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Appl. Sci. 2013, 3(2), 457-468; doi:10.3390/app3020457
Published: 16 April 2013
Abstract: A series of new 1,3-diaryl-5-(1-phenyl-3-methyl-5-chloropyrazol-4-yl)-4,5-dihydropyrazole derivatives have been synthesized under sonication conditions in ethanol or methanol/glacial acetic acid mixture (5/1 ratio) with two equivalents of hydrazines and seven kinds of chalcone-like heteroanalogues obtained from 5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-carbaldehyde. The structures were established on the basis of NMR, IR, MS and element analysis. This method provides several advantages over current reaction methodologies, including a simple work-up procedure, shorter reaction times (2–20 min) and good yields (65%–80%).
Pyrazole and pyrazoline (dihydropyrazoles) derivatives are a class of heterocyclic compounds that have drawn much attention, due to their biological and pharmaceutical activities . A brief survey on the biological activities of various pyrazole and pyrazoline derivatives showed anti-inflammatory [2,3,4,5,6], antitumor [7,8,9,10], antifungal [11,12,13], antiviral and antibacterial [12,14,15], as well as fluorescent properties [16,17,18,19,20,21]. In addition to these effects, in the last decade, pyrazolines and substituted pyrazolines have emerged as promising anti-depressant and anti-convulsant agents [22,23,24,25]. Of all the synthesized pyrazoline derivatives, the 1,3,5-tri-substituted derivatives are of particular importance. So, it is important to find simple and convenient procedures for pyrazole and pyrazoline preparations with different substituent in their moiety, with the aim of obtaining some novel heterocyclic compounds with potentially enhanced properties.
The development of new, rapid and clean synthetic routes toward focused libraries of nitrogen-containing heterocycles is of great importance to both synthetic and medicinal chemists. They have been reported in literature procedures for the design and development of new heterocycles (pyrazole and pyrazoline derivatives) by means of multistep reactions [26,27,28], metal-catalyzed synthesis [29,30], domino reaction of 2-acylaziridines with the Huisgen zwitterions  and 1,3-dipolar cycloaddition reactions  to access important heterobiaryls.
The first synthesis of the pyrazoline framework by the reaction of an α,β-enone with a hydrazine derivative was published by Fischer and Knoevenagel . Then, the reaction of α,β-unsaturated aldehydes and ketones with hydrazine derivatives became one of the most popular methods for the synthesis of pyrazolines [34,35,36,37].
Cyclization of chalcones, leading to pyridine, pyrimidine and pyrazoline derivatives, has been a developing field within the realm of heterocyclic chemistry for the past several years, because of their ready accessibility and the broad spectrum of biological activity of the products [38,39,40,41,42,43,44]. These observations led us to synthesize chalcones and its corresponding pyrazoline, exploring simple procedures.
Sonochemistry is attracting considerable research activity within the synthetic chemistry community, because it offers a new approach to the preparation of organic compounds. In the last two decades, sonochemical methods have become widely used in organic synthesis [45,46,47]. Nowadays, the ultrasonic irradiation technique has been employed, not only to decrease reaction times, but also to improve yields in a large variety of polyfunctionalized heterocycles. Compared with traditional methods, this method is more convenient and easily controlled. A large number of organic reactions can be carried out in a higher yield shorter reaction time and milder conditions under ultrasound [48,49,50,51,52].
2. Experimental Section
2.1. Apparatus and Analysis
Melting points were determined using a Thermo Scientific Fluke 51 II, model IA 9100 melting point apparatus and are reported uncorrected. 1H NMR (400 MHz) and 13C NMR (100 MHz) spectra were recorded at room temperature on a Bruker Ultra Shield 400 using tetramethylsilane (TMS) as the internal standard and deuterated chloroform (CDCl3) as the solvent. EI-MS were run on a Shimadzu GC-MS 2010 spectrometer, which was operating at 70 eV. IR spectra were recorded as KBr pellets on a Shimadzu FTIR-8400 instrument. The ultrasonic irradiation was performed by using a Branson ultrasonic cleaner bath, model 1510, AC input 115 V, output 50 W, 1.9 liters with a mechanical timer (60 min with continuous hold) and heater switch, 47 KHz. High Resolution Mass Spectra (HRMS) were recorded in a Waters Micromass AutoSpec NT spectrometer (STIUJA). The elemental analyses have been obtained using a LECO CHNS-900 and Thermo Finnigan FlashEA1112 CHNS-O (STIUJA) elemental analyzers. The hydrazines and solvents used, such as, ethanol, dichloromethane, glacial acetic acid and ethyl acetate, were obtained from Merck Chemical Company. The chalcone-like heteroanalogues 1 were obtained according to the methodology described [39,53,54].
