Triethanolamine as an inexpensive and efficient catalyst for the green synthesis of novel 1H-pyrazolo[1,2-a]pyridazine-5,8-diones under ultrasound irradiation in water and their antibacterial activity

Article abstract of DOI:10.1039/c4ra07096h

Triethanolamine was found to be an efficient catalyst for the synthesis of new 1H-pyrazolo[1,2-a]pyridazine-5,8-diones by a one-pot reaction of maleic hydrazide, with aromatic aldehydes and malononitrile in H₂O under ultrasonic irradiation. The advantages of this method are the use of an inexpensive and readily available catalyst, easy workup, improved yields, and the use of H₂O as a green solvent. To assess their antibacterial activity, all the synthesized compounds were dissolved in DMSO and subjected to biological evaluation using the disc diffusion method against 3 Gram positive and 3 Gram negative bacteria. This journal is

Full text of DOI:10.1039/c4ra07096h

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Triethanolamine as an inexpensive and efficient
catalyst for the green synthesis of novel 1H-
pyrazolo[1,2-a]pyridazine-5,8-diones under
ultrasound irradiation in water and their
antibacterial activity†
Cite this: RSC Adv., 2014, 4, 47721
a
Ahmad Khoraamabadi-zad, Mohammad Azadmanesh,a Roya Karamian,b
*
Mostafa Asadbegyb and Maryam Akbarib
Triethanolamine was found to be an efficient catalyst for the synthesis of new 1H-pyrazolo[1,2-a]
pyridazine-5,8-diones by
a one-pot reaction of maleic hydrazide, with aromatic aldehydes and
malononitrile in H2O under ultrasonic irradiation. The advantages of this method are the use of an
inexpensive and readily available catalyst, easy workup, improved yields, and the use of H2O as a green
solvent. To assess their antibacterial activity, all the synthesized compounds were dissolved in DMSO and
subjected to biological evaluation using the disc diffusion method against 3 Gram positive and 3 Gram
negative bacteria.
Received 14th July 2014
Accepted 23rd September 2014
DOI: 10.1039/c4ra07096h
www.rsc.org/advances
The chemical applications of ultrasound, “Sonochemistry”, molecules with several degrees of structural diversity.6,7 An
have become an exciting new eld of research which has been MCR is a reaction in which three or more different starting
increasingly used in organic synthesis in recent years. This is materials react to form a product, where most, if not all of the
because a large number of organic reactions can be carried out atoms are incorporated in the nal product. This reaction tool
in higher yields, shorter reaction times and milder conditions allows heterocyclic compounds to be synthesized in a few steps
under ultrasonic irradiation.1–3 This may be due to the fact that and usually in a one-pot operation.8
the ultrasound (20–100 kHz, >10 W cmꢀ2) uses the energy to
Nitrogen-containing heterocyclic compounds are wide-
create cavitations, which involve the formation, growth, and spread in nature, and their applications to biologically active
implosive collapse of microscopic bubbles in a liquid. These pharmaceuticals, agrochemicals, and functional materials
bubbles are generated when the “negative” pressure during the are becoming more and more important.9 For example, pyr-
rarefaction phase of the sound wave is sufficiently large to azole derivatives exhibit important biological properties such
disrupt the liquid. The implosive collapse of the bubbles can as anti-inammatory,10 antifungal,11 anticancer,12 antiviral,13
locally produce extreme temperatures and pressures (5000 C, antitumor,14 anticoagulant15 and antibacterial activities.16
ꢁ
20 MPa) for very short times, because of compression of the gas The development of new efficient methods to synthesize N-
phase inside the cavity. These hotspots may lead to irreversible heterocycles with structural diversity is therefore one major
changes such as the formation of excited states, bond breakage, interest of modern synthetic organic chemists.17,18 Among a
and the generation of radicals.4 Ultrasonication can also accel- large variety of nitrogen-containing heterocyclic compounds
erate many multi-component reactions (MCRs) as well as those containing bridgehead hydrazine have received
condensation of maleic hydrazide with Knoevenagel conden- considerable attention because of their pharmacological
sation product.
properties and clinical applications.19–21 The special impor-
Multi-component reactions (MCRs) have been known for tance of heterocycles in synthesis and medicinal chemistry,
over 150 years.5 They play an important role in combinatorial and the key role of pyrazole moiety in numerous biologically
chemistry because of their ability to synthesize small drug-like active compounds,13,22 prompted us to synthesize a series of
1H-pyrazolo[1,2-a]pyridazine-5,8-dione derivatives by the
three-component reaction of maleic hydrazide, malononi-
aFaculty of Chemistry, Bu-Ali Sina University, Hamedan 6517838695, Iran. E-mail:
trile and aromatic benzaldehydes (Scheme 1) followed by
khoram@gmail.com; Fax: +98-81-38380709; Tel: +98-81-38282807
subjection of these novel heterocycles to biological
evaluation.
bDepartment of Biology, Faculty of Science, Bu-Ali Sina University, Hamedan
651754161, Iran
† Electronic supplementary information (ESI) available: Including Mass, HNMR
and CNMR spectral data. See DOI: 10.1039/c4ra07096h
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Bacillus cereus (PTCC 1247), Bacillus thuringiensis (BT) and
Staphylococcus aureus (Wild) and also 3 Gram negative bacteria,
namely Escherichia coli (Wild), Serratia marcescens (PTCC 1111),
and Shigella boydii (ATCC 9905).23 All tests were carried out
using 10 mL of suspension containing 1.5 ꢂ 108 bacteria per mL
and spread on nutrient agar medium. Negative controls were
prepared by using pure DMSO. Gentamicin (10 mg), penicillin
(10 IU) and cephalexin (30 mg) antibiotic discs were used as
positive reference standards.
As it is well known, Staphylococcus aureus and Bacillus
species, especially Bacillus cereus, are food poisoning agents.24
Since DMSO was used as a solvent, it was also screened against
all bacteria in this study and no activity was found. Generally
antibacterial activity of a compound is attributed mainly to its
major components. However, today it is known that the syner-
gistic or antagonistic effect of one component in minor
percentage in a mixture has to be considered.25,26 The results
showed that, all the tested compounds displayed signicant
activities against Bacillus cereus and Bacillus thuringiensis, while,
only compounds 4d and 4e (Table 2) were active against Shigella
Scheme 1 Synthesis of 1H-pyrazolo[1,2-a]pyridazine-5,8-diones.
Antibacterial activity
All 1H-pyrazolo[1,2-a]pyridazine-5,8-dione derivatives were
separately dissolved to a nal concentration of 1 mg mLꢀ1 and
sterilized by ltration using 0.45 mm Millipore. DMSO solutions
were then tested by disc diffusion method against a panel of
microorganisms including 3 Gram positive bacteria, namely
Table 1 Synthesis of 1H-pyrazolo[1,2-a]pyridazine-5,8-diones using maleic hydrazide, aromatic aldehydes, malononitrile and 1–2 drops of
triethanolamine as a catalyst in conventional and ultrasonic method
Conventional methodb
Time (min)
Ultrasonic methodc
Time (min)
Entry
R
Product
Yield (%)a
Yield (%)a
1
2
3
4
5
6
7
8
H
4a
4b
4c
4d
4e
4f
400
210
180
150
120
240
200
260
15
60
65
65
73
40
65
45
90
35
26
20
15
70
50
65
40
70
73
70
80
55
75
55
2,4-DiCl
2-Cl
2,6-DiCl
2-Br
3-NO2
2-OCH3
3-Cl
4g
4h
9
4-CH3
4-OCH3
4-Br
6
7
3
88
85
89
2
95
90
90
10
11
3
<1
12
4-Cl
5
87
1
92
a
c
Isolated yields. b Method A. Method B.
47722 | RSC Adv., 2014, 4, 47721–47725
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Table 2 Antibacterial activity of 1H-pyrazolo[1,2-a]pyridazine-5,8-diones derivativesa
Inhibition zone (mm)
Compound*
Concentration
B.c (+)
S.a (+)
B.t (+)
E.c (ꢀ)
S.b (ꢀ)
S.m (ꢀ)
4b
1 (mg mLꢀ1
)
15 ꢃ 0.43a
13 ꢃ 0.33b
11 ꢃ 0.28c
10 ꢃ 0.28a
8 ꢃ 0.12b
NA
NA
NA
NA
NA
NA
NA
19 ꢃ 0.14a
16 ꢃ 0.16b
11 ꢃ 0.14c
11 ꢃ 0.33a
8 ꢃ 0.36b
7 ꢃ 0.00c
24 ꢃ 0.48a
16 ꢃ 0.54b
14 ꢃ 0.36c
10 ꢃ 0.23a
8 ꢃ 0.44b
NA
9 ꢃ 0.34a
7 ꢃ 0.16b
NA
NA
NA
11 ꢃ 0.41a
9 ꢃ 0.18b
NA
11 ꢃ 0.26a
9 ꢃ 0.55b
NA
0.1 (mg mLꢀ1
0.01 (mg mLꢀ1
)
)
4c
1 (mg mLꢀ1
)
9 ꢃ 0.21a
7 ꢃ 0.16b
NA
13 ꢃ 0.25a
11 ꢃ 0.22b
8 ꢃ 0.12c
8 ꢃ 0.17a
7 ꢃ 0.10b
NA
0.01 (mg mLꢀ1
0.01 (mg mLꢀ1
)
)
NA
4d
1 (mg mLꢀ1
)
16 ꢃ 0.26a
14 ꢃ 0.11b
10 ꢃ 0.47c
15 ꢃ 0.11a
12 ꢃ 0.47b
8 ꢃ 0.13c
15 ꢃ 0.26a
12 ꢃ 0.13b
8 ꢃ 0.16c
17 ꢃ 0.13a
15 ꢃ 0.21b
11 ꢃ 0.15c
10 ꢃ 0.37a
8 ꢃ 0.10b
NA
11 ꢃ 0.21a
9 ꢃ 0.33b
8 ꢃ 0.56c
21 ꢃ 0.17a
18 ꢃ 0.16b
14 ꢃ 0.14c
NA
NA
NA
NA
NA
7 ꢃ 0.00
NA
NA
NA
0.01 (mg mLꢀ1
0.01 (mg mLꢀ1
)
)
NA
NA
4e
1 (mg mLꢀ1
)
10 ꢃ 0.53a
9 ꢃ 0.24b
NA
7 ꢃ 0.55
13 ꢃ 0.46a
10 ꢃ 0.12b
7 ꢃ 0.38c
9 ꢃ 0.17a
7 ꢃ 0.00b
NA
0.01 (mg mLꢀ1
)
)
NA
0.01 (mg mLꢀ1
NA
4g
1 (mg mLꢀ1
)
10 ꢃ 0.17a
7 ꢃ 0.00b
NA
8 ꢃ 0.34a
7 ꢃ 0.14b
NA
8 ꢃ 0.46a
0.1 (mg mLꢀ1
0.01 (mg mLꢀ1
1 (mg mLꢀ1
0.1 (mg mLꢀ1
0.01 (mg mLꢀ1
1 (mg mLꢀ1
0.1 (mg mLꢀ1
0.01 (mg mLꢀ1
)
NA
NA
)
)
)
4f
)
12 ꢃ 0.23a
10 ꢃ 0.44b
7 ꢃ 0.00c
8 ꢃ 0.19
NA
9 ꢃ 0.17a
8 ꢃ 0.00b
NA
7 ꢃ 0.54
14 ꢃ 0.56a
11 ꢃ 0.16b
9 ꢃ 0.18c
7 ꢃ 0.33
NA
)
NA
NA
NA
NA
NA
NA
4h
)
9 ꢃ 0.18b
7 ꢃ 0.33
)
NA
NA
NA
NA
NA
NA
Positive control
Gentamaicin 10 mg
Penicillin 10 IU
Cephalexin 30 mg
DMSO
25 ꢃ 0.18
35 ꢃ 0.24
26 ꢃ 0.17
NA
NA
NA
NA
26 ꢃ 0.17
18 ꢃ 0.46
NA
NA
NA
NA
NA
22 ꢃ 24
NA
NA
20 ꢃ 0.12
NA
20 ꢃ 0.34
NA
16 ꢃ 0.15
NA
Negative control
NA
a
a, b and c show that the SD values are different for different concentrations (P < 0.05). NA: not active. *: see Table 1.
boydii. When comparing the antibacterial activity of the tested malononitrile with substituted benzaldehydes and also the
samples to those of reference antibiotics, the inhibitory potency reaction of the condensation product with maleic hydrazide.27,28
of some of the tested compounds were found to be good. As is seen in Table 1, for entries 9–12, the reaction stops at the
Although all the above bacteria were resistant to Penicillin, the Knoevenagel condensation product. A closer inspection reveals
antibacterial effects of some tested samples were higher than that such products are stabilized through conjugation of the
those of Penicillin on these bacteria. The above results indicate phenyl ring with the double bond moiety. The percentages and
that the synthesized compounds may be used in treatment of reaction times of other entries of Table 1 prove that the pres-
diseases caused by tested bacteria.
ence of substituents at 3 and especially at 2 positions of the
Data obtained from antibacterial assays are the averages of phenyl ring prevents the above said conjugation and hence
triplicate analyses and recorded as means ꢃ standard deviation. makes the reaction to proceed.
Analysis of variance was performed by Excel and SPSS procedures
In addition, the results of biological assessment clearly
using Student's t-test, and p value < 0.05 was regarded as signi- demonstrate that all the 1H-pyrazolo[1,2-a]pyridazine-5,8-
cant. Results of antibacterial assessment are presented in Table 2. diones exhibit antibacterial properties which may be helpful
in developing new therapeutic agents and preventing the
progress of various diseases. Future research should envision
studies on modication of these compounds to increase their
Conclusions
antibacterial activity (see Table 2).
In this work, novel 1H-pyrazolo[1,2-a]pyridazine-5,8-diones
have been synthesized in the presence of a catalytic amount
of triethanolamine, which is itself a relatively benign compound
used as an emulsier and surfactant in many industrial prod-
ucts such as liquid laundry detergents, dishwashing liquids,
general cleaners, hand cleaners, printing inks etc. The advan-
tages of this procedure are green reaction conditions, good
yields, short reaction times and the availability of the catalyst
(see Table 1 for comparison of yields and reaction times of
conventional and sonication procedures). Notably, triethanol-
amine catalyzes both the Knoevenagel condensation of
Acknowledgements
We gratefully acknowledge the support of this work by Research
Council of Bu-Ali Sina University.
Notes and references
1 J. T. Li, Y. J. Bian, H. J. Zang and T. S. Li, Synth. Commun.,
2002, 32, 547–551.
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2 J. L. Luche, Synthetic Organic Sonochemistry, Plenum Press, 27 Preparation of maleic hydrazide, Hydrazine hydrate (1.2
New York, 1998.
mmol, 98%) was added drop-wise to an ice-cold solution of
maleic anhydride (1.0 mmol) in 10 mL acetic acid and the
reaction mixture was reuxed for 4 h. A solid was obtained
aer cooling the reaction mixture to room temperature.
This crude product was ltered and washed with 50%
ethanol to give maleic hydrazide. (Yield: 75%; Mp: >300
ꢁC)., General procedure for the synthesis of 1H-pyrazolo
[1,2-a]pyridazine-5,8-diones, Conventional method, Maleic
hydrazide (3.0 mmol), aromatic aldehyde (3.0 mmol),
3 M. R. Nabid, S. J. T. Rezaei, R. Ghahremanzadeh and
A. Bazgir, Ultrason. Sonochem., 2010, 17, 159–161.
4 F. M. Herman, Encyclopedia of Polymer Science and
Technology, John Wiley & Sons Inc, New York, 3rd edn, 2004.
5 A. Strecker, Ann. Chem. Pharm., 1850, 75, 27–45.
6 B. B. Toure and D. G. Hall, Chem. Rev., 2009, 109, 4439–4486.
7 K. C. Nicolaou, R. Hanko and W. Hartwig, Chemistry –
Handbook of Combinatorial Chemistry – Drugs, Catalysts,
Materials, John Wiley & Sons Inc, 2002.
malononitrile
(3.0
mmol)
and
1–2
drops
of
8 L.-W. Xu, C.-G. Xia and L. Li, J. Org. Chem., 2004, 69, 8482–
8484.
9 E. C. Franklin, Chem. Rev., 1935, 16, 305–361.
10 T. Nakamura, M. Sato, H. Kakinuma, N. Miyata,
K. Taniguchi, K. Bando, A. Koda and K. Kameo, J. Med.
Chem., 2003, 46, 5416–5427.
11 O. Prakash, R. Kumar and V. Parkash, Eur. J. Med. Chem.,
2008, 43, 435–440.
12 M. A. F. Vera-DiVaio, A. C. C. Freitas, H. C. A. Castro,
S. d. Albuquerque, L. M. Cabral, C. R. Rodrigues,
triethanolamine (0.3 mmol, 10 mol%) were stirred and
reuxed in 10 mL ethanol–H2O (30 : 70). The progress of
the reaction was monitored by TLC. Aer completion of
the reaction, the mixture was poured into the cold water
(50 mL), the yellow precipitate ltered, washed several
times with 1 M sodium bicarbonate solution, water and
nally with hot 50% ethanol then ltered and dried,
Ultrasonic method, Maleic hydrazide (3.0 mmol), aromatic
aldehyde (3.0 mmol), malononitrile (3.0 mmol) and 1–2
drops of triethanolamine (0.3 mmol, 10 mol%) were added
to 5 mL H2O and the reaction vessel was placed in
ultrasonic bath at 60 ꢁC. The progress of the reaction was
monitored by TLC. Aer completion of the reaction, the
mixture was poured in cold water (50 mL), the precipitated
solid was ltered, washed several times with 1 M sodium
bicarbonate solution, water and nally with hot 50%
ethanol then ltered and dried. The experimental results
are summarized in Table 1. All the new compounds were
characterized by their spectral data (NMR, IR, Mass
spectra). For more details see ESI†
M.
G.
Albuquerque,
R.
C.
A.
Martins,
M. G. M. O. Henriques and L. R. S. Dias, Bioorg. Med.
Chem. Lett., 2009, 17, 295–302.
13 M. J. Genin, C. Biles, B. J. Keiser, S. M. Poppe, S. M. Swaney,
W. G. Tarpley, Y. Yagi and D. L. Romero, J. Med. Chem., 2000,
43, 1034–1040.
14 F. Wei, B. X. Zhao, B. Huang, L. Zhang, C. H. Sun,
W. L. Dong, D. S. Shin and J. Y. Miao, Bioorg. Med. Chem.
Lett., 2006, 16, 6342–6347.
15 Y. Xia, Z. W. Dong, B. X. Zhao, X. Ge, N. Meng, D. S. Shin and
J. Y. Miao, Bioorg. Med. Chem. Lett., 2007, 15, 6893–6899.
16 P. C. Lv, J. Sun, Y. Luo, Y. Yang and H. L. Zhu, Bioorg. Med.
Chem. Lett., 2010, 20, 4657–4660.
17 A. Padwa and A. G. Waterson, Curr. Org. Chem., 2000, 4, 175–
203.
18 R. V. A. Orru and M. De Greef, Synthesis, 2003, 1471–1499.
19 R. A. Clement, J. Org. Chem., 1960, 25, 1724–1727.
20 M. P. Clark, S. K. Laughlin, M. J. Laufersweiler,
R. G. Bookland, T. A. Brugel, A. Golebiowski, M. P. Sabat,
J. A. Townes, J. C. VanRens, J. F. Djung, M. G. Natchus,
B. De, L. C. Hsieh, S. C. Xu, R. L. Walter, M. J. Mekel,
S. A. Heitmeyer, K. K. Brown, K. Juergens, Y. O. Taiwo and
M. J. Janusz, J. Med. Chem., 2004, 47, 2724–2727.
21 H. W. Heine, R. Henrie, L. Heitz and S. R. Kovvali, J. Org.
Chem., 1974, 39, 3187–3191.
