HETEROCYCLES

Paper | Regular issue | Vol. 87, No. 11, 2013, pp. 2249-2266
Received, 1st August, 2013, Accepted, 17th September, 2013, Published online, 3rd October, 2013.
DOI: 10.3987/COM-13-12799

■ A Novel Synthetic Approach towards 1H-Pyrazole-5-carboxylic Acid Derivatives Using 4-(4-Methylbenzoyl)-5-(4-methylphenyl)furan-2,3-dione

Elif Korkusuz,* Ismail Yıldırım, and Ertan Şahin

Kayseri Vocational College, Erciyes University, Kayseri 38039, Turkey

Abstract

The 1H-pyrazole-5-carboxylic acid derivatives were obtained by reactions of 4-(4-methylbenzoyl)-5-(4-methylphenyl)furan-2,3-dione with 2,4-dinitrophenyhydrazine. So, new derivatives of 1H-pyrazole-5-carboxylic acid which are potential biological active compounds, were synthesized for the first time. The structures of all new synthesized products were characterized by IR, 1H-, 13C NMR, APT, and 2D NMR (HETCOR, COSY) spectroscopic data and elemental.

INTRODUCTION
The pyrazole scaffold represents a common motif in many pharmaceutical active and remarkable compounds demonstrating a wide range of pharmacological activities; the most important activities are the anti-inflammatory,1 the antibacterial, antifungal,2-5 the hypoglycemic,6,7 the anti-hyperlipidemic,8 the inhibition of cyclooxigenase-2,9,10 p38 MAP kinase11 and CDK2/Cyclin A,12,13 and the antiangiogenic.13 Some bioactive small molecules with pyrazole substructure are currently used as therapeutic agents (Figure 1). Therefore, continuous efforts are being made to develop a more efficient and generally applicable synthetic protocol for the synthesis of diversified pyrazole derivatives.

2,3-Furandiones are very susceptible to attacking of nucleophiles and are very important synthons for lots of heterocyclic compounds,14-17 one of which is pyrazole derivatives. The reactions of furan-2,3-diones of type 1 with various hydrazines to yield derivatives of pyrazole-3-carboxylic acid were reported by Akçamur and co-workers,14-17 but they couldn’t obtain 1H-pyrazole-5-carboxylic acid derivatives. Herein, we report the first synthesis of a new 1H-pyrazole-5-carboxylic acid derivative 3 from the reactions of 4-(4-methylbenzoyl)-5-(4-methylphenyl)furan-2,3-dione (1) with 2,4-dinitrophenylhydrazine (Scheme 1). In progression of our study, we also present new reactions of 1H-pyrazole-5-carboxylic acid 3 with various N- and O-nucleophiles such as amine, hydrazine and alcohol derivatives (see Scheme 3). As seen from Scheme 1 in particular, the compound 3 has been first synthesized from these reactions, and the results obtained from all experiments are discussed in this study.

RESULTS AND DISCUSSION
The reaction of the compound 1 with 2,4-dinitrophenylhydrazine led to the formation of the corresponding white colored 1H-pyrazole-5-carboxylic acid 3 under reflux in toluene. The progress of the reactions was monitored by thin-layer chromatography until complete consumption of the starting materials. Work-up of the reaction did not yield the expected pyrazole-3-carboxylic acid, however, the 1H-pyrazole-5-carboxylic acid 3 was obtained in 77% yield (Scheme 1). The moderate to good yield of the reaction can be explained by the chemical behavior of furan-2,3-dione, similar to the behavior of the compound 1 toward N-nucleophiles.14-23 Due to the presence of three electrophilic sites with different reactivity at C2, C3 and C5 in furandiones of type 1 that can react with nucleophiles, the reactions of 1 with 2,4-dinitrophenylhydrazine may produce three isomeric products (see Scheme 2). When the reaction mixture was analyzed, signals corresponding to the second product 2 was observed in both 1H and 13C NMR spectra. We then proved the effect of solvent for any noticeable change in selectivity and yield for the reaction of the compound 1 with 2,4-dinitrophenylhydrazine. Various other solvents such as toluene, benzene, xylene, and acetonitrile were used as the reaction medium to optimize the reaction conditions. The reaction in toluene reached completion in 30 min, with isolated yield of 77% of the product. This result indicated that toluene was the suitable solvent for the formation of the compound 3. On the other hand, the reaction in benzene reached completion in 5 h, with isolated yield of 45% of the product. This result indicated that benzene was the suitable solvent for the compound 2. The formation of the products 2 and 3 was identified by elemental analyses and IR, 1H- and 13C NMR spectroscopic data. The 1H NMR spectrum of 2, displays a singlet at 10.30 ppm attributable to the -OH proton (D2O exchangeable) of the pyridazine ring. The singlets at 2.31 and 2.19 ppm could be ascribed to the -CH3 protons of the phenyl and benzoyl ring. The IR spectra of the pyridazin-3(2H)-one 2 showed characteristic absorption bands at 3288 cm−1 and 1786, 1689 cm−1 due to O-H stretchings and two C=O groups, respectively. The product 2 did not show any tendency to tautomer 2B both in DMSO and acetone, therefore, its 2A was anticipated to be more stabilized form by spectroscopic analyses and intramolecular hydrogen bridges. The IR spectra of the 1H-pyrazole-5-carboxylic acid 3 showed broad absorption in the region 3162-3048 cm−1 indicating the appearance of CO2H. 1H NMR spectra of the compound 3 have signals of all corresponding protons and the integration curves to prove the number of protons. The 11 aromatic protons of the aryl groups in compound 3 appear as a ABX and two AA’BB’ spin systems in the area of 9.10-7.03 ppm. Two methyl groups have two singlet signals in the area of 2.41 and 2.28 ppm. The 1H-decoupled 13C NMR spectrum of 3 showed 21 resonances, in good agreement with the proposed structure (see Experimental Section). The values of the elementel analysis were found to be in good agreement (±0.3) with the calculated values. The structures of all new synthesized products were also based on an X-ray study (5b).
The formation of compounds 2 and 3 may be initiated by Michael addition, via nucleophilic attack at C5 atom of the furan ring in 1 by the NH2 group of 2,4-dinitrophenylhydrazine. Whereas, in the previous reactions, nucleophilic attack of the NH2 groups of the hydrazines occurred at C3 atom of the furan ring. However, unlike the reaction to the literature,14-16,21 the nucleophilic attack of the hydrazine derivative took place at C5 instead of C3 atom of the furan ring in 1. 2,4-Dinitrophenylhydrazine behaved differently in these reactions. This situation is compatible with the fact that the 2,4-dinitrophenyl group is electron acceptor group due to the inductive and resonance effects and steric hindrance. Then, the compounds 2 and 3 obtained with an attack of second NH group to the antibonding (π*) orbitals at the carbonyl carbons at C2 and C3 positions, respectively. Therefore, the new products 2 and 3 obtained arise from the sequential attacks of the hydrazine derivative at the lactone moiety of 1, followed by the elimination of a molecule of water. In addition, the reaction speeds of the final steps of these reactions should probably be much slower than the reaction speeds of their first steps. A reasonable proposal for the reaction pathways from furandione 1 to the pyridazin-3(2H)-one 2 and 1H-pyrazole-5-carboxylic acid derivative 3 is outlined briefly in Scheme 2.

The compound 3 can easily be transformed into the corresponding 1H-pyrazole-5-carboxylic acid chloride 4 by usual chemical procedures15 (see Scheme 3). Substituted furan-2,3-dione, acid 3 and acid chloride 4, which are used as an important initial materials in the synthesis of the target heterocycles, were prepared using the literature procedures.14,15,23 The structure of 4 was confirmed by analytical and spectral data. In addition, conversion of 1H-pyrazole-5-carboxylic acid 3 into their corresponding ester derivative 5 has been accomplished by Fischer esterification. The structure of the product 5 was confirmed by spectroscopic data. The IR spectrum of 1H-pyrazole-5-carboxylate derivative 5a showed broad absorption bands at 1722 (O-C=O), 1659 cm-1 (Ar-C=O) due to carbonyl groups. In the 1H NMR spectrum of 5a revealed three singlet signals at 3.43, 2.38, 2.25 ppm due to methyl protons (MeO, 2 MeC6H4, respectively). The 13C NMR spectrum of 5a exhibited signals at 190.84 (Ar-C=O) and 177.80 ppm (O-C=O).

The structure of the product 5b is based on an X-ray study of ethyl 4-(4-methylbenzoyl)-3-(4- methylphenyl)-1-(2,4-nitrophenyl)-1H-pyrazole-5-carboxylate, thus excluding the other possible isomers. An ORTEP plot of the 5b is shown in the Figure 4.

The compound 5b crystallizes in triclinic space group P-1 with two molecules in the unit cell. The structure contains the central pyrazole ring and 4-methylphenyl, 2,4-dinitrophenyl, 4-methylbenzoyl and formic acid ethyl ester units. The pyrazole ring adopts planar conformation. The sum of the angles at N3 of the pyrazole ring (359.87°) is in accordance with sp2 hybridization.24 The C—N bond lengths in the pyrazole ring are 1.327 (2) and 1.371 (2) Å, which are shorter than a C—N single bond length of 1.443 Å, but longer than a double bond length of 1.269 Å,25 indicating electron delocalization. It is likely that four substituent groups influence the aromaticity of that ring. Dinitrophenyl, tolyl and C21/C26 phenyl rings are significantly twisted from the pyrazole ring as can be seen from the inter-ring dihedral angles of 50.88 (9)°, 33.84 (11)° and 72.05 (9)° respectively.
There are intermolecular non-classic hydrogen bonds C5–H5···O7i and C6–H6···O7i [symmetry code (i): -x+2,-y,-z+1] forming centrosymmetric dimers, as shown in Figure 2b with C-H···O contacts of 3.228(4) and 3.269(4) Å, respectively.
Reactions of pyrazole derivatives having the dicarbonyl groups with hydrazine derivatives may be a convenient method to build the pyrazolo[3,4-d]pyridazine systems.20-22 Thus, the pyrazole acid chloride 4 and some hydrazines were refluxed in xylene with no catalytic amounts of pyridine for 1-6 h and cyclized to pyrazolo[3,4-d]pyridazinones 7a-d, in approximately 77, 65, 70, 63% yields without any side reaction, while with 2,4-dinitrophenylhydrazine the corresponding derivative 8 was obtained. In contrast, the reaction of 4 with 2,4-dinitrophenylhydrazine instead of hydrazine hydrate or phenylhydrazine did not lead to form the corresponding pyrazolo[3,4-d]pyridazine derivative. However, 2,4-dinitrophenylhydrazine was added to 4 to yield a new pyrazole acid derivative 8 containing a hydrazino group, as the literature procedure.16 The difficulty in forming the pyridazine nucleus from 8 can be explained by steric hindrances of the nitro groups attached to the phenyl ring (see Scheme 3 and Experimental Section). In the 1H NMR spectra of 8 the NH and OH signals revealed the presence of keto (%48) and enol (%52) tautomers in DMSO-d6 solution. The structures of all compounds were established by elemental analysis, IR and NMR spectroscopy.
We also investigated the reactions of the compound 4 with amine derivatives. It was performed in refluxing xylene to furnish the corresponding 1H-pyrazole-5-carboxamides 9a-c as the single proudct. The formation of 9a was supported by the results of both analytical and spectroscopic measurements, particularly by the presence of characteristic absorption bands (IR: 3103 cm-1) for N-H group, (IR: 1674 cm-1) for carbonyl group and the skeleton bands of benzene or pyrazole rings observed at 1601-1450 cm-1 (C...C, C...N). Important structural information about 9a could be obtained from its 13C NMR spectrum. The 13C NMR peaks were found to be at δ 190.86 (Ar-C=O), 153.05 (N-C=O), 148.13 (C3), 141.82 (C6), 139.82 (C11), 139.13, 135.28, 135.07, 133.75, 132.54, 130.17, 129.97, 135.60, 133.75, 132.54, 130.17, 129.97, 129.60, 129.52, 129.02, 128.97, 128.48, 127.75, 127.22, 124.01, 121.25, 120.75 (C-Ph), 21.21 (CH3), 21.17 (CH3). The 1H NMR spectrum of 9a showed signals for NH (10.67 ppm, it was exchanged with D2O), the aromatic substituent protons (8.98-7.06 ppm) and methyl groups (2.45, 2.39 ppm). Other spectral and analytical data of all synthesized compounds are in good agreement with their proposed structures.

ACKNOWLEDGEMENT
Financial support from the Research Center of Erciyes University, is gratefully acknowledged (Project no: FBT-07-41).

EXPERIMENTAL
Reagents and solvents were purchased from Merck, Fluka and Sigma, used without further purification. For purity tests, tlc: Merck precoated silica gel plates 60 F 254. Melting point: Electrothermal 9200 apparatus; uncorrected. IR Spectra: Shimadzu 8400 FT-IR spectrometer; in cm-1. 1H- and 13C NMR Spectra: Bruker Avance III Ultrashield spectrometer operating at 400.13 MHz (1H) and 100.61 MHz (13C) in DMSO-d6 and/or CDCl3; δ in ppm, coupling constants J in Hz. The following abbreviations are used: singlet (s), doubled (d), triplet (t), doubled triplet (dt), doubled doupled (dd), multiplet (m), broad signal (br). When necessary to identify all carbon atoms, complementary NMR experiments (COSY and APT) were performed. Elemental analyses (C, H, N, S): LECO-932 CHNS-O analyzer. X-Ray: Rigaku R-AXIS RAPID-S diffractometer.

4-Hydroxy-5-(4-methylbenzoyl)-2-(4-methylphenyl)-6-(2,4-dinitrophenyl)pyridazin-3(2H)-one (2). Compound 1 (0.31 g, 1 mmol) and 2,4-dinitrophenylhydrazine (0.20, 1 mmol) were dissolved in dry benzene (30 mL) and refluxed for 30 min. After cooling to rt, the red precipitate was separated by filtering and recrystallized from butanol to give 0.14 g (45%) of 2. mp 238 °C; IR (ATR, cm-1): 3288 (N-H), 3086 (arom.CH), 2976 (alip. CH), 1786, 1689 (C=O), 1602, 1587, 1580, 1520, 1450 (C...C, C...N); 1H NMR (400 MHz, acetone-d6): δ 10.30 (s, 1H, NH), 8.98 (d, 1H, 9-H, 4J = 2.61), 8.54 (dd, 1H, 11-H, 3J = 9.40, 4J = 2.61), 8.29 (d, 1H, 12-H, 3J = 9.40.), 7.69 (quasi d, 2H, A part of AA’BB’ system, 14- and 18-H, 3J = 8.17), 7.29 (quasi d, 2H, A part of AA’BB’ system, 21- and 25-H, 3J = 8.20), 7.14 (quasi d, 2H, B part of AA’BB’ system, 15- and 17-H, 3J = 8.17), 7.03 (quasi d, 2H, B part of AA’BB’ system, 22- and 24-H, 3J = 8.20), 2.31 (s, 3H, CH3), 2.19 (s, 3H, CH3); 13C NMR (100 MHz, acetone-d6): δ 188.78, 177.70 (C=O), 170.69 (C-OH), 159.77, 148.00, 144.02, 143.97, 139.20, 134.91, 131.26, 131.18, 129.96, 129.86, 129.59, 129.18, 123.84, 123.51, 116.99, 115.04 (C-Ph), 21.67, 21.57 (CH3). Anal. Calcd for C25H18N4O7 (486.43): C, 61.73; H, 3.73; N, 11.52. Found: C, 61.99; H, 3.74; N, 11.49.

4-(4-Methylbenzoyl)-3-(4-methylphenyl)-1-(2,4-dinitrophenyl)-1H-pyrazole-5-carboxylic acid (3). A milliequimolar mixture of furan-2,3-dione 1 (0.31 g, 1 mmol) and 2,4-dinitrophenylhydrazine (0.20, 1 mmol) was refluxed in 30 mL of dry toluene for aproximately 5 h. After evaporation, obtained was treated with dry Et2O. The crude product formed was recrystallized from toluene to give 0.24 g (77%) of 3, mp 156 °C; IR (ATR, cm-1): 3162-3048 (b, O-H, COOH), 1695 (Ar-C=O), 1659 (C=O, COOH), 1605, 1533, 1498, 1448, 1435 (C...C, C...N); 1H NMR (DMSO-d6): δ 9.10 (d, 1H, 10-H, 4J = 2.48), 8.64 (dd, 1H, 8-H, 3J = 8.69, 4J = 2.48), 7.90 (d, 1H, 7-H, 3J = 8.69), 7.69 (d, 2H, A part of AA’BB’ system, 26- and 30-H, 3J = 8.23), 7.29 (d, 2H, A part of AA’BB’ system, 17- and 21-H, 3J = 7.62), 7.14 (d, 2H, B part of AA’BB’ system, 18- and 20-H, 3J = 7.62), 7.03 (d, 2H, B part of AA’BB’ system, 27- and 29-H, 3J = 8.23), 2.41 (s, 3H, CH3), 2.28 (s, 3H, CH3); 13C NMR (DMSO-d6): δ 193.28 (C=O, benzoyl); 158.29 (C=O, COOH), 153.72 (C3), 151.93 (C-NO2), 147.80, 145.56, 145.09, 139.31, 138.63, 134.07, 131.63, 130.23, 129.35, 129.27, 128.13, 128.08, 127.46, 122.80, 120.91 (C-Ph), 21.78, 21.21 (CH3). Anal. Calcd for C25H18N4O7 (486.43): C, 61.73; H, 3.73; N, 11.52. Found: C, 61.72; H, 3.75; N, 11.47.

4-(4-Methylbenzoyl)-3-(4-methylphenyl)-1-(2,4-dinitrophenyl)-1H-pyrazole-5-carbonyl chloride (4). Acid 2 (0.49 g, 1 mmol) and thionyl chloride (1.64 g, 13.80 mmol) were refluxed on a steam bath for 5 h. After cooling, the crude precipitate was filtered off and recyrstallized from xylene, yield 0.20 g (41%) of 4, mp 160 °C; IR (ATR, cm-1): 3082 (arom. CH), 2951 (alip. CH), 1791 (C=O, COCl), 1662 (Ar-C=O), 1600, 1537, 1498, 1453, 1438 (C...C, C...N); 1H NMR (DMSO-d6): δ 8.98 (d, 10-H, 4J = 2.56), 8.75 (dd, 8-H, 3J = 8.72, 4J = 2.56), 8.33 (d, 7-H, 3J = 8.72), 7.78 (d, 2H, A part of AA’BB’ system, 26- and 30-H, 3J = 8.24), 7.37 (d, 2H, A part of AA’BB’ system, 17- and 21-H, 3J = 7.65), 7.25 (d, 2H, B part of AA’BB’ system, 18- and 20-H, 3J = 7.65), 7.15 (d, 2H, B part of AA’BB’ system, 27- and 29-H, 3J = 8.24), 2.29 (s, 3H, CH3), 2.25 (s, 3H, CH3); 13C NMR (DMSO-d6): δ 191.16 (C=O, benzoyl); 159.15 (C=O, COCl), 150.52 (C3), 147.90 (C-NO2), 145.31, 145.28, 139.24, 137.83, 135.22, 132.50, 129.92, 129.67, 129.34, 128.95, 128.64, 127.14, 123.88, 121.09 (C-Ph), 21.65, 21.45 (CH3). Anal. Calcd for C25H17N4O6Cl (504.88): C, 59.47; H, 3.39; N, 11.10. Found: C, 59.50; H, 3.40; N, 11.20.

Methyl 4-(4-methylbenzoyl)-3-(4-methylphenyl)-1-(2,4-dinitrophenyl)-1H-pyrazole-5-carboxylate (5a).
General Procedure: To the cold solution of the pyrazole acid 2 (0.49 g, 1mmol) in a few drops of sulfuric acid was added a large exess of MeOH with stirring. Then the reaction mixture was refluxed on a steam bath for 8 h with stirring. After cooling to 5 °C, the precipitate formed was filtered off and recrystallized from the same alcohol to give 0.24 g (49%) of 5a, mp 184 °C; IR (ATR, cm-1): 3064 (arom. CH), 2974 (aliph. CH), 1722 (O-C=O), 1659 (Ar-C=O), 1610, 1533, 1450, 1443 (C...C, C...N); 1H NMR (DMSO-d6): δ 9.00 (d, 1H, 10-H, 4J = 2.52), 8.78 (dd, 1H, 8-H, 3J = 8.76, 4J = 2.52), 8.39 (d, 1H, 7-H, 3J = 8.76), 7.78 (d, 2H, A part of AA’BB’ system, 26- and 30-H, 3J = 8.20), 7.38 (d, 2H, A part of AA’BB’ system, 17- and 21-H, 3J = 8.00), 7.32 (d, 2H, B part of AA’BB’ system, 27- and 29-H, 3J = 8.20), 7.18 (d, 2H, B part of AA’BB’ system, 18- and 20-H, 3J = 8.00), 3.43, (s, 3H, OCH3), 2.38 (s, 3H, CH3), 2.25 (s, 3H, CH3); 13C NMR (DMSO-d6): δ 190.84 (Ar−C=O), 177.80 (C=O, ester), 158.10 (C3), 150.63 (C-NO2), 146.13, 145.50, 145.34, 139.43, 137.35, 135.07, 133.75, 132.54, 130.17, 129.97, 127.95, 121.25 (C-Ph), 53.10 (OCH3), 21.27, 21.20 (2xCH3). Anal. Calcd for C26H20N4O7 (500.46): C, 62.40; H, 4.03; N, 11.19. Found: C, 62.43; H, 4.00; N, 11.18.

Ethyl 4-(4-methylbenzoyl)-3-(4-methylphenyl)-1-(2,4-dinitrophenyl)-1H-pyrazole-5-carboxylate (5b). Compound 5b was obtained by the general procedure above with a reflux time of 7 h. Yield: 0.23g (47%); mp 153 °C (EtOH); IR (ATR, cm-1): 3072 (arom. CH), 2974 (aliph. CH), 1734 (O-C=O), 1651 (Ar-C=O), 1601, 1553, 1457, 1415 (C...C, C...N); 1H NMR (DMSO-d6): δ 9.08 (d, 1H, 10-H, 4J = 2.52), 8.65 (dd, 1H, 8-H, 3J = 8.69, 4J = 2.52), 7.95 (d, 1H, 7-H, 3J = 8.69), 7.87 (d, 2H, A part of AA’BB’ system, 26- and 30-H, 3J = 8.16), 7.54 (d, 2H, A part of AA’BB’ system, 17- and 21-H, 3J = 7.99), 7.33 (d, 2H, B part of AA’BB’ system, 18- and H-20, 3J = 7.99), 7.13 (d, 2H, B part of AA’BB’ system, 27- and H-29, 3J = 8.16), 4.00 (q, 2H, CH2, 3J = 7.12), 2.40 (s, 3H, CH3), 2.30 (s, 3H, CH3), 0.85 (t, 3J = 7.14, 3H, CH3); 13C NMR (DMSO-d6): δ 191.13 (Ar-C=O), 170.89 (O-C=O), 158.03 (C3), 152.36 (C-NO2), 147.66, 145.14, 143.02, 142.31, 139.31, 138.31, 135.14, 131.83, 130.94, 129.43 129.22, 129.15, 128.28, 127.98, 124.36, 124.03, 121.34, 120.74, 110.94 (C-Ph), 63.26 (CH2), 21.77, 21.69 (CH3), 13.67 (CH3). Anal. Calcd for C27H22N4O7 (514.49): C, 63.03; H, 4.31; N, 10.89. Found: C, 63.05; H, 4.26; N, 10.92.

Propyl 4-(4-methylbenzoyl)-3-(4-methylphenyl)-1-(2,4-dinitrophenyl)-1H-pyrazole-5-carboxylate (5c). Compound 5c was obtained by the general procedure above with a reflux time of 6 h. Yield: 0.21 g (43%); mp 104 °C; (n-PrOH); IR (ATR, cm-1): 3088 (arom. CH), 2959 (aliph. CH), 1703 (O-C=O), 1674 (Ar-C=O), 1604, 1533, 1447 (C...C, C...N); 1H NMR (DMSO-d6): δ 8.95 (d, 1H, 10-H, 4J = 2.56), 8.75 (dd, 1H, 8-H, 3J = 8.77, 4J = 2.56), 8.35 (d, 7-H, 3J = 8.77), 7.77 (d, 2H, A part of AA’BB’ system, 26- and 30-H, 3J = 8.20), 7.39 (d, 2H, A part of AA’BB’ system, 17- and 21-H, 3J = 8.15), 7.31 (d, 2H, B part of AA’BB’ system, 18- and 20-H, 3J = 8.20), 7.19 (d, 2H, B part of AA’BB’ system, 27- and 29-H, 3J = 8.15), 3.40 (t, 2H, CH2, 3J = 7.20), 2.35 (s, 3H, CH3), 2.21 (s, 3H, CH3), 1.35 (m, 2H, CH2), 0.88 (t, 3H, CH3, 3J = 7.18); 13C NMR (DMSO-d6): δ 191.17 (Ar-C=O), 170.25 (O-C=O), 159.19 (C3), 150.51 (C-NO2), 147.90, 145.31, 145.28, 139.24, 137.83, 135.22, 132.49, 130.08, 129.92, 129.67, 128.95, 127.14, 123.87, 121.09 (C-Ph), 60.82 (CH2), 23.05 (CH2), 21.68 (CH3), 21.18 (CH3), 14.28 (CH3). Anal. Calcd for C28H24N4O7 (528.51): C, 63.63; H, 4.58; N, 10.60. Found: C, 63.59; H, 4.61; N, 10.58.

i-Propyl 4-(4-methylbenzoyl)-3-(4-methylphenyl)-1-(2,4-dinitrophenyl)-1H-pyrazole-5-carboxylate (5d). Compound 5d was obtained by the general procedure above with a reflux time of 6 h. Yield: 0.18 g (37%); mp 124 °C; (i-PrOH); IR (ATR, cm-1): 3096 (arom. CH), 2959 (aliph. CH), 1722 (O-C=O), 1674 (Ar-C=O), 1606, 1530 1452 (C...C, C...N); 1H NMR (DMSO-d6): δ 9.00 (d, 1H, 10-H, 4J = 2.57), 8.80 (dd, 1H, 8-H, 3J = 8.78, 4J = 2.57), 8.35 (d, 1H, 7-H, 3J = 8.78), 7.80 (d, 2H, A part of AA’BB’ system, 26- and 30-H, 3J = 8.20), 7.40 (d, 2H, A part of AA’BB’ system, 17- and 21-H, 3J = 8.16), 7.32 (d, 2H, B part of AA’BB’ system, 18 and 20-H, 3J = 8.20), 7.19 (d, 2H, B part of AA’BB’ system, 27- and 29-H, 3J = 8.16), 3.85 (m, 1H, CH), 2.40 (s, 3H, CH3), 2.21 (s, 3H, CH3), 1.02 (d, 6H, 2CH3, 3J = 7.35); 13C NMR (DMSO-d6): δ 191.17 (Ar-C=O), 170.89 (O-C=O), 159.14 (C3), 150.51 (C9), 147.90 (C11), 145.31 (C5), 145.28, 139.24, 137.83, 135.22, 135.11, 132.49, 130.08, 129.92, 129.67, 128.95, 128.14, 127.13, 123.86, 121.09 (C-Ph), 62.47 (CH), 21.68 (CH3), 21.19 (CH3), 14.41 (CH3). Anal. Calcd for C28H24N4O7 (528.51): C, 63.63; H, 4.58; N, 10.60. Found: C, 63.61; H, 4.56; N, 10.61.

Butyl 4-(4-methylbenzoyl)-3-(4-methylphenyl)-1-(2,4-dinitrophenyl)-1H-pyrazole-5-carboxylate (5e). Compound 5e was obtained by the general procedure above with a reflux time of 5 h. Yield: 0.16 g (33%); mp 142 °C; (n-BuOH); IR (ATR, cm-1): 3088 (arom. CH), 2959 (aliph. CH), 1722 (O-C=O), 1674 (Ar-C=O), 1604, 1533, 1460, 1408 (C...C, C...N); 1H NMR (DMSO-d6): δ 9.00 (d, 1H, 10-H, 4J = 2.57), 8.80 (dd, 1H, 8-H, 3J = 8.77, 4J = 2.57), 8.35 (d, 1H, 7-H, 3J = 8.77), 7.80 (d, 2H, A part of AA’BB’ system, 26- and 30-H, 3J = 8.21), 7.38 (d, 2H, A part of AA’BB’ system, 17- and 21-H, 3J = 8.16), 7.34 (d, 2H, B part of AA’BB’ system, 18- and 20-H, 3J = 8.21), 7.15 (d, 2H, B part of AA’BB’ system, 27- and 29-H, 3J = 8.16), 3.85 (q, 2H, CH2), 2.54 (s, 3H, CH3), 2.21 (s, 3H, CH3), 1.10 (m, 2H, CH2), 0.80 (m, 2H, CH2), 0.60 (t, 3H, CH3); 13C NMR (DMSO-d6): δ 190.85 (Ar-C=O), 170.20 (O-C=O), 157.77 (C3), 150.73 (C-NO2), 148.12, 145.61, 145.37, 139.40, 137.48, 135.07, 133.69, 132.49, 130.13, 129.98, 129.04, 127.92, 127.17, 123.80, 121.10 (C-Ph), 66.09 (OCH2), 29.86 (CH2), 21.71 (CH2), 21.20 (CH3), 18.70 (CH2), 13.70 (CH3). Anal. Calcd for C29H26N4O7 (542.54): C, 64.20; H, 4.83; N, 10.33. Found: C, 64.23; H, 4.83; N, 10.32.

Pentyl 4-(4-methylbenzoyl)-3-(4-methylphenyl)-1-(2,4-dinitrophenyl)-1H-pyrazole-5-carboxylate (5f). Compound 5f was obtained by the general procedure above with a reflux time of 5 h. Yield: 0.19 g (39%); mp 120 °C; (n-PeOH); IR (ATR, cm-1): 3088 (arom. CH), 2959 (aliph.CH), 1718 (O-C=O), 1675 (Ar-C=O), 1609, 1536, 1434, 1405 (C...C, C...N); 1H NMR (DMSO-d6): δ 9.05-7.12 (m, 11H, phenyl protons), 3.77 (q, 2H, CH2), 2.48 (s, 3H, CH3), 2.20 (s, 3H, CH3), 1.65 (m, 2H, CH2), 1.30 (m, 2H, CH2), 1.08 (m, 2H, CH2), 0.86 (t, 3H, CH3); 13C NMR (DMSO-d6): δ 191.17 (Ar-C=O), 170.17 (O-C=O), 159.15 (C3), 157.78 (C-NO2), 150.72, 150.51, 148.11, 147.89, 145.58, 145.28, 139.39, 137.84, 137.51, 135.22, 132.69, 130.13, 129.97, 129.68, 129.04, 127.91, 127.14, 123.83, 121.08 (C-Ph), 66.41 (OCH2), 37.48 (CH2), 27.64 (CH2), 27.57 (CH2), 21.68 (CH3), 21.19 (CH3), 13.99 (CH3). Anal. Calcd for C30H28N4O7 (556.56): C, 64.74; H, 5.07; N, 10.07. Found: C, 64.73; H, 5.07; N, 10.08.

