Synthesis of novel pyrazolo[3,4-d]pyridazine, pyrido[1,2-a]benzimidazole, pyrimido[1,2-a]benzimidazole and triazolo[4,3-a]pyrimidine derivatives

Article abstract of DOI:10.1002/jhet.5570450627

(Chemical Equation Presented) 4-Acetyl-5-methyl-1-phenyl-1H-pyrazole reacts with dimethylformamide dimethylacetal (DMF-DMA) to afford the corresponding (E)1-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-3-(N,N-dimethylamino)-2-propen-1-one. The latter product under

Full text of DOI:10.1002/jhet.5570450627

Nov-Dec 2008
1739
Synthesis of Novel Pyrazolo[3,4-d]pyridazine,
Pyrido[1,2-a]benzimidazole, Pyrimido[1,2-a]benzimidazole
and Triazolo[4,3-a]Pyrimidine Derivatives
Mohamed R. Shaaban, Taha M. A. Eldebss, Ahmed F. Darweesh, and Ahmad M. Farag*
Department of Chemistry, Faculty of Science, Cairo University, Giza 12613, Egypt
Email: afarag49@yahoo.com
Received August 12, 2007
Ph
Me
N
N
N
N
N
N
Me
N
Ar
O
H3C
Me
Me
N
N
N
N
N
Ph
Ph
Ph
N
N
N
Me
Me
N
Ph
N
N
N
N
CN
N
N
N
4-Acetyl-5-methyl-1-phenyl-1H-pyrazole reacts with dimethylformamide dimethylacetal (DMF-DMA)
to afford the corresponding (E)1-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-3-(N,N-dimethylamino)-2-propen-
1-one. The latter product undergoes regioselective 1,3-dipolar cycloaddition with nitrilimines and nitrile
oxides to afford the novel 3-aroyl-4-(5-methyl-1-phenyl-1H-pyrazol-4-yl)carbonyl-1-phenylpyrazole and
3-aroyl-4-(5-methyl-1-phenyl-1H-pyrazol-4-yl)carbonyl isoxazole derivatives, respectively. It reacts also
with 1H-benzimidazole-2-acetonitrile, 2-aminobenzimidazole and 3-amino-1,2,4-triazole to afford the
novel pyrido[1,2-a]benzimidazole, pyrimido[1,2-a]benzimidazole and the triazolo[4,3-a]pyrimidine
derivatives, respectively. The reaction of 3-aroyl-4-(5-methyl-1-phenyl-1H-pyrazol-4-yl) carbonyl-1-
phenylpyrazole derivatives with hydrazine hydrate led to a new pyrazolo[3,4-d]pyridazine derivatives.
J. Heterocyclic Chem., 45, 1739 (2008).
INTRODUCTION
the latter product displayed a singlet signal at ꢀ 2.98 due
to N,N-dimethyl protons, a singlet signal at ꢀ 2.59 due to
methyl group, two doublets at ꢀ 5.51 and 7.69 (J = 12.3
Hz) due to olefinic protons, a singlet signal at ꢀ 7.91 due
to pyrazole-5-CH protons, in addition to an aromatic
multiplets in the region ꢀ 7.25-7.45. The value of the
coupling constant (J = 12.3 Hz) for the ethylenic protons
indicates that the enaminone 2 exists exclusively in the E-
configuration.
Enaminone derivatives are highly reactive inter-
mediates and are extensively used for the synthesis of a
wide variety of heterocyclic systems [1-3]. On the other
hand, a great deal of interest has been focused on the
synthesis of functionalized pyrazole derivatives due to
their synthetic and biological potentialities [4-6]. In
continuation of our interest in the synthesis of hetero-
cycles containing a pyrazole moiety for biological
screening [7,8], we report here on the synthesis of 1-(5-
methyl-1-phenyl-1H-pyrazol-4-yl)-3-(N,N-dimethylamino)-
2-propen-1-one (2) and its utility in 1,3-dipolar cyclo-
addition reactions with nitrilimines 4a-g and nitrile oxides
11a-c. The behavior of compound 2 toward some nitrogen
nucleophiles was also investigated.
The regioselectivity in 1,3-dipolar cycloaddition of
nitrilimines 4a-g with the enaminone 2 was investigated,
for example, reaction of the enaminone 2 with the
nitrilimines 4a (generated in situ by the action of
triethylamine on the hydrazonoyl chloride 3a) afforded a
single product (as examined by TLC and 1H nmr
spectroscopy) for which the two regioisomeric
cycloadducts 5a and 7a seemed possible (Scheme 1).
