- About this Journal ·
- Abstracting and Indexing ·
- Advance Access ·
- Aims and Scope ·
- Annual Issues ·
- Article Processing Charges ·
- Articles in Press ·
- Author Guidelines ·
- Bibliographic Information ·
- Citations to this Journal ·
- Contact Information ·
- Editorial Board ·
- Editorial Workflow ·
- Free eTOC Alerts ·
- Publication Ethics ·
- Reviewers Acknowledgment ·
- Submit a Manuscript ·
- Subscription Information ·
- Table of Contents
Journal of Chemistry
Volume 2013 (2013), Article ID 636280, 7 pages
Alkylation and 1,3-Dipolar Cycloaddition of 6-Styryl-4,5-dihydro-2H-pyridazin-3-one: Synthesis of Novel N-Substituted Pyridazinones and Triazolo[4,3-b]pyridazinones
1Laboratoire de Chimie Organique et Analytique, Faculté des Sciences et Techniques, Université Sultan Moulay Slimane, BP 523, Béni-Mellal, Morocco
2Department of Chemistry and QOPNA, University of Aveiro, 3810-193 Aveiro, Portugal
3Laboratoire de Diffraction des Rayons X, Centre Nationale pour la Recherche, Scientifique et Technique, Rabat, Morocco
Received 9 June 2012; Accepted 18 September 2012
Academic Editor: Julia Revuelta
Copyright © 2013 Souad Mojahidi et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Some new N-substituted pyridazinones and triazolo[4,3-b]pyridazinones were synthesized, respectively, by simple alkylation and 1,3-dipolar cycloaddition of pyridazin-3-one with nitrile imines. The regioselectivity of the reactions was ascertained by 1H, 13C NMR spectroscopy and X-ray diffraction of the synthesized compounds.
Pyridazinone derivatives have been reported to exhibit a wide range of pharmacological activities such as antihypertensive [1, 2], anti-HIV , antibacterial,  aldose reductase inhibitors , hepatoprotective agents , and COX-2 inhibitors . It has also been reported that pyridazinone derivatives have remarkable anticancer activity [8, 9]. Recently, our research group has reported the synthesis and the antiproliferative activities of new pyridazinone derivatives. Some of these compounds exhibited significant cytotoxicity against human and murine cell lines (A2780, A549, P388, and P815) [10, 11]. As a part of our program we focused on pyridazinones with biological activity, and in connection with our interest in the chemistry of annelated pyridazinones [10–12], in this paper we report the synthesis of a new series of N-substituted pyridazinones and triazolo[4,3-b]pyridazinones, which were obtained, respectively, by alkylation and 1,3-dipolar cycloaddition of 6-styryl-4,5-dihydro-2H-pyridazin-3-one.
2. Experimental Section
Melting points were determined using a Büchi-Tottoli apparatus and are uncorrected. 1H and 13C NMR spectra were recorded in CDCl3 or DMSO-d6 and solution (unless otherwise specified) with TMS as an internal reference using a Bruker AC 300 (1H) or 75 MHz (13C) instruments. Chemical shifts are given in δ parts per million (ppm). Multiplicities of 13C NMR resources were assigned by distortionless enhancement by polarization transfer (DEPT) experiments. IR spectra were recorded on a Perkin-Elmer 577 spectrometer (Perkin-Elmer, USA) using KBr disks; only noteworthy IR absorptions are listed (cm−1). High resolution mass spectra were recorded on an Agilent ESI-TOF mass spectrometer. Column chromatography was carried out on SiO2 (silica gel 60 Merck 0.063–0.200 mm). Thin-layer chromatography (TLC) was carried out on SiO2 (silica gel 60, F 254 Merck 0.063–0.200 mm), and the spots were located with UV light (254 nm). Commercial reagents were used without further purification unless stated. Compounds 4a, b were prepared according to the literature methods [13, 14].
2.1. Synthesis of Pyridazin-3-ones 4a, b
A mixture of the appropriate aldehyde (4 mmol), levulinic acid (4 mmol, 0.46 g), morpholine (3 drops), and glacial acetic acid (9 drops) was heated in toluene at 60°C for 12 h. The solvent was evaporated; the reaction mixture was cooled and washed with acetic acid : water (1 : 4). In each case the formed precipitate was filtered and dried to give the corresponding compound 3. A solution of each compound 3a, b (4.3 mmol) in 20 mL of glacial acetic acid containing hydrazine hydrate (0.5 g, 10 mmol) was heated at reflux for 30 h. The acetic acid was evaporated under vacuum and the residue was taken up with cold water. The precipitate was filtered, washed with cold water, dried, and purified by column chromatography (EtOAc/hexane 4/6).
2.2. 6-Styryl-4,5-dihydro-2H-pyridazin-3-one (4a)
Yield: 65%; mp: 160–162°C; IR (KBr, cm−1): 3420–3350 (NH), 1680 (CO); 1H NMR (DMSO-d6): δ 2.42 (t, 2H, CH2, Hz), 2.78 (t, 2H, CH2, Hz), 6.88 (d, 1H, Hz), 7.05 (d, 1H, Hz), 7.27–7.41 (m, 3H, ArH), 7.57–7.60 (m, 2H, ArH), 10.89 (s, 1H, NH); 13C NMR (DMSO-d6): 20.6 (CH2), 26.3 (CH2), 126.8 (CH-vinyl), 127.4 (2CH), 128.9 (CH), 129.3 (2CH), 133.9 (CH-vinyl), 136.5 (C), 151.2 (C), 167.7 (CO).
2.3. 6-[2-(4-Methoxyphenyl)vinyl]-4,5-dihydro-2H-pyridazin-3-one (4b)
Yield: 62%; mp: 164–166°C; IR (KBr, cm−1): 3450–3350 (NH), 1685 (C=O); 1H NMR (DMSO-d6): δ 2.38 (t, 2H, CH2, Hz), 2.75 (t, 2H, CH2, Hz), 3.78 (s, 3H, CH3O), 6,74 (d, 1H, Hz), 6.92 (d, 2H, Hz), 6.98 (d, 1H, Hz), 7.50 (d, 2H, Hz), 10.80 (s, 1H, NH); 13C NMR (DMSO-d6): 20.6 (CH2), 26.4 (CH2), 55.6 (CH3O), 114.7 (2CH), 124.6 (CH-vinyl), 128.8 (2CH), 129.2 (C), 133.6 (CH-vinyl), 151.4 (C), 160.1 (C), 167.7 (CO).
2.4. Synthesis of N-Substituted Pyridazinones 5a–c
To a solution of compound 4a (1.22 g, 6.13 mmol) in dry THF (30 mL) was added potassium carbonate (2.50 g, 18.30 mmol). The selected alkyl halide (7.40 mmol) was added dropwise. Upon disappearance of the starting material as indicated by TLC, the solvent was evaporated under vacuum. The crude material was dissolved with CH2Cl2 (50 mL), washed with water and brine, dried over MgSO4 and the solvent was evaporated at reduced pressure. The resulting residue was purified by column chromatography (EtOAc/hexane 3/7).
2.5. 2-Methyl-6-styryl-4,5-dihydro-2H-pyridazin-3-one (5a)
Yield: 85%; mp: 136–138°C; IR (KBr, cm−1): 1666 (CO); 1H NMR (CDCl3): δ 2.53 (t, 2H, CH2, Hz), 2.79 (t, 2H, CH2, Hz), 3.45 (s, 3H, NCH3), 6.84 (d, 1H, Hz), 6.93 (d, 1H, Hz), 7.24–7.48 (m, 5H); 13C NMR (CDCl3): δ 21.2 (CH2), 26.8 (CH2), 36.6 (NCH3), 126.8 (CH-vinyl), 127.4 (2CH), 128.7 (CH), 128.9 (2CH), 134.5 (CH-vinyl), 135.8 (C), 151.7 (C), 165.8 (CO); HRMS (ESI-TOF) m/z: calculated for C13H15N2O [M + H]+: 215.11844 found: 215.11816.
2.6. 2-Allyl-6-styryl-4,5-dihydro-2H-pyridazin-3-one (5b)
Yield: 72%; mp: 178–180°C; IR (KBr, cm−1): 1670 (CO); 1H NMR (CDCl3): δ 2.57 (t, 2H, CH2, Hz), 2.81 (t, 2H, CH2, Hz), 4.41–4.44 (m, 2H, NCH2), 5.18–5.26 (m, 2H, =CH2), 5.86–5.97 (m, 1H, =CH), 6,86 (d, 1H, Hz), 6.94 (d, 1H, Hz), 7.31–7.39 (m, 3H), 7.46–7.50 (m, 2H); 13C NMR (CDCl3): δ 21.1 (CH2), 26.9 (CH2), 50.9 (NCH2), 117.0 (=CH2), 126.1 (CH), 127.0 (2CH), 128.4 (CH), 128.9 (2CH), 132.8 (CH), 134.4 (CH), 135.8 (C), 151.9 (C), 165.4 (CO); HRMS (ESI-TOF) m/z: calculated for C15H17N2O [M + H]+: 241.13950 found: 241.13936.
2.7. 2-(2-Oxo-2-phenylethyl)-6-styryl-4,5-dihydro-2H-pyridazin-3-one (5c)
Yield: 60%; mp: 88–90°C; IR (KBr, cm−1): 1675 (CO), 1690 (CO); 1H NMR (CDCl3): δ 2.67 (t, 2H, CH2, Hz), 2.91 (t, 2H, CH2, Hz), 5.25 (s, 2H, NCH2), 6.85 (d, 1H, Hz), 6.92 (d, 1H, Hz), 7.29–7.38 (m, 3H), 7.45–7.52 (m, 4H), 7.57–7.62 (m, 1H), 7.96–8.00 (m, 2H); 13C NMR (CDCl3): δ 21.2 (CH2), 26.6 (CH2), 55.2 (NCH2), 125.9 (CH), 127.1 (2CH), 128.0 (2CH), 128.4 (CH), 128.7 (2CH), 128.9 (2CH), 133.6 (CH), 134.6 (CH), 135.0 (C), 135.8 (C), 152.2 (C), 166.5 (CO), 192.9 (CO). HRMS (ESI-TOF) m/z: calculated for C20H19N2O2 [M + H]+: 319.14465 found: 319.14438.
2.8. General Procedure for the Preparation of Triazolo[4,3-b]pyridazinones 8a–e
To a solution of pyridazin-3(2H)-one (4a) (1.0 g, 5 mmol) and ethyl hydrazono-α-bromoglyoxylate (6a–e)(5 mmol) in dry THF (50 mL), K2CO3 (2.1 g, 15 mmol) was added. The mixture was refluxed in each case for 5–8 h. After evaporation of the solvent, the residue was purified by column chromatography on silica gel using Hexane-EtOAc 80 : 20 as eluent.
2.9. 6-Oxo-8a-styryl-1-p-tolyl-1,5,6,7,8,8a-hexahydro-[1,2,4]triazolo[4,3-b]pyridazine-3-carboxylic Acid Ethyl Ester (8a)
Yield: 56%; mp: 182–184°C; IR (KBr, cm−1): 1685 (CONH), 1710 (CO ester), 3050 (NH); 1H NMR (CDCl3): δ 1.40 (t, 3H, CH3, Hz), 2.28 (s, 3H, CH3), 2.26–2.39 (m, 3H), 2.78–2.89 (m, 1H), 4.37 (q, 2H, CH2O, Hz), 6,49 (d, 1H, Hz), 6.83 (d, 1H, Hz), 7.08 (d, 2H, Hz), 7.22 (d, 2H, Hz), 7.28–7.39 (m, 3H, ArH), 7.43–7.46 (m, 2H, ArH), 7.53 (s, 1H, NH); 13C NMR (CDCl3): δ 14.2 (CH3), 20.7 (CH3), 28.6 (CH2), 29.5 (CH2), 62.2 (CH2O), 88.1 (C-8a), 117.8 (2CH), 127.1 (2CH), 128.7 (2CH), 128.9 (CH), 129.8 (2CH), 133.0 (C), 133.5 (CH), 135.3 (C), 138.4 (C), 140.6 (C), 146.1 (C), 158.2 (CO), 174.3 (CO ester); HRMS (ESI-TOF) m/z: calculated for C23H25N4O3 [M + H]+: 405.19212 found: 405.19201.
2.10. 1-(4-Chloro-phenyl)-6-oxo-8a-styryl-1,5,6,7,8,8a-hexahydro-[1,2,4]triazolo[4,3-b]pyridazine-3-carboxylic Acid Ethyl Ester (8b)
Yield: 65%; mp: 185–187°C; IR (KBr, cm−1): 1680 (CONH), 1720 (CO ester), 3035 (NH); 1H NMR (CDCl3): δ 1.40 (t, 3H, CH3, Hz), 2.29–2.44 (m, 3H), 2.83–2.90 (m, 1H), 4.38 (q, 2H, CH2O, Hz), 6,48 (d, 1H, Hz), 6.81 (d, 1H, Hz), 7.21–7.30 (m, 4H, ArH), 7.33–7.44 (m, 5H, ArH), 7.54 (s, 1H, NH); 13C NMR (CDCl3): δ 14.2 (CH3), 28.7 (CH2), 29.4 (CH2), 62.4 (CH2O), 87.7 (C-8a), 118.1 (2CH), 127.1 (2CH), 128.5 (CH), 128.8 (2CH), 129.0 (CH), 129.8 (2CH), 134.1 (CH), 135.0 (C), 139.3 (C), 140.2 (C), 145.9 (C), 158.5 (CO), 174.1 (CO ester); HRMS (ESI-TOF) m/z: calculated for C22H21ClN4O3Na [M + Na]+: 447.11944 found: 447.11900.
2.11. 1-(4-Nitro-phenyl)-6-oxo-8a-styryl-1,5,6,7,8,8a-hexahydro-[1,2,4]triazolo[4,3-b]pyridazine-3-carboxylic Acid Ethyl Ester (8c)
Yield: 49%; mp: 168–170°C; IR (KBr, cm−1): 1530, 1320 (NO2), 1670 (CONH), 1725 (CO ester), 3050 (NH); 1H NMR (CDCl3): δ 1.41 (t, 3H, CH3, Hz), 2.24–2.36 (m, 3H), 2.74–2.81 (m, 1H), 4.39 (q, 2H, CH2O, Hz), 6,22 (d, 1H, Hz), 6.85 (d, 1H, Hz), 7.32–7.39 (m, 6H, ArH), 7.71 (s, 1H, NH), 7.73–7.78 (m, 1H, ArH), 8.03–8.13 (m, 2H, ArH); 13C NMR (CDCl3): δ 14.1 (CH3), 29.1 (CH2), 30.4 (CH2), 62.5 (CH2O), 86.8 (C-8a), 122.1 (2CH), 122.8 (CH), 126.4 (2CH), 126.9 (2CH), 128.9 (2CH), 129.1 (CH), 132.5 (CH), 134.8 (C), 140.1 (C), 142.2 (C), 146.4 (C), 157.9 (CO), 172.1 (CO ester); HRMS (ESI-TOF) m/z: calculated for C22H22N5O5 [M + H]+: 436.16155 found: 436.16116.
2.12. 1-(2-Methyl-3-nitro-phenyl)-6-oxo-8a-styryl-1,5,6,7,8,8a-hexahydro-[1,2,4]triazolo[4,3-b]pyridazine-3-carboxylic Acid Ethyl Ester (8d)
Yield: 51%; mp: 136–138°C; IR (KBr, cm−1): 1545, 1310 (NO2), 1670 (CONH), 1710 (CO ester), 3060 (NH); 1H NMR (CDCl3): δ 1.40 (t, 3H, CH3, Hz), 2.01–2.11 (m, 1H), 2.40 (s, 3H, CH3), 2.45–2.64 (m, 3H), 4.40 (q, 2H, CH2O, Hz), 6,15 (d, 1H, Hz), 6.86 (d, 1H, Hz), 7.29–7.41 (m, 6H, ArH), 7,52 (d, 1H, Hz), 7.76 (s, 1H, NH), 7,80 (d, 1H, Hz); 13C NMR (CDCl3): δ 14.1 (CH3), 16.0 (CH3), 28.6 (CH2), 30.3 (CH2), 62.6 (CH2O), 88.9 (C-8a), 123.8 (CH), 126.2 (CH), 126.7 (CH), 127.0 (2CH), 128.9 (2CH), 129.1 (CH), 131.9 (C), 133.0 (CH), 133 (CH), 134.9 (C), 140.2 (C), 147.4 (C), 157.8 (CO), 171.9 (CO ester).
2.13. 1-(2,4-Dibromo-phenyl)-6-oxo-8a-styryl-1,5,6,7,8,8a-hexahydro-[1,2,4]triazolo[4,3-b]pyridazine-3-carboxylic Acid Ethyl Ester (8e)
Yield: 46%; mp: 160–162°C; IR (KBr, cm−1): 1675 (CONH), 1715 (CO ester), 3060 (NH); 1H NMR (CDCl3): δ 1.38 (t, 3H, CH3, Hz), 2.08–2.18 (m, 1H), 2.45–2.62 (m, 2H), 2.78–2.90 (m, 1H), 4.39 (q, 2H, CH2O, Hz), 6,20 (d, 1H, Hz), 6.79 (d, 1H, Hz), 7,14 (d, 1H, Hz), 7.32–7.38 (m, 5H, ArH), 7,40 (dd, 1H, and 2.2 Hz), 7.61 (s, 1H, NH), 7,80 (d, 1H, Hz); 13C NMR (CDCl3): δ 14.2 (CH3), 28.9 (CH2), 31.9 (CH2), 62.5 (CH2O), 88.0 (C-8a), 122.2 (C), 123.8 (C), 127.0 (2CH), 128.8 (2CH), 128.9 (CH), 131.1 (CH), 131.9 (CH), 133.0 (CH), 136.7 (CH), 138.5 (CH), 142.5 (C), 146.2 (C), 157.9 (CO), 173.1 (CO ester).
3. Results and Discussion
The starting compounds 6-(styryl)-4,5-dihydropyridazinones 4a, b used for alkylation reaction and 1,3-dipolar cycloadditions, were prepared from levulinic acid 1 according to Scheme 1. The treatment of compound 1 with the aromatic aldehydes 2a, b produced the intermediate benzylidenelevulinic acid 3a, b. The derivatives 3a, b obtained were then treated with hydrazine hydrate in refluxing acetic acid in order to achieve the desired styrylpyridazinones 4a, b.
The structure of compound 4a was confirmed for the first time by X-ray crystallography (Figures 1 and 2 and Table 1). The crystal structure of this compound, whose molecular formula is C12H12N2O, was determined by single-crystal diffraction methods. The compound crystallizes in the monoclinic unit cell space group symmetry with lattice parameters: Å, Å, Å, and ; Å3 and D (calc., ) = 1.261 Mg m−3. A total of 11692 data reflections were collected over the range of ; of these, 1647 (independent and with I ≥2σ(I)) were used in the structural analysis. The final and residuals were 0.054 and 0.179, respectively.
In compound 4a, the dihydropyridazinone ring is oriented at dihedral angles of 17.11 (9)° with respect to the benzene ring. In the crystal, the molecules are linked by N–H…O hydrogen bonds (Figure 2).
The N-alkylation reaction in the pyridazinone series is generally used for the introduction of pharmacophoric groups; consequently first of all it is necessary to study the alkylation reaction in the presence of 4,5-dihydropyridazinone and base in order to establish their reactivity and possible regioselectivity. The treatment of 6-styryl-4,5-dihydropyridazinone (4a) with alkyl halides (CH3I, BrCH2CH=CH2 and BrCH2COC6H5) in the presence of anhydrous K2CO3 in dry THF gave only the N-substituted-pyridazinones 5a–c in moderate to good yields (Scheme 2).
The structures of N-substituted pyridazinones 5a–c were characterized using 1H NMR and 13C NMR spectra. The exclusive alkylation at the 2-N position was confirmed by X-ray crystallography of compound 5a (Figures 3 and 4 and Table 2). The crystal structure of compound 5a, whose molecular formula is C13H14N2O, was also determined by single-crystal diffraction methods. The compound crystallizes in the monoclinic unit cell space group symmetry with lattice parameters: Å, Å, Å, and ; Å3 and D (calc., ) = 1.261 Mg m−3. A total of 13216 data were collected over the range of ; of these, 3329 (independent and with I ≥2σ(I)) were used in the structural analysis. The final and residuals were 0.051 and 0.167, respectively.
In compound 5a, the dihydropyridazinone ring is oriented at dihedral angles of 20.96 (8)° with respect to the benzene ring. In the crystal, molecules are linked by C–H…O hydrogen bonds (Figure 4).