i-Pentyl 4-(4-methylbenzoyl)-3-(4-methylphenyl)-1-(2,4-dinitrophenyl)-1H-pyrazole-5-carboxylate (5g). Compound 5g was obtained by the general procedure above with a reflux time of 5 h. Yield: 0.17 g (35%); mp 128 °C; (i-PeOH); IR (ATR, cm-1): 3088 (arom. CH), 2951 (aliph.CH), 1699 (O-C=O), 1670 (Ar-C=O), 1604, 1536, 1435, 1460 (C...C, C...N); 1H NMR (DMSO-d6): δ 9.05-7.12 (m, 11H, phenyl protons), 3.80 (t, 2H, CH2), 2.41 (s, 3H, CH3), 2.22 (s, 3H, CH3), 1.65 (m, 2H, CH2), 1.35 (m, 2H, CH2), 0.80 (d, 6H, 2 CH3); 13C NMR (DMSO-d6): δ 191.17 (Ar-C=O), 170.15 (O-C=O), 159.15 (C3), 157.74 (C-NO2), 150.77, 150.51, 148.12, 147.89, 145.61, 145.28, 139.42, 139.23, 137.54, 135.22, 133.69, 132.67, 130.08, 129.97, 129.06, 127.91, 123.76, 121.04 (C-Ph), 66.34 (OCH2), 37.44 (CH2), 24.69 (CH2), 22.26 (CH2), 21.68 (CH3), 21.19 (2 × CH3). Anal. Calcd for C30H28N4O7 (556.57): C, 64.74; H, 5.07; N, 10.07. Found: C, 64.76; H, 5.05; N, 10.06.

4-(4-Methylbenzoyl)-3-(4-methylphenyl)-1-(2,4-dinitrophenyl)-1H-pyrazole (6). Compound 3 (0.49 g, 1 mmol) was heated to 180 oC in an oil bath for about 30 min without any solvent. After cooling to room temperature, the residue was treated with ether to give the crude product, which was recrystallized from MeOH, to yield 0.37 g (75% ); mp 193 °C; IR (ATR, cm-1): 3096, 3034 (arom. CH), 2978 (aliph. CH), 1639 (C=O), 1601, 1549, 1545, 1534, 1450 (C...C, C...N); 1H NMR (400 MHz, CDCl3): δ 9.03 (s, 1H, H5), 8.92 (quasi d, 1H, 10-H, 4J = 2.56), 8.66 (dd, 1H, 8-H, 3J = 8.96, 4J = 2.56), 8.32 (d, 1H, 7-H, 3J = 8.96), 7.85 (d, 2H, A part of AA’BB’ system, 26- and 30-H, 3J = 8.20), 7.45 (d, 2H, A part of AA’BB’ system, 17- and 21-H, 3J = 8.12), 7.37 (d, 2H, B part of AA’BB’ system, 18- and 20-H, 3J = 8.12), 7.20 (d, 2H, B part of AA’BB’ system, 27- and 29-H, 3J = 8.20), 2.41 (s, 3H, CH3), 2.28 (s, 3H, CH3); 13C NMR (DMSO-d6): δ 188.95 (C=O), 146.44 (C3), 144.31 (C11), 139.05 (C9), 136.89 (C28), 135.74 (C19), 130.11, 129.78, 129.37, 128.70, 128.61, 128.43 (C-Ph), 126.84 (C4), 121.64 (C10), 21.63 (CH3), 21.32 (CH3). Anal. Calcd for C24H18N4O5 (442.42): C, 65.15; H, 4.10; N, 12.66. Found: C, 65.13; H, 4.11; N, 12.69.

General Procedure for the compounds 7 and 8. A milliequimolar mixture of 4 and hydrazine hydrate were refluxed in xylene for 1-6 h. The solvent was evaporated, then the oily residue was treated with Et2O and the formed crude product was crystallized from proper solvent.

3,4-Di(4-methylphenyl)-1-(2,4-dinitrophenyl)-1,6-dihydropyrazolo[3,4-d]pyridazin-7-one (7a). Compound 7a was prepared according to the general procedure above with a reflux time of 1 h resulting in yield 0.39 g (77%) of 7a, mp 218 oC; (benzene); IR (ATR, cm-1): 3200 (NH), 3085 (arom. CH), 2976 (aliph. CH), 1649 (C=O), 1607, 1533, 1505, 1344 (C...C, C...N); 1H NMR (DMSO-d6): δ 13.31 (s, 1H, NH), 8.98 (quasi d, 1H, 10-H, 4J = 2.52), 8.76 (dd, 1H, 8-H, 3J = 8.80, 4J = 2.52), 8.29 (d, 1H, 7-H, 3J = 8.80), 7.13-6.92 (2xAA’BB’ systems, 8H, phenyl protons), 2.27 (s, 3H, CH3), 2.26 (s, 3H, CH3); APT (DMSO-d6): δ 153.34 (+), 150.15 (+), 147.45 (+), 144.23 (+), 143.99 (+), 138.82 (+), 136.09 (+), 134.55 (+), 131.93 (+), 131.90 (-), 129.64 (-), 129.10 (-), 128.83 (-), 128.80 (-), 128.75 (-), 127.75 (+), 121.30 (-), 118.90 (+), 21.28 (-). Anal. Calcd for C25H18N6O5 (482.45): C, 62.24; H, 3.76; N, 17.42. Found: C, 62.22; H, 3.80; N, 17.44.

