the synthesis of compounds 5a-h
o
Entry
Intermediate
Temp
Time (h)
Entry
Product
Time (h)
Mp ( C)
Yield (%)
2
65-266
dec.)
1
reflux
1
1
1.5
85
(
4
a
5a
2
85-286
2
3
4
reflux
1
2
1
93
(dec.)
4
b
5
b
r.t
8
330
3
4
1
1
84
78
(dec.)
4
c
5
c
2
80
r.t
10
(dec.)
5
d
4
d
2
68-270
(dec.)
5
6
7
0.5
0.75
1
90
88
90
5
r.t
4
5
e
4
e
2
75
(dec.)
6
r.t
4.5
5
f
4
f
2
96-298
dec.)
(
7
r.t
7
5
g
4
g
8
2
249
83
8
reflux
2
5
h
4
h

The proposed mechanisms for the sequence are shown in
Scheme 2. The first step involves the attack of the endocyclic
Synthesis of derivatives 4b-h:
nitrogen
atom
of
5-amino-3-arylamino-1H-pyrazole-4-
The reaction procedure was as described for 4a, but the
reaction time and conditions were as those reported in Table 1.
Only the intermediate 4a was isolated in pure form and its
structure was determined by FT-IR, H NMR, C NMR and
elemental analysis. The other intermediates were not isolated and
the subsequent reactions was carried out following evaporation of
the solvent and addition of EtOH to the residue.
carbonitrile 3a-f, which is more nucleophilic due to the electron-
withdrawing effect of the pyrazole ring, onto α-
bromoacetophenone 2a,b to form intermediates 4a-h. These are
converted into the desired products 5a-h through intramolecular
cyclocondensation of the amino and carbonyl groups.
1
13
General procedure for the synthesis of 2-aryl-6-
(arylamino)-1H-imidazo[1,2-b]pyrazole-7-carbonitiles 5a-h:
Synthesis of 2-phenyl-6-(phenylamino)-1H-imidazo[1,2-
b]pyrazole-7-carbonitrile (5a):
A
suspension
of
5-amino-1-(2-oxo-2-phenylethyl)-3-
(phenylamino)-1H-pyrazole-4-carbonitrile (4a) (317 mg,
1
mmol) in absolute EtOH (15 mL) and concentrated HCl (4 drops)
was refluxed for 1.5 h. The mixture was cooled to room
temperature and poured in cold H O (30 mL). The pH of solution
2
was adjusted to 7-8 by addition of dilute NaOH and the
precipitate was filtered and washed with cold H O (3×5 mL) and
2
dried to give the cyclocondensation product 5a as a white solid,
o
Mp. 265-266 (dec.) C.
Scheme 2. The proposed reaction mechanisms for the
formation of 4a-h and 5a-h.
-1
FT-IR (KBr) (νmax, cm ): 3235, 3201, 3161, 3072, 2204,
622, 1555, 1482, 1301, 692. H NMR (400 MHz, DMSO-d ) δ
ppm): 12.74 (1H, br s, NH, exchanged by D O addition), 8.88
1H, s, NH, exchanged by D O addition), 8.22 (1H, s, arom),
.74 (2H, d, J = 8 Hz, arom), 7.59 (2H, d, J = 8.4 Hz, arom), 7.46
2H, t, J = 7.6 Hz, arom), 7.34 (1H, t, J = 7.2 Hz, arom), 7.26
2H, t, J = 7.6 Hz, arom), 6.84 (1H, t, J = 7.2 Hz, arom).
NMR (100 MHz, DMSO-d ) δ (ppm): 156.32, 142.03, 140.70,
1
1
(
(
7
(
(
6
H
1
The structures of all products were confirmed from their H
2
1
3
NMR, C NMR and FT-IR spectral data and by elemental
analysis.
2
1
3
In summary, we have described a convenient and facile
synthesis of 2-aryl-6-(arylamino)-1H-imidazo[1,2-b]pyrazole-7-
carbonitriles by reaction of 5-amino-3-arylamino-1H-pyrazole-4-
carbonitriles with α-bromoacetophenones in the presence of
C
6
C
1
1
30.31, 129.12, 129.08, 128.69, 127.93, 124.24, 120.02, 116.82,
15.29, 106.32, 55.57. Anal. Calcd for C H N : C, 72.23; H,
4.38; N, 23.40. Found: C, 72.32; H, 4.21; N, 23.49.
1
8
13
5
K CO , followed by the cyclocondensation of the resulting 5-
2
3
amino-1-(2-oxo-2-arylethyl)-3-(arylamino)-1H-pyrazole-4-
carbonitrile intermediates. The salient features of this procedure
are mild reaction conditions, good yields, operational simplicity,
ready availability of the starting materials and applications
potential for the synthesis of other heterocyclic compounds.