1,3-Dipolar cycloadditions offer a convenient one-step concerted route for the construction of five-membered heterocycles with multiple stereogenic centers [15–21]. In the present work, we report a full account on the examination on 1,3-dipolar cycloaddition reaction of 6-styryl-4,5-dihydropyridazinone 4a with nitrile imines. The former compound has three potential dipolarophilic sites: the C=N double bond, the C=C double bond, and the C=O double bond. The reaction of compound 4a with N-aryl-C-ethoxycarbonyl nitrile imines 7a–e, generated in situ from ethyl hydrazono-α-bromoglyoxylates 6a–e  and K2CO3, was performed in refluxing dry THF. In all cases, only one type of triazolo[4,3-b]pyridazinone (8a–e) was obtained in moderate to good yields (Scheme 3). No adducts resulting from condensation on the double bonds C=C and/or C=O were detected. The reaction was exclusively site- and regioselective.
The structural assignments of the triazolo[4,3-b]pyridazinones 8a–e are based on a full characterization by 1H NMR and 13C NMR spectra.
The 1H NMR spectra of the compounds 8a–e, show in particular the presence of two doublet signals at ranges 6.15–6.49 ppm and 6.79–6.86 ppm corresponding to the vinylic protons of the double bond HC=CH with a coupling constant of ca. 16.1–16.5 Hz; this excludes the addition of the dipole to the double bond HC=CH.
The 13C NMR spectra of cycloadducts 8a–e, exhibit a signal at 157.8–158.5 ppm assigned to the resonance of carbonyl carbon C=O; this excludes also the addition of the nitrile imine to the double bond C=O. These results demonstrate the site selectivity of the double bond C=N; the 13C NMR spectra of cycloadducts 8a–e, exhibit in each case a signal at 85.9–89.6 ppm due to the resonance of each quaternary carbon C-8. These carbon centres are then slightly deshielded. Such fact confirms the direction of the dipole addition to the C=N double bond; otherwise, the C-8 signals would appear upfield (the value would be <60 ppm).
The reaction is thus regioselective and no 1,2,3-triazole is formed.
In summary, with a simple approach, a series of new N-substituted pyridazinones and triazolo[4,3-b]pyridazinones can be synthesized, from moderate to good yields, by reaction of 6-styryl-4,5-dihydro-2H-pyridazin-3-one 4a with alkyl halides and using N-aryl-C-ethoxycarbonyl nitrile imines as 1,3-dipoles.
The authors thank the FCT-Portugal and CNRST-Morocco for financial assistance to the joint collaborative project. Thanks are also due to the Portuguese Foundation for Science and Technology (FCT) and FEDER, for funding the Organic Chemistry Research Unit—QOPNA (Project PEst-C/QUI/UI0062/2011).
- S. Demirayak, A. C. Karaburun, and R. Beis, “Some pyrrole substituted aryl pyridazinone and phthalazinone derivatives and their antihypertensive activities,” European Journal of Medicinal Chemistry, vol. 39, no. 12, pp. 1089–1095, 2004.
- A. A. Siddiqui, R. Mishra, and M. Shaharyar, “Synthesis, characterization and antihypertensive activity of pyridazinone derivatives,” European Journal of Medicinal Chemistry, vol. 45, no. 6, pp. 2283–2290, 2010.
- Z. K. Sweeney, J. P. Dunn, Y. Li et al., “Discovery and optimization of pyridazinone non-nucleoside inhibitors of HIV-1 reverse transcriptase,” Bioorganic and Medicinal Chemistry Letters, vol. 18, no. 15, pp. 4352–4354, 2008.
- M. Sonmez, I. Borber, and E. Akbas, “Synthesis, antibacterial and antifungal activity of some new pyridazinone metal complexes,” European Journal of Medicinal Chemistry, vol. 41, no. 1, pp. 101–105, 2006.
- L. Costantino, G. Rastelli, G. Cignarella, and D. Barlocco, “Synthesis and aldose reductase inhibitory activity of a new series of benzo[h]cinnolinone derivatives,” Farmaco, vol. 55, no. 8, pp. 544–552, 2000.
