Synthesis of some novel imidazopyrazole and pyrazolopyrimidine derivatives

Article abstract of DOI:10.1002/jhet.1701

Figure Persented 5-Amino-3-anilino-1H-pyrazole-4-carbonitrile 1 was alkylated with various halo reagents under phase transfer conditions to give the corresponding imidazopyrazole derivatives 2a-2c -6. Pyrazolo[1,5-a] pyrimidine derivatives 11, 12, 13, 14 were prepared by treating compound 1 with different dicarbonyl reagents, namely, diethymalonate, ethyl 3-oxo-3-phenylpropanoate, pentane-2,4-dione or ethyl 3-oxobutanoate.

Full text of DOI:10.1002/jhet.1701

1476
Synthesis of Some Novel Imidazopyrazole and Pyrazolopyrimidine Derivatives
Vol 51
*
Ahmed M. M. Soliman,* Mahmoud. Abd El-Aleem. Ali. Ali. El-Remaily, Adel. A. Sultan, and Hossam. Abdel-Ghany
Chemistry Department, Faculty of Science, Sohag University, Sohag, Egypt
*
E-mail: a_sol2000@yahoo.com; msremaily@yahoo.com
Received January 30, 2012
DOI 10.1002/jhet.1701
Published online 4 February 2014 in Wiley Online Library (wileyonlinelibrary.com).
NC
PhNH
NC
NC
PhNH
H
N
NH2
NH
N
fusion
PTC
PhNH
N
N
N
N
N
5-Amino-3-anilino-1H-pyrazole-4-carbonitrile 1 was alkylated with various halo reagents under phase
transfer conditions to give the corresponding imidazopyrazole derivatives 2a–c-6. Pyrazolo[1,5-a] pyrimidine
derivatives 11–14 were prepared by treating compound 1 with different dicarbonyl reagents, namely, diethymalonate,
ethyl 3-oxo-3-phenylpropanoate, pentane-2,4-dione or ethyl 3-oxobutanoate.
J. Heterocyclic Chem., 51, 1476 (2014).
INTRODUCTION
catalysis conditions with each of chloroacetonitrile and
2-bromo-1-phenylethanone to give compounds 8 and 9,
respectively. Compound 9 was refluxed in ethanol in the
presence of sodium ethoxide as a catalyst for 3 h to give
product 10 (Scheme 1). The structures of the products 5, 9,
and 10 were confirmed by the elemental analyses and the
spectroscopic data. The IR spectrum of product 5 showed
characteristic absorption band at 1680 assignable to CO
Heterocyclic compounds containing two nitrogen atoms
in the molecule (diazoles) represent a very important group
of organic molecules because many of them exhibit signifi-
cant biological activity [1,2], including anti-microbial [3,4]
and pharmacological effects [5–7]. The pyrazole derivatives
are mainly used as anti-inflammatory, anti-pyretic, and
analgesic drugs [8–10].
1
group. The H nmr spectrum of product 9 showed a signal
Pyrazolopyrimidines and related-fused heterocycles
are of interest potential bioactive molecules. They are
known to exhibit pharmacological activities such as
CNS depressant [11], neuroleptic [12], and tuberculo-
static [13]. In view of these versatile benefits and in
connection with our efforts directed towards the syn-
thesis of heterocyclic ring systems [14–23], we aimed
in this study to obtain some new heterocyclic com-
pounds with an expected wide spectrum of potential
applications.
at d 12.97 and 3.56 assignable to OH and CH2 groups, respec-
tively, whereas compound 10 did not show any signals
corresponding to OH or CH2 while showed a signal at d
7.99 assignable to CH of pyrimidine ring.