2.2. General Procedure for the Synthesis of 5-pyrazol-4,5-dihydropyrazoles Derivatives 3
A solution of equimolar amounts of chalcone-like heteroanalogues 1 (1 mmol) and hydrazine 2 (1 mmol), using as solvent ethanol or methanol/acetic acid mixture (5/1 ratio, 10 mL) in an Erlenmeyer, was placed in a water bath and sonicated at ambient conditions (35–40 °C), for an appropriate time (Table 2), until the reaction was completed (the reaction was monitored by TLC). The reaction mixture was then treated with cold ethanol and filtered to leave a solid product, which was crystallized from a hexane/ethanol mixture to yield pure product 3. All the products were characterized by their physical and spectral data (IR, MS, 1H NMR, 13C NMR) and elemental analysis.
2.2.1. Compound 3a
5-Chloro-4-(4,5-dihydro-1-phenyl-3-p-tolyl-1H-pyrazol-5-yl)-3-methyl-1-phenyl-1H-pyrazole. Yellow solid, 80%. mp 133–136 °C. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 2.12 (s, 3H, CH3), 2.32 (s, 3H, CH3), 3.32 (m, 1H, CH2), 3.92 (m, 1H, CH2), 5.66 (m, 1H, CH), 6.95 (t, 1H, Hp, N-Ph, J = 7.43 Hz), 7.17 (d, 2H, Ho, N-Ph, J = 8.28 Hz), 7.28 (t, 2H, Hm, N-Ph, J = 8.54 Hz), 7.39 (t, 1H, Hp, N-Ph, J = 7.54 Hz), 7.47 (t, 2H, Hm, N-Ph, J = 8.28 Hz), 7.49 (d, 2H, Hm, 3-aryl, J = 7.54 Hz), 7.52 (d, 2H, Ho, N-Ph, J = 8.45 Hz), 7.63 (d, 2H, Ho, 3-aryl, J = 7.53 Hz). 13C NMR δ (ppm): 13.3 (CH3), 14.8 (CH3), 41.7 (CH2), 54.3 (CH), 113.8 (Cm, N-Ph), 118.5 (C4 pyrazole), 120.1 (Cp, N-Ph), 121.6 (Cp, 3-aryl), 125.0 (Co, N-Ph), 126.8 (Cm, 3-aryl), 127.9 (Cp, N1-Ph), 128.7 (Cm, N1-Ph), 129.1 (Co, N1-Ph), 131.5 (Ci, 3-aryl), 132.0 (Co, 3-aryl), 137.6 (Ci, N1-Ph), 144.3 (C5 pyrazole), 145.8 (C3 pyrazoline), 147.7 (C3 pyrazole). HR-MS Calc. For C26H23ClN4, 426.1611, found 426.1618. FT-IR (KBr, ν en cm−1), 1592 (C=N, st), 1502 (C=C, st). A. E: Calc. For C26H23ClN4 C: 73.14, H: 5.43, N: 13.12, found C: 73.28, H: 5.93, N: 12.99.