- S. K. Kwon and A. Moon, “Synthesis of 3-alkylthio-6-allylthiopyridazine derivatives and their antihepatocarcinoma activity,” Archives of Pharmacal Research, vol. 28, no. 4, pp. 391–394, 2005.
- R. R. Harris, L. Black, S. Surapaneni et al., “ABT-963 [2-(3,4-difluoro-phenyl)-4-(3-hydroxy-3-methyl-butoxy)-5-(4- methanesulfonyl-phenyl)-2H-pyridazin-3-one], a highly potent and selective disubstituted pyridazinone cyclooxgenase-2 inhibitor,” Journal of Pharmacology and Experimental Therapeutics, vol. 311, no. 3, pp. 904–912, 2004.
- W. Malinka, A. Redzicka, and O. Lozach, “New derivatives of pyrrolo[3,4-d]pyridazinone and their anticancer effects,” Farmaco, vol. 59, no. 6, pp. 457–462, 2004.
- N. F. Abd El-Ghaffar, M. K. Mohamed, M. S. Kadah, A. M. Radwan, G. H. Said, and S. N. Abd el Al, “Synthesis and anti-tumor activities of some new pyridazinones containing the 2-phenyl-1H-indolyl moiety,” Journal of Chemical and Pharmaceutical Research, vol. 3, no. 3, pp. 248–259, 2011.
- S. Mojahidi, E. M. Rakib, H. Sekkak et al., “Synthesis and in-vitro cytotoxic evaluation of novel pyridazin-4-one derivatives,” Archiv der Pharmazie, vol. 343, no. 5, pp. 310–313, 2010.
- H. Sekkak, S. Mojahidi, E. M. Rakib et al., “Synthesis and antiproliferative evaluation of spirothiadiazolopyridazine derivatives,” Letters in Drug Design and Discovery, vol. 7, no. 10, pp. 743–746, 2010.
- S. Abouricha, E. M. Rakib, N. Benchat, M. Alaoui, H. Allouchi, and B. El Bali, “Facile synthesis of new spirothiadiazolopyridazines by 1,3-dipolar cycloaddition,” Synthetic Communications, vol. 35, no. 16, pp. 2213–2221, 2005.
- S. H. Zaheer, I. K. Kacker, and N. S. Rao, “Über die Kondensation von Lavulinsaure mit aromatischen Aldehyden,” Chemische Berichte, vol. 89, no. 2, pp. 351–354, 1956.
- I. Sircar, R. P. Steffen, G. Bobowski et al., “Cardiotonic agents. 9. Synthesis and biological evaluation of a series of (E)-4,5-dihydro-6-[2-[4-(1H-imidazol-1-yl)phenyl]ethenyl]-3(2H)-pyridazinones: a novel class of compounds with positive inotropic, antithrombotic, and vasodilatory activities for the treatment of congestive heart failure,” Journal of Medicinal Chemistry, vol. 32, no. 2, pp. 342–350, 1989.
- R. Huisgen, “1,3-dipolar cycloadditions. Past and future,” Angewandte Chemie, vol. 2, no. 10, pp. 565–598, 1963.
- R. Huisgen, “Kinetics and mechanism of 1,3-dipolar cycloadditions,” Angewandte Chemie, vol. 2, no. 11, pp. 633–645, 1963.
- A. Padwa, Ed., 1,3-Dipolar Cycloaddition Chemistry, Wiley, New York, NY, USA, 1984.
- K. V. Gothelf and K. A. Jorgensen, “Asymmetric 1,3-dipolar cycloaddition reactions,” Chemical Reviews, vol. 98, no. 2, pp. 863–909, 1998.
- A. Padwa and A. M. Schoffsttall, in Advances in Cycloaddition, D. P. Curran, Ed., vol. 2, pp. 1–89, JAI, London, UK, 1990.
- S. Kobayashi and K. A. Jorgensen, Eds., Cycloaddition Reactions in Organic Synthesis, Wiley-VCH, Weinheim, Germany, 2002.
- A. Padwa, Synthetic Applications of 1, 3-Dipolar Cycloaddition Chemistry Toward Heterocycles and Natural Products, John Wiley & Sons, 2002.
- D. B. Sharp and C. S. Hamilton, “Derivatives of 1,2,4-triazole and of pyrazole,” Journal of the American Chemical Society, vol. 68, no. 4, pp. 588–591, 1946.