Compound 1 was fused at 200 ꢀC with different dicarbo-
nyl reagents namely diethymalonate, ethyl 3-oxo-3-phenyl-
propanoate, pentane-2,4-dione or ethyl 3-oxobutanoate to
obtain pyrazolo[1,5-a]pyrimidine derivatives 11–14, respec-
tively. On refluxing compound 1 with ketenedithioacetal
([bis(methylthio)methylene] malononitrile) in absolute
ethanol, in presences of TEA as a catalyst until evolution
of methyl mercaptane was ceased, compound 15 was
separated which in turn fused with aniline to give compound
16. Also, compound 16 was yielded from the reaction
of compound 1 with ketene aminothioacetal ([anilino
(methylthio) methylene] malononitrile under the same
previous reaction conditions, (Scheme 2). The assign-
ments of the structures of products 11 and 12 were based
on their correct elemental analyses and spectroscopic data.
The IR spectrum of product 11 showed two characteristic
absorption bands at 3344 and 3205 cm-1, assignable to
OH and NH groups, respectively, whereas product 12
showed two characteristic absorption bands at 3442 and
3333 assignable to 2NH groups and clear band at 1652
assignable to CO group.
RESULTS AND DISCUSSION
Under phase transfer conditions using dioxane as the
organic phase, potassium carbonate as the solid phase,
and tetrabutylammonium bromide as a catalyst, the key
precursor 5-Amino-3-anilino-1H-pyrazole-4-carbonitrile 1
[24], containing NH2 adjacent to the NH group, was
alkylated with various halo reagents, namely, 1,2-
dibromoethane, 1,3-dibromopropane, 1,4-dibromo- butane,
2-bromo-1-phenylethanone,
chloroacetonitrile,
ethyl
bromoacetate or 2,3-dichloroquinoxaline followed by
intramolecular cyclyzation to give the corresponding imida-
zopyrazole derivatives 2a–c-6, respectively, in good yield.
Compound 7 was yielded via treatment of compound 1 with
2,5-dimethoxytetrahydrofuran in refluxing glacial acetic acid
which in turn reacted under the same previous phase transfer
Also, compound 1 was refluxed in excess formic acid to
give 3-anilino-1H-pyrazolo[3,4-d]pyrimidin-4-ol 17. The
© 2014 HeteroCorporation

September 2014
Synthesis of Imidazopyrazole and Pyrazolopyrimidine Derivatives
1477
Scheme 1
NC
H
N
NH2
NC
PhNH
H
N
N
NC
N
H
N
O
4
PhNH
N
5
N
N
PhNH
N
Ph
N
3
BrCH2COPh/
ClCH2CN/PTC
BrCH2COOEt/
PTC
PTC
N
N
N
PhNH
NC
NC
NH2
H
N
N
H
(CH2)nBr2
PTC
i
NC
(
)n
NH
PhNH
6
PhNH
O
PTC
N
N
N
1
n=1,2,3
2a-c
H
H
AcOH
OMe
MeO
NC
N
NC
N
BrCH2COPh
PTC
ClCH2CN
NC
N
OH
Ph
PhNH
N
N
PTC
N
PhNH
CH2CN
NH
N
8
9
PhNH
N
EtONa
NC
7
N
Cl
Cl
N
PhNH
N
i =
N
Ph
N
10
Scheme 2
NC
PhNH
H
N
N
CH3
NC
Ph
N
PhNH
N
N
N
CH3
13
CH2(COCH3)2
PhCOCH2COOEt
O
12
NC
NC
PhNH
NC
PhNH
NH2
N
OH
N
CH3
CH3COCH2COOEt
CH2(COOEt)2
PhNH
NH
N
N
N
N
1
N
OH
11
OH
14
CH3S
PhNH
CN
CN
CH3S
CH3S
CN
CN
NC
PhNH
NC
N
NH2
N
PhNH2
NH2
CN
PhNH
N
N
N
CN
NHPh
16
N
SMe
15
acetylation of compound 1 with chloroacetyl chloride in
pyridine gave 6-anilino-2-hydroxy-1H-imidazo[1,2-b]
pyrazole-7-carbonitrile 18 and when treated with acetyl
chloride or acetic anhydride gave the acetylated compound
19. Also, ethoxymethylenemalononitrile, triorthoformate,
and Lawesson’s reagent were allowed to react with
compound 1 to give compounds 20–22, respectively
(Scheme 3). The structures of the products 17 and 18 were
confirmed by the correct elemental analyses and spectro-
scopic data. The IR spectra of products 17 and 18 showed
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet.1701

1478
A. M. M. Soliman, M. A E.-A. A. A. El-Remaily, A. A. Sultan, and H. Abdel-Ghany
Vol 51
Scheme 3
NC
NHCOCH3
NH
NC
PhNH
H
N
CH3COCl
PhNH
O
N
N
N
19
18
or (AcO)2O
ClCOCH2Cl
O
PhNH
N
NC
CN
CN
NC
PhNH
N
NH2
NH
NH
EtOCH
HCOOH
PhNH
N
N
N
N
N
1
CN
H
TEA/EtOH
NH2
17
LR
20
NH2
S
PhNH
NC
PhNH
CH(OEt)3
N=CHOEt
N
S
P
N
N
NH
H
N
21
22
OMe
characteristic absorption bands corresponding to NH
groups and two absorption bands at 1675, 1698 assignable
to CO groups in each compound, respectively.
NH phenyl), 7.60–6.75(m, 5H, phenyl), 6.47 (s, 1H, NH
imidazolidine), 4.37–4.12(m, 4H, 2CH2); Anal. calcd. for
C12H11N5 (225.25): C, 63.99; H, 4.92; N, 31.09. Found: C,
63.79; H,4.62; N,31.12.
When compound 21 was subjected to react with hydrazine
or phenylhydrazine, the starting compound 1 was separated
and did not give the cyclic compound as we expected. This
was interpreted by calculating the minimized energy
structure by (MM2 and AM1) of compound 21, which
revealed that the imidoformate lies out of plan with the cyano
group in Figure 1, so underwent hydrolysis.
2-Anilino-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-
carbonitrile (2b).
Yield: 2.2 g, 92%, buff, mp 149–
150 ꢀC; IR: 3335, 3208 (2NH), 2206 (CN) cm-1; 1H nmr: d
8.40 (br, 1H, NH phenyl), 7.45–6.76(m, 5H, phenyl), 6.52
(s, 1H, NH hydro- pyrimidine), 3.86 (br, 4H, 2CH2), 2.03
(br, 2H, CH2); Anal. calcd. for C13H13N5 (239.28): C,
65.25; H, 5.48; N, 29.27. Found: C, 65.05; H, 5.28; N, 29.57
2-Anilino-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepine-
3-carbonitrile (2c). Yield: 2.1 g, 83%, buff, mp 138–140 ꢀC;
IR: 3343 (2NH), 2206 (CN) cm-1; H nmr: d 8.40 (br, 1H,
1
EXPERIMENTAL
All melting points were determined on a Kofler melting point
apparatus and are uncorrected. IR spectra were obtained on a
1
Nicolet 710 FT-IR spectrometer. H nmr spectra were recorded
on a Varian Gemini at 200 MHz using Trimethyl selenium as
an internal reference and DMSO-d6 as a solvent. Elemental
analyses were performed on a Perkin-Elmer CHN-2400 C
analyzer model.
General procedure for preparation of imidazopyrazole
derivatives 2a–c-6, 8, and 9.
An equimolar mixture of
compound 1 (1.99 g, 0.01 mol) and the halo reagents, namely,
1,2-dibromoethane, 1,3-dibromopropane, 1,4-dibromo butane,
2-bromo-1-phenylethanone, chloroacetonitrile, ethyl bromo-
acetate, 2,3-dichloroquinoxaline or chloroacetonitrile in
dioxane (50 mL) was treated with anhydrous potassium
carbonate (9 g) and a catalytic amount of tetrabutylammonium
bromide (6% mol/mol of substrate). The reaction mixture was
stirred 2 h at 60–70 ꢀC, left to cool, filtered off, and the filtrate
was evaporated in vacuo, and the resulting solid was
Figure 1. Minimized energy structure by (MM2 and AM1) of compound
21. The optimization was carried out using semi-empirical calculation
with MM2 and AM1 force fields. The optimization was carried out for
50,000 steps. Calculations were performed using ChemOffice software
developed by Cambridge Soft. [Color figure can be viewed in the online
issue, which is available at wileyonlinelibrary.com.]
recrystallized from ethanol.