28 3-Amino-5,8-dioxo-1-phenyl-5,8-dihydro-1H-pyrazolo[1,2-a]-
pyridazine-2-carbonitrile (4a), m.p.: 291–294 ꢁC (dec.) 1H
NMR (400 MHz, DMSO-d6) d(ppm) 5.97 (s, 1H), 7.03 (s,
2H), 7.34 (m, 5H), 7.98 (s, 2H); 13C NMR (100 MHz, DMSO-
d6) d(ppm) 63.19, 64.90, 117.28, 128.31, 129.99, 130.19,
136.75, 137.41, 139.15, 151.82, 154.64, 157.69; IR (KBr,
cmꢀ1): 3388, 3328, 3236, 2196, 1666, 1645, 1559, 1437,
1370, 1287, 1173, 852, 699, 489; MS, m/z (%): 266 (M+)., 3-
Amino-1-(2,4-dichlorophenyl)-5,8-dioxo-5,8-dihydro-1H-
pyrazolo[1,2-a]pyridazine-2-carbonitrile (4b), m.p.: 273–
1
ꢁ
275 C (dec.) H NMR (400 MHz, DMSO-d6) d(ppm) 6.28 (s,
1H), 7.01–7.10 (dd, 2H), 7.42 (d, 1H), 7.58 (d, 1H), 7.63 (s,
1H), 8.07 (s, 2H); 13C NMR (100 MHz, DMSO-d6) d(ppm)
60.53, 61.77, 117.21, 129.65, 130.79, 133.89, 135.36, 136.79,
137.04, 152.50, 154.27, 157.68; IR (KBr, cmꢀ1): 3375, 3252,
3183, 3063, 2197, 1666, 1589, 1562, 1476, 1436, 1374, 1285,
1257, 1147, 1123, 1048, 992, 850, 815, 655, 581,487; MS, m/
z (%): 334 (M+)., 3-Amino-1-(2-chlorophenyl)-5,8-dioxo-5,8-
22 S. K. Singh, P. G. Reddy, K. S. Rao, B. B. Lohray, P. Misra,
S. A. Rajjak, Y. K. Rao and A. Venkateswarlu, Bioorg. Med.
Chem. Lett., 2004, 14, 499–504.
23 O. A. Awoyinka, I. O. Balogun and A. A. Ogunnowo, J. Med.
Plants Res., 2007, 1, 63–65.
dihydro-1H-pyrazolo[1,2-a]pyridazine-2-carbonitrile
(4c),
m.p.: 271–273 ꢁC (dec.); 1H NMR (400 MHz, DMSO-d6)
d(ppm) 6.31 (s, 1H), 7.03 (d, 1H), 7.09 (d, 1H), 7.35 (s, 2H) ,
7.47 (d, 2H), 8.04 (s, 2H); 13C NMR (100 MHz, DMSO-d6)
d(ppm) 62.83, 64.52, 117.00, 129.46, 131.54, 131.67, 132.82,
136.94, 137.16, 152.40, 154.52, 157.71, 158.09; IR (KBr,
cmꢀ1): 3384, 3265, 3185, 3062, 2202, 1698, 1677, 1644,
1586, 1562, 1476, 1436, 1371, 1336, 1288, 1255, 1123, 1048,
24 R. Vila, Flavonoids and further Polyphenols in the genus
Thymus, Thyme, Tyler and Francis, London, 2002.
25 S. Burt, Int. J. Food Microbiol., 2004, 94, 223–253.
26 P. J. K. Delaquis, K. Stanich, B. Girard and G. Mazza, Int. J.
Food Microbiol., 2002, 74, 101–109.
