A facile access to polysubstituted bipyrazoles and pyrazolylpyrimidines

Article abstract of DOI:10.1002/jccs.200400128

3-(Pyrazol-3-yl)-3-oxo-propanenitrile derivative reacts with several nitrogen nucleophiles to give bipyrazole, pyrazolyloxazole, and pyrazolylpyrimidine derivatives. The structures of the products were confirmed on the basis of their elemental and spectral analyses.

Full text of DOI:10.1002/jccs.200400128

Journal of the Chinese Chemical Society, 2004, 51, 853-857
853
A Facile Access to Polysubstituted Bipyrazoles and Pyrazolylpyrimidines
Kamal M. Dawood,* Ahmad M. Farag and Eman A. Ragab
Department of Chemistry, Faculty of Science, Cairo University, Giza 12613, Egypt
3-(Pyrazol-3-yl)-3-oxo-propanenitrile derivative reacts with several nitrogen nucleophiles to give
bipyrazole, pyrazolyloxazole, and pyrazolylpyrimidine derivatives. The structures of the products were con-
firmed on the basis of their elemental and spectral analyses.
Keywords: Pyrazoles; Hydrazonoyl halides; Enaminonitriles; Bipyrazoles; Pyrazolyloxazoles;
Pyrazolylpyrimidines.
INTRODUCTION
Scheme I
NH2
NH
CN
N
Bipyrazole derivatives are very interesting class of
heterocyclic compounds that have remarkable pharmacologi-
cal activity. They have proven to be useful as potential anti-
inflammatory agents,1,2 cytotoxic agents,3 insecticides,4 her-
bicides,5 and fungicides.6-8 In continuation of our recent work
aiming at the synthesis of a wide variety of 3,3¢-bipyrazole
systems,9,10 we report herein a facile route to various 3,3¢- and
3,5¢-bipyrazoles, pyrazolyloxazoles, and pyrazolylpyrimi-
dines. In this manner, we have found that 3-(4-cyano-1,5-
diphenyl-1H-pyrazol-3-y1)-3-oxo-propanenitrile (4) is an
excellent building block for the synthesis of the entitled ob-
jectives.
Ph
N
N
5
Ph
NH2NH2
O
CN
Ph
Ph
CN
O
CN
Ph
MeCN/NaH
1
NaOEt
EtOH
N
N
Ph
OEt
+
Ph
O
CN
N
N
Cl
O
3
4
EtO
N NH Ph
2
Me2NCH(OMe)2
Ph
CN
Ph
CN
RNHNH2
N
O
N
O
Ph
Ph
N
N
NH-NHR
NMe2
NMe2
NC
NC
6
7
-Me2NH
-H2O
RESULTS AND DISCUSSION
-Me2NH
7-9
a
b
R
H
C6H5
Ph
CN
R
NH2
The starting compound 4 could be synthesized through
treatment of 4-cyano-1,5-diphenyl-1H-pyrazole-3-carbox-
ylic acid ethyl ester (3) with acetonitrile in the presence of so-
dium hydride, in refluxing benzene (Scheme I). The structure
of compound 4 was established on the basis of its elemental
analysis and spectral data. For example, its 1HNMR spectrum
displayed a singlet signal at d 4.14 characteristic for active
methylene protons, whereas its IR spectrum revealed two ab-
sorption bands at 2270 and 2230 cm-1 due to two nitrile
groups and a strong absorption band at 1710 due to a carbonyl
group.
CN
O
R
N
N
N
Ph
Ph
N
N
N
N
N
NC
Ph
9
8
sponding 3,3¢-bipyrazole derivative 5 (Scheme I). The struc-
ture of compound 5 was confirmed on the basis of its elemen-
tal analysis and spectral data. The IR spectrum of compound
5 revealed three bands in the region 3371-3248 cm-1 corre-
sponding to NH and NH2 groups and showed only one nitrile
absorption band at 2230 cm-1. Its 1H NMR spectrum revealed
two broad bands (D2O-exchangeable) at d 5.41 and 11.9 due
to NH2 and NH protons, respectively, in addition to a multi-
Treatment of the cyanoacetylpyrazole derivative 4 with
hydrazine hydrate, in refluxing ethanol afforded the corre-
* Corresponding author. E-mail: dr_dawood@yahoo.com

854 J. Chin. Chem. Soc., Vol. 51, No. 4, 2004
Dawood et al.
plet at d 7.37-7.47 due to aromatic protons.