6-Anilino-2,3-dihydro-1H-imidazo[1,2-b]pyrazole-7-carbonitrile
(2a).
Yield: 1.95 g, 87%, pale brown, mp 164–166 ꢀC;
1
IR:3342 (2NH), 2208 (CN) cm-1; H nmr: d 8.40 (br, 1H,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet.1701

September 2014
Synthesis of Imidazopyrazole and Pyrazolopyrimidine Derivatives
1479
NH phenyl), 7.47–6.75(m, 5H, phenyl), 6.60 (s, 1H, NH
diazepane), 3.90–3.80(m, 4H, 2CH2), 1.86–1.67 (m, 4H,
2CH2); Anal. calcd. for C14H15N5 (253.30): C, 66.38; H,
5.97; N, 27.65. Found: C, 66.55; H, 5.75; N, 27.95.
6-Anilino-2-phenyl-1H-imidazo[1,2-b]pyrazole-7-carbonitrile
(3). Yield: 2.4 g, 80%, yellow, mp 268–270 ꢀC; IR: 3335
(2NH), 2212 (CN) cm-1; 1H nmr: d9.62 (br, 1H, NH
imidazole), 8.32 (br, 1H, NH phenyl), 8.13–7.10(m, 11H,
2phenyl, CH imidazole); Anal. calcd. for C18H13N5
(299.33): C, 72.23; H, 4.92; N,23.40. Found: C, 72.45; H,
(288.31): C, 66.66; H, 4.20; N, 29.15. Found: C, 66.38; H,
3.90; N, 29.45
General procedure for preparation of pyrazolopyrimidine
derivatives (11–14).
A
mixture of compound
1
(0.005 mol, 1 g) and 10 ml of diethylmalonate, ethyl
benzoylacetate, acetylacetone, or ethylacetoacetate was
heated at 200 ꢀC for 1 h. The solid products were filtered
off and washed with ethanol.
2-Anilino-5,7-dihydroxypyrazolo[1,5-a]pyrimidine-3-carbonitrile
(11). Yield: 2.2 g, 82%, redish brown, mp 320–322 ꢀC; IR:
3344 (OH), 3205 (NH), 2217 (CN) cm-1; 1H nmr: d 9.16 (br,
2H, OH), 8.90 (br, 1H, NH phenyl), 7.95–6.90 (m, 5H,
arom.), 4.12 (s, 1H, CH pyrimidine); Anal. calcd. for
C13H9N5O2 (267.24): C, 58.43; H, 3.39; N, 26.21. Found:
4.62; N, 23.75.
2-Amino-6-anilino-1H-imidazo[1,2-b]pyrazole-7-carbonitrile
(4).
Yield: 1.25 g, 53%, brown, mp 225–227 ꢀC; IR:
3435, 3351, 3240 (NH, NH2), 2209 (CN) cm-1; H nmr:
d 8.73(br, 1H, NH, imidazol),8.40 (br, 1H, NH phenyl),
7.45–6.80 (m, 5H, phenyl), 5.30 (br, 2H, NH2,), 4.66
(s, 1H, CH, imidazol); Anal. calcd. for C12H10N6
(238.25): C, 60.50; H,4.23; N,35.27. Found: C, 60.30; H,
1
C, 58.68; H, 3.70; N, 26.51.
2-Anilino-7-oxo-5-phenyl-4,7-dihydropyrazolo[1,5-a]pyrimidine-
3-carbonitrile (12).