2.2.2. Compound 3b
4-(3-(4-Bromophenyl)-4,5-dihydro-1-phenyl-1H-pyrazol-5-yl)-5-chloro-3-methyl-1-phenyl-1H-pyrazole. Yellow solid, 75%. mp 163–165 °C. 1H NMR (400 MHz, CDCl3 RT) δ (ppm): 2.17 (CH3), 3.20–3.79 (m, 2H, CH2), 5.38 (q, 1H, CH), 6.86 (t, 1H, Hp, N-Ph, J = 7.28 Hz), 7.13 (d, 2H, Ho, N-Ph, J = 8.53 Hz), 7.25 (t, 2H, Hm, N-Ph, J = 7.28 Hz), 7.41 (t, 1H, Hp, N-Ph, J = 7.03 Hz), 7.49 (t, 2H, Hm, N-Ph, J = 8.03 Hz), 7.54 (d, 2H, Hm, 3-aryl, J = 8.54 Hz), 7.55 (d, 2H, Ho, N-Ph, J = 7.03 Hz), 7.63 (d, 2H, Ho, 4-(3-aryl), J = 8.53 Hz). 13C NMR δ (ppm): 13.3 (CH3), 40.7 (CH2), 55.3 (CH), 113.4 (Cm, N-Ph), 117.5 (C4 pyrazole), 119.7 (Cp, N-Ph), 122.6 (Cp, 3-aryl), 124.8 (Co, N-Ph), 127.1 (Cm, 3-aryl), 128.2 (Cp, N1-Ph), 129.0 (Cm, N1-Ph), 129.1 (Co, N1-Ph), 131.5 (Ci, 3-aryl), 131.8 (Co, 3-aryl), 138.0 (Ci, N1-Ph), 144.3 (C5 pyrazole), 145.6 (C3 pyrazoline), 147.7 (C3 pyrazole). MS (70 eV) m/z (%) = 494/492 (M+2/M+, 8/29), 490(23), 91(100), 77(61), 64(28), 51(28). HR-MS Calc. For C25H20BrClN4, 490.0560, found 490.0579. FT-IR (KBr, ν en cm−1), 1594 (C=N, st), 1498 (C=C, st). A. E: Calc. For C25H20BrClN4 C: 61.05, H: 4.10, N: 11.39, found C: 61.07, H: 3.83, N: 11.28.
2.2.3. Compound 3c
5-Chloro-4-(3-(4-chlorophenyl)-4,5-dihydro-1-phenyl-1H-pyrazol-5-yl)-3-methyl-1-phenyl-1H-pyrazole. Yellow solid, 70%. mp 153–156 ºC. 1H NMR (400 MHz, CDCl3 RT) δ (ppm): 2.07 (s, 3H, CH3), 3.28 (m, 1H, CH2), 3.88 (m, 1H, CH2), 5.46 (m, 1H, CH), 6.77 (t, 1H, Hp, J = 7.24 Hz), 7.03 (d, 2H, Ho, aryl, J = 7.65 Hz), 7.21 (t, 2H, Hm, J = 7.24 Hz), 7.43–7.54 (m, 7H, Hm, Hp, Ho aryl, Hp aryl), 7.77 (d, 2H, Ho, J = 8.48 Hz). 13C NMR δ (ppm): 12.8 (CH3), 40.1 (CH2), 54.4 (CH), 112.8 (Cm), 117.3 (C4 pyrazole), 119.1 (Cp), 124.4 (Ci), 124.6 (Co), 127.3 (Cm aryl), 128.3 (Cp), 128.7 (Co aryl), 129.0 (Cm), 129.2 (Co), 131.0 (Ci aryl), 133.1 (Cp aryl), 137.5 (Ci), 143.8 (C5 pyrazole), 146.5 (C3 dihidropyrazole), 147.1 (C3 pyrazole). HR-MS Calc. For C25H20Cl2N4 446.1065, found 446.1064. FT-IR (KBr, ν en cm−1), 1598 (C=N, st), 1495 (C=C, st). A. E: Calc. For C25H20Cl2N4 C: 67.12, H: 4.51, N: 12.52, found C: 67.14, H: 4.49, N: 12.51.
2.2.4. Compound 3d
5-Chloro-4-(4,5-dihydro-3-(4-nitrophenyl)-1-phenyl-1H-pyrazol-5-yl)-3-methyl-1-phenyl-1H-pyrazole. Yellow solid, 80%. mp 178–180 °C. 1H NMR (400 MHz, CDCl3 RT) δ (ppm): 2.30 (CH3), 3.17 (m, 1H, CH2), 3.44 (m, 1H, CH2), 5.11 (q, 1H, CH), 7.48 (m, 5H, CH), 7.80 (d, 2H, Hm, 3-aryl, J = 9.1 Hz), 8.23 (d, 2H, Ho, 3-aryl, J = 9.1 Hz). 13C NMR δ (ppm): 13.4 (CH3), 37.6 (CH2), 55.3 (CH), 116.3 (C4, pyrazole), 123.7 (Cm, 3-aryl), 124.6 (Co), 125.9 (Cm), 128.0 (Cp), 128.7 (Co, 3-aryl), 128.9 (Ci, 3-aryl), 137.7 (Ci), 138.6 (Cp, 3-aryl), 147.1 (C5, pyrazole), 147.8 (C3, pyrazole), 148.5 (C3, pyrazoline). HR-MS Calc. For C19H16ClN5O2 381.0993, found 381.0983. FT-IR (KBr, ν en cm−1), 1595 (C=N, st), 1502 (C=C, st). A. E: Calc. For C19H16ClN5O2 C: 59.77, H: 4.22, N: 18.34, found C: 59.28, H: 3.93, N: 17.99.