Scheme II
Treatment of the 3-(pyrazol-3-yl)-3-oxo-propanenitrile
derivative 4 with dimethylformamide-dimethylacetal (DMF/
DMA) in dry xylene, at refluxing temperature, afforded a yel-
low crystalline product identified as 3-(4-cyano-1,5-diphen-
yl-1H-pyrazol-3-yl)-2-(N,N-dimethylamino)methylene-3-
oxo-propanenitrile (6) (Scheme I). Its IR spectrum revealed
two absorption bands at 2230 and 2205 cm-1 due to two nitrile
functions and a carbonyl band at 1693 cm-1. 1H NMR spec-
trum of 6 exhibited two characteristic singlet signals at d 3.33
and at d 8.42 due to the N,N-dimethylamino and methine pro-
tons, respectively.
Ph
CN
Ph
CN
NH2
N
N
N
O
N
Ph
Ph
N
N
N
NC
NC
13
12
NH
-Me2NH
-H2O
H2N
CN
NH2
Ph
N
Ph
CN
NH2OH
O
Ph
N
O
Ph
N
NC
N
NMe2
NH2
NH-OH
NC
The reactivity of the enaminonitrile 6 towards some ni-
trogen nucleophiles was investigated. Thus, treatment of
compound 6 with hydrazine hydrate, in refluxing ethanol, af-
forded a colorless product for which the two possible struc-
tures 8a and 9a can be formulated (Scheme I). The spectral
data of the isolated product was, however, in complete agree-
ment with structure 8a [see Experimental Part].
6
NMe2
10
N
R
N
14
-Me2NH
NH2
Ph
CN
N
CN
CN
N
O
N
Ph
Ph
O
N
N
N
N
N
Similarly, compound 6 reacted with phenylhydrazine in
ethanol, at refluxing temperature to afford a yellow colored
product that was identified as 1,5,1¢-triphenyl-1H,1¢H-3,5¢-
bipyrazolyl-4,4¢-dicarbonitrile (8b).
Ph
11
R
15
4
NMe2
N
NH2
Me2NCH(OMe)2
N
R
N
The formation of compounds 8a,b is assumed to take
place via a Michael-type addition of the amino group of hydr-
azines to the enamine double bond in 6 that undergoes intra-
molecular cyclization into the pyrazole derivatives 8a,b via
the loss of dimethylamine and water molecules (Scheme I).
In contrast to its behaviour towards hydrazine deriva-
tives, compound 6 reacted with hydroxylamine in ethanol,
and afforded one product for which the aminoisoxazole struc-
ture 11 was established on the basis of the elemental analysis
and spectral data of the isolated product (Scheme II).
IR spectrum of 11 revealed a strong carbonyl absorp-
tion at 1659 cm-1 and one nitrile absorption band at 2230 cm-1
in addition to two bands at 3425 and 3333 cm-1 corresponding
to an amino group. The isolated product is assumed to be
formed via the addition of the NH2 group of hydroxylamine
to the activated double bond in compound 6 to form the
non-isolable intermediate 10 which underwent intramolecu-
lar cyclization via loss of a dimethylamine molecule to afford
the isoxazole derivative 11 (Scheme II).
R
N
16
N
14
14-16
a
b
R
C6H5
CH3
bonitrile (13) according to its elemental and spectral analy-
ses.
