HETEROCYCLES

Short Paper | Regular issue | Vol. 89, No. 7, 2014, pp. 1645-1655
Received, 13th September, 2013, Accepted, 12th May, 2014, Published online, 20th May, 2014.
DOI: 10.3987/COM-13-12840

■ The Synthesis of Dipyrazolylmethanes, X-Ray Structure Analysis

Yuan Ma, Jinxia Wang, and Hengchang Ma*

Key Laboratory of Eco-Environment-Related Polymer Materials Ministry of Education, College of Chemistry and Chemical Engineering, Northwest Normal University, Lanzhou, Gansu 730070, China

Abstract

A small dipyrazoylmethane compounds library was established via the reaction of 5-alkyl- and 5-aryl-2-aryl-3H-pyrazol-3-ones with DMSO in the presence of NaOAc·3H2O as base using LiBr·H2O as additive at 100 oC.

Dipyrazoylmethane derivatives are important functional or bioactive materials.1,2 The synthesis of dipyrazoylmethane by the reaction of 5-methyl-6-phenyl-1,2,4-triazine 4-oxide with pyazolone in dimethyl sulfoxide (DMSO) has been reported by Yurii Azev in 1995.3 And in 2012, they reported the synthesis of dipyrazoylmethane by the reaction of unsubstituted quinoxaline with 3-methyl-1-phenylpyrazol-5-one (1a) in DMSO in the presence of triethylamine, or 1a with glyoxal.4 Wong and Huang reported the preparation method of dipyrazolylmethane derivatives by using formamide and phosphoryl chloride (POCl3).5 These findings confirmed the formation of the key intermediate of 1a, which is produced from the reaction between 1a and DMSO or Vilsmeier-type methylenation reactions from 1a and N-methylformamide in the presence of POCl3. However, tedious synthetic procedures and very limited functional group tolerance prevented it from real application.
DMSO has been developed as very useful synthetic reagents, which was extensively employed in the well known Pummerer and related rearragement reactions as well as the formation of thionium ion intermediate.6 For example, Fei disclosed that DMSO could be applied as a powerful carbon source, leading to the formylation of indoles.7 Liu also reported a quite similar reaction using DMSO involving Pummerer type reaction.8
Considering the significance to establish a library of structurally diversified dipyrazoylmethane derivatives, we found that treatment of 3-methyl-1-(m-tolyl)-1H-pyrazol-5(4H)-one (1f) with NaOAc·3H2O and LiBr·H2O in the solvent of DMSO at 90-100 oC could led to a new transformation. The resulted product 2f was fully characterized by IR, 1H, 13C NMR spectroscopies and mass spectrometry. In IR spectrum, a reactively strong C=O absorption band stretch at 1616 cm-1. Meanwhile, a cluster of bands between 2922 and 2852 cm-1 were detected, which are demonstrated as the most intensed peaks in the spectrum. And also, a broad weak absorption band centered at 3446 cm-1. NMR spectrum of 2f indicated one set of chemical shifts for the two halves of the molecule. Of some significance was the δ 1H (OH) value in CDCl3 solution of 18.00 ppm.9-11 The crystal structure revealed (Figure 1) that the corresponding bonds in the two pyrazolone moieties have essentially the same lengths (see values in Table 1), with an extensive delocalization in the central O-C-C-C-C-C-O fragment of the molecule.12 As a result, an octatomic ring formed via a hydrogen bond13-15 between C=O and H-O-C with near linear O-H…O bond angles, and all C-O bond lengths were in the narrow range of 1.281(4)-1.290(4) Å values between those expected for single and double bonds, and two pairs of C8-C9 and C11-C13, C10-C11 and C10-C8 bond lengths are mensurated in the region of 1.437(4)-1.434(4), and 1.381(5)-1.382(5) respectively. These results confirmed that the two independent molecules exhibit only subtle differences in bond angles and lengths. Each molecule is of extensive delocalization and overall the molecule exhibits a structure almost midway between the two tautomeric forms 2f and 2f’ (Scheme 1).