Yield: 2.85g, 87%, pale yellow, mp
358–360 ꢀC; IR: 3442, 3333 (2NH), 2220 (CN), 1652
1
(CO) cm-1; H nmr: d 9.24 (s, 1H, NH phenyl), 7.97–6.88
4.00; N,35.57
(br, 11H, 2 phenyl + NH), 6.40 (s, 1H, CH pyrimidine);
Anal.calcd. for C19H13N5O (327.34): C, 69.71; H, 4.00; N,
6-Anilino-2-oxo-2,3-dihydro-1H-imidazo[1,2-b]pyrazole-7-
carbonitrile (5). Yield: 1.3 g, 55%, buff, mp 160–162 ꢀC;
21.39. Found: C, 69.41; H, 3.70; N, 21.07.
1
IR: 3341 (2NH), 2218 (CN), 1680 (CO) cm-1; H nmr: d
2-Anilino-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carbonitrile
(13). Yield: 2.25 g, 86%, pale brown, mp 280–282 ꢀC; IR:
8.73(br, 1H, NH, imidazol), 8.40 (br, 1H, NH phenyl),
7.45–6.80 (m, 5H, phenyl), 4.80(s, 2H, CH2); Anal. calcd.
for C12H9N5O (239.23): C, 60.25; H, 3.79; N, 29.27.
3318 (NH), 2209 (CN) cm-1; 1H nmr: d 9.38 (s, 1H,
NHphenyl), 7.74 (d, 2H, Ho), 7.29 (t, 2H, Hm), 6.93
(d, 1H, Hp), 6.88 (d, 4H, 7-aryl), 7.43 (s, 1H, CH
pyrimidine, 2.60–2.46 (m, 6H, 2CH3); Anal. calcd. for
C15H13N5 (263.30): C, 68.72; H, 4.65; N, 26.30. Found: C,
Found: C, 60.50; H, 3.55; N, 29.60.
2-Anilino-4H-pyrazolo[1’,5’:1,2]imidazo[4,5-b]quinoxaline-
3-carbonitrile (6). Yield: 2.8 g, 86%, yellow, mp 360 ꢀC;
1
IR: 3414, 3337 (2NH), 2213 (CN) cm-1; H nmr: d 9.40
68.80; H, 4.50; N, 26.23.
2-Anilino-7-hydroxy-5-methylpyrazolo[1,5-a]pyrimidine-3-
(br, 2H, NH), 8.00–7.00 (m, 9H, 2 phenyl); Anal. calcd. for
carbonitrile (14).
Yield: 2.10g, 79%, pale brown, mp
C18H11N7 (325.33): C, 66.45; H, 3.41; N, 30.14. Found: C,
360ꢀC; IR: 3329 (OH), 3160 (NH), 2223 (CN) cm-1; H
nmr: d 13.00 (OH), 9.15 (s, 1H, NH phenyl), 7.74 (d, 2H,
Ho), 7.28 (t, 2H, Hm), 6.92 (d, 1H, Hp), 5.78 (s, 1H, CH
pyrimidine, 2.29 (s, 3H, CH3); Anal. calcd. for C14H11N5O
(265.27): C, 63.39; H, 4.18, N, 26.40. Found: C, 63.55; H,
1
66.70; H, 3.11; N, 30.44.
3-Anilino-5-(1H-pyrrol-1-yl)-1H-pyrazole-4-carbonitrile (7). An
equimolar ratio of compound 1 (0.005 mol, 1 g) and 2,5-
dimethoxytetrahydro furan (0.4 ml) in 10 ml of glacial
acetic acid was heated under reflux for 1 h, left to cool, and
then poured onto ice cold water. The precipitated solid was
filtered off, washed well with water, dried, and crystallized
from ethanol. Yield: 2.3 g, (92%), pale brown, mp 290ꢀC;
3.90, N, 26.70.
5-Amino-2-anilino-7-(methylthio)pyrazolo[1,5-a]pyrimidine-
3,6-dicarbonitrile (15). An equimolar ratio of compound 1
1
IR: 3207 (NH), 2217 (CN) cm-1; H nmr: d 13.10 (br, 1H,
(0.005 mol, 1 g) and [bis(methylthio)methylene] malononitrile
(0.005 mol, 0.85 g) in absolute ethanol (20 mL) and few
drops of TEA as a catalyst was refluxed. The solid product
started to form after 15–20 min, whereas refluxing was
continued until the evolution of methyl mercaptan was
ceased. The reaction mixture was filtered on hot, and the
precipitate was crystallized from ethanol. Yield: 2.6 g,
81%, yellow, mp 313–315 ꢀC; IR: 3454, 3332, 3157 (NH,
NH2), 2208 (CN), cm-1; 1H nmr: d 9.52 (s, 1H, NH
phenyl), 7.80–7.05 (br, 7H, phenyl, NH2), 3.03 (s, 3H,
CH3); Anal. calcd. for C15H11N7S (321.36): C, 56.06; H,
3.45; N; 30.51. Found: C, 56.36; H, 3.15; N; 30.81.