Synthesis of 2-aryl-6-(arylamino)-1H-imidazo[1,2-b]pyrazole-
7
-carbonitiles 5b-h:
Absolute EtOH and concentrated HCl were added to the the
residue 4b-h and the mixture was refluxed for appropriate
amount of time (Table 2). The mixture was left to cold to room
General procedure for the synthesis of 5-amino-1-(2-oxo-2-
arylethyl)-3-(arylamino)-1H-pyrazole-4-carbonitriles 4a-h:
temperature. The resulting precipitate was washed with cold H O
2
(3×5 mL) and cold MeOH (5 mL) and dried to give the desired
products 5b-h.
5
-Amino-1-(2-oxo-2-phenylethyl)-3-(phenylamino)-1H-
pyrazole-4-carbonitrile (4a): A suspension of compound 3a (199
mg, 1 mmol), α-bromoacetophenone 2 (199 mg, 1 mmol) and
K CO (140 mg, 1 mmol) in dry acetone (15 mL) and DMF (3
Acknowledgments
2
3
The authors gratefully acknowledge the financial assistance
from Urmia University.
drops) was refluxed for 1 h. The mixture was cooled to room
temperature and poured into cold H O (30 mL). The precipitate
2
was filtered, washed with cold H O (3×5 mL) and dried to give
2
5
4
-amino-1-(2-oxo-2-phenylethyl)-3-(phenylamino)-1H-pyrazole-
-carbonitrile (4a) as a yellow solid Mp. 197 C.
References and notes
o
1
.
Kinnamon, K. E.; Engle, R. R.; Poon, B. T.; Ellis, W. Y.; McCall, J.
-
1
FT-IR (KBr) (νmax, cm ): 3426, 3335, 3242, 3058, 2920,
W.; Pzimianski, M. T. Proc. Soc. Exp. Biol. Med. 2000, 224, 45.
2. Keshi, O.; Bahar, I.; Jernigan, R. L.; Beutler, J. A.; Shoemaker, R.
1
2
205, 1691, 1440, 1559, 1494, 1451, 1225, 745, 686, 561. H
NMR (400 MHz, DMSO-d ) δ (ppm): 8.44 (1H, s, NH,
H.; Sausville, E. A. Covell, D. G. Anti-Cancer Drug. Des. 2000, 15,
6
H
7
9-98.
exchanged by D O addition), 8.04 (2H, d, J = 7.2 Hz, arom), 7.73
2
3
.
Ennis, H. L.; Möller, L.; Wang, J. J.; Selawry, O. S. Biochem.
Pharmacol. 1971, 20, 2639.
(
(
2H, t, J = 7.4 Hz, arom), 7.61 (2H, t, J = 7.8 Hz, arom), 7.48
2H, dd, J = 8.8 Hz, J = 1.2 Hz, arom), 7.72 (2H, t, J = 8 Hz,
1
2
4. Vicentinia, C. B.; Manfrinia, M.; Mazzantia, M.; Scatturina, A.;
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arom), 6.79 (2H, br s, NH , exchanged by D O addition), 5.50
2
2
1
3
(
2H, s, CH2). C NMR (100 MHz, DMSO-d ) δ (ppm): 193.26,
6 C
5
.
Dombroski, M. A.; Letavic, M. A.; McClure, K. F. WO 02072576,
002.
1
1
53.42, 150.67, 142.85, 134.97, 134.33, 129.31, 128.89, 128.52,
19.70, 116.73, 115.59, 63.82, 54.46. Anal. Calcd for
2
6
7
.
.
Pelling, J. C.; Shipman, C. J. Biochem. Pharmacol. 1976, 25, 2377.
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1
8
15
5
4
.62; N, 22.21.
1
990, 2, 1.

4
Tetrahedron Letters
8
.
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82.
Elguero, J.; Knutsson, L.; Mignonac-Monden, S. Bull. Chem. Soc.
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4
9
.
1
1
1
1
1
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1
1
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1
7. Farag, A. M.; Dawood, K. M. Heteroatom Chem. 1997, 8, 129.
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2
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2
2
2
8. General procedure for the synthesis of 5-amino-3-arylamino-1H-
pyrazole-4-carbonitrile derivatives 3a-f. Malononitrile (1 mmol)
was added to a solution of sodium ethoxide (1 mmol) in EtOH (10
mL) and the reaction mixture was stirred at r.t. for 15 min. An
arylisothiocyanate (1 mmol) was added to the reaction mixture
and stirring was continued overnight. Iodomethane (1 mmol) was
added and the mixture was stirred for 4-6 h. After completion of
the reaction (TLC), cold H
precipitate was filtered off, washed with cold H
2
O (10 mL) was added and the
O, and dried to
2
give the corresponding methylene malononitrile derivatives. The
methylene malononitrile derivatives (1 mmol) were dissolved in
absolute EtOH (10 ml) and hydrazine hydrate (80%, 5 mmol) was
added at RT. The reaction mixture was stirred at r.t. until the
completion of reaction (TLC) using CHCl
3
/MeOH/MeCN (30:3:1)
as eluent. Addition of ice-H O (10 mL) and filtration of the
2
precipitate gave the corresponding pyrazole derivatives in 86-95%
yield.