As we found that the presense of dimethyl sulfoxide is critical to the reaction. Therefore, in order to elucidate how DMSO is involved in the procedure, the deuteration experiments were conducted by using DMSO-d6 as reaction medium. Then, the D-labeled product was obtained predominantly. The reliable results indicated that dimethyl sulfoxide is served as the reaction participate in this transformation. And an active species generated from DMSO couples two 2,4-dihydro-5-methyl-2-(3-methylphenyl)-3H-pyrazol-3-one motifs to produce the three rings fused compound. The discrepancy of the typical peak in the DEPT NMR shifted at 137 ppm confirmed the result.

We commenced our study by examining the intermolecular cyclization of pyrazolone 1a to dipyrazolylmethane 2a in the presence of different bases and additives. The results were summarized in Table 1. From Table 1, it was observed that higher temperature is very necessary in the activation of DMSO in the presence of the more weak base NaOAc·3H2O. Heating of 1a at 60 oC for 7 h generates a trace amount of 2a, and an increase of the reaction temperature up to 100 oC could raise the yield up to 70% (Entries 8 and 9). However, elevating the reaction temperature to 120 oC produces lower yield of 2a (60%), accompanied by substantial starting material decomposition (Entry 10). Note that Cs2CO3 is not favored in the reaction possibly because Cs2CO3 is too hygroscopic under the air conditions. Pyridine and Et3N could not be available in the transformation (Entries 1, 2, and 3). As tested that CF3CO2Na is also suitable for the transformation, product 2a could be achieved in 72% isolated yield. Considering that NaOAc·3H2O is relatively cheap compared to CF3CO2Na, therefore NaOAc·3H2O was tested as the base for the following experiments. Additionally, bromine salts were found to improve the reaction efficiency. Comparably, LiBr·H2O demonstrated slightly better performance and the corresponding product was obtained in 70% yield (Entry 7). In the cases of KBr and NaBr, 2a was produced with lower yield of 55 and 58%, respectively. Therefore the most efficient conditions for carrying out the reaction were addition of pyrazolone derivatives in DMSO solution and in the presence of 1.5 equiv. of NaOAc·3H2O and LiBr·H2O and warmed at 100 oC.

With the optimized set of reaction conditions, a variety of dipyrazoylmethanes were synthesized and the corresponding products 2b-s were produced in good to excellent yields (Table 2). Electron-donating groups, such as Me, n-propyl, isopropyl, and phenyl were tolerated in the reaction system. Alkyl and aryl substituents at the 5-positions did not adversely affect for the reaction. It was obvious that the yield of the product decrease along with the increase of chain length the aliphatic substituents. For instance, the yields of 2a and 2c were decreased to 70 and 47%, respectively (Entries 1 and 3). Isopropyl apparently disfavored the formation of the more sterically hindered products, (2d: 68%, 2q: 46%, 2r: 50%, 2s: 42%) (Entries 4, 17, 18, and 19). As can be seen from Table 2, the reactions of Cl and Br groups substituted reactants proceeded smoothly to afford the corresponding products in average to excellent yields. Especially, Cl and Br located on the meta-position of aromatic rings accelerated the formation of 2g (92%), 2h (88%), and 2n (90%) (Entries 7, 8, and 14). However, in the cases of 2o, 2q, and 2r, the isolated yields decreased to 46, 46, and 50%, respectively, which presumably due to the existence of more sterically hindered n-propyl, isopropyl in 3H-pyrazol-3-one ring (Entries 15, 17, and 18). The more electron-donating MeO group in benzene ring could slightly promote the transformation, and better results were achieved (2e: 94%, 2j: 67%, 2l: 71%) (Entries 5, 10, and 12).

A plausible mechanism for this reaction was proposed in Scheme 2. It may involve a Pummerer rearrangement of DMSO in the presence of NaOAc under elevated temperature, affording the active species of I. Then, an intermolecular nucleophilic addition of 1a to the C=S bond of I takes place to afford the intermediate II.8 Subsequently, the second nucleophilic addition between II and I occurs, leading to the formation of sulfonium III. Finally, the SN2 nucleophilic reaction of intermediate III attacked by H2O takes place to form the hydroxymethylation product IV, which is oxidized to the formylation product V by Swern oxidation.7 Meanwhile, the nucleophilic attack of V by another molecule 1a affords the final product 2a.5

In conclusion, a novel, simple, and highly efficient method for the establishment of a library of structurally diversified dipyrazoylmethane derivatives with 5-alkyl- and 5-aryl-2-aryl-3H-pyrazol-3-ones and DMSO under relatively mild conditions has been developed. A detailed mechanistic study and further investigation on the application of this reaction system are currently underway in our laboratory.