NH pyrazole), 9.30 (br, 1H, NH phenyl), 7.33–6.98(br, 7H,
phenyl + pyrrole), 6.30 (s, 2H, pyrrole); Anal. calcd. for
C14H11N5 (249.27): C, 67.46; H, 4.45; N, 28.10. Found:
C, 87.46; H, 4.15; N, 28.40.
3-Anilino-1-(cyanomethyl)-5-(1H-pyrrol-1-yl)-1H-pyrazole-
4-carbonitrile (8). Yield: 2.6 g, 70%, pale brown, mp 178–
1
180 ꢀC; IR: 3420 (OH), 3220 (NH), 2221 (CN) cm-1; H
nmr: d 13.10 (br, 1H, OH), 9.30 (br, 1H, NH phenyl),
7.80–7.00 (br, 13H, 2 phenyl + pyrrole), 6.30 (s, 2H, CH2);
Anal. calcd. for C22H17N5O (367.40): C, 71.92; H, 4.66; N,
19.06. Found: C, 71.72; H, 4.41; N, 19.37.
2-Anilino-6-hydroxy-6-phenyl-5,6-dihydropyrazolo[1,5-a]
5-Amino-2,
7
-dianilinopyrazolo[1,5-a]pyrimidine-3,6-
pyrrolo[1,2-c] pyrimidine-1-carbonitrile (9).
Yield: 2.15 g,
dicarbonitrile (16). An equimolar ratio of compound 1
(0.005 mol, 1 g) and [anilino(methylthio) methylene]
malononitrile (0.005 mol, 1.1 g) in absolute ethanol
(20 mL) and few drops of TEA as a catalyst was refluxed
75%, buff, mp 303–305 ꢀC; IR: 3214 (NH), 2217 (CN)
1
cm-1; H nmr: d 8.40 (br, 1H, NH phenyl), 7.30–6.80 (m,
5H, arom.), 6.10 (br, 2H, CH2); Anal. calcd. for C16H12N6
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A. M. M. Soliman, M. A E.-A. A. A. El-Remaily, A. A. Sultan, and H. Abdel-Ghany
Vol 51
for 3 h. The reaction mixture was left to cool; the obtained
solid was filtered and crystallized from ethanol. Yield:
2.7 g, 74%, buff, mp 318–320 ꢀC; IR: 3465, 3371, 3297,
3143 (2NH, NH2), 2205 (CN),cm-1; 1H nmr: d 10.11
(s, 1H, NH phenyl-5), 9.20 (s, 1H, NH phenyl-3), 7.85
(d, 2H, Ho), 7.27 (t, 2H, Hm), 6.90 (d, 1H, Hp), 7.44 (s,
2H, NH2); Anal. calcd. for C20H14N8 (366.38): C, 65.56;
phenyl, NH2); Anal. calcd. for C14H9N7 (275.27): C,
61.09; H, 3.30; N, 35.62. Found: C, 61.32; H, 3.05; N, 35.92.
Ethyl (3-amino-4-cyano-1H-pyrazol-5-yl)imidoformate (21).
A
mixture of compound 1 (0.005 mol, 1 g), triethyl orthoformate
(3 mL) and acetic anhydride (10 mL) was heated under reflux
for 4 h. The reaction mixture was concentrated and poured
onto ice cold water. The solid product was filtered and
recrystallized from ethanol. Yield: 1.7 g, 67%, brown, mp
H, 3.85; N, 30.58. Found: C, 65.21; H,3.55; N; 30.88.