However, the regioisomer 6a was assigned for the
RESULTS AND DISCUSSION
1
Treatment of 4-acetyl-5-methyl-1-phenyl-1H-pyrazole
(1) with dimethylformamide dimethylacetal (DMF-DMA)
afforded a single product identified as (E)-1-(5-methyl-
1-phenyl-1H-pyrazol-4-yl)-3-(N,N-dimethylamino)-2-
propen-1-one (2) in a high yield. The 1H nmr spectrum of
reaction product on the basis of its H nmr spectrum and
1
its chemical transformation outlined in Scheme 2. The H
nmr spectrum of the isolated product revealed four
singlets at ꢀ 2.46, 2.59, 8.00 and 8.97 due to acetyl-CH3,
pyrazole ring-methyl protons, pyrazole-3-CH proton and

1740
M. R. Shaaban, T. M. A. Eldebss, A. F. Darweesh, and A. M. Farag
Vol 45
Scheme 1
O
Z
O
R
H3C
Me
OMe
Me2N CH
OMe
+
ArHN
N
N
Ph
N
3
Z = Cl, Br
1
TEA
R = Me, OEt
Me2N
O
Me
O
R
N
Ar-N
N
Ph
N
4
2
O
O
H
O
H
Ar
N
Me
N
R
Me
N
N
Ph
H
Ph
N
N
N
H
N
NMe2
O
Ar
NMe2
R
5
7
-HNMe2
Me
-HNMe2
Ph
O
O
Ar
N
N
O
Me
N
R
N
N
N
Ph
N
N
O
Ar
6 a
b
c
R
8
R= Me
R= Me
R= Me
Ar = C6H5
Ar = p-Me-C6H4
Ar = p-Cl-C6H4
d
e
f
R= MeMe Ar = m-Br-C6H4
R= OEt
R= OEt
R= OEt
Ar = C6H5
Ar = p-Me-C6H4
Ar = p-Cl-C6H4
g
pyrazole-5-CH proton, respectively, in addition to an
aromatic multiplet in the region ꢀ 7.45-7.62. Its ir
spectrum showed two carbonyl absorption bands at 1690
and 1635 cm-1. The formation of the pyrazole 6a is
Scheme 2
Me
Me
N
N
N
N
O
N
Ar
N
Ar
NH2NH2
O
assumed to take place via
a regioselective 1,3-
cycloaddition of the nitrilimine intermediate 4a to the
activated double bond of the enaminone 2 to form the
non-isolable intermediate 5a, followed by elimination of
dimethylamine under the reaction conditions.
Me
Me
N
N
N
N
Ph
9a-d
Ph
6a-d
A further confirmation of the structure of compound 6a
comes from its reaction with hydrazine to afford the
corresponding 4-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-7-
methyl-2-phenylpyrazolo[3,4-d]pyridazine (9a) (Scheme 2).
Prompted by the forgoing results and in order to
generalize this reaction, the enaminone 2 was allowed to
react with the nitrilimines 4b-g under the same
6, 9 a
Ar = C6H5
b Ar = p-Me-C6H4
c Ar = p-Cl-C6H4
d Ar = m-Br-C6H4
were established on the basis of their elemental analyses
and spectral data (see Experimental part).
Similarly, the enaminone 2 reacts with nitrileoxides
11a-c [liberated, in situ, from hydroximoyl chlorides 10a-
c] to afford the corresponding isoxazole derivatives 13a-c
via the elimination of dimethylamine molecule from the
non-isolable intermediates 12.
regioisomeric structure 15 was easily ruled out on the
experimental
conditions,
which
afforded
the
corresponding pyrazole derivatives 6b-g (Scheme 1). The
products 6b-d underwent cyclocondensation upon
treatment with hydrazine hydrate to give the
corresponding pyrazolo[3,4-d]pyridazine derivatives 9a-d
(Scheme 2). The structures of the products 6b-d and 9b-d
The other possible
1
basis of the spectral data of the isolated products. The H

Nov-Dec 2008
Synthesis of Novel Pyrazolo[3,4-d]pyridazine, Pyrido[1,2-a]benzimidazole,
Pyrimido[1,2-a]benzimidazole and Triazolo[4,3-a]Pyrimidine Derivatives
1741
nmr spectrum of compound 13a as a typical example of
the prepared series, revealed singlet signal
corresponding to the isoxazole H-5 proton at ꢀ 10.02
which is in complete agreement with the proposed
structure.