2.2.5. Compound 3e
5-Chloro-4-(4,5-dihydro-3-(4-methoxyphenyl)-1-phenyl-1H-pyrazol-5-yl)-3-methyl-1-phenyl-1H-pyrazole. Yellow solid, 80%, mp 130–132 °C. 1H NMR CDCl3 δ: 2.14 (CH3), 3.40–3.88 (m, 2H, CH2), 3.91 (s, 3H, OCH3), 5.25 (q, 1H, CH), 6.43 (d, 2H, Hm 4-(3-aryl), J = 8.78 Hz), 7.68 (d, 2H, Ho 4-(3-aryl), J = 8.79 Hz), 7.12 (d, 2H, Ho 4-(N-aryl) J = 9.07 Hz), 7.15 (d, 2H, Hm 4-(N-aryl), J = 9.04 Hz), 7.39 (t, 1H, Hp, N-Ph), 7.47 (t, 2H, Hm, N-Ph), 7.52 (d, 2H, Ho, N-Ph, J = 7.53 Hz), 7.03 (d, 2H, CHo, N1-aryl, J = 8.78 Hz), 7.19 (d, 2H, CHm, N1-aryl, J = 9.04 Hz), 7.40 (m, 3H, CHp N-Ph, CHm C3-aryl, J = 8.53 Hz), 7.49 (t, 2H, CHm N-Ph), 7.54 (d, 2H, CHo-Ph), 7.68 (d, 2H, CHo C3-aryl, J = 8.54 Hz). 13C NMR δ (ppm): 12.7 (CH3), 41.0 (CH2), 55.1 (CH), 114.0 (C4, pyrazole), 123.8 (Cm, 3-aryl), 124.6 (Co), 126.9 (Cm), 128.1 (Cp), 128.8 (Co, 3-aryl), 129.4 (Ci, 3-aryl), 137.8 (Ci), 140.0 (Cp, 3-aryl), 147.7 (C5, pyrazole), 148.9 (C3, pyrazole), 151.7 (C3, pyrazoline). MS (70 eV) m/z (%) = 442 (M+2, 96), 440 (100), 405 (59), 91 (75), 77 (83). FT-IR (KBr, ν en cm-1), 1597 (C=N, st), 1497 (C=C, st). A. E: Calc. For C26H23ClN4O C: 70.50, H: 5.23, N: 12.65, found C: 70.08, H: 5.03, N: 11.99.
2.2.6. Compound 3f
5-Chloro-4-(4,5-dihydro-3-(3,4,5-trimethoxyphenyl)-1-phenyl-1H-pyrazol-5-yl)-3-methyl-1-phenyl-1H-pyrazole. Yellow solid, 75%, mp 118–120 °C. 1H NMR CDCl3 δ: 2.12 (CH3), 3.78 (m, 9H, methoxyl, 1H, CH2), 3.42–3.48, 3.90–3.95 (m, 2H, CH2), 5.34–5.39 (q, 1H, CH), 6.88 (t, 1H, Hp, N-Ph), 7.19 (d, 2H, Ho, N-Ph), 7.25 (t, 2H, Hm, N-Ph), 7.38 (t, 1H, Hp, N1-Ph), 7.49 (t, 2H, Hm, N1-Ph), 7.51 (d, 2H, Hm, 4-(3-aryl), J = 8.53 Hz), 7.55 (d, 2H, Ho, N1-Ph), 7.60 (d, 2H, Ho, 4-(3-aryl), J = 8.55 Hz). FT-IR (KBr, ν en cm−1), 1595 (C=N, st), 1500 (C=C, st).