EXPERIMENTAL

General. All NMR spectra were recorded on MERCURY (400 MHz for 1H NMR, 100 MHz for 13C NMR) spectrometers; chemical shifts were expressed in parts per million relative to TMS signal as an internal reference in CDCl3. Fourier transform infrared (FT-IR) spectra for the solids were recorded over the wavenumber range from 400 to 4000 cm-1 on a Nicolet AVATAR 360 FT-IR spectrophotometer. Samples were prepared by mixing the powdered solids with KBr (the blank). Mass spectra were recorded on a HP5989B mass spectrometer. The crystal structure was recorded on a Bruker APEX-II CCD. All reagents and starting materials were obtained from commercial suppliers and were used without further purification.

General Procedure for the Synthesis of 1a-d. Dicarbonyl compound (1.1 mmol) and phenylhydrazine (108.2 mg, 1.0 mmol) were added in 2 mL of EtOH, and the mixture was stirred at 75 oC until complete reaction of the phenylhydrazine (observed by TLC, 5-7 h). At the end of the reaction, the solution was concentrated under reduced pressure to afford crude product. The corresponding compounds 1a-d were obtained by simple recrystallizing from a mixture of EtOAc and petroleum ether.

General Procedure for the Synthesis of 1e-s. Dicarbonyl compound (1.0 mmol) and phenylhydrazine hydrochloride (144.6 mg, 1.0 mmol) were added into 2 mL of EtOH, and the mixture was stirred at 75 oC until complete reaction of the dicarbonyl compound (observed by TLC, 6-9 h). The solution was purified by column chromatography on silica gel with a mixture of EtOAc and petroleum ether as eluent to afford the corresponding compounds.

General Procedure for the Synthesis of 2a-s. Pyrazolone (1.0 mmol), NaOAc·3H2O (136 mg, 1.5 mmol), and LiBr·H2O (103.9 mg, 1.5 mmol) were added in a 10 mL flask containing 2 mL of DMSO, and the mixture was stirred at 100 oC under natural condition until complete consumption of the pyrazolone (observed by TLC, 6-8 h). At the end of the reaction, 5 mL of water was charged, and the solution was extracted with CH2Cl2 (3×5 mL). The organic phases were then dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with a mixture of EtOAc and petroleum ether as eluent.
Because the 1a-m, 1o,16 2a-d, and 2j, k have been obtained by published methods and are well characterized and described in the reports, so the detailed spectral analysis of them are not necessary in the EXPERIMENTAL (2a-d, and 2j, k see the Supporting Information).

1-(3-Bromophenyl)-3-propyl-1H-pyrazol-5(4H)-one (1n) White solid; Mp 110-112 oC; 1H NMR (CDCl3, 400 MHz): δ = 8.08 (s, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.34-7.18 (m, 2H), 2.50 (dt, J = 15.2, 7.5 Hz, 2H), 1.76-1.62 (m, 2H), 1.10-0.96 (m, 3H); 13C NMR (CDCl3, 101 MHz): δ = 170.46, 160.20, 139.24, 130.08, 127.70, 122.47, 121.39, 116.91, 41.72, 33.09, 19.91, 13.73; MS (FAB): m/z = 280.02 [M+H]+; IR (KBr): 3440, 2962, 2926, 2870, 1578, 1550, 1476, 1437, 1384, 1316, 1196, 1151, 1091, 845, 803, 771, 726, 622 cm-1. Anal. Calcd for C12H13BrN2O; C, 51.26; H, 4.66; Br, 28.42; N, 9.96. Found: C, 51.24; H, 4.68; Br, 28.44; N, 9.94.

1-(3,5-Dimethylphenyl)-3-propyl-1H-pyrazol-5(4H)-one (1p) White solid; Mp 105-107 oC; 1H NMR (CDCl3, 400 MHz): δ = 7.37 (d, J = 84.9 Hz, 2H), 6.83 (s, 1H), 2.48 (t, J = 7.6 Hz, 2H), 2.34 (s, 6H), 1.75-1.62 (m, 2H), 1.02 (t, J = 7.4 Hz, 3H); 13C NMR (CDCl3, 101 MHz): δ = 170.47, 159.70, 138.47, 137.88, 126.83, 116.80, 41.65, 33.12, 21.45, 20.12, 13.75; MS (FAB): m/z = 230.14 [M+H]+; IR (KBr): 3450, 2962, 2921, 2872, 2620, 1609, 1552, 1467, 1393, 1335, 1240, 1144, 1006, 837, 743, 626 cm-1. Anal. Calcd for C14H18N2O; C, 73.01; H, 7.88; N, 12.16. Found: C, 73.00; H, 7.86; N, 12.14.