The reactivity of enaminonitrile 6 towards some het-
erocyclic amines was also investigated. Thus, when com-
pound 6 was treated with 5-amino-3-aryl-(1H)-pyrazoles
14a,b, in refluxing ethanol and in the presence of a catalytic
amount of piperidine, it furnished in each case, a single prod-
uct. The structures of the isolated products were identified as
the pyrazolo[1,5-a]pyrimidine derivatives 15a,b, on the basis
of their elemental analyses and spectral data. Further evi-
dence for the proposed structure 15 was obtained by an inde-
pendent synthesis of compound 15a via the reaction of 5-
N-(N,N-dimethylaminomethylene)imino-3-phenyl-1H-pyr-
azole (16) with the cyanoacetylpyrazole 4, in refluxing etha-
nol and in the presence of a catalytic amount of piperidine
that afforded a product identical in all respects (m.p., TLC
and spectra) with that obtained from the reaction of the
enaminonitrile 6 and 5-amino-3-phenyl-1H-pyrazole 14a
(Scheme II).
The enaminonitrile 6 reacts also with guanidine in
refluxing ethanol to give a high yield of a single product (as
examined by TLC) that was identified as 2-amino-4-(4-
cyano-1,5-diphenyl-1H-pyrazol-3-yl)pyrimidine-5-car-

Pyrazoles and Pyrazolopyrimidines
J. Chin. Chem. Soc., Vol. 51, No. 4, 2004 855
Similarly, the aminopyrazole derivative 5 reacted with
the enaminonitrile 6 under similar reaction conditions to af-
ford the pyrazolo[1,5-a]pyrimidine derivative 17 according
to its elemental analysis and spectral data [see Experimental
Part].
carboxylic acid ethyl ester (3) (15.85 g, 50 mmol), aceto-
nitrile (2.7 mL, 50 mmol) and dimethylformamide (10 mL),
in dry benzene (200 mL) was added sodium hydride (1.2 g,
85%). The reaction mixture was refluxed for 4 h, then al-
lowed to cool. The solid that precipitated was collected by fil-
tration, washed with petroleum ether (60-80 °C) and dried.
The crude product was dissolved in water (50 mL) and the re-
sulting alkaline solution was treated with concentrated hy-
drochloric acid until it became neutral (pH = 7). The precipi-
tated solid product was filtered off, washed with water, dried
and finally recrystallized from ethanol to afford 11.7 g (75%
yield) of 4, mp. 195-6 °C (EtOH); IR (KBr) n/cm-1 2270,
2230 (2CºN), 1710 (C=O), 1593 (C=N); 1H NMR (CDCl3) d
4.14 (s, 2H, CH2), 7.23-7.40 (m, 10H, ArH’s); MS, m/z 312
(M+), 273, 141, 77. Anal. Calcd for C19H12N4O: C, 73.07; H,
3.87; N, 17.94. Found: C, 73.1; H, 3.9; N, 18.0%.
In a similar manner, compound 6 reacted with 3-ami-
no-1,2,4-triazole (18) to afford the 1,2,4-triazolo[1,5-a]py-
rimidine derivative 19 (Scheme III). The mass spectrum of
the product revealed a peak at m/z 388 corresponding to its
molecular ion. Its IR spectrum revealed the appearance of
two nitrile absorption bands at 2237 and 2210 cm-1 and
showed the lack of a band characteristic for a carbonyl group.
Scheme III
Ph
N
N
CN
Ph
N
Ph
Ph
Synthesis of 5¢-amino-1,5-diphenyl-3,3¢-bipyrazolyl-4-
carbonitrile (5)
CN
N
N
N
N
CN
17
A mixture of cyanoacetylpyrazole 4 (6.24 g, 20 mmol)
and hydrazine hydrate (1 mL, 80%) in absolute ethanol (20
mL) was refluxed for 4 h. The reaction mixture was allowed
to cool and then diluted with water. The precipitated solid
was collected by filtration, washed with water and dried.
Recrystallization from ethanol afforded 5¢-amino-1,5-di-
phenyl-3,3¢-bipyrazolyl-4-carbonitrile (5). Yield 73%; mp.
250-2°; IR (KBr) n cm-1 3371, 3248 (NH, NH2), 2230 (CºN);
1H NMR (DMSO-d6) d 5.14 (br, s, 2H, NH2, D2O-ex-
changable), 5.81 (s, 1H, CH), 7.37-7.47 (m, 10H, ArH’s),
11.9 (br, s, 1H, NH, D2O-exchangable) ppm. Anal. Calcd for
C19H14N6: C, 69.93; H, 4.32; N, 25.75. Found: C, 70.0; H, 4.2;
N, 25.8%.