3-Anilino-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one
(17). Compound 1 (0.005 mol, 1 g) and excess of formic
1
140 ꢀC; IR: 3390, 3331 (2NH), 2219 (CN) cm-1; H nmr: d
8.34 (s, 1H, NH phenyl), 7.42–6.40 (m, 5H, phenyl), 5.20 (s,
1H, CH), 3.33 (q, 2H, CH2), 1.80 (t, 3H, CH3); Anal. calcd.
for C13H13N5O (255.28): C, 61.17; H, 5.13; N, 27.43. Found:
acid (10 mL ) was heated under reflux for 10 h. The
mixture was left to cool and poured onto ice cold water.
The obtained solid product was filtered, washed with
water, and crystallized from ethanol. Yield: 1.8 g, 79%,
brown, mp 358–360 ꢀC; IR: 3414, 3203, (2NH), 1675
(CO), cm-1; 1H nmr: d 12.85 (s, 1H, NH pyrimidine),
12.03 (s, 1H, NH pyrazole), 7.99 (s, 1H, CH pyrimidine),
7.86 (s, 1H, NH phenyl), 7.67 (d, 2H, Ho), 7.23 (t, 2H,
Hm), 6.87 (t, 1H, Hp); Anal. calcd. for C11H9N5O
(227.22): C, 58.14; H,3.99; N; 30.82. Found: C, 58.44; H,
C, 61.39; H, 4.90; N, 27.70.
2-(4-Methoxyphenyl)-N5-phenyl-2,7-dihydropyrazolo[3,4-d]
[1,3,2]thiaza-phosphinine-4,5-diamine 2-sulfide (22).
A
mixture of compound 1 (0.005 mol, 1 g) and 2,4-bis
(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-dithione
(Lawesson’s reagent) (0.005 mol, 2.1 g) in dry p-xylene
(20 ml) was heated under reflux for 6 h. The solvent was
removed under reduced pressure, and the obtained residue
was triturated with cold methanol (20 ml). The precipitate
was filtered off and crystallized from dioxane. Yield: 2.95 g,
74%, reddish brown, mp 298–300 ꢀC; IR: 3423, 3330
3.65; N; 30.52.
6-Anilino-2-oxo-2,3-dihydro-1H-imidazo[1,2-b]pyrazole-7-
carbonitrile (18).
To a solution of compound 1
1
(NH2) cm-1; H nmr: d 10.00 (s, 1H, NH phenyl), 7.67–
(0.005mol, 1 g) in pyridine (15 mL), chloroacetyl chloride
(0.005mol, 0.4 ml) was added dropwise with stirring at
room temperature for 30 min and then refluxed for 6 h. The
precipitated solid was filtered and crystallized from
ethanol. Yield: 1.50 g, 63%, dark brown, mp 360 ꢀC; IR:
6.26 (m, 11H, 2 phenyl, NH2), 3.78 (s, 3H, CH3);
Anal. calcd. for C17H16N5S2OP (401.45): C, 50.86; H,
4.02; N, 17.45; S, 15.97. Found: C, 50.61; H, 3.80; N,
17.65; S, 15.62.
1
3419 (NH), 2220 (CN), 1698 (CO) cm-1; H nmr: d9.67
(s, 1H, NH imidazolidine), 8.35 (br, 1H, NH phenyl),
7.65–6.80 (m, 5H, phenyl), 3.67 (s, 2H, CH2
imidazolidine); Anal. calcd. for C12H9N5O (239.23): C,
60.25; H, 3.79; N, 29.27. Found: C, 60.55; H, 3.49; N, 29.57.
N-(3-anilino-4-cyano-1H-pyrazol-5-yl)acetamide (19).