47724 | RSC Adv., 2014, 4, 47721–47725
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1022, 992, 848, 753, 702, 611, 560, 487; MS, m/z (%): 300
(M+).,
3-amino-1-(2,6-dichlorophenyl)-5,8-dioxo-5,8-
DMSO-d6) d(ppm) 62.03, 93.97, 117.26, 123.47, 125.08,
131.85, 135.32, 137.11, 141.48, 149.55, 152.28, 154.86,
157.78; IR (KBr, cmꢀ1): 3383, 3262, 3182, 3071, 2199, 1674,
1645, 1584, 1544, 1436, 1353, 1289, 1153, 994, 849, 731,
688, 594, 570, 488; MS, m/z (%): 311 (M+)., 3-Amino-1-(2-
methoxyphenyl)-5,8-dioxo-5,8-dihydro-1H-pyrazolo[1,2-a]
pyridazine-2-carbonitrile (4g), m.p.: 258–260 ꢁC (dec.); 1H
NMR (400 MHz, DMSO-d6) d(ppm) 3.73 (s,3H), 6.17 (s, 1H),
6.92 (d, 1H), 7.00–7.08 (m, 3H), 7.22 (d, 1H), 7.28 (t, 1H),
7.92 (s, 2H); 13C NMR (100 MHz, DMSO-d6) d(ppm) 57.41,
61.35, 62.24, 113.26, 122.26, 126.35, 129.18, 131.15, 136.57,
137.32, 152.23, 154.30, 157.68, 158.06; IR (KBr, cmꢀ1):
3371, 3245, 3181, 3062, 2197, 1686, 1669, 1644, 1588, 1563,
1492, 1442, 1373, 1344, 1291, 1247, 1027, 993, 850, 758,
749, 559, 489; MS, m/z (%): 296 (M+)., 3-Amino-1-(3-
chlorophenyl)-5,8-dioxo-5,8-dihydro-1H-pyrazolo[1,2-a]
pyridazine-2-carbonitrile (4h), m.p.: 278–280 ꢁC (dec.); 1H
NMR (400 MHz, DMSO-d6) d(ppm) 6.31 (s, 1H), 7.03 (d,
1H), 7.09 (d, 1H), 7.35 (s, 2H), 7.44–7.50 (m, 2H), 8.04 (s,
2H); 13C NMR (100 MHz, DMSO-d6) d(ppm) 58.43, 60.93,
117.86, 123.75, 124.68, 131.67, 134.79, 136.94, 141.58,
149.55, 152.22, 155.16, 157.71; IR (KBr, cmꢀ1): 3384, 3265,
3062, 2202, 1689, 1676, 1645, 1437, 1288, 849, 753, 561;
MS, m/z (%): 300 (M+).
dihydro-1H-pyrazolo[1,2-a]pyridazine-2-carbonitrile (4d),
m.p.: 274–276 ꢁC (dec.); 1H NMR (400 MHz, DMSO-d6)
d(ppm) 6.75 (s, 1H), 7.06 (d, 1H), 7.12 (d, 1H), 7.39 (t, 1H),
7.45 (d, 1H,), 7.56 (d, 1H), 8.17 (s, 2H); 13C NMR (100 MHz,
DMSO-d6) d(ppm) 58.18, 61.20, 116.61, 130.76, 130.92,
132.08, 132.53, 134.05, 136.79, 136.88, 153.18, 154.25,
157.62; IR (KBr, cmꢀ1): 3381, 3261, 2193, 1696, 1671, 1645,
1561, 1438, 1370, 1288, 1256, 1121, 840, 782, 559, 485; MS,
m/z (%): 334 (M+)., 3-Amino-1-(2-bromophenyl)-5,8-dioxo-
5,8-dihydro-1H-pyrazolo[1,2-a]pyridazine-2-carbonitrile
1
ꢁ
(4e), m.p.: 287–289 C (dec.); H NMR (400 MHz, DMSO-d6)
d(ppm) 6.30 (s, 1H), 7.03 (d, 1H), 7.09 (d, 1H), 7.26–7.48
(m, 3H), 7.61 (d, 1H), 8.04 (s, 2H); 13C NMR (100 MHz,
DMSO-d6) d(ppm)58.39, 61.90, 117.08, 129.41, 130.54,
131.97, 135.82, 136.94, 137.26, 154.40, 157.22, 158.71,
158.90; IR (KBr, cmꢀ1): 3381, 3310, 3263, 3184, 2199, 1697,
1673, 1649, 1585, 1562, 1470, 1436, 1367, 1288, 1144, 1020,
991, 849, 749, 487; MS, m/z (%): 346 (M+ + 2), 344 (M+)., 3-
Amino-1-(3-nitrophenyl)-5,8-dioxo-5,8-dihydro-1H-pyrazolo-
ꢁ
[1,2-a]pyridazine-2-carbonitrile(4f), m.p.: 269–271 C (dec.);
1H NMR (400 MHz, DMSO-d6) d(ppm) 6.22 (s, 1H), 7.01 (d,
1H), 7.07 (d, 1H), 7.68 (d, 1H), 7.92 (d, 1H, J¼7.4 Hz), 8.09
(s, 1H), 8.18 (d, 1H), 8.34 (s, 2H); 13C NMR (100 MHz,
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RSC Adv., 2014, 4, 47721–47725 | 47725