5
NH2
N
N
Ph
CN
N
NH2
N
H
N
N
Ph
O
20
18
N
NMe2
N
CN
N
Ph
NC
CN
CN
N
N
6
N
Ph
N
Ph
Ph
N
N
N
N
CN
N
21
19
At the end, the enaminonitrile 6 reacted also with 2-
aminobenzimidazole (20) to give 2-(4-cyano-1,5-diphenyl-
1H-pyrazol-3-yl)-benzo[4,5]imidazo[1,2-a]-pyrimidine-
3-carbonitrile (21) (Scheme III). The structure of the isolated
product was confirmed on the basis of its elemental analysis
and spectral data [see Experimental Part].
3-(4-Cyano-1,5-diphenyl-1H-pyrazol-3-yl)-2-(N,N-dimeth-
ylamino)-methylene-3-oxopropanenitrile (6)
A mixture of cyanoacetylpyrazole 4 (6.24 g, 20 mmol)
and dimethylformamide dimethylacetal (DMF-DMA) (2.66
mL, 20 mmol) in dry xylene (30 mL) was refluxed for 3 h,
then allowed to cool. The orange yellow precipitate was fil-
tered off, washed with petroleum ether (60/80 °C) and dried.
Recrystallization from ethanol/DMF gave 6.76 g of com-
pound 6 (92% yield); mp. 223-5°; IR (KBr) n cm-1 2230, 2205
EXPERIMENTAL
Benzoylacetonitrile (1),11 and hydrazonoyl chlorides
2,12 pyrazole derivatives 3,13 1414 and 1615 were prepared ac-
cording to literature procedures.
1
(2CºN), 1693 (C=O). H NMR (DMSO-d6) d 3.33 (s, 6H,
3-(4-Cyano-1,5-diphenyl-1H-pyrazol-3-yl)-3-oxopropane-
nitrile (4)
2CH3), 7.39-7.49 (m, 10H, ArH’s), 8.42 (s, 1H, CH); MS, m/z
367 (M+), 273, 180, 123, 77. Anal. Calcd for C22H17N5O: C,
71.92; H, 4.66; N, 19.06. Found: C, 71.8; H, 4.7; N, 19.2%.
To a mixture of 4-cyano-1,5-diphenyl-1H-pyrazole-3-

856 J. Chin. Chem. Soc., Vol. 51, No. 4, 2004
Dawood et al.
Reactions of enaminonitrile 6 with hydrazines
Reaction of enaminonitrile 6 with heterocyclic amines 5,
14, 18 and 20
To a solution of the enaminonitrile 6 (0.73 g, 2 mmol) in
ethanol (20 mL), hydrazine hydrate (80%, 0.2 mL) or phenyl
hydrazine (0.2 mL, 2 mmol) was added and the reaction mix-
ture was refluxed for 4 h, then left to cool. The solid product
that formed was filtered off, washed with ethanol and dried.
Recrystallization from dimethylformamide/ethanol afforded
yellow crystals of 3,3¢-bipyrazolyl-4,4¢-dicarbonitrile (8a)
and 3,5¢-bipyrazolyl-4,4¢-dicarbonitrile (8b), respectively.
General procedure
To a mixture of the enaminonitrile 6 (0.73 g, 2 mmol)
and the appropriate heterocyclic amine 5, 14, 18 or 20 (2.2
mmol) in ethanol (30 mL), was added a few drops of piper-
idine. The reaction mixture was refluxed for 4 h, then left to
cool at room temperature. The precipitated product was fil-
tered off, washed with ethanol, dried and finally recrys-
tallized from DMF to afford the corresponding products 17,
15a,b, 19 and 21, respectively.