2.2.7. Compound 3g
4-(3-(Benzo[d][1,3]dioxol-6-yl)-4,5-dihydro-1-phenyl-1H-pyrazol-5-yl)-5-chloro-3-methyl-1-phenyl-1H-pyrazole. Brown solid, 65%, mp 220–222 °C. 1H NMR CDCl3 δ: 2.79 (CH3), 3.52–3.57, 3.80–3.88 (m, 2H, CH2), 5.90 (s, 2H, CH2-dioxol), 5.38–5.41(q, 1H, CH), 6.88 (t, 1H, Hp, N-Ph), 7.19 (d, 2H, Ho, N-Ph), 7.25 (t, 2H, Hm, N-Ph), 7.38 (t, 1H, Hp, N1-Ph), 7.49 (t, 2H, Hm, N1-Ph), 7.51 (d, 2H, Hm, 4-(3-aryl), J = 8.53 Hz), 7.55 (d, 2H, Ho, N1-Ph), 7.60 (d, 2H, Ho, 4-(3-aryl), J = 8.55 Hz). 13C NMR δ (ppm): 12.9 (CH3), 41.2 (CH2), 55.3 (CH), 114.2 (Co, 3-aryl), 119.1 (C4, pyrazole), 124.8 (Co), 127.1 (Cm), 128.4 (Cp), 133.8 (Ci), 149.1 (C5, pyrazole). HR-MS Calc. For C26H21ClN4O2 456.2112, found 456.1217. FT-IR (KBr, ν en cm-1), 1598 (C=N, st), 1498 (C=C, st).
2.2.8. Compound 3h
5-Chloro-4-(1-(4-chlorophenyl)-4,5-dihydro-3-p-tolyl-1H-pyrazol-5-yl)-3-methyl-1-phenyl-1H-pyrazole. Yellow solid, 80%, mp 158–160 °C. 1H NMR (400 MHz, CDCl3 RT) δ (ppm): 2.13 (CH3), 2.38 (CH3), 3.20 (m, 1H, CH2), 3.79 (m, 2H, CH2), 5.29 (q, 1H, CH), 7.01 (d, 2H, Hm, N-aryl, J = 9.11 Hz), 7.16 (d, 2H, Ho, N-aryl, J = 9.09 Hz), 7.21 (d, 2H, Hm, 3-aryl, J = 7.86 Hz), 7.39 (t, 1H, Hp, J = 7.24 Hz), 7.47 (t, 2H, Hm, J = 7.86 Hz), 7.52 (d, 2H, Ho, J = 7.24 Hz), 7.63 (d, 2H, Ho, 3-aryl, J = 8.27 Hz). 13C NMR δ (ppm): 13.3 (CH3), 21.4 (CH3), 41.2 (CH2), 55.1 (CH), 114.3 (Co, N-aryl), 117.3 (C4, pyrazole), 124.0 (Ci, N-aryl), 124.8 (Co), 125.7 (Co, 3-aryl), 128.2 (Cp), 128.9 (Cm, N-aril), 129.0 (Cm), 129.4 (Cm, 3-aryl), 133.9 (Ci, 3-aryl), 138.0 (Ci), 139.1 (Cp, 3-aryl), 143.2 (Cp, N-aryl), 147.6 (C3, pyrazole), 147.8 (C3, pyrazoline), 149.0 (C5, pyrazole). HR-MS Calc. For C26H22Cl2N4 460.1222, found 460.1217. FT-IR (KBr, ν en cm−1), 1592 (C=N, st), 1491 (C=C, st).
2.2.9. Compound 3i
4-(1,3-bis(4-Chlorophenyl)-4,5-dihydro-1H-pyrazol-5-yl)-5-chloro-3-methyl-1-phenyl-1H-pyrazole. Yellow solid, 70%. mp 150–152 °C. 1H NMR (400 MHz, CDCl3 RT) δ (ppm): 2.14 (CH3), 3.21 (m, 1H, CH2), 3.80 (m, 1H, CH2), 5.36 (q, 1H, CH), 7.03 (d, 2H, Ho, N1-aryl, J = 8.78 Hz), 7.19 (d, 2H, Hm, N1-aryl, J = 9.04 Hz), 7.40 (m, 3H, Hp N-Ph, Hm C3-aryl, J = 8.53 Hz), 7.49 (t, 2H, Hm N-Ph), 7.54 (d, 2H, Ho Ph, J = 8.28 Hz), 7.68 (d, 2H, Ho C3-aryl, J = 8.54 Hz). 13C NMR δ (ppm): 12.9 (CH3), 40.6 (CH2), 54.9 (CH), 114.1 (Cm, N1-aryl), 116.8 (C4 pyrazole), 124.2 (Ci N1-aryl), 124.5 (Co N1-aryl), 124.7 (C5 pyrazole), 126.6 (Cm C3-aryl), 127.9 (Cp Ph), 128.6 (Co C3-aryl), 128.7 (Co Ph), 130.5 (Ci C3-aryl), 134.4 (Cp C3-aryl), 137.6 (Ci-Ph), 142.5 (Ci N1-aryl), 145.9 (C3), 147.3 (C3 pyrazole). MS (70 eV) m/z (%) = 485/483 (M+5/M+3, 3/9), 484/482 (M+4/M+2, 11/31), 480 (M+, 33), 321/320/319 (7/4/16), 139/137 (4/11), 127/125 (26/73), 113/111 (5/15), 99/97 (5/20), 87/85 (3/12), 83/81 (23/52), 79/77 (6/20), 71/69 (21/100), 57 (33), 55 (29). HR-MS Calc. For C25H19Cl3N4 480.0675, found 480.0663. FT-IR (KBr, ν en cm−1), 1584 (C=N, st), 1488 (C=C, st).