Next, the behavior of the enaminone 2 toward some
nitrogen nucleophiles was also explored. Thus, heating
equimolar amounts of compound 2 with 1H-benz-
a
imidazol-2-ylacetonitrile (16) in the presence of
a
catalytic amount of piperidine, resulted in the formation
of a single product (as examined by TLC). The structure
of the isolated product was identified as 3-(5-methyl-1-
phenyl-1H-pyrazol-4-yl)-benzo[4,5]imidazo[1,2-a]pyridine-
4-carbonitrile (18). The IR spectrum of compound 18
revealed a characteristic nitrile absorption band at 2191
Scheme 3
O
O
Cl
Et3N
+
Ar
Ar
1
cm-1, whereas its H nmr spectrum displayed two singlets
_
N
N
O
OH
at ꢀ 2.24 and 8.05 due to CH3 and pyrazole-3-CH protons,
respectively, two doublets at ꢀ 7.04 and 8.32 due to two
pyridine protons, in addition to an aromatic multiplet in
the region ꢀ 7.02-7.71.
10a-c
11a-c
2
Compound 2 reacted also with 2-aminobenzimidazole
(19) under the same experimental conditions and gave one
isolable product identified as 4-(5-methyl-1-phenyl-1H-
Ph
N
O
Me
N
N
O
H
N
O
pyrazol-4-yl)-benzo[4,5]imidazo[1,2-a]pyrimidine
(21)
Ar
Ph
O
NMe2
O
Me
(Scheme 4). The IR spectrum of the reaction product
revealed no bands due to amino or carbonyl functions.
H
N
N
NMe2
12a-c
O
1
14
Ar
-Me2NH
Meover, its H nmr spectrum revealed singlet signal at ꢀ
2.28 due to CH3, two doublets at ꢀ 7.07 (J = 4.20 Hz) and
8.85 (J = 4.20 Hz) due two pyrimidine-CH protons, and a
singlet at ꢀ 8.11 due to pyrazole-3-CH, in addition to an
aromatic multiplet in region ꢀ 7.28-7.91. The formation of
compound 21 is assumed to take place via the addition of
the exocyclic amino group in 2-aminobenzimidazole (19)
to the activated double bond in the enaminone 2 to give
the acyclic non-isolable intermediate 20, which undergoes
intramolecular cyclization and subsequent aromatization
-Me2NH
Me
O
N
N
Ph
O
O
N
N
Ph
Ar
Me
O
O
N
N
O
Ar
13a-c
15
10, 13 a Ar = C6H5
b Ar = p-Me-C6H4
c Ar = p-Br-C6H4
Scheme 4
H
CN
N
O
Me
N
H
Me
N
Me2N
N
N
16
- Me2NH
Ph
Ph
N
N
N
CN
N
N
CN
18
17
Ph
N
N
N
N
O
H
Me
N
H
N
Me
Me2N
HN
NH2
N
Ph
- Me2NH
19
N
2
N
NH
N
20
21
Ph
N
NH2
N
NH
N
N
O
Me
H
Me
N
Me2N
HN
- Me2NH
22
N
N
Ph
N
N
NH
N
N
N
24
23

1742
M. R. Shaaban, T. M. A. Eldebss, A. F. Darweesh, and A. M. Farag
Vol 45
Recrystallization from ethanol afforded the corresponding
pyrazole or isoxazole derivatives 6a-g and 11a-c, respectively.
3-Acetyl-4-(5-methyl-1-phenyl-1H-pyrazol-4-carbonyl)-1-
phenylpyrazole (6a). Yield (74%); mp. 178-179˚C; ir (KBr)
ꢀmax/cm-1: 1690 (C=O), 1635 (C=O), 1598 (C=N); 1H nmr
(CDCl3): ꢁ 2.46 (s, 3H, CH3CO), 2.59 (s, 3H, CH3), 7.45-7.62
(m, 10H, ArH’s), 8.00 (s, 1H, pyrazole-3-CH), 8.97 (s, 1H,
pyrazole-5-CH); 13C nmr ꢁ 12.13, 27.58, 27.48, 119.01, 120.06,
123.42, 124.08, 126.37, 129.41, 130.09, 135.54, 136.60, 138.96,
142.33, 143.48, 149.57, 182.56, 192.01; MS (m/z): 370 (M+);
Found: C, 71.39; H, 4.81; N, 15.16%. C22H18N4O2 requires C,
71.34; H, 4.90; N, 15.13%
via the loss of dimethylamine and water molecules to
afford the final product 21 as depicted in Scheme 4.
The enaminone 2 reacted also with 3-amino-1,2,4-
triazole (22) and afforded a high yield of 5-(5-methyl-1-
phenyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyrimidine
(24) which was assigned based on its elemental analysis
and spectral data. A plausible mechanism for the
formation of compound 24 is outlined in Scheme 4. The
latter product is assumed to be formed via an initial
addition of an amino group of 3-amino-1,2,4-triazole to
the activated double bond in the enaminone 2 followed by
elimination of dimethylamine and water molecules from
the non-isolable intermediate 23 to afford the final
product 24.
3-Acetyl-4-(5-methyl-1-phenyl-1H-pyrazol-4-carbonyl)-1-
(4-methylphenyl)pyrazole (6b). Yield (74%); mp. 160-161˚C;
1
ir (KBr) ꢀmax/cm-1: 1688 (C=O), 1636 (C=O), 1597 (C=N); H
nmr (CDCl3): ꢁ 2.25 (s, 3H, CH3) , 2.46 (s, 3H, CH3CO), 2.59 (s,
3H, CH3), 7.25-7.62 (m, 9H, ArH’s), 8.00 (s, 1H, pyrazole-3-
CH), 8.97 (s, 1H, pyrazole-5-CH); 13C nmr: ꢁ 12.21, 20.58,
27.58, 119.51, 121.06, 124.42, 125.37, 128.80, 129.41, 130.09,
130.76, 136.54, 137.50, 138.26, 143.03, 143.28, 149.54, 182.91,
193.06; MS (m/z): 384 (M+);Found: C, 71.94; H, 5.31; N,
14.66%. C23H20N4O2 requires C, 71.86; H, 5.24; N, 14.57%.
3-Acetyl-4-(5-methyl-1-phenyl-1H-pyrazol-4-carbonyl)-1-
(4-chlorophenyl)pyrazole (6c). Yield (75%); mp. 197-198˚C; ir
(KBr) ꢀmax/cm-1: 1691 (C=O), 1634 (C=O), 1595 (C=N); 1H nmr
(CDCl3): ꢁ 2.46 (s, 3H, CH3CO), 2.59 (s, 3H, CH3), 7.26-7.65
(m, 9H, ArH’s), 8.02 (s, 1H, pyrazole-3-CH), 8.97 (s, 1H,
pyrazole-5-CH); 13C nmr: ꢁ 12.22 27.63, 101.39, 120.96, 121.32,
124.62, 125.38, 128.83, 129.48, 129.68, 131.80, 137.59, 138.23,
143.08, 143.38, 149.95, 182.69, 193.03; MS (m/z): 404 (M+);
Found: C, 65.31; H, 4.45; Cl, 8.83; N, 13.93%. C22H17ClN4O2
requires C, 65.27; H, 4.43; Cl, 8.76; N, 13.84%.
EXPERIMENTAL
All melting points were measured on a Gallenkamp melting
point apparatus. The infrared spectra were recorded in potassium
bromide disks on a pye Unicam SP 3300 and Shimadzu FTIR
8101 PC infrared spectrophotometers. The nmr spectra were
1
recorded on a Varian Mercury VX-300 nmr spectrometer. H
spectra were run at 300 MHz and 13C spectra were run at 75.46
MHz in deuterated chloroform (CDCl3) or dimethylsulphoxide
(DMSO-d6). Chemical shifts were related to that of the solvent.
Mass spectra were recorded on a Shimadzu GCMS-QP 1000 EX
mass spectrometer at 70 eV. Elemental analyses were carried out
at the Microanalytical Center of Cairo University, Giza, Egypt.
The hydrazonoyl halides 3a-g [9-13], hydroximoyl chlorides
10a-c [14-16], 4-acetyl-5-methyl-1- phenyl-1H-pyrazole (1) [17]
and 1H-benzimidazol-2-ylacetonitrile (16) [18], were prepared
according to procedures reported in the literature
3-Acetyl-4-(5-methyl-1-phenyl-1H-pyrazol-4-carbonyl)-1-
(3-bromophenyl)pyrazole (6d). Yield (81%); mp. 202-203˚C;
1
ir (KBr) ꢀmax/cm-1: 1691 (C=O), 1634 (C=O), 1595 (C=N); H
1-(5-Methyl-1-phenyl-1H-pyrazol-4-yl)-3-(N,N-dimethyl-
amino)-2-propen-1-one (2). A mixture of 4-Acetyl-methyl-1-
phenylpyrazole (1) (4.0 g, 20 mmol) and dimethylformamide-
dimethylacetal (DMF-DMA) (2.66 mL, 20 mmol) in dry xylene
(20 mL) was refluxed for 8 hours then left to cool to room
temperature. The reddish-brown precipitated product was
collected by filtration, washed with light petroleum ether (40-
60°C), and dried. Recrystallization from benzene afforded 4.64 g
(91%) of the enaminone 2, mp. 159-160°C; ir (KBr) ꢀmax/cm-1:
nmr: (CDCl3) ꢁ 2.46 (s, 3H, CH3CO), 2.59 (s, 3H, CH3), 7.26-
7.87 (m, 9H, ArH’s), 7.98 (s, 1H, pyrazole-3-CH), 8.97 (s, 1H,
pyrazole-5-CH); 13C nmr ꢁ 12.12, 27.61, 118.49, 120.80, 122.09,
122.33, 124.47, 125.27, 128.73, 130.53, 131.53, 131.30, 131.57,
138.13, 139.83, 143.00, 143.32, 150.03, 182.43, 192.98; Found:
C, 58.88; H, 3.87; Br, 17.81; N, 12.55%. C22H17BrN4O2 requires
C, 58.81; H, 3.81; Br, 17.78; N, 12.47%.
Ethyl-4-(5-methyl-1-phenyl-1H-pyrazol-4-carbonyl)-1-
phenylpyrazole-3-carboxylate (6e). Yield (72%); mp. 165-
166˚C; ir (KBr) ꢀmax/cm-1: 1716 (C=O), 1634 (C=O),
1
1644 (conjugated C=O), 1598 (C=N); H nmr (CDCl3): ꢁ 2.59
(s, 3H), 2.98 (s, 6H), 5.51 (d, 1H, J = 12.3 Hz), 7.25-7.45 (m,
5H, ArH’s), 7.69 (d, 1H, J = 12.3 Hz), 7.91 (s, 1H); 13C nmr: ꢁ
11.98, 28.74, 93.73, 122.26, 125.25, 128.16, 129.33, 138.90,
140.71, 142.23, 152.48, 182.29; MS (m/z): 255 (M+); Found: C,
70.61; H, 6.79; N, 16.43%. C15H17N3O requires C, 70.56; H,
6.71; N, 16.46%.
3-Aroyl-4-(5-methyl-1-phenyl-1H-pyrazol-4-yl)carbonyl-1-
phenylpyrazoles 6a-g and 3-Aroyl-4-(5-methyl-1-phenyl-1H-
pyrazol-4-yl)carbonyl isoxazoles 13a-c. General Procedure:
To a stirred solution of the appropriate hydrazonoyl halide 3 or
hydroximoyl chloride 10 (2 mmol) and the enaminone 2 (0.51 g,
2 mmol) in dry benzene (20 mL) was added triethylamine (0.2
mL) portionwise over a period of 30 minutes, and the mixture
was stirred at room temperature for 24 hours. The precipitated
triethylamine hydrochloride was filtered off, and the filtrate was
evaporated under reduced pressure. The residue was triturated
with ethanol. The solid product, so formed in each case, was
collected by filtration, washed with water, and dried.
1
1597(C=N); H nmr (CDCl3): ꢁ 1.25 (t, 3H, J = 6.9Hz CH3),
2.56 (s, 3H, CH3), 4.29 (q, 2H, J = 6.9Hz CH2), 7.44-7.98 (m,
10H, ArH’s), 8.10 (s, 1H, pyrazole-3-CH), 9.02 (s, 1H,
pyrazole-5-CH); 13C nmr: ꢁ 12.16, 13.83, 61.11, 100.64, 119.76,
120.87, 125.08, 125.38, 127.97, 128.86, 129.45, 129.70, 130.85,
138.25, 138.73, 142.65, 143.50, 161.69, 181.72; MS (m/z): 400
(M+); Found: C, 68.96; H, 5.04; N, 13.97%. C23H20N4O3 requires
C, 68.99; H, 5.03; N, 13.99%.
Ethyl-4-(5-methyl-1-phenyl-1H-pyrazol-4-carbonyl)-1-(4-
methylphenyl)-pyrazole-3-carboxylate (6f). Yield (74%); mp.
162-163˚C; ir (KBr) ꢀmax/cm-1: 1716 (C=O), 1634 (C=O), 1595
(C=N); 1H nmr (CDCl3): ꢁ 1.21(t, 3H, J = 7.2 Hz CH3), 2.26 (s,
3H, CH3), 2.55 (s, 3H, CH3), 4.27 (q, 2H, J = 7.2 Hz CH2), 7.34-
7.93 (m, 9H, ArH’s), 8.10 (s, 1H, pyrazole-3-CH), 9.01 (s, 1H,
pyrazole-5-CH); 13C nmr: ꢁ 12.16, 13.83, 20.75, 61.07, 100.19,
119.64, 124.98, 125.37, 128.86, 129.45, 130.06, 130.64, 136.52,
137.54, 138.25, 140.60, 142.62, 143.48,161.72, 181.75; MS

Nov-Dec 2008
Synthesis of Novel Pyrazolo[3,4-d]pyridazine, Pyrido[1,2-a]benzimidazole,
Pyrimido[1,2-a]benzimidazole and Triazolo[4,3-a]Pyrimidine Derivatives
1743
(m/z): 414 (M+); Found: C, 69.61; H, 5.21; N, 13.45%.
C24H22N4O3 requires C, 69.55; H, 5.35; N, 13.52%.
ꢁ 2.25 (s, 3H, CH3), 2.59 (s, 3H, CH3), 7.29-7.73 (m, 9H,
ArH’s), 8.02(s, 1H, pyrazole-3-CH), 9.01 (s, 1H, pyrazole-5-
CH); MS (m/z): 400 (M+); Found: C, 65.85; H, 4.19; Cl, 8.73 N,
20.50%. C22H17ClN6 requires C, 65.92; H, 4.27; Cl, 8.84, N,
20.69%.
Ethyl-4-(5-methyl-1-phenyl-1H-pyrazol-4-carbonyl)-1-(4-
chlorophenyl)pyrazole-3-carboxylate (6g). Yield (78%); mp.
195-196˚C; ir (KBr) ꢀmax/cm-1: 1718 (C=O), 1630 (C=O), 1595
(C=N); 1H nmr (CDCl3): ꢁ 1.19 (t, 3H, J = 7.2 Hz CH3), 2.56 (s,
3H, CH3), 4.27 (q, 2H, J = 7.2 Hz CH2), 7.36-7.97 (m, 9H,
ArH’s), 8.10 (s, 1H, pyrazole-3-CH), 9.04 (s, 1H, pyrazole-5-
CH); 13C nmr: ꢁ 12.17, 13.83, 61.17, 100.46, 120.77, 121.45,
125.17, 125.38, 128.86, 129.44, 129.62, 131.08, 137.55, 138.23,
142.69, 143.56, 145.97, 161.58, 181.53; MS (m/z): 434 (M+);
Found: C, 63.49; H, 4.43; Cl, 8.13;N, 12.91%. C23H19ClN4O3
requires C, 63.52; H, 4.40; Cl, 8.15; N, 12.88%.
4-(5-Methyl-1-phenyl-1H-pyrazol-4-yl)-2-(3-bromophenyl)-
7-methyl-pyrazolo[3,4-d]pyridazine (9d). Yield (92%); mp. >
1
300˚C; ir (KBr) ꢀmax/cm-1: 1589 (C=N); H nmr (DMSO-d6): ꢁ
2.26 (s, 3H, CH3), 2.61 (s, 3H, CH3), 7.26-7.87 (m, 9H, ArH’s),
8.00(s, 1H, pyrazole-3-CH), 8.95 (s, 1H, pyrazole-5-CH); MS
(m/z): 445 (M+); Found: C, 59.27; H, 3.77; Br, 17.89; N,
18.79%. C22H17BrN6 requires C, 59.34; H, 3.85; Br, 17.94; N,
18.87%.
4-(5-Methyl-1-phenyl-1H-pyrazol-4-carbonyl)-3-benzoyl-
isoxazole (13a). Yield (60%); mp. 219-220˚C; ir (KBr)
ꢀmax/cm-1: 1690 (C=O), 1636 (C=O), 1589 (C=N); 1H nmr
(CDCl3): ꢁ 2.59 (s, 3H, CH3), 7.52-7.95 (m, 10H, ArH’s), 8.05
(s, 1H, pyrazole-3-CH), 10.02 (s, 1H, isoxazole-5-CH); Found:
C, 70.56; H, 4.22; N, 11.79%. C21H15N3O3 requires C, 70.58; H,
4.23; N, 11.76%.
4-(5-Methyl-1-phenyl-1H-pyrazol-4-carbonyl)-3-(4-methyl-
benzoyl)isoxazole (13b). Yield (58%); mp. 214-215˚C; ir (KBr)
ꢀmax/cm-1: 1687 (C=O), 1636 (C=O), 1589 (C=N); 1H nmr
(CDCl3): ꢁ 2.21 (s, 3H, CH3), 2.59 (s, 3H, CH3), 7.49-7.96 (m,
9H, ArH’s), 8.02 (s, 1H, pyrazole-3-CH), 10.02 (s, 1H,
isoxazole-5-CH); MS (m/z): 371 (M+); Found: C, 71.13; H, 4.66;
N, 11.34%. C22H17N3O3 requires C, 71.15; H, 4.61; N, 11.31%.
4-(5-Methyl-1-phenyl-1H-pyrazol-4-carbonyl)-3-(4-bromo-
benzoyl)isoxazole (13c). Yield (64%); mp. 259-260˚C; ir (KBr)
ꢀmax/cm-1: 1689 (C=O), 1634 (C=O), 1589 (C=N); 1H nmr
(CDCl3): ꢁ 2.59 (s, 3H, CH3), 7.49-7.91 (m, 9H, ArH’s), 8.05 (s,
1H, pyrazole-3-CH), 10.04 (s, 1H, isoxazole-5-CH); Found: C,
57.87; H, 3.25; Br, 18.30; N, 9.67%. C21H14BrN3O3 requires C,
57.82; H, 3.23; Br, 18.32; N, 9.63%.
3-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-benzo[4,5]imidazo-
[1,2-a]pyridine-4-carbonitrile (18), 4-(5-methyl-1-phenyl-1H-
pyrazol-4-yl)-benzo[4,5]imidazo[1,2-a]pyrimidine (21) and 5-
(5-methyl-1-phenyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]-
pyrimidine (24). General Procedure: To a mixture of the
enaminone
2 (0.51g, 2 mmol) and 1H-benzimidazol-2-
yleacetonitrile (16), 2-aminobenzimidazole (19), or 3-amino-
1,2,4-triazole (22) (2 mmol) in absolute ethanol (20 mL) was
added piperidine (0.3 mL). The mixture was refluxed for 12
hours then left to cool to room temperature. The precipitated
product was collected by filtration, washed with ethanol, and
dried. Recrystallization from DMF afforded the corresponding
benzo[4,5]imidazo[1,2-a]pyridine,
benzo[4,5]imidazo[1,2-
a]pyrimidine and the triazolo[4,3-a]pyrimidine derivatives 18,
21, and 24, respectively.
3-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-benzo[4,5]imidazo-
[1,2-a]pyridine-4-carbonitrile (18). Yield (86%); mp. 209-
1
210˚C; ir (KBr) ꢀmax/cm-1: 2191 (CꢀN), 1633 (C=N); H nmr
(DMSO-d6): ꢁ 2.24 (s, 3H, CH3), 7.04 (d, 1H, pyridine-CH, J =
7.2 Hz), 7.20-7.71 (m, 9H, ArH’s), 8.05 (s, 1H, pyrazole-3-CH),
8.32 (d, 1H, pyridine-CH, J = 7.2 Hz); 13C nmr: ꢁ 11.12, 99.38,
113.30, 115.90, 119.73, 121.91, 125.03, 125.42, 126.27, 129.41,
129.47, 137.76, 138.89, 138.95, 139.11, 139.55, 144.36, 146.82;
MS (m/z): 349 (M+);Found: C, 75.57; H, 4.29; N, 19.85%.
C22H15N5 requires C, 75.63; H, 4.33; N, 20.04%.
Reaction of 6a-d with Hydrazine. General Procedure: A
mixture of the appropriate pyrazole 6a-d (1 mmol) and
hydrazine hydrate (80%), 0.2 mL) in absolute ethanol (20 mL)
was refluxed for 1 hour then left to cool to room temperature.
The orange-yellow precipitated product was collected by
filtration, washed with ethanol and dried. Recrystallization from
dimethylformamid (DMF) afforded the pyrazolo[3,4-
d]pyridazine derivatives 9a-d.
4-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-benzo[4,5]imidazo-
[1,2-a]pyrimidine (21). Yield (88%); mp. 196-197˚C; ir (KBr)
ꢀ
max/cm-1: 1600 (C=N); 1H nmr (DMSO-d6): ꢁ 2.28 (s, 3H, CH3),
7.07 (d, 1H, J = 4.2 Hz pyrimidine-3-CH), 7.28-7.91 (m, 9H,
ArH’s), 8.11 (s, 1H, pyrazole-3-CH), 8.85 (d, 1H, J = 4.2 Hz
pyrimidine-2-CH); MS (m/z): 325 (M+); Found: C, 73.90; H,
4.58; N, 21.46%. C20H15N5 requires C, 73.83; H, 4.65; N,
21.52%.
4-(5-Methyl-1-phenyl-1H-pyrazol-4-yl)-7-methyl-2-phenyl-
pyrazolo[3,4-d]pyridazine (9a). Yield (91%); mp. 231-232˚C;
1
ir (KBr) ꢀmax/cm-1: 1597 (C=N); H nmr (DMSO-d6): ꢁ 2.24 (s,
3H, CH3), 2.63 (s, 3H, CH3), 7.45-7.75 (m, 10H, ArH’s), 8.13
(s, 1H, pyrazole-3-CH), 8.95 (s, 1H, pyrazole-5-CH); 13C nmr: ꢁ
12.98, 18.05, 115.46, 116.77, 121.32, 124.59, 125.34, 128.32,
129.17, 129.32, 129.79, 138.91, 139.09, 139.27, 140.52, 143.58,
149.12, 149.91; MS (m/z): 366 (M+); Found: C, 72.19; H, 4.85;
N, 22.86%. C22H18N6 requires C, 72.11; H, 4.95; N, 22.94%.
4-(5-Methyl-1-phenyl-1H-pyrazol-4-yl)-7-methyl-2-(4-
methylphenyl)pyrazolo[3,4-d]pyridazine (9b). Yield (96%);
mp. 219-220˚C; ir (KBr) ꢀmax/cm-1: 1590 (C=N); 1H nmr
(DMSO-d6): ꢁ 2.19 (s, 3H, CH3), 2.22 (s, 3H, CH3), 2.59 (s,
3H, CH3), 7.25-7.73 (m, 9H, ArH’s), 8.11(s, 1H, pyrazole-3-
CH), 8.95 (s, 1H, pyrazole-5-CH); MS (m/z): 380 (M+); Found:
C, 72.51; H, 5.23; N, 21.90%. C23H20N6 requires C, 72.61; H,
5.30; N, 22.09%.
5-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-
a]pyrimidine (24). Yield (94%); mp. 179-180˚C; ir (KBr)
ꢀ
max/cm-1: 1611 (C=N); 1H nmr (DMSO-d6): ꢁ 2.56 (s, 3H, CH3),
7.45 (d, 1H, J= 4.8 Hz pyrimidine-3-CH), 7.52-7.62 (m, 5H,
ArH’s,), 8.59 (s, 1H, pyrazole-3-CH), 8.72 (s, 1H, triazole), 8.88
(d, 1H, J= 4.8 Hz pyrimidine-2-CH); 13C nmr ꢁ 12.75, 108.25,
110.61, 125.36, 128.69, 128.96, 129.09, 129.38, 138.44, 140.77,
141.33, 154.53, 155.23; MS (m/z): 276 (M+); Found: C, 65.14;
H, 4.42; N, 30.31%. C15H12N6 requires C, 65.21; H, 4.38; N,
30.42%.
REFERENCES
4-(5-Methyl-1-phenyl-1H-pyrazol-4-yl)-2-(4-chlorophenyl)-
7-methyl-pyrazolo[3,4-d]pyridazine (9c). Yield (86%); mp.
263-264˚C; ir (KBr) ꢀmax/cm-1: 1587 (C=N); 1H nmr (DMSO-d6):
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