Compound 1 (0.005 mol, 1 g) in DMF (15 mL) and acetyl
chloride (0.005 mol, 0.4 ml) or acetic anhydride (10 mL)
was stirred at room temperature for 30 min. The reaction
mixture was refluxed for 3 h and then allowed to cool. The
precipitated solid was filtered and crystallized from
ethanol. Yield: 1.70 g, 71%, pale orange, mp 240 ꢀC; IR:
3401, 3221 (2NH), 2219 (CN), 1667 (CO) cm-1; 1H nmr: d
12.90 (s, 1H, NH acetyl), 10.77 (s, 1H, NH pyrazole), 8.45
(br,1H, NH phenyl), 7.60–6.75 (m, 5H, phenyl), 2.00 (s,
3H, CH3); Anal. calcd. for C12H11N5O (241.25): C, 59.74;
REFERENCES AND NOTES
[1] Brown, E. G. The Biochemistry of N-Heterocycles; Kluwer
Academic Publishers: Dordrecht, 1998.
[2] Katritzky, A. R.; Rees C. W.; Scriven E. F. Comprehensive
Heterocyclic Chemistry II, vol. 3, Pergamon: Oxford, 1996.
[3] Koos, M.; Steiner, B.; Repas, M. Chem Papers 1991, 45, 279.
[4] Koos, M.; Steiner, B.; Novotna, Z. Chem Papers 1994, 48, 54.
[5] Brodgen, R. N. Drugs 1986, 31, 81.
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[7] El-Hawash, S. A.; El-Mallah, A. I. Pharmazie 1998, 53, 368.
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[9] Giri, A. K.; Mukhopadhyay, A. Mutat Res 1998, 262, 15420.
[10] Goodman, L. S.; Gilman, A. The Pharmacological Basis of
Therapeutics; Macmillan: New York, 1975.
[11] (a) Julino, M.; Stevens, M. F. G. J Chem Soc Perkin Trans 1
1998, 10, 1677; (b) Ibrahim Abdou, M.; Saleh, A. M.; Zohdi, H. F. Mole-
cules 2004, 9,109.
H, 4.60; N, 29.03. Found: C, 59.44; H, 4.30;N, 29.35.
7-Amino-2-anilinopyrazolo[1,5-a]pyrimidine-3,6-dicarbonitrile
(20). An equimolar ratio of compound 1 (0.005 mol, 1 g)
[12] Filler, R. Chem Technol 1974, 4, 752.
and (ethoxymethylene) malononitrile (0.005 mol, 0.3 g) in
absolute ethanol (30 ml) and three drops of TEA
was heated under reflux for 6 h. The reaction mixture was
concentrated and left to cool. The solid product was
separated by filtration and crystallized from ethanol. Yield:
2.0 g, 73%, brown, mp 180ꢀC; IR: 3409, 3326, 3207 (NH,
NH2), 2200 (CN) cm-1; 1H nmr: d 9.34 (s, 1H, NH
phenyl), 8.42 (s, 1H, CH pyimidine), 7.89–6.96 (m, 7H,
[13] Ghorab, M. M.; Ismail, Z. H.; Abdel-Gawad, S. M.; Abdel
Aziem, A. Heteroatom Chemistry 2004, 15, 57.
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Sulfur and Silicon 1994, 97, 1.
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[17] Soliman, A. M.; El-Saghier Synth Commun 2001, 31,
2149.
[18] Soliman, A. M. J Heterocyclic Chem 2002, 39, 1.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet.1701

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Synthesis of Imidazopyrazole and Pyrazolopyrimidine Derivatives
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[19] Soliman, A. M.; Khodairy, A.; Ahmed, E. A. Phosphorus
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[22] Mohamed, S. K.; Soliman, A. M.; El-Remaily, M. A. A.; Abdel-
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Abdel-Ghany, H. Eur J Med Chem 2012, 47, 138.
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Ghany, H. Synth Commun 2012, 42, 2748.
[23] Mohamed, S. K.; Soliman, A. M.; El-Remaily, M. A. A.;
Abdel-Ghany, H. J Heterocyclic Chem 2012 (accepted).
[24] Zaharan, M. A.; El-Sharief, A. M. Sh.; El-Gaby, M. S. A.;
Ammar, Y. A.; El-Said, U. H., II Farmaco 2001, 56, 277.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet.1701