1-(3-Bromophenyl)-3-isopropyl-1H-pyrazol-5(4H)-one (1q) Yellow solid; Mp 84-86 oC; 1H NMR (CDCl3, 400 MHz): δ = 8.08 (s, 1H), 7.90 (d, J = 7.9 Hz, 1H), 7.27 (dd, J = 16.3, 8.3 Hz, 2H), 2.79 (dt, J = 13.6, 6.8 Hz, 1H), 2.17 (s, 2H), 1.25 (d, J = 6.9 Hz, 6H); 13C NMR (CDCl3, 101 MHz): δ = 170.51, 164.60, 139.33, 130.08, 127.69, 122.47, 121.40, 116.93, 39.87, 30.82, 20.04; MS (FAB): m/z = 280.02 [M+H]+; IR (KBr): 3436, 2966, 2870, 2748, 1717, 1616, 1475, 1398, 1334, 1270, 1186, 1074, 991, 875, 770, 712 cm-1. Anal. Calcd for C12H13BrN2O; C, 51.26; H, 4.66; Br, 28.42; N, 9.96. Found: C, 51.25; H, 4.67; Br, 28.45; N, 9.95.

1-(3-Chlorophenyl)-3-isopropyl-1H-pyrazol-5(4H)-one (1r) Yellow solid; Mp 80-82 oC; 1H NMR (CDCl3, 400 MHz): δ = 7.94 (s, 1H), 7.85 (d, J = 8.2 Hz, 1H), 7.33-7.26 (m, 1H), 7.14 (d, J = 7.9 Hz, 1H), 3.44 (s, 2H), 2.78 (dd, J = 13.7, 6.8 Hz, 1H), 1.26 (d, J = 6.8 Hz, 6H); 13C NMR (CDCl3, 101 MHz): δ = 170.51, 164.56, 139.23, 134.48, 129.80, 124.73, 118.56, 116.44, 39.88, 30.81, 20.02; MS (FAB): m/z = 236.07 [M+H]+; IR (KBr): 3072, 2967, 2868, 2749, 1616, 1589, 1479, 1401, 1338, 1269, 1186, 1077, 874, 770, 729, 681 cm-1. Anal. Calcd for C12H13ClN2O; C, 60.89; H, 5.54; Cl, 14.98; N, 11.84. Found: C, 60.90; H, 5.55; Cl, 14.96; N, 11.88.

1-(3,5-Dimethylphenyl)-3-isopropyl-1H-pyrazol-5(4H)-one (1s) Yellow solid; Mp 80-81 oC; 1H NMR (CDCl3, 400 MHz): δ = 7.59 (s, 2H), 6.80 (s, 1H), 2.62 (s, 2H), 2.34 (s, 6H), 1.59 (d, J= 12.0 Hz, 1H), 1.38-1.30 (m, 6H); 13C NMR (CDCl3, 101 MHz): δ = 164.00, 155.49, 138.48, 138.26, 126.29, 124.64, 116.77, 30.88, 29.88, 21.51, 20.92; MS (FAB): m/z = 230.14 [M+H]+; IR (KBr): 3069, 2967, 2869, 2748, 1609, 1588, 1477, 1400, 1393, 1335, 1270, 1240, 1140, 1076, 874, 837 cm-1. Anal. Calcd for C14H18N2O; C, 73.01; H, 7.88; N, 12.16. Found: C, 73.03; H, 7.89; N, 12.17.

(4Z)-2,4-Dihydro-4-[[5-hydroxy-3-methyl-1-(4-methoxyphenyl)-1H-pyrazol-4-yl]methylene]-5-
methyl-2-(4-methoxyphenyl)-3H-pyrazol-3-one (2e) Yellow solid; Mp 212-214 oC; 1H NMR (CDCl3, 400 MHz): δ = 17.82 (s, 1H), 7.79-7.76 (d, J = 8.8 Hz, 4H), 7.24 (s, 1H), 6.97-6.94 (d, J = 9.2 Hz, 4H), 3.84 (s, 6H), 2.36 (s, 6H); 13C NMR (CDCl3, 100 MHz): δ = 161.7, 158.0, 152.4, 138.1, 130.8, 122.8, 114.0, 109.2, 55.5, 12.9; MS (FAB): m/z = 418.16 [M+H]+; IR (KBr): 3447, 2921, 2846, 1618, 1546, 1508, 1440, 1331, 1246, 1168, 1117, 1079, 1034, 1006, 827 cm-1. Anal. Calcd for C23H22N4O4; C, 66.02; H, 5.30; N, 13.39. Found: C, 66.05; H, 5.32; N, 13.37.

(4Z)-2,4-Dihydro-4-[[5-hydroxy-3-methyl-1-(3-methylphenyl)-1H-pyrazol-4-yl]methylene]-5-
methyl-2-(3-methylphenyl)-3H-pyrazol-3-one (2f) Yellow solid; Mp 155-157 oC; 1H NMR (CDCl3, 400 MHz): δ = 17.96 (s, 1H), 7.71-7.69 (d, J = 8.8 Hz, 4H), 7.35-7.33 (m, 2H), 7.30 (s, 1H), 7.11-7.09 (d, J = 7.6 Hz, 4H), 2.41 (s, 6H), 2.38 (s, 6H); 13C NMR (CDCl3, 100 MHz): δ = 161.2, 152.6, 138.9, 138.2, 137.5, 128.7, 127.4, 121.7, 118.3, 109.4, 21.5, 12.9; MS (FAB): m/z = 386.3 [M+H]+; IR (KBr): 3446, 2922, 2852, 1616, 1546, 1493, 1457, 1418, 1382, 1327, 1103, 1010, 923, 785, 687 cm-1. Anal. Calcd for C23H22N4O2; C, 71.48; H, 5.74; N, 14.50. Found: C, 71.46; H, 5.71; N, 14.53.

(4Z)-2-(3-Bromophenyl)-4-[[1-(3-bromophenyl)-5-hydroxy-3-methyl-1H-pyrazol-4-yl]methylene]-2-4-dihydro-5-methyl-3H-pyrazol-3-one (2g) Yellow solid; Mp 238-240 oC; 1H NMR (CDCl3, 400 MHz): δ = 17.82 (s, 1H), 8.16-8.15 (m, 2H), 7.94-7.91 (d, J = 8.6 Hz, 2H), 7.42-7.40 (d, J = 9.2 Hz, 4H), 7.33-7.29 (m, 2H), 7.25 (s, 1H), 2.38 (s, 6H); 13C NMR (CDCl3, 100 MHz):δ = 161.2, 152.9, 138.8, 138.6, 134.4, 129.1, 126.8, 120.1, 118.3, 109.4, 12.9; MS (FAB): m/z = 515.96 [M+H]+; IR (KBr): 3447, 2922, 2857, 1621, 1586, 1552, 1478, 1449, 1377, 1329, 1077, 1013, 903, 772, 716 cm-1. Anal. Calcd for C21H16Br2N4O2; C, 48.86; H, 3.12; Br, 30.96; N, 10.85. Found: C, 48.90; H, 3.11; Br, 30.94; N, 10.86.

(4Z)-2-(3-Chlorophenyl)-4-[[1-(3-chlorophenyl)-5-hydroxy-3-methyl-1H-pyrazol-4-yl]methylene]-2-4-dihydro-5-methyl-3H-pyrazol-3-one (2h) Yellow solid; Mp 208-210 oC; 1H NMR (CDCl3, 400 MHz): δ = 17.82 (s, 1H), 8.00-7.99 (m, 2H), 7.88-7.86 (d, J = 8.0 Hz, 2H), 7.38-7.37 (d, J = 7.6 Hz, 2H), 7.35 (s, 1H), 7.24-7.23 (m, 2H), 2.35 (s, 6H); 13C NMR (CDCl3, 100 MHz): δ = 161.5, 153.0, 138.6, 138.4, 134.6, 129.9, 126.4, 120.8, 118.7, 109.6, 12.9; MS (FAB): m/z = 426.07 [M+H]+; IR (KBr): 3446, 2920, 2852, 1618, 1588, 1547, 1482, 1418, 1381, 1327, 1087, 1006, 779, 737, 681 cm-1. Anal. Calcd for C21H16Cl2N4O2; C, 59.03; H, 3.77; Cl, 16.59; N, 13.11. Found: C, 59.01; H, 3.76; Cl, 16.57; N, 13.15.

