untitled European Journal of Chemistry 4 (2) (2013) 176‐179 European Journal of Chemistry ISSN 2153‐2249 (Print) / ISSN 2153‐2257 (Online)  2013 EURJCHEM DOI:10.5155/eurjchem.4.2.176‐179.757 European Journal of Chemistry Journal homepage: www.eurjchem.com Synthesis of pyrazoline derivatives from the 1,3‐dipolar cycloadditions using α,β‐unsaturated cyclohexanone derivatives Nouara Ziani a,b,*, Kaddour Lamara c, Assia Sid c, Quentin Willem d, Benjamin Dassonneville d and Albert Demonceau d a Département de Chimie, Faculté des Sciences, Université Ferhat Abbas, Sétif, 19000, Algérie b Laboratoire de Chimie et Chimie de l’Environnement, Université El‐Hadj Lakhdar, Batna, 05000, Algérie c Laboratory of Applied Chemistry and Materials Technology, Chemistry Institute, University Larbi Ben M’hidi of Oum El Bouaghi, Rue de Constantine, 04000, Algeria d Laboratoire de Chimie Macromoléculaire et de Catalyse Organique, Département de Chimie, Université de Liège, Sart‐Tilman (B.6a), B‐4000 Liège, Belgique *Corresponding author at: Département de Chimie, Faculté des Sciences, Université Ferhat Abbas, Sétif, 19000, Algérie. Tel.: +213.36620139; fax: +213.36620139. E‐mail address: nouarachem2013@hotmail.com (N. Ziani). ARTICLE INFORMATION ABSTRACT Received: 21 February 2013 Received in revised form: 04 April 2013 Accepted: 05 April 2013 Online: 30 June 2013 KEYWORDS A series of 2‐pyrazolines (3a‐d) were obtained by reaction 1,3‐dipolar cycloadditions of α,β‐ unsaturated cyclohexanone derivatives (2a‐c) with hydrazine hydrate and 4‐ nitrophenylhydrazine in the presence of acetic acid and ethanol as solvents. The structures of the synthesized compounds were confirmed by spectroscopic methods; IR, 1H and 13C NMR. Acetic acid Pyrazolines Spectroscopy Hydrazine hydrate 1,3‐Dipolar cycloadditions α,β‐Unsaturated cyclohexanone derivatives 1. Introduction Pyrazoline belongs to a class of five‐membