Convenient method for synthesis of various fused heterocycles via utility of 4-acetyl-5-methyl-1-phenyl-pyrazole as precursor

Article abstract of DOI:10.3906/kim-1311-12

A new, less expensive, solvent-free procedure was developed for the synthesis of some new derivatives of various fused heterocyclic ring systems, namely azolopyridazine, azolotriazine, azinotriazine, thienopyridine, and pyrazolopyridine. The structures of the products prepared were established by their spectral data and elemental analyses. Eight compounds were evaluated for their in vitro antimicrobial activity. Some of the tested compounds exhibited moderate to significant antibacterial and antifungal activities.

Full text of DOI:10.3906/kim-1311-12

Turk J Chem
Turkish Journal of Chemistry
(2014) 38: 865 – 879
¨
http://journals.tubitak.gov.tr/chem/
˙
c
⃝ TUBITAK
doi:10.3906/kim-1311-12
Research Article
Convenient method for synthesis of various fused heterocycles via utility of
4-acetyl-5-methyl-1-phenyl-pyrazole as precursor
Sobhi MOHAMED GOMHA, Ahmad SAMI SHAWALI, Abdou OSMAN ABDELHAMID∗
Department of Chemistry, Faculty of Science, University of Cairo, Giza, Egypt
Received: 07.11.2013
•
Accepted: 16.04.2014
•
Published Online: 15.08.2014
•
Printed: 12.09.2014
Abstract: A new, less expensive, solvent-free procedure was developed for the synthesis of some new derivatives
of various fused heterocyclic ring systems, namely azolopyridazine, azolotriazine, azinotriazine, thienopyridine, and
pyrazolopyridine. The structures of the products prepared were established by their spectral data and elemental analyses.
Eight compounds were evaluated for their in vitro antimicrobial activity. Some of the tested compounds exhibited
moderate to significant antibacterial and antifungal activities.
Key words: Azolopyridazine, azolotriazine, azinotriazine, thienopyridine, pyrazolopyridine, antimicrobial activities
1. Introduction
A literature survey revealed that many fused heterocyclic systems exhibit diverse biological activities. For
example, some pyrazolo[3,4-d]pyridazines were reported to show good antimicrobial, anti-inflammatory, and
analgesic activities1 as well as antibacterial and antifungal activities.2 Moreover, pyrazolo[5,1-c][1,2,4]triazines
were reported to exhibit remarkable cytotoxic activity against colon, breast, and lung carcinoma cells,3 while
some other derivatives were reported to have selective cytotoxicity in hypoxic and normoxic conditions.4
Furthermore, some thieno[2,3-b]pyridines exhibit inhibitory activity against c-Src5 and eEF2-K.6 Pyrazolo[3,4-
b]pyridines were reported to act as potent A1 adenosine antagonists.7 In the light of these findings and in
continuation of our interest in the synthesis of various heterocycles via the utility of hydrazonoyl halides as useful
precursors,8−10 we wish to report herein a new synthetic strategy for synthesis of pyrazolo[3,4-d]pyridazine
and isoxazolo[3,4-d]pyridazine derivatives of expected biological interest. The previously reported method for
synthesis of the former ring system depends on the conversion of the title compounds into the corresponding
enaminones via their reaction with DMF-DMA, which is an expensive reagent. Instead of this method, we
report herein the use of a much less expensive reagent, namely ethyl formate/sodium methoxide, to convert the
title compound into the corresponding sodium salt of the enol tautomer of 3-(5-methyl-1-phenyl-1H -pyrazol-
4-yl)-3-oxopropanaldehyde 3 (Scheme 1). The latter salt proved to be a very useful precursor for solvent-free
synthesis of the target compounds as indicated below.
2. Results and discussion
Treatment of 4-acetyl-5-methyl-1-phenylpyrazole11 1 with ethyl formate in sodium methoxide afforded the
sodium 3-(5-methyl-1-phenyl-1H -pyrazol-4-yl)-3-oxoprop-1-en-1-olate12 3 (Scheme 1). In this investigation,
∗Correspondence: abdelhamid45@gmail.com
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MOHAMED GOMHA et al./Turk J Chem
grinding of the latter sodium salt 3 with each of the hydrazonoyl halides 4 in the presence of sodium carbonate
gave, in each case, one isolable product as evidenced by TLC analysis of the crude product. The isolated
products proved, on the basis of their spectra (IR, MS, and 1 H- and 13 C-NMR) and elemental analyses (see
Experimental), to have structure 5 (Scheme 1).
O
O
ONa
CH3
NaOCH3
+
HCOOC2H5
N
N
Me
Me
N
N
2
Ph
Ph
3
1
R-COC(X)=NNHAr
4
O
O
COR
COR
NNHAr
N
N
CHO
Me
N
N
Ar
Me
N
N
Ph
Ph
5
Y
H2NNH2.H2O
R
5a, CH3
b, CH3
c, CH3
d, CH3
e, CH3
f, CH3
g, C2H5O
h, C2H5O 4-CH3
i, C2H5O 4-Cl
H
N
N
4-CH3
4-Cl
4-Br
4-OCH3
4-NO2
H
N
N
R'
Ph
Me
N
N
X = Cl or Br
Ar = YC6H5
Ar
6
R'
Y
j, PhNH
H
k,PhNH 4-CH3
l, PhNH 4-Cl
6a, CH3
g, OH H
H
Scheme 1. Synthesis of pyrazolo[3,4-d]pyridazines.
For example, the IR spectra of all compounds revealed a common C=O band in the region υ 1630–
1658 cm−1 . In addition, the IR spectra of compounds 5a–f exhibited an acetyl C=O band in the region υ
1685–1691 cm−1 and compounds 5g–i and 5j–l showed their ester and anilide C=O bands near 1716 and
1681 cm−1 , respectively. The 1 H NMR spectra of compounds 5 revealed, in addition to the aromatic proton
signals, a characteristic singlet signal near δ 8.95 assignable to H-5 of the pyrazole ring residue.13 In addition,
866

MOHAMED GOMHA et al./Turk J Chem
the assigned structures for the isolated products were confirmed by the similarity of the physical properties of
compounds 5a–c and 5g–i with those previously reported.14
Furthermore, the structures of the products 5 were established by their chemical reaction with hydrazine
hydrate. Thus, grinding each of the 2 products 5a and 5g with hydrazine hydrate resulted in their conversion
into the pyrazolo[3,4-d]pyridazine derivatives 6a and 6g, respectively (Scheme 1).
The structures of the products 6a and 6g were elucidated on the basis of their spectra (IR, MS, 1 H
NMR) and elemental analytical data (see Experimental). For example, while the IR spectrum of 6a revealed
the absence of carbonyl absorption bands, the spectrum of 6g showed an OH band near 3521 cm−1 . The 1 H
NMR spectrum of 6g revealed the absence of the triplet and quartet signals of the – COOCH2 CH3 group
present in the spectrum of 5g.
Similarly, reactions of the salt 3 with each of the hydroximoyl chlorides 7 under the same reaction
conditions furnished the products 8 (Scheme 2). The assigned structures of the latter new products 8 were
consistent with their spectroscopic data (IR, MS, 1 H NMR) and elemental analyses (see Experimental). For
example, the IR spectra exhibited, in each case, 2 common C=O absorption bands in the regions υ 1636–1638
and υ 1690–1697 cm−1 . Moreover, the 1 H NMR spectra of compounds 8 revealed, in addition to the aromatic
proton signals, a characteristic singlet signal in the region δ 10.02–10.12 assignable to H-5 of the isoxazole ring
residue.13 This finding indicates that reactions of 3 with 7 follow a regioselective pathway similar to that found
for the reactions of 3 with hydrazonoyl halides 4. This conclusion was further confirmed by our finding that
grinding each of the products 8 with hydrazine hydrate afforded the corresponding isoxazolo[3,4-d]pyridazine
derivatives 9 (Scheme 2). The structures of the latter products 9 were also consistent with their spectral
data (IR, 1 H NMR, and MS) and elemental analyses (see Experimental). For example, while their IR spectra
revealed no C=O absorption bands, their 1 H NMR spectra exhibited signals in the region δ 2.57– 2.62 (CH3),
8.09–8.14 (pyrazole H-3), and 10.10–10.15 (isoxazole H-5).
R
O
O
O
ONa
NOH
RCOC(Cl)=NOH
7
CHO
CH3
N
N
CH3
N
N
Ph
Ph
3
R
N
R
O
N
O
N
O
H2NNH2.H2O
N
O
N
N
CH3
CH3
N
N
Ph
Ph
8
9
7-9 : R : a, Ph; b, 2-thienyl; c, 2-furyl; d, 2-naphthyl
Scheme 2. Synthesis of isoxazolo[3,4-d]pyridazines.
867

MOHAMED GOMHA et al./Turk J Chem
Next, reactions of 3 with diazotized substituted 5-amino-pyrazoles were examined. Thus, reaction
of 3 with each of diazotized 5-amino-substituted pyrazoles, 3-amino-1,2,4-triazole, 2-aminobenzimidazole,
and 5-amino-2,4-dimethyl-pyrazolo[3,4-b]pyridine in ethanol in the presence of sodium acetate at 0–5 ◦ C
yielded the corresponding pyrazolo[5,1-c][1,2,4]triazene, 1,2,4-triazolo[3,4-c][1,2,4]triazene, benzoimidazo[2,1-
c][1,2,4]triazene, and pyrazolo[3,4-b]pyrido[7,1-c][1,2,4]triazene derivatives 10–13, respectively (Scheme 3). The
formation of such products seems to result via initial substitution of the α-hydrogen in the 3-oxopropanol
3 to form the respective azo coupling intermediate, which then undergoes in situ dehydrative cyclization.
This suggested pathway is consistent with that reported for coupling diazotized heterocyclic amines with
enaminones.15,16 Structures of the products 10–13 were assigned on the basis of their elemental and spec-
tral (MS, IR, and 1 H NMR) analyses (see Experimental). The IR spectra of the isolated products 10–13
showed absorption bands characteristic for a C=O group in the region 1630–1660 cm−1 . Their mass spectra
gave the molecular ion peaks at m/z (%): 380 (65), 329 (22), 305 (76), 354 (8), 383 (87), for compounds 10a,
10b, 11–13, respectively.
O
ii
N
N
i
O
N
X
N
N
N
N
O
N
N
ONa
CH3
N
N
Y
N
CH3
N
Ph
11
10
N
Ph
CH3
N
Ph
3
O
N
iv
N
N
iii
CH3
O
N
N
N
N
N
N N
CH3
CH3
N
H3C
N
Ph
N
13
Ph
12
X
N
Y
N
N
N
i =
ii =
N2 SO4H
iii =
N2Cl
N2 NO3
N
H
N
H
N
H
+
CH3
N2Cl
iv =
N
X/ Y : a, Ph / H; b, H / CN
N
H
H3C
N
Scheme 3. Synthesis of pyrazolo[5,1-c]triazines, [1,2,4] triazolo[5,1-c][1,2,4]triazine, benzo[4,5]imidazo[2,1-c][1,2,4]triazine,
and pyrido[2’,3’:3,4]pyrazolo[5,1-c][1,2,4]triazines.
868

MOHAMED GOMHA et al./Turk J Chem
Furthermore, condensation of compound 1 with 4-chlorobenzaldehyde in ethanol in the presence of
sodium hydroxide afforded 4-(4-chlorocinnamoyl)-5-methyl-1-phenylpyrazole17 (14) (Scheme 4). Grinding of
14 with each of 2-cyanoacetamide, 2-cyanoacetohydrazide, and 2-cyanoethanethioamide yielded products whose
elemental analyses and spectral (IR, 1 H NMR, and MS) data were consistent with the structures 15–17,
respectively (Scheme 4).
Scheme 4. Synthesis of 3-cyanopyridine derivatives.
To account for the formation of the latter products, it is suggested, as depicted in Scheme 4, that the
reactions started with the initial formation of the corresponding Michael adducts as intermediates, which in
turn undergo tandem in situ cyclization, dehydration, and oxidation to give the corresponding 15–17 as end
products.
Finally, we studied the reactions of pyridinethione 17 with ethyl chloroactate, ω-bromoacetophenone,
and hydrazine hydrate. In our hands, grinding of 17 with each of such reagents in the presence of potassium
carbonate yielded the products 18–20, respectively (Scheme 5). The structures of 18–20 were confirmed by
elemental analyses and spectral data (see Experimental).
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MOHAMED GOMHA et al./Turk J Chem
Cl
CN
N
H
S
N
N
Me
Ph
17
iii
ii
i
Cl
Cl
NH2
NH2
N
O
S
OEt
Cl
N
N
H
N
N
N
N
N
Me
18
Ph
Me
20
Ph
NH2
O
S
Ph
N
N
N
i = ClCH2CO2C2H5
ii = C6H5COCH2Br
iii = NH2NH2.H2O
Me
19
Ph
Scheme 5. Synthesis of thieno[2,3-b]pyridines and pyrazolo[3,4-b]pyridine.
2.1. Antimicrobial activity
The synthesized products 5a, 5b, 6a, 6g, 8a, 9a, 13, and 17 were screened for their antimicrobial activities
in vitro against the gram-positive bacterium Staphylococcus aureus (S. aureus), gram-negative bacterium
Escherichia coli (E. coli), and the fungus Candida albicans (C. albicans) under the same conditions using
trimethoprim as reference. The bacteria and fungus were subjected to susceptibility testing on Mueller-Hinton
agar medium by the disk agar diffusion method.18,19 The results are summarized in the Table.
Such results indicate the following:
1. Compounds 5a, 6a, 9a, and 13 exhibit high inhibitory effects against S. aureus and E. coli, while
compounds 5b, 8a, and 17 have moderate inhibitory effect. On the other hand, compound 6g has
no inhibitory effect towards either species, while compound 17 has no inhibitory effect towards E. coli.
2. Compounds 6a and 13 exhibit high inhibitory activities against C. albicans, while compounds 5a, 8a,
and 9a have moderate inhibitory activity and compounds 5b, 6g, and 17 have no activity against this
species.
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MOHAMED GOMHA et al./Turk J Chem
Table. Antimicrobial activity of the tested compounds.
Inhibition zone diameter (mm/mg sample)
S. aureus E. coli C. albicans
Sample number
5a
5b
6a
6g
16
12
17
-
17
10
16
-
10
-
16
-
8a
9a
13
17
12
17
16
12
19
14
15
19
-
12
14
18
-
Trimethoprim
21
21
(-) No inhibition zone
3. Experimental
All melting points were measured on Electrothermal IA 9000 series digital melting point apparatus. The
IR spectra were recorded in potassium bromide disks on a Pye Unicam SP 3300 and Shimadzu FT IR 8101
PC infrared spectrophotometer. The 1 H and 13 C NMR spectra were recorded at 270 MHz on a Varian
Mercury VX-300 NMR spectrometer. 1 H NMR (300 MHz) was run in CDCl3 and (CD3)2 SO solutions and
chemical shifts are expressed in ppm units using TMS as an internal reference. Mass spectra were recorded on
a Shimadzu GCMS-QP1000 EX mass spectrometer at 70 eV. Elemental analyses and the biological evaluation
of the products were carried out at the Microanalytical Center of Cairo University, Giza, Egypt. All reactions
were followed by TLC (Silica gel, Aluminum Sheets 60 F254, Merck). 4-Acetyl-5-methyl-1-phenyl-pyrazole11 1,
3-(4-chlorophenyl)-1-(5-methyl-1-phenyl-1H -pyrazol-4-yl)prop-2-en-1-one17 14, hydrazonoyl halides20,21 4a–l
and hydroximoyl chlorides22−25 7a–d were prepared as previously reported in the literature.
3.1. Synthesis of pyrazoles (5a–l) and isoxazoles derivatives (8a–d)
General procedure:
A mixture of sodium salt 3 (0.25 g, 1 mmol) and each of the appropriate hydrazonoyl halides 4a–d or
hydroximoyl chlorides 7a–d (1 mmol) and sodium carbonate (0.3 g) was thoroughly ground with a pestle in an
open mortar at room temperature for 3–5 min until the mixture turned into a melt and grinding was continued
for further 5–10 min and the reaction was monitored by TLC. The solid formed was washed with water and
crystallized from the appropriate solvent to give corresponding pyrazole 5a–l and isoxazoles 8a–d derivatives,
respectively. The synthesized compounds 5a–l and 8a–d together with their physical and spectral data are
listed below.
3.1.1. 3-Acetyl-4-(5’-methyl-1’-phenyl-pyrazol-4’-oyl)-1-phenyl-pyrazole (5a)
. Pale yellow solid; Yield 86%; mp 179 ◦ C (Lit.26 mp 178–179 ◦ C).
3.1.2. 3-Acetyl-1-(4-methylphenyl)-4-(5’-methyl-1’-phenyl-pyrazol-4’-oyl)pyrazole (5b)
Pale yellow solid; Yield 84%; mp 160–161 ◦ C (Lit.26 mp 160–161 ◦ C).
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MOHAMED GOMHA et al./Turk J Chem
3.1.3. 3-Acetyl-1-(4-chlorophenyl)-4-(5’-methyl-1’-phenyl-pyrazol-4’-oyl)pyrazole (5c)
Pale yellow solid; Yield 84%; mp 197–198 ◦ C (Lit.26 mp 197–198 ◦ C).
3.1.4. 3-Acetyl-1-(4-bromophenyl)-4-(5’-methyl-1’-phenyl-pyrazol-4’-oyl)pyrazole (5d)
Pale yellow solid; Yield 87%; mp 164–166 ◦ C. IR (KBr): v 1687, 1656 (2C=O), 1591 (C=N) cm−1 1 H NMR
;
(DMSO-d6): δ 2.38 (s, 3H, CH3 CO), 2.54 (s, 3H, CH3), 7.21–7.67 (m, 9H, ArH’s), 8.08 (s, 1H, pyrazole
H-3), 8.95 (s, 1H, pyrazole H-5); 13 C NMR (DMSO-d6): δ 12.34, 27.24, 121.55, 125.26, 126.00, 128.59, 133.70,
136.42, 140.63, 141.76, 142.58, 144.18, 150.94, 176.46, 195.12; MS m/z(%): 449 (M+ , 48), 406 (24), 292 (63),
185 (92), 78 (100), 51 (52). Anal. Calcd for: C22 H17 BrN4 O2 (449.30): C, 58.81; H, 3.81; N, 12.47. Found: C,
58.68; H, 3.65; N, 12.37%.
3.1.5. 3-Acetyl-1-(4-methoxyphenyl)-4-(5’-methyl-1’-phenyl-pyrazol-4’-oyl)pyrazole (5e)
Pale yellow solid; Yield 84%; mp 144–146 ◦ C. IR (KBr): v 1686, 1632 (2C=O), 1592 (C=N) cm−1 1 H NMR
;
(DMSO-d6): δ 2.54 (s, 3H, CH3 CO), 2.59 (s, 3H, CH3), 3.54 (s, 3H, OCH3) 7.22–7.68 (m, 9H, ArH’s), 8.04
(s, 1H, pyrazole H-3), 8.96 (s, 1H, pyrazole H-5); 13 C NMR (DMSO-d6): δ 11.45, 27.12, 55.75, 113.42, 122.63,
125.74, 126.27, 128.54, 136.12, 138.86, 140.65, 141.74, 142.24, 150.75, 160.32, 178.46, 194.67; MS m/z(%): 400
(M+ , 81), 243 (100), 130 (16), 78 (32), 51 (15). Anal. Calcd for: C23 H20 N4 O3 (400.43): C, 68.99; H, 5.03;
N, 13.99. Found: C, 68.76; H, 5.01; N, 13.87%.
3.1.6. 3-Acetyl-1-(4-nitrophenyl)-4-(5’-methyl-1’-phenyl-pyrazol-4’-oyl)pyrazole (5f)
Pale yellow solid; Yield 84%; mp 160–162 ◦ C. IR (KBr): v 1688, 1658 (2C=O), 1593 (C=N) cm−1 1 H NMR
;
(DMSO-d6): δ 2.46 (s, 3H, CH3 CO), 2.59 (s, 3H, CH3), 7.26-7.65 (m, 9H, ArH’s), 8.02 (s, 1H, pyrazole H-3),
8.97 (s, 1H, pyrazole H-5); 13 C NMR (DMSO-d6): δ 11.85, 27.11, 122.21, 124.85, 125.88, 126.66, 128.89,
136.24. 140.47, 141.62, 142.17, 146.77, 147.54, 150.85, 178.65, 194.77; MS m/z(%): 415 (M+ , 67), 371 (19),
185 (69), 78 (100), 51 (38). Anal. Calcd for: C22 H17 N5 O4 (415.40): C, 63.61; H, 4.12; N, 16.86. Found: C,
63.46; H, 4.10; N, 16.76%.
3.1.7. Ethyl 1-phenyl-4-(5’-methyl-1’-phenyl-pyrazol-4’-oyl)pyrazole 3-carboxylate (5g)
Pale yellow solid; Yield 88%; mp 165–167 ◦ C (Lit.26 mp 165–166 ◦ C).
3.1.8. Ethyl 1-(4-methylphenyl)-4-(5’-methyl-1’-phenyl-pyrazol-4’-oyl)pyrazole 3-carboxylate (5h)
Pale yellow solid; Yield 86%; mp 162–163 ◦ C (Lit.26 mp 162–163 ◦ C).
3.1.9. Ethyl 1-(4-chlorophenyl)-4-(5’-methyl-1’-phenyl-pyrazol-4’-oyl)pyrazole 3-carboxylate (5i)
Pale yellow solid; Yield 82%; mp 195–196 ◦ C (Lit.26 mp 195–196 ◦ C).
3.1.10. N -Phenyl-(1-phenyl-4-(5’-methyl-1’-phenyl-pyrazol-4’-oyl)pyrazole-3- carboxamide (5j)
Pale yellow solid; Yield 86%; mp 167–168 ◦ C. IR (KBr): v 3346 (NH), 1684, 1631 (2C=O), 1600 (C=N) cm−1
;
1 H NMR (DMSO-d6): δ 2.54 (s, 3H, CH3), 7.19–7.73 (m, 15H, ArH’s), 8.24 (s, 1H, pyrazole H-3), 9.08 (s, 1H,
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MOHAMED GOMHA et al./Turk J Chem
pyrazole H-5), 11.63 (s, 1H, br, NH); 13 C NMR (DMSO-d6): δ 12.11, 118.65, 119.25, 122.78, 125.79, 126.11,
127.86, 129.24, 129.88, 130.56, 136.58, 136.94, 137.68, 141.68, 142.79, 150.38, 152.66, 176.67; MS m/z(%): 447
(M+ , 53), 341 (24), 185 (67), 118 (77), 92 (84), 78 (100), 51 (54). Anal. Calcd for C27 H21 N5 O2 (447.49): C,
72.47; H, 4.73; N, 15.65. Found: C, 72.38; H, 4.56; N, 15.34%.
3.1.11. N -Phenyl-(1-(4-methylphenyl)-4-(5’-methyl-1’-phenyl-pyrazol-4’-oyl)pyrazole-3-carboxa-
mide (5k)
Pale yellow solid; Yield 88%; mp 178–179 ◦ C. IR (KBr): v 3389 (NH), 1681, 1637 (2C=O), 1601 (C=N) cm−1
;
1 H NMR (DMSO-d6): δ 2.28 (s, 3H, CH3), 2.52 (s, 3H, CH3), 7.16–7.78 (m, 14H, ArH’s), 8.24 (s, 1H, pyrazole
H-3), 9.10 (s, 1H, pyrazole H-5), 11.67 (s, 1H, br, NH); 13 C NMR (DMSO-d6): δ 12.60, 21.37, 119.80, 120.12,
122.45, 125.22, 126.00, 128.74, 130.01, 130.45, 132.78, 136.42, 136.57, 137.12, 141.08, 142.13, 150.00, 152.77,
176.51; MS m/z(%): 461 (M+ , 73), 341 (24), 186 (42), 118 (91), 92 (84), 66 (100), 51 (38). Anal. Calcd for
C28 H23 N5 O2 (461.51): C, 72.87; H, 5.02; N, 15.17. Found: C, 72.76; H, 5.00; N, 15.05%.
3.1.12. N -Phenyl-(1-(4-chlorophenyl)-4-(5’-methyl-1’-phenyl-pyrazol-4’-oyl)-pyrazole-3-carboxa-
mide (5l)
Pale yellow solid; Yield 86%; mp 185–187 ◦ C. IR (KBr): v 3378 (NH), 1686, 1634 (2C=O), 1597 (C=N) cm−1
;
1 H NMR (DMSO-d6): δ 2.54 (s, 3H, CH3), 7.13–7.86 (m, 14H, ArH’s), 8.26 (s, 1H, pyrazole H-3), 9.12 (s, 1H,
pyrazole H-5), 11.82 (s, 1H, br, NH); 13 C NMR (DMSO-d6): δ 11.85, 27.22, 122.34, 124.78, 125.89, 126.54,
128.35, 136.54, 140.32, 141.54, 142.45, 145.89, 147.57, 150.37, 178.88.95.12; MS m/z(%): 481 (M+ , 100), 306
(54), 185 (37), 118 (80), 66 (16), 51 (38). Anal. Calcd for C27 H20 ClN5 O2 (481.93): C, 67.29; H, 4.18; N,
14.53. Found: C, 67.21; H, 4.12; N, 14.36%.
3.1.13. 3-Benzoyl-4-(5’-Methyl-1’-phenyl-1H-pyrazol-4’-yl)isoxazole (8a)
Yield 86%; Pale yellow solid; mp 220 ◦ C (Lit.26 mp 219–220 ◦ C).
3-(2-Thienyl)-4-(5’-methyl-1’-phenyl-1H -pyrazol-4’-oyl)isoxazole (8b). Yellow solid; Yield 86%;
;
mp 234–236 ◦ C. IR (KBr): v 1692, 1633 (2 C=O), 1590 (C=N) cm−1 1 H NMR (DMSO-d6): δ 2.57 (s, 3H,
CH3), 7.52–8.12 (m, 9H, ArH’s and pyrazole H-3), 10.03 (s, 1H, isoxazole H-5); 13 C NMR (DMSO-d6): δ
12.12, 113.74, 122.89, 125.75, 126.10, 129.24, 132.77, 136.89, 142.68, 147.99, 150.67, 158.23, 178.87, 178.41,
180.32; MS m/z(%): 363 (M+ , 100), 319 (22), 212 (60), 51 (65). Anal. Calcd for C19 H13 N3 O3 S (363.39): C,
62.80; H, 3.61; N, 11.56. Found: C, 62.76; H, 3.45; N, 11.48%.
3.1.14. 3-(2-Furyl)-4-(5’-methyl-1’-phenyl-1H -pyrazol-4’-oyl)isoxazole (8c)
Yellow solid; Yield 88%; Pale yellow solid; mp 247–249 ◦ C. IR (KBr): v 1697, 1638 (2C=O), 1596 (C=N)
cm−1 1 H NMR (DMSO-d6): δ 2.59 (s, 3H, CH3), 6.90–8.14 (m, 9H, ArH’s and pyrazole H-3), 10.12 (s, 1H,
;
isoxazole H-5); 13 C NMR (DMSO-d6): δ 11.97, 111.12, 122.54, 126.00, 127.58, 129.11, 135.99, 137.56, 142.57,
146.32, 150.54, 152.12, 152.89, 176.95, 178.22, 180.49; MS m/z(%): 347 (M+ , 90), 319 (34), 212 (100), 51 (84).
Anal. Calcd for C19 H13 N3 O4 (347.32): C, 65.70; H, 3.77; N, 12.10. Found: C, 65.61; H, 3.56; N, 11.92%.
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MOHAMED GOMHA et al./Turk J Chem
3.1.15. 3-(2-Naphthyl)-4-(5’-methyl-1’-phenyl-1H -pyrazol-4’-oyl)isoxazole (8d)
Pale yellow solid; Yield 83%; mp 242–244 ◦ C. IR (KBr): v 1697, 1638 (2 C=O), 1596 (C=N) cm−1 1 H NMR
;
(DMSO-d6): δ 2.55 (s, 3H, CH3), 7.51–8.11 (m, 12H, ArH’s and pyrazole H-3), 8.44 (s, 1H, naphthalene H-1),
10.13 (s, 1H, isoxazole H-5); 13 C NMR (DMSO-d6): δ 11.82, 118.11, 122.45, 124.42, 126.00, 126.98, 128.10,
128.64, 128.95, 130.21, 131.62, 132.78, 134.13, 134.86, 135.75, 142.82, 150.94, 152.58, 177.95, 185.74, 187.53; MS
m/z(%): 407 (M+ , 100), 337 (45), 164 (53), 105 (100). Anal. Calcd for C25 H17 N3 O3 (407.42): C, 73.70; H,
4.21; N, 10.31. Found: C, 73.58; H, 4.13; N, 10.22%.
3.2. Synthesis of pyrazolo[3,4-d]pyridazines (6a,g) and isoxazolo[3,4-d]-pyridazines (9a–d)
A mixture of the appropriate pyrazoles 5a and 5g (5 mmol) and hydrazine hydrate (1 g, 10 mmol) was thoroughly
ground with a pestle in an open mortar at room temperature for 3–5 min until the mixture turned into a melt.
The initial syrupy consistency continued for 5–10 min and the reaction was monitored by TLC. The solid
was washed with water and crystallized from the appropriate solvent to give the corresponding pyrazolo[3,4-
d]pyridazines 6a and 6g. When the above procedure was repeated using the appropriate isoxazole 8a–5 in
place of the pyrazole 5, the corresponding isoxazolo[3,4-d]pyridazines 9a–d, respectively were obtained. The
physical constants of the products 6a and 6g and 9a–d are given below.
3.2.1. 7-Methyl-4-(5-methyl-1-phenyl-1H -pyrazol-4-yl)-2-phenyl-2H -pyrazolo[3,4-d]pyridazine (6a)
Pale yellow solid; Yield 89%; mp 232 ◦ C (Lit.26 mp 231–232 ◦ C).
3.2.2. 4-(5-Methyl-1-phenyl-1H -pyrazol-4-yl)-2-phenyl-2H -pyrazolo[3,4-d]-pyridazin-7-ol (6g)
Pale yellow solid; Yield 88%; mp 266–268 ◦ C. IR (KBr): v 1612 (C=N), 3521(OH) cm−1 1 H NMR (DMSO-
;
d6): δ 2.61 (s, 3H, CH3), 7.40–7.89 (m, 11H, ArH’s and OH), 8.13 (s, 1H, pyrazole H-3), 8.96 (s, 1H, pyrazole
H-5); 13 C NMR (DMSO-d6): δ 11.82, 116.50, 119.94, 121.02, 125.71, 126.00, 127.51, 129.27, 129.98, 138.21,
140.02, 146.63, 146.57, 146.99, 156.12; MS m/z(%): 369 (M+ +1, 11), 368 (M+ , 26), 352 (100), 105 (42), 77
(34), 51 (75). Anal. Calcd for C21 H16 N6 O (368.39): C, 68.47; H, 4.38; N, 22.81. Found: C, 68.58; H, 4.30; N,
22.57%.
3.2.3. 4-(5-Methyl-1-phenyl-1H -pyrazol-4-yl)-7-phenylisoxazolo[3,4-d]pyridazine (9a)
Pale yellow solid; Yield 90%; mp 277–279 ◦ C. IR (KBr): v 1604 (C=N) cm−1 1 H NMR (DMSO-d6): δ 2.57
;
(s, 3H, CH3), 7.43–7.94 (m, 10H, ArH’s), 8.12 (s, 1H, pyrazole H-3), 10.10 (s, 1H, isoxazole H-5); 13 C NMR
(DMSO-d6): δ 10.84, 112.41, 116.03, 121.81, 126.00, 128.32, 128.67, 128.98, 131.15, 135.48, 137.22, 141.24,
143.18, 150.43, 152.13, 156.78; MS m/z(%): 353 (M+ , 47), 277 (42), 158 (67), 78 (100). Anal. Calcd for:
C21 H15 N5 O (353.38): C, 71.38; H, 4.28; N, 19.82. Found: C, 71.31; H, 4.18; N, 19.67%.
3.2.4. 4-(5-Methyl-1-phenyl-1H -pyrazol-4-yl)-7-(thien-2-yl)isoxazolo[3,4-d]-pyridazine (9b)
Pale yellow solid; Yield 88%; mp 255–257 ◦ C. IR (KBr): v 1599 (C=N) cm−1 1 H NMR (DMSO-d6): δ 2.60
;
(s, 3H, CH3), 7.43–7.92 (m, 8H, ArH’s), 8.09 (s, 1H, pyrazole H-3), 10.05 (s, 1H, isoxazole H-5); 13 C NMR
(DMSO-d6): δ 10.89, 112.71, 116.03, 121.35, 126.00, 128.32, 128.67, 129.98, 132.11, 135.89, 141.35, 143.55,
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MOHAMED GOMHA et al./Turk J Chem
148.12, 152.92, 157.92, 162.89; MS m/z(%): 359 (M+ , 64), 277 (100), 212 (53), 84 (42), 51 (65). Anal. Calcd
for C19 H13 N5 OS (359.40): C, 63.49; H, 3.65; N, 19.49. Found: C, 63.34; H, 3.72; N, 19.37%.
3.2.5. 7-(Furan-2-yl)-4-(5-methyl-1-phenyl-1H -pyrazol-4-yl)isoxazolo[3,4-d]-pyridazine (9c)
Pale yellow solid; Yield 88%; mp 269–271 ◦ C. IR (KBr): v 1602 (C=N) cm−1 1 H NMR (DMSO-d6): δ 2.62
;
(s, 3H, CH3), 7.52–7.94 (m, 8H, ArH’s), 8.14 (s, 1H, pyrazole H-3), 10.06 (s, 1H, isoxazole H-5); 13 C NMR
(DMSO-d6): δ 10.54, 112.26, 112.62, 114.78, 116.32, 121.28, 126.00, 130.42, 136.24, 141.25, 146.88, 149.57,
151.28, 154.32, 155.89, 157.87; MS m/z(%): 343 (M+ , 40), 277 (100), 212 (94), 51 (84). Anal. Calcd for
C19 H13 N5 O2 (343.34): C, 66.47; H, 3.82; N, 20.40. Found: C, 66.23; H, 3.65; N, 20.24%.
3.2.6. 4-(5-Methyl-1-phenyl-1H -pyrazol-4-yl)-7-(naphth-2-yl)isoxazolo[3,4-d]- pyridazine (9d)
Pale yellow solid; Yield 89%; mp 280–282 ◦ C. IR (KBr): v 1608 (C=N) cm−1 1 H NMR (DMSO-d6): δ 2.59
;
(s, 3H, CH3), 7.42–7.81 (m, 11H, ArH’s), 8.16 (s, 1H, pyrazole H-3), 8.47 (s, 1H, naphthalene H-1), 10.15 (s,
1H, isoxazole H-5); 13 C NMR (DMSO-d6): δ 10.54, 112.56, 121.62, 123.42, 125.67, 125.99, 126.18, 127.54,
128.64, 130.11, 130.68, 130.67, 131.47, 135.75, 136.77, 141.60, 141.89, 150.12, 152.33, 156.57; MS m/z(%): 403
(M+ , 15), 277 (87), 185 (60), 128 (100). Anal. Calcd for C25 H17 N5 O (403.44): C, 74.43; H, 4.25; N, 17.36.
Found: C, 74.23; H, 4.35; N, 17.24%.
3.3. Synthesis of pyrazolo[5,1-c]triazines, [1,2,4] triazolo[5,1-c][1,2,4]triazine, benzo[4,5]imidazo[2,1-
c][1,2,4]triazine, and pyrido[2’,3’:3,4]pyrazolo[5,1-c][1,2,4]triazines 10–13.
A solution of the appropriate diazonium salt of the appropriate amine, namely 3-amino-5-phenylpyrazole (ia),
3-amino-4-cyanopyrazole (ib), 3-amino-1,2,4-triazole (ii), 2-amino-benzimidazole (iii), or 3-amino-4,6-dimethyl-
2H -pyrazolo[3,4-b]pyridine (iv), prepared as previously reported,23 was added to a cold mixture of the sodium
salt (3) (5 mmol) and sodium acetate (0.65 g, 5 mmol) in ethanol (40 mL) at 0–5 ◦ C, while stirring for 30 min.
The reaction mixture was stirred for a further 3 h. The resulting solid was collected and crystallized from the
appropriate solvent to give the corresponding 10a,b, 11, 12, and 13, respectively.
3.3.1. (5-Methyl-1-phenyl-1H -pyrazol-4-yl)(7-phenylpyrazolo[5,1-c][1,2,4]triazin-4-yl)methanone
(10a)
Pale yellow solid; Yield 84%; mp 242–244 ◦ C. IR (KBr): v 1622 (C=O), 1597 (C=N) cm−1 1 H NMR (DMSO-
;
d6): δ 2.56 (s, 3H, CH3), 6.31 (s, 1H, pyrazole H-4), 7.33–8.12 (m, 10H, ArH’s), 8.65 (s, 1H, pyrazole H-3), 9.64
(s, 1H, triazine H-5); 13 C NMR (DMSO-d6): δ11.12, 105.65, 121.78, 122.43, 126.00, 127.79, 128.34, 129.12,
129.89, 134.88, 135.57, 140.55, 151.26, 152.07, 153.44, 154.29, 179.46; MS m/z(%): 380 (M+ , 65), 352 (34),
235 (22), 184 (61), 117 (75), 78 (100), 51 (74). Anal. Calcd for: C22 H16 N6 O (380.40): C, 69.46; H, 4.24; N,
22.09. Found: C, 69.41; H, 4.17; N, 22.02%.
3.3.2. 4-(5-Methyl-1-phenyl-1H -pyrazole-4-carbonyl)pyrazolo[5,1-c][1,2,4]triazine-8-carbonitrile
(10b)
Pale yellow solid; Yield 80%; mp 192–194 ◦ C. IR (KBr): v 2231 (CN), 1639 (C=O) cm−1 1 H NMR (DMSO-
;
d6): δ 2.57 (s, 3H, CH3), 7.31–7.82 (m, 5H, ArH’s), 8.51 (s, 1H, pyrazole H-3), 8.87 (s, 1H, pyrazole H-3), 9.69
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MOHAMED GOMHA et al./Turk J Chem
(s, 1H, triazine H-5); 13 C NMR (DMSO-d6): δ 11.12, 84.97, 115.15, 121.58, 122.78, 126.00, 130.47, 140.58,
141.89, 143.98, 151.43, 154.23, 179.52; MS m/z(%): 329 (M+ , 22), 243 (27), 185 (100), 118 (51), 78 (74), 51
(60). Anal. Calcd for C17 H11 N7 O (329.32): C, 62.00; H, 3.37; N, 29.77. Found: C, 61.87; H, 3.30; N, 29.62%.
3.3.3. [1,2,4]Triazolo[5,1-c][1,2,4]triazin-4-yl(5-methyl-1-phenyl-1H-pyrazol-4-yl)methanone (11)
Pale yellow solid; Yield 84%; mp 180–182 ◦ C. IR (KBr): v 1639 (C=O) cm−1 1 H NMR (DMSO-d6): δ 2.56
;
(s, 3H, CH3), 7.30–7.77 (m, 5H, ArH’s), 8.51 (s, 1H, pyrazole H-3), 8.65 (s, 1H, triazole H-5), 9.72 (s, 1H,
triazine H-5); 13 C NMR (DMSO-d6): δ 11.12, 121.57, 122.61, 126.00, 129.43, 131.00, 135.94, 140.67, 146.58,
153.11, 154.48, 155.21, 179.45; MS m/z(%): 305 (M+ , 76), 250 (22), 186 (20), 156 (45), 104 (18), 78 (100), 51
(98). Anal. Calcd for C15 H11 N7 O (305.29): C, 59.01; H, 3.63; N, 32.12. Found: C, 58.87; H, 3.54; N, 32.01%.
3.3.4. Benzo[4,5]imidazo[2,1-c][1,2,4]triazin-4-yl(5-methyl-1-phenyl-1H-pyrazol-4-yl)methanone
(12)
Pale yellow solid; Yield 80%; mp 346–348 ◦ C. IR (KBr): v 1651 (C=O) cm−1
;
1 H NMR (DMSO-d6): δ
2.51 (s, 3H, CH3), 7.26–7.60 (m, 9H, ArH’s), 8.37 (s, 1H, pyrazole H-3), 9.70 (s, 1H, triazine H-5); 13 C NMR
(DMSO-d6): δ 11.10, 120.47, 121.47, 122.61, 124.42, 126.00, 129.46, 129.89, 132.45, 140.48, 145.11, 149.23,
150.67, 150.98, 182.54; MS m/z(%): 354 (M+ , 8), 185 (100), 118 (43), 106 (15), 78 (64), 51 (59). Anal. Calcd
for C20 H14 N6 O (354.36): C, 67.79; H, 3.98; N, 23.72. Found C, 67.64; H, 3.92; N, 23.57%.
3.3.5. (8,10-Dimethylpyrido[2’,3’:3,4]pyrazolo[5,1-c][1,2,4]triazin-4-yl)(5-methyl-1-phenyl-1H -
pyrazol-4-yl)methanone (13)
Pale yellow solid; Yield 80%; mp 174–176 ◦ C. IR (KBr): v 1651 (C=O) cm−1 1 H NMR (DMSO-d6): δ 2.50
;
(s, 3H, CH3), 2.75 (s, 3H, CH3), 2.88 (s, 3H, CH3), 6.95 (s, 1H, pyridine H-5), 7.53–7.74 (m, 5H, ArH’s), 8.68
(s, 1H, pyrazole H-3), 9.89 (s, 1H, triazine H-5); 13 C NMR (DMSO-d6): δ 11.01, 20.32, 21.89, 101.88, 117.45,
119.61, 121.34, 122.36, 126.00, 126.89, 128.62, 129.16, 135.94, 140.58, 150.98, 154.22, 158.67, 165.24, 179.56;
MS m/z(%): 383 (M+ , 87), 186 (76), 130 (55), 78 (100), 51 (77). Anal. Calcd for C21 H17 N7 O (383.41): C,
65.79; H, 4.47; N, 25.57. Found: C, 65.56; H, 4.40; N, 25.44%.
3.4. Synthesis of pyridine derivatives (15-17)
Method A: A mixture of 4-(4-chlorocinnamoyl)-5-methyl-1-phenyl-pyrazole (14) (0.32 g, 1 mmol); the appro-
priate 2-cyanoacetamide, 2-cyanoacetohydrazide, or 2-cyanoethanethioamide (1 mmol); and few drops of acetic
acid was thoroughly ground with a pestle in an open mortar at room temperature for 3–5 min until the mixture
turned into a melt. The initial syrupy consistency continued for 5–10 min and the reaction was monitored by
TLC. The solid was washed with water and crystallized from the appropriate solvent to give 15–17, respectively.
Method B: A mixture of 4-(4-chlorocinnamoyl)-5-methyl-1-phenyl-pyrazole (14) (0.322 g, 1 mmol); 2-
cyanoacetamide, 2-cyanoacetohydrazide, or 2-cyanoethanethioamide (1 mmol); and sodium hydroxide (0.3 g)
in ethanol (20 mL) was refluxed for 6 h. The resulting solid was collected and crystallized from ethanol to give
the respective pyridine derivatives (15–17).
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3.4.1. 4-(4-Chlorophenyl)-1,2-dihydro-6-(5-methyl-1-phenyl-1H -pyrazol-4-yl)-2-oxopyridine-3-
carbonitrile (15)
Pale yellow solid; Yield 78%; mp 116–118 ◦ C. IR (KBr): v 3412 (NH), 2219 (CN), 1652 (C=O) cm−1 1 H
;
NMR (DMSO-d6): δ 2.44 (s, 3H, CH3), 6.91 (s, 1H, Pyridine H), 7.43–7.75 (m, 9H, ArH’s), 7.96 (s, 1H,
pyrazole H-3), 10.36 (s, br, 1H, NH); 13 C NMR (DMSO-d6): δ 10.11, 91.87, 109.23, 111.96, 115.99, 122.37,
126.32, 128.35, 128.96, 132.71, 134.51, 136.52, 139.52, 142.57, 146.68, 156.21, 158.24; MS m/z(%): 386 (M+ ,
19), 322 (68), 185 (100), 128 (65), 78 (75), 51 (47). Anal. Calcd for C22 H15 ClN4 O (386.83): C, 68.31; H, 3.91;
N, 14.48. Found C, 68.23; H, 3.98; N, 14.34%.
3.4.2. 1-Amino-4-(4-chlorophenyl)-6-(5-methyl-1-phenyl-1H -pyrazol-4-yl)-2-oxo-1,2-dihydropyri-
dine-3-carbonitrile (16)
Pale yellow solid; Yield 76%; mp 178–179 ◦ C. IR (KBr): v 3422, 3184 (NH2), 2213 (CN), 1632 (C=O) cm−1
;
1 H NMR (DMSO-d6): δ 2.49 (s, 3H, CH3), 6.87 (s, br, 2H, NH2), 6.99 (s, 1H, Pyridine H), 7.43–7.75 (m,
9H, ArH’s), 7.88 (s, 1H, pyrazole H-3); 13 C NMR (DMSO-d6): δ 10.24, 91.75, 108.35. 114.27, 118.64, 121.32,
126.00, 128.45, 128.96, 132.45, 133.57, 135.67, 137.34, 139.84, 147.96, 150.23, 157.46; MS m/z(%): 401 (M+ ,
100), 334 (31), 184 (29), 127 (28), 78 (46), 51 (21). Anal. Calcd for C22 H16 ClN5 O (401.85): C, 65.76; H, 4.01;
N, 17.43. Found C, 65.65; H, 4.01; N, 17.23%.
3.4.3. 4-(4-Chlorophenyl)-1,2-dihydro-6-(5-methyl-1-phenyl-1H -pyrazol-4-yl)-2-thioxopyridine-3-
carbonitrile (17)
Pale yellow solid; Yield 86%; mp 266–268 ◦ C. IR (KBr): v 3446 (NH), 2218 (CN) cm−1 1 H NMR (DMSO-d6):
;
δ 2.48 (s, 3H, CH3), 6.98 (s, 1H, Pyridine H), 7.40–7.79 (m, 9H, ArH’s), 7.92 (s, 1H, pyrazole H-3), 13.86 (s,
br, 1H, NH); 13 C NMR (DMSO-d6): δ 10.24, 108.35. 110.45, 118.64, 121.32, 126.00, 128.45, 129.46, 132.45,
135.67, 137.23, 139.43, 140.76, 151.23, 154.46, 188.21; MS m/z(%): 402 (M+ , 18), 385 (52), 370 (87), 185 (67),
119 (39), 78 (100), 51 (44). Anal. Calcd for C22 H15 ClN4 S (402.90): C, 65.58; H, 3.75; N, 13.91. Found: C,
65.51; H, 3.65; N, 13.86%.
3.5. Synthesis of thieno[2,3-b]pyridine derivatives (18 and 19)
Method A: A mixture of the thione 17 (0.40 g, 1 mmol), potassium carbonate (0.14 g, 1 mmol) and the
appropriate ω-bromoacetophenone or ethyl chloroacetate (1 mmol each) was thoroughly ground with a pestle
in an open mortar at room temperature for 3–5 min until the mixture turned into a melt. The initial syrupy
consistency continued for 5–10 min and the reaction was monitored by TLC. The solid was washed with water
and crystallized from the appropriate solvent to give 18 and 19, respectively.
Method B: A mixture of the thione 17 (0.402 g, 1 mmol) and potassium hydroxide (0. 0.056 g, 1
mmol) in N, N -dimethylformamide (10 mL) was stirred for 2 h at room temperature. The appropriate ω-
bromoacetophenone or ethyl chloroacetate (1 mmol each) was added and stirring was continued for 2 h. The
resulting solid was collected and crystallized from ethanol to give 18 and 19, respectively.
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3.5.1. Ethyl 3-amino-4-(4-chlorophenyl)-6-(5-methyl-1-phenyl-1H -pyrazol-4-yl)thieno[2,3-b]pyri-
dine-2-carboxylate (18)
Pale yellow solid; Yield 68%; mp 142–144 ◦ C. IR (KBr): v 3434, 3312 (NH2), 1714 (C=O) cm−1 1 H NMR
;
(DMSO-d6): δ 1.33 (t, J = 7.2 Hz, 3H, CH2 CH3), 2.48 (s, 3H, CH3), 4.18 (q, J = 7.2 Hz, 2H, CH2 CH3),
7.82 (s, 1H, pyridine H-5), 7.41–7.86 (m, 11H, ArH’s and NH2), 7.93 (s, 1H, pyrazole H-3); 13 C NMR (DMSO-
d6): δ 11.75, 14.89, 60.30, 106.75, 119.58, 122.74, 126.00, 128.94, 132.17, 133.27, 135.69, 136.28, 136.32, 140.15,
144.58, 154.29, 155.78, 156.59, 164.00, 165.55; MS m/z(%): 488 (M+ , 19), 397 (51), 290 (39), 117 (100), 105
(80), 77 (63), 51 (58). Anal. Calcd for C26 H21 ClN4 O2 S (488.99): C, 63.86; H, 4.33; N, 11.46. Found: C,
63.82; H, 4.18; N, 11.27%.
3.5.2. (3-Amino-4-(4-chlorophenyl)-6-(5-methyl-1-phenyl-1H -pyrazol-4-yl)thieno[2,3-b]pyridin-2-
yl)(phenyl)methanone (19)
Pale yellow solid; Yield 88%; mp 124–126 ◦ C. IR (KBr): v3435, 3268 (NH2), 1666 (CO) cm−1 1 H NMR
;
(DMSO-d6): δ 2.49 (s, 3H, CH3), 7.12 (s, 1H, pyridine H-5), 7.23–7.68 (m, 16H, ArH’s, NH2), 7.94 (s, 1H,
pyrazole H-3); 13 C NMR (DMSO-d6): δ 11.43, 118.33, 118.48, 122.89, 125.13, 126.00, 128.12, 128.64, 128.92,
132.19, 132.88, 123.98, 133.00, 133.28, 135.32, 136.27, 140.18, 144.85, 146.68, 154.89, 156.67, 162.38, 187.11; MS
m/z(%): 522 (M+2, 5), 520 (M+ , 15), 415 (44), 305 (16), 185 (15), 151 (69), 77 (100), 51 (54). Anal. Calcd
for C30 H21 ClN4 OS (521.03): C, 69.16; H, 4.06; N, 10.75; S, 6.15. Found C, 69.43; H, 4.11; N, 10.94%.
3.5.3. Synthesis of 3-amino-4-(4-chlorophenyl)-6-(5-methyl-1-phenyl-1H -pyrazol-4-yl)-1H -pyrazolo
[4’,3’:4,5]thieno[2,3-b]pyridine (20)
To a solution of the thione 17 (0.40 g, 1 mmol) in ethanol (10 mL) was added hydrazine hydrate (1 mL) and
the mixture was heated under reflux for 20 h. The solution was poured over an ice-water mixture and then
neutralized by HCl. The solid product was filtered off, dried, and crystallized from ethanol to afford compound
20. Yellow crystals; Yield 67%; mp 316–318 ◦ C; IR (KBr): v 3385, 3196 (NH2 and NH), 1599 (C=N) cm−1
;
1 H NMR (DMSO-d6): δ2.53 (s, 3H, CH3), 5.98 (s, br, 2H, NH2), 7.23–7.78 (m, 10H, ArH’s and pyridine H-5),
8.04 (s, 1H, pyrazole H-3), 11.43 (s, br, 1H, NH); 13 C NMR (DMSO-d6): δ 11.38, 113.48, 114.99, 117.11, 126.00,
128.45, 128.98, 135.48, 136.07, 137.07, 137.95, 140.10, 141.67, 144.85, 151.89, 157.32, 162.16; MS m/z(%): 402
(M+ +2, 37), 400 (M+ , 63), 183 (18), 117 (48), 77 (93), 51 (100). Anal. Calcd for C22 H17 ClN6 (400.86): C,
65.92; H, 4.27; N, 20.96; Found: C, 65.77; H, 4.15; N, 20.76%.
3.6. Preliminary antimicrobial screening
Overnight culture was streaked on the surface of a Mueller-Hinton agar plate. A sterile filter paper disk was
saturated with 10 µL of 0.5 mg/mL w/v solution of the compound under investigation in DMSO. The plates
and disks were then incubated at 37 ◦ C (for bacteria) and at 28 ◦ C (for fungi) for 24 h and examined for
inhibition zones to determine the activity of the tested compounds.
4. Conclusion
Compound 3 proved to be a useful precursor for synthesis of various fused heterocycles via its reactions with
hydrazonoyl halides, hydroximoyl chlorides, and diazotized heterocyclic amines. Moreover, compound 14 proved
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MOHAMED GOMHA et al./Turk J Chem
a useful precursor in the synthesis of various pyridine and thieno[2,3-b]pyridine derivatives. The structures of
the newly synthesized compounds were confirmed by spectral data and elemental analyses. The results of the
antimicrobial activity of the synthesized products were promising.
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