(4Z)-2,4-Dihydro-4-[[5-hydroxy-3-methyl-1-(3,5-dimethylphenyl)-1H-pyrazol-4-yl]methylene]-5- methyl-2-(3,5-dimethylphenyl)-3H-pyrazol-3-one (2i) Yellow solid; Mp 233-235 oC; 1H NMR (CDCl3, 400 MHz): δ = 17.86 (s, 1H), 7.51 (s, 4H), 7.24 (s, 1H), 6.92 (s, 2H), 2.36 (s, 18H); 13C NMR (CDCl3, 100 MHz): δ = 161.1, 152.5, 138.6, 138.1, 137.5, 128.3, 119.0, 109.4, 21.4, 12.9; MS (FAB): m/z = 414.4 [M+H]+; IR (KBr): 3447, 2922, 2853, 1620, 1593, 1551, 1470, 1372, 1372, 1326, 1154, 1097, 1013, 805, 690 cm-1. Anal. Calcd for C25H26N4O2; C, 72.44; H, 6.32; N, 13.52. Found: C, 72.41; H, 6.33; N, 13.50.

(4Z)-2,4-Dihydro-4-[[5-hydroxy-1-(4-methoxyphenyl)-3-propyl-1H-pyrazol-4-yl]methylene]-2-(4- methoxyphenyl)-5-propyl-3H-pyrazol-3-one (2l) Yellow solid; Mp 138-140 oC; 1H NMR (CDCl3, 400 MHz): δ = 17.88 (s, 1H), 7.79-7.77 (d, J = 8.0 Hz, 4H), 7.32 (s, 1H), 6.96-6.94 (d, J = 8.0 Hz, 4H), 3.83 (s, 6H), 2.69-2.66 (m, 4H), 1.81-1.75 (m, 4H), 1.08-1.05 (m, 6H); 13C NMR (CDCl3, 100 MHz): δ = 161.7, 158.0, 155.9, 137.8, 130.9, 122.8, 114.0, 108.5, 55.5, 29.1, 22.1, 14.1; MS (FAB): m/z = 474.23 [M+H]+; IR (KBr): 3443, 2959, 2931, 1609, 1533, 1512, 1443, 1357, 1248, 1218, 1171, 1121, 1089, 1036, 832 cm-1. Anal. Calcd for C27H30N4O4; C, 68.34; H, 6.37; N, 11.81. Found: C, 68.35; H, 6.33; N, 11.80.

(4Z)-2,4-Dihydro-4-[[5-hydroxy-1-(3-methylphenyl)-3-propyl-1H-pyrazol-4-yl]methylene]-2-(3- methylphenyl)-5-propyl-3H-pyrazol-3-one (2m) Yellow solid; Mp 123-125 oC; 1H NMR (CDCl3, 400 MHz): δ = 17.86 (s, 1H), 7.71-7.70 (d, J = 7.6 Hz, 4H), 7.34-7.32 (m, 2H), 7.30 (s, 1H), 7.10-7.09 (d, J = 8.0 Hz, 2H), 2.71-2.67 (m, 4H), 2.41 (s, 6H), 1.82-1.78 (m, 4H), 1.09-1.06 (m, 6H); 13C NMR (CDCl3, 100 MHz): δ = 161.2, 156.1, 138.8, 137.9, 137.5, 128.6, 127.3, 121.8, 118.4, 108.7, 29.1, 22.1, 21.5, 14.1; MS (FAB): m/z = 442.24 [M+H]+; IR (KBr): 3443, 2960, 2929, 1611, 1535, 1491, 1457, 1358, 1323, 1240, 1221, 1113, 898, 779, 683 cm-1. Anal. Calcd for C27H30N4O2; C, 73.28; H, 6.83; N, 12.66. Found: C, 73.30; H, 6.82; N, 12.62.

(4Z)-2-(3-Bromophenyl)-4-[[1-(3-bromophenyl)-5-hydroxy-3-propyl-1H-pyrazol-4-yl]methylene]-2-4-dihydro-5-propyl-3H-pyrazol-3-one (2n) Yellow solid; Mp 171-172 oC; 1H NMR (CDCl3, 400 MHz): δ = 17.88 (s, 1H), 8.15-8,14 (m, 2H), 7.94-7.92 (d, J = 7.2 Hz, 2H), 7.41-7.39 (d, J = 6.4 Hz, 2H), 7.32 (s, 1H), 7.30-7.28 (m, 2H), 2.68-2.65 (m, 4H), 1.81-1.76 (m, 4H), 1.09-1.05 (m, 6H); 13C NMR (CDCl3, 100 MHz): δ = 161.5, 156.4, 138.8, 138.0, 130.1, 129.3, 123.7, 122.5, 119.2, 108.8, 29.1, 21.8, 14.0; MS (FAB): m/z = 572.02 [M+H]+; IR (KBr): 3445, 2959, 2922, 1618, 1586, 1541, 1477, 1443, 1356, 1188, 1085, 1013, 876, 778, 679 cm-1. Anal. Calcd for C25H24Br2N4O2; C, 52.47; H, 4.23; Br, 27.92; N, 9.79. Found: C, 52.50; H, 4.21; Br, 27.94; N, 9.76.

(4Z)-2-(3-Chlorophenyl)-4-[[1-(3-chlorophenyl)-5-hydroxy-3-propyl-1H-pyrazol-4-yl]methylene]-2-4-dihydro-5-propyl-3H-pyrazol-3-one (2o) Yellow solid; Mp 168-170 oC; 1H NMR (CDCl3, 400 MHz): δ = 17.87 (s, 1H), 8.01-8,00 (m, 2H), 7.90-7.88 (d, J = 8.4 Hz, 2H), 7.39-7.35 (m, 2H), 7.33 (s, 1H), 7.26-7.24 (d, J = 8.4 Hz, 2H), 2.70-2.67 (m, 4H), 1.82-1.77 (m, 4H), 1.10-1.05 (m, 6H); 13C NMR (CDCl3, 100 MHz): δ = 161.3, 156.6, 138.6, 137.9, 135.0, 130.9, 122.6, 116.4, 116.0, 113.8, 29.2, 21.5, 14.0; MS (FAB): m/z = 482.13 [M+H]+; IR (KBr): 3447, 2964, 2925, 1622, 1588, 1546, 1481, 1412, 1359, 1217, 1088, 1014, 872, 777, 670 cm-1. Anal. Calcd for C25H24Cl2N4O2; C, 62.12; H, 5.00; Cl, 14.67; N, 11.59. Found: C, 62.10; H, 5.01; Cl, 14.64; N, 11.56.

(4Z)-2,4-Dihydro-4-[[5-hydroxy-1-(3,5-dimethylphenyl)-3-propyl-1H-pyrazol-4-yl]methylene]-2-(3-5-dimethylphenyl)-5-propyl-3H-pyrazol-3-one (2p) Yellow solid; Mp 194-196 oC; 1H NMR (CDCl3, 400 MHz): δ = 17.85 (s, 1H), 7.51 (s, 4H), 7.33 (s, 1H), 6.93 (s, 2H), 2.71-2.67 (m, 4H), 2.37 (s, 12H), 1.83-1.74 (m, 4H), 1.09-1.05 (m, 6H); 13C NMR (CDCl3, 100 MHz): δ = 161.1, 153.7, 139.0, 138.4, 137.6, 129.6, 118.9, 109.7, 29.1, 22.1, 21.4, 14.1; MS (FAB): m/z = 470.27 [M+H]+; IR (KBr): 3445, 2959, 2924, 1622, 1591, 1546, 1472, 1366, 1331, 1297, 1242, 1159, 1105, 847, 683 cm-1. Anal. Calcd for C29H34N4O2; C, 74.01; H, 7.28; N, 11.91. Found: C, 74.02; H, 7.30; N, 11.90.

(4Z)-2-(3-Bromophenyl)-4-[[1-(3-bromophenyl)-5-hydroxy-3-isopropyl-1H-pyrazol-4-yl]methylene]-2,4-dihydro-5-isopropyl-3H-pyrazol-3-one (2q) Yellow solid; Mp 219-221 oC; 1H NMR (CDCl3, 400 MHz): δ = 17.74 (s, 1H), 8.17-8,16 (m, 2H), 7.98-7.95 (d, J = 8.2 Hz, 2H), 7.44 (s, 1H), 7.41-7.38 (d, J = 8.0 Hz, 2H), 7.33-7.28 (m, 2H), 3.13-3.06 (m, 2H), 1.40-1.39 (d, J = 6.8 Hz, 12H); 13C NMR (CDCl3, 100 MHz): δ = 161.7, 160.7, 138.9, 137.5, 130.1, 129.2, 123.7, 122.5, 119.3, 107.9, 26.9, 21.5; MS (FAB): m/z = 572.02 [M+H]+; IR (KBr): 3441, 2965, 2926, 1622, 1586, 1541, 1480, 1381, 1358, 1261, 1111, 1000, 862, 777, 692 cm-1. Anal. Calcd for C25H24Br2N4O2; C, 52.47; H, 4.23; Br, 27.92; N, 9.79. Found: C, 52.50; H, 4.21; Br, 27.94; N, 9.80.

(4Z)-2-(3-Chlorophenyl)-4-[[1-(3-chlorophenyl)-5-hydroxy-3-isopropyl-1H-pyrazol-4-yl]methylene]-2,4-dihydro-5-isopropyl-3H-pyrazol-3-one (2r) Yellow solid; Mp 212-214 oC; 1H NMR (CDCl3, 400 MHz): δ = 17.74 (s, 1H), 8.03-8,02 (m, 2H), 7.93-7.81 (d, J = 8.0 Hz, 2H), 7.45 (s, 1H), 7.39-7.35 (m, 2H), 7.25-7.23 (d, J = 7.6 Hz, 2H), 3.11-3.08 (m, 2H), 1.41-1.39 (d, J = 7.6 Hz, 12H); 13C NMR (CDCl3, 100 MHz): δ = 161.8, 160.8, 138.8, 137.5, 134.6, 129.9, 126.3, 120.9, 118.8, 107.9, 26.9, 21.5; MS (FAB): m/z = 482.13 [M+H]+; IR (KBr): 3449, 2963, 2922, 1624, 1559, 1541, 1482, 1381, 1357, 1259, 1094, 859, 775, 745, 682 cm-1. Anal. Calcd for C25H24Cl2N4O2; C, 62.12; H, 5.00; Cl, 14.67; N, 11.59. Found: C, 62.11; H, 5.02; Cl, 14.66; N, 11.58.

(4Z)-2,4-Dihydro-4-[[5-hydroxy-3-isopropyl-1-(3,5-dimethylphenyl)-1H-pyrazol-4-yl]methylene]-5- isopropyl-2-(3,5-dimethylphenyl)-3H-pyrazol-3-one (2s) Yellow solid; Mp 184-186 oC; 1H NMR (CDCl3, 400 MHz): δ = 17.74 (s, 1H), 7.52 (s, 4H), 7.46 (s, 1H), 6.92 (s, 2H), 3.14-3.07 (m, 2H), 2.37 (s, 12H), 1.41-1.39 (d, J = 6.8 Hz, 12H); 13C NMR (CDCl3, 100 MHz): δ = 161.2, 160.3, 138.6, 138.0, 137.2, 129.9, 118.8, 109.7, 26.9, 21.6, 21.4; MS (FAB): m/z = 470.27 [M+H]+; IR (KBr): 3441, 2963, 2922, 1613, 1585, 1536, 1472, 1379, 1357, 1257, 1156, 1089, 926, 847, 686 cm-1. Anal. Calcd for C29H34N4O2; C, 74.01; H, 7.28; N, 11.91. Found: C, 74.03; H, 7.31; N, 11.89.

ACKNOWLEDGEMENTS
We are grateful for the financial support of the National Natural Science Foundation of China (No. 21202133) and Young Teacher Research Foundation of Northwest Normal University (NWNU-LKQN-08-8, NWNU-kjcxgc-03-73, kjcxgc-03-63). We also thank Key Laboratory of Eco-Environment-Related Polymer Materials (Northwest Normal University), Ministry of Education, for financial support. We also thank Dr. Hanfeng Ding (zhejiang university) for fruitful discussions.

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