2.2.10. Compound 3j
5-Chloro-4-(1-(4-chlorophenyl)-4,5-dihydro-3-(4-methoxyphenyl)-1H-pyrazol-5-yl)-3-methyl-1-phenyl-1H-pyrazole. Yellow solid, 80%. mp 128–130 °C. 1H NMR (400 MHz CDCl3 RT) δ (ppm): 2.13 (CH3), 3.19 (m, 1H, CH2), 3.78 (m, 1H, CH2), 3.85 (s, 3H, OCH3), 5.27 (q, 1H, CH), 6.93 (d, 2H, Hm 3-aryl, J = 8.78 Hz), 7.00 (d, 2H, Ho N-aryl J = 9.03 Hz), 7.15 (d, 2H, Hm N-aryl, J = 9.04 Hz), 7.39 (t, 1H, Hp, N-Ph, J = 7.78 Hz), 7.47 (t, 2H, Hm, N-Ph, J = 8.03 Hz), 7.52 (d, 2H, Ho, N-Ph, J = 7.53 Hz), 7.68 (d, 2H, Ho 3-aryl, J = 8.79 Hz). 13C NMR δ (ppm): 13.3 (CH3), 41.6 (CH2), 55.4 (OCH3), 55.7 (CH), 114.8 (Cm, 3-aryl), 128.0 (Co, 3-aryl), 125.7 (Ci, 3-aryl), 161.3 (Cp, 3-aryl), 148.6 (C3 pyrazoline), 118.1 (C4 pyrazole), 124.0 (Co, N1-aryl), 124.6 (Ci, N1-aryl), 114.9 (Cm, N1-aryl), 144.2 (C5 pyrazole), 148.3 (C3 pyrazole), 137.8 (Ci, N-Ph), 125.6 (Co, N-Ph), 128.9 (Cp, N-Ph), 129.6 (Cm, N-Ph). MS (70 eV) m/z (%) = 480/478 (M+2/M+, 11/71), 477/475 (30/100), 315 (46), 127 (23), 125 (64), 90 (28), 77 (56), 51 (30). FT-IR (KBr, ν en cm−1), 1597 (C=N, st), 1498 (C=C, st).
3. Results and Discussion
We continue our study to obtain functionalized heterocycles through the development of synthetic strategies. The starting compounds 1 were synthesized by Claisen-Schmidt condensation of 5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-carbaldehyde with acetophenones [53,54]. As part of our ongoing research on the application of ultrasonic irradiation as a clean and useful technique in organic synthesis, we described in this work the synthesis of 5-(pyrazol-4-yl)-4,5-dihydropyrazole derivatives under ultrasound irradiation (Scheme 1).
We preliminarily examined the cyclocondensation reaction of (E)-3-(5-chloro-3-methyl-1-phenyl-1H-pyrazol-4-yl)-1-arylprop-2-en-1-one 1 with hydrazines in the presence of ethanol or methanol and acetic acid as the catalyst under sonication. To achieve suitable reaction conditions in terms of reaction time and catalysis at ambient conditions, we tested different proportions of a mixture of ethanol/methanol and acetic acid. The results are summarized in Table 1.
|Table 1. Effect of reaction conditions. Green factors.|
|Entry||Conditions||Time (min)||Yield b (%)|
|1||Ethanol or Methanol||35||60|
|2||Ethanol or Methanol/Acetic acid (10/1)||20||75|
|3||Ethanol or Methanol/Acetic acid (5/1)||20||80|
|4||Ethanol or Methanol/Acetic acid (10/3)||20||75|
|5||Ethanol or Methanol||20||50|
|6||Ethanol or Methanol/Acetic acid (10/1)||15||65|
|7||Ethanol or Methanol/Acetic acid (5/1)||15||80|
|8||Ethanol or Methanol/Acetic acid (10/3)||15||75|
b Isolated yields using ethanol as solvent.