1,5-Diphenyl-1H,1¢H-3,3¢-bipyrazolyl-4,4¢-dicarbonitrile
(8a)
(15a): Yield 76%; mp. 257-9°; IR (KBr) n cm-1 2230,
1
Yield 73%; mp. >300°; IR (KBr) n cm-1 3263 (NH),
2219 (2CºN); H NMR (DMSO-d6) d 7.44-7.56 (m, 16H,
ArH’s), 7.69 (s, 1H, CH). MS, m/z 463 (M+), 387, 361, 244,
219, 143, 77. Anal. Calcd for C29H17N7: C, 75.15; H, 3.70; N,
21.15. Found: C, 75.3; H, 3.6; N, 21.3%.
1
2230 (2CºN); H NMR (DMSO-d6) d 3.35 (s, br, 1H, NH),
7.33-7.59 (m, 10H, ArH’s), 8.81 (s, 1H, CH). MS, m/z 336
(M+), 310, 284, 244, 92, 77. Anal. Calcd for C20H12N6: C,
71.42; H, 3.60; N, 24.99. Found: C, 71.5; H, 3.4; N, 25.1%.
(15b): Yield 73%; mp. 274-6°; IR (KBr) n cm-1 2239,
2224 (2CºN). Anal. Calcd for C24H15N7: C, 71.81; H, 3.77;
N, 24.42. Found: C, 71.9; H, 3.8; N, 24.5%.
(17): Yield 76%; mp. >300 °C; IR (KBr) n cm-1 2230,
2199 (3CºN); MS, m/z 630 (M+), 315, 244, 180, 142, 77.
Anal. Calcd for C39H22N10: C, 74.27; H, 3.52; N, 22.21.
Found: C, 74.3; H, 3.4; N, 22.0%.
1,5,1¢-Triphenyl-1H,1¢H-3,5¢-bipyrazolyl-4,4¢-dicarboni-
trile (8b)
Yield 76%; mp. 262-4°; IR (KBr) n cm-1 2230, 2210
(2CºN). Anal. Calcd for C26H16N6: C, 75.71; H, 3.91; N,
20.38. Found: C, 75.5; H, 4.0; N, 20.5%.
(19): Yield 70%; mp. 260-2°; IR (KBr) n cm-1 2237,
2210 (2CºN); MS, m/z 338 (M+), 362, 244, 168, 144, 77.
Anal. Calcd for C22H12N8: C, 68.03; H, 3.11; N, 28.85. Found:
C, 68.3; H, 3.3; N, 28.6%.
Synthesis of 5-aminoisoxazole 11 and 2-aminopyrimidine
13
General procedure
To a mixture of the enaminonitrile 6 (0.73 g, 2 mmol)
and hydroxylamine hydrochloride or guanidine nitrate (2.3
mmol) in ethanol (30 mL), anhydrous potassium carbonate
(0.552 g, 4 mmol) was added. The resulting mixture was
refluxed for 6 h and allowed to cool to room temperature then
diluted with water (20 mL). The solid products that formed
were collected by filtration, washed with water and dried.
Recrystallization from DMF afforded the 5-aminoisoxazole
11 and 2-aminopyrimidine 12, respectively.
(21): Yield 69%; mp. 285-7°; IR (KBr) n cm-1 2220,
2206 (2CºN); MS, m/z 437 (M+), 273, 244, 192, 189, 133, 77.
Anal. Calcd for C27H15N7: C, 74.13; H, 3.46; N, 22.41.
Found: C, 74.0; H, 3.5; N, 22.3%.
Received November 10, 2003.
(11): Yield 81%; mp. 215-6°; IR (KBr) n cm-1 3425,
3333 (NH2), 2230 (CºN), 1659 (C=O); 1H NMR (DMSO-d6)
d 3.58 (s, br, 2H, NH2, D2O-exchangable), 7.35-7.52 (m, 10H,
ArH’s), 7.53 (s, 1H, CH) ppm. Anal. Calcd for C20H13N5O2: C,
67.60; H, 3.69; N, 19.71. Found: C, 67.5; H, 3.8; N, 19.7%.
(13): Yield 83%; mp. 293-5°; IR (KBr) n cm-1 3337,
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