3,4-Di(4-methylphenyl)-1-(2,4-dinitrophenyl)-6-phenyl-1,6-dihydropyrazolo[3,4-d]pyridazin-7-one (7b). Compound 7b was prepared according to the general procedure above with a reflux time of 3 h resulting in yield 0.33 g (65%), mp 245 °C; (benzene); IR (ATR, cm-1): 3033 (arom. CH), 2989 (aliph. CH), 1623 (C=O), 1599, 1501, 1404, 1344 (C...C, C...N); 1H NMR (DMSO-d6): δ 8.95 (quasi d, 1H, 10-H, 4J = 2.56), 8.74 (dd, 1H, 8-H, 3J = 8.84, 4J = 2.56), 8.23 (d, 1H, 7-H, 3J = 8.84), 7.50-6.80 (m, 13H, phenyl protons), 2.32, (s, 3H, CH3), 2.23 (s, 3H, CH3); 13C NMR (DMSO-d6): δ 170.45 (C=O), 157.83 (C3), 147.31 (C11), 144.99 (C9), 144.49, 144.41, 139.79, 138.63, 134.41, 131.91, 130.58, 129.52, 129.05, 128.74, 128.65, 128.53, 127.05, 126.82, 121.01, 120.58 (C-Ph), 21.21, 21.15 (CH3). Anal. Calcd for C31H22N6O5 (558.54): C, 66.66; H, 3.97; N, 15.05. Found: C, 66.69; H, 3.89; N, 15.09.

3,4-Di(4-methylphenyl)-1-(2,4-dinitrophenyl)-6-(hydroxyethyl)-1,6-dihydropyrazolo[3,4-d]pyridazin-7-one (7c). Compound 7c was prepared according to the general procedure above with a reflux time of 4 h resulting in yield 0.35 g (69%), mp 210 °C; (xylene); IR (ATR, cm-1): 3499 (OH), 3088 (arom. CH), 2920 (aliph. C-H), 1647 (C=O), 1608, 1545, 1540, 1499, 1446, 1340 (C...C, C...N); 1H NMR (DMSO-d6): δ 8.96 (quasi d, 1H, 10-H, 4J = 2.56), 8.76 (dd, 1H, 8-H, 3J = 80, 4J = 2.56), 8.26 (d, 1H, 7-H, 3J = 8.80), 7.16-6.96 (2 × AA’BB’ systems, 8H, phenyl protons), 3.83 (t, 1H, OH, 3J = 5.84), 4.24 (t, 2H, CH2, 3J = 5.92), 3.78 (q, 2H, CH2, 3J = 5.76), 2.25 (s, 3H, CH3), 2.27 (s, 3H, CH3); 13C NMR (DMSO-d6): δ 170.00 (C=O); 152.31, 149.91, 147.53, 144.46, 142.97, 139.01, 138.92, 136.16, 134.50, 132.06, 131.76, 129,63, 128.81, 128.72, 127.74, 121.20, 118.54 (C-Ph), 59.06 (CH2), 52.75 (CH2), 21.28 (2 × CH3). Anal. Calcd for C27H22N6O6 (526.50): C, 61.59; H, 4.21; N, 15.96. Found: C, 61.60; H, 4.20; N, 15.97.

3,4-Di(4-methylphenyl)-1-(2,4-dinitrophenyl)-6-(2,5-dichlorophenyl)-1,6-dihydropyrazolo[3,4-d]pyridazin-7-one (7d). Compound 7d was prepared according to the general procedure above with a reflux time of 6 h resulting in yield 0.32 g (63%), mp 257 °C; (EtOH); IR (ATR, cm-1): 3034 (arom. CH), 2989 (aliph. CH), 1690 (C=O), 1602, 1556, 1540, 1483, 1440 (C...C, C...N); 1H NMR (DMSO-d6): δ 8.96 (quasi d, 1H, 10-H, 4J = 2.56), 8.76 (dd, 1H, 8-H, 3J = 8.84, 4J = 2.56), 8.29 (d, 1H, 7-H, 3J = 8.84), 7.83 (quasi d, 1H, X part of ABX spin system, 4J = 2.48), 7.84 (quasi d, 1H, A part of ABX spin system, 3J = 8.69), 7.62 (dd, 1H, B part of ABX spin system, 3J = 8.69, 4J = 2.48), 7.19-6.87 (2 × AA’BB’ spin systems, 8H, phenyl protons), 2.30, (s, 3H, CH3), 2.29 (s, 3H, CH3); 13C NMR (DMSO-d6): δ 170.39 (C=O), 155.83, 152.56, 151.74, 149.81, 147.31, 144.99, 144.49, 144.41, 139.79, 138.63, 134.41, 131.91, 130.58, 129.71, 129.24, 128.91, 128.78, 128.67, 126.82, 121.01, 119.78 (C-Ph), 21.20 (2 CH3). Anal. Calcd for C31H20Cl2N6O5 (627.43): C, 59.34; H, 3.21; N, 13.39. Found: C, 59.39; H, 3.20; N, 13.39.

N’-Bis-(2,4-dinitrophenyl)-4-(4-methylbenzoyl)-3-(4-methylphenyl)-1H-pyrazole-5-carbohydrazide (8). Compound 8 was prepared according to the general procedure above with a reflux time of 2 h resulting in yield 0.27 g (54%), mp 211 oC; (i-PrOH); IR (ATR, cm-1): 3346 (NH), 3080 (arom. CH), 2966 (aliph. CH), 1707 (C=O), 1612 (C=O), 1599, 1518, 1510, 1445 (C...C, C...N); 1H NMR (DMSO-d6): δ 14.16 (s, 0.52H, OH), 11.75 (s, 0.48H, NH), 7.73 (s, 1H, NH), 8.94-7.12 (m, 11H, phenyl protons), 2.38 (s, 1.44H, CH3), 2.32 (s, 1.56H, CH3), 2.30 (s, 1.44H, CH3), 2.27 (s, 1.56H, CH3). Anal. Calcd for C31H22N8O10 (666.55): C, 55.86; H, 3.33; N, 16.81. Found: C, 55.88; H, 3.30; N, 16.80.

N-Phenyl-1-(2,4-dinitrophenyl)-4-(4-methylbenzoyl)-3-(4-methylphenyl)-1H-pyrazole-5-carboxamide (9a).
General Procedure. Acid chloride 4 (0.51 g, 1 mmol) and aniline (0.19 g, 2 mmol) were refluxed in xylene for about 3 h. After evaporation, the oily residue was treated with dry ether and the crude product formed was crystallized from EtOH to give 0.25 g (50%) of 9a; mp 298 °C; (EtOH); IR (ATR, cm-1): 3103 (NH), 3018 (arom. CH), 2959 (aliph. CH), 1674 (broad, C=O), 1601, 1537, 1506, 1450 (C...C, C...N); 1H NMR (DMSO-d6): δ 10.67 (s, 1H, NH), 8.98 (quasi d, 1H, 10-H, 4J = 2.56), 8.77 (dd, 1H, 8-H, 3J = 8.76, 4J = 2.56), 8.19 (d, 1H, 7-H, 3J = 8.76), 7.80-7.06 (m, 13H, phenyl protons), 2.45 (s, 3H, CH3), 2.39 (s, 3H, CH3); 13C NMR (DMSO-d6): δ 190.86 (Ar-C=O), 153.05 (N-C=O), 148.13 (C3), 141.82, 139.82, 139.13, 135.28, 133.75, 132.54, 130.17, 129.97, 135.60, 133.75, 132.54, 130.17, 129.97, 129.60, 129.02, 128.97, 128.48, 127.75, 124.01, 121.25, 120.75 (C-Ph), 21.21 (CH3), 21.17 (CH3). Anal. Calcd for C31H23N5O6 (561.54): C, 66.30; H, 4.13; N, 12.47. Found: C, 66.33; H, 4.12; N, 12.48.

N-Cyclohexyl-1-(2,4-dinitrophenyl)-4-(4-methylbenzoyl)-3-(4-methylphenyl)-1H-pyrazole-5-carbox-amide (9b). Compound 9b was prepared according to the general procedure above with a reflux time of 6 h resulting in yield 0.28 g (56%), mp 156 °C; (EtOH); IR (ATR, cm-1): 3354-3111 (NH), 3054 (arom. CH), 2943 (aliph. CH), 1655, 1614 (C=O), 1606, 1518, 1423, 1398 (C...C, C...N); 1H NMR (DMSO-d6): δ 8.85-7.38 (m, 11H, phenyl protons), 7.24 (d, 1H, NH), 3.84 (m, 2H, CH), 3.00 (s, 3H, CH3), 2.88 (s, 3H, CH3), 1.85-1.56 (m, 6H, CH2), 1.15 (m, 4H, CH2); 13C NMR (DMSO-d6): δ 190.08 (Ar-C=O), 171.18 (N-C=O), 152.18 (C3), 145.86, 141.33, 141.10, 138.66, 135.75, 129.99, 129.64, 129.08, 128.87, 127.36, 122.45, 121.68, 116.03 (C-Ph), 51.67 (CH), 32.02 (2xCH2), 25.31 (2xCH2), 24.04 (CH2), 21.88 (2 × CH3). Anal. Calcd for C31H29N5O6 (567.59): C, 65.60; H, 5.15; N, 12.34. Found: C, 65.63; H, 5.12; N, 12.33.

N,N-Diisopropyl-1-(2,4-dinitrophenyl)-4-(4-methylbenzoyl)-3-(4-methylphenyl)-1H-pyrazole-5-carboxamide (9c). Compound 9c was prepared according to the general procedure above with a reflux time of 6 h resulting in yield 0.27 g (54%), mp 197 °C; (benzene); IR (ATR, cm-1): 3080 (arom. CH), 2966, 2873 (aliph. CH), 1670 (N-C=O), 1647 (C=O), 1601, 1533, 1339 (C...C, C...N); 1H NMR (DMSO-d6): δ 8.80-7.12 (m, 11H, phenyl protons), 2.65 (m, 1H, CH), 2.35 (s, 3H, CH3), 2.21 (s, 3H, CH3), 1.40 (d, 9H, CH3); 13C NMR (DMSO-d6): δ 192.35 (Ar-C=O), 170.93 (N-C=O), 160.09 (C3), 149.50, 146.54, 145.34, 143.82, 143.63, 139.75, 138.33, 138.34, 136.45, 131.63, 129.61, 129.51, 129.45, 128.14, 127.04, 121.45, 120.18 (C-Ph), 48.54 (CH), 21.59 (CH3), 21.18 (CH3), 19.26 (CH3). Anal. Calcd for C31H31N5O6 (569.61): C, 65.37; H, 5.49; N, 12.30. Found: C, 65.39; H, 5.48; N, 12.28.

Crystallography
For the crystal structure determination, single-crystal of compound 5b was used for data collection on a four-circle Rigaku R-AXIS RAPID-S diffractometer (equipped with a two-dimensional area IP detector). Graphite-monochromated Mo-Kα radiation (λ = 0.71073 Å) and oscillation scans technique with Δw = 5º for one image were used for data collection. The lattice parameters were determined by the least-squares methods on the basis of all reflections with F2 > 2σ(F2). Integration of the intensities, correction for Lorentz and polarization effects and cell refinement was performed using CrystalClear (Rigaku/MSC Inc., 2005) software.26 The structures were solved by direct methods using SHELXS-9727 and refined by a full-matrix least-squares procedure using the program SHELXL-9727 H atoms were positioned geometrically and refined using a riding model. The final difference Fourier maps showed no peaks of chemical significance. Crystal data for 5b: C27H22N4O7, crystal system, space group: triclinic, P-1; (no:2); unit cell dimensions: a = 9.6716(2), b = 10.3003(2), c = 12.7144(3), Å, α=89.716(4), β = 89.395(5), γ = 86.708(4)º; volume: 1264.44(5) Å3; Z = 2; calculated density: 1.351 g/cm3; absorption coefficient: 0.100 mm-1; F(000):536; θ-range for data collection 2.5–26.4º; refinement method: full matrix least-square on F2; data/parameters: 5154/347; goodness-of-fit on F2: 1.019; final R-indices [I > 2r(I)]: R1 = 0.0626, wR2 = 0.147; largest diff. peak and hole: 0.284 and -0.213 e Å-3.
Crystallographic data that were deposited in CSD under CCDC-928430 registration number contain the supplementary crystallographic data for this Letter. These data can be obtained free of charge from the Cambridge Crystallographic Data Centre (CCDC) via www.ccdc.cam.ac.uk/data_request/cif and are available free of charge upon request to CCDC, 12 Union Road, Cambridge, UK (fax: +441223 336033, e-mail: deposit@ccdc.cam.ac.uk).

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