The reaction worked out best under sonication conditions in a mixture of ethanol or methanol/acetic acid (5/1) at ambient temperature (35–40 °C) to provide good yield (65%–80%) in a short time (2–20 min), and the results are summarized in Table 2. To develop the scope of the reaction, we were encouraged to extend this reaction to a variety of (E)-3-(5-chloro-3-methyl-1-phenyl-1H-pyrazol-4-yl)-1-arylprop-2-en-1-one 1 with different substituents under the determined optimum conditions.
|Table 2. The synthesized 1,3-diaryl-5-(1-phenyl-3-methyl-5-chloro-pyrazol)-4,5-dihydropyrazole derivatives under ultrasonic irradiation at ambient conditions (35–40 °C).|
|Compound 3||Ar||Ar′||Time reaction (min)||M.p. °C||Yield (%)|
We found that the results were excellent compared with 5-pyrazole-4,5-dihidropyrazoline derivatives reported in the literature . Thus, ultrasonic irradiation was found to have a beneficial effect on the synthesis of 1,3-diaryl-5-(1-phenyl-3-methyl-5-chloro-pyrazol)-4,5-dihydropyrazole derivatives, which was superior to the traditional method with respect to yields, reaction times, simplicity and safety. The impact of acoustic energy was evident in reduction of the processing time; a physical process that builds, enlarges and collapses gaseous and vaporous cavities in an irradiated liquid, hence enhancing the mass transfer and allowing chemical reactions to occur [56,57,58].
To the best of our knowledge, this new procedure provides the first example of an efficient and ultrasound-promoted approach for the synthesis of 1,3-diaryl-5-(1-phenyl-3-methyl-5-chloro-pyrazol)-4,5-dihydropyrazoles. This method is the most simple and convenient and would be applicable for the synthesis of different types of nitrogen-containing heterocyclic compounds. The structures of all the synthesized compounds were established by their NMR, IR, MS and analysis elemental.
The FT−IR spectra of synthesized 5-pyrazol-4,5-dihydropyrazole derivatives 3 showed bands at stretching frequencies in the range of 1584–1598 cm−1 and 1488–1502 cm−1, which are characteristic of –C=N and –C=C groups. No peak appeared in the range of 1650–1750 cm−1, which indicated the disappearance of the carbonyl group (C=O) of the (E)-3-(5-chloro-3-methyl-1-phenyl-1H-pyrazol-4-yl)-1-arylprop-2-en-1-one 1. The 1H NMR spectrum for compound 3 showed proton signals of the pyrazoline moiety as an ABX-type spin system, and the proton signals were observed as double doublets, due to the spin coupling in the range of 3.17–3.95 ppm. The signal of –CH3 pyrazole and aryl protons in compound was observed between 2.07–2.79 and 6.43–8.23 ppm, respectively.
The ultrasound promoted reaction of (E)-3-(5-chloro-3-methyl-1-phenyl-1H-pyrazol-4-yl)-1-arylprop-2-en-1-one with hydrazines afforded the corresponding 1,3-diaryl-5-(1-phenyl-3-methyl-5-chloro-pyrazol)-4,5-dihydropyrazole derivatives, good yields and short reaction times at ambient conditions in a simple, facile and efficient fashion. Due to the broad spectrum of biological activities of pyrazolines, evaluation of the biological activity and fluorescence properties of the new compounds are in progress.
The authors thank “Servicios Técnicos de Investigación of Universidad de Jaén” and the staff for data collection and the Consejería de Innovación, Ciencia y Empresa (Junta de Andalucía, Spain) at the Universidad de Jaén for financial support. JT and JQ thank COLCIENCIAS, UNIATLANTICO (Universidad del Atlántico, Colombia) and UNIVALLE (Universidad del Valle, Colombia) for financial support.
Conflict of Interest
The authors declare no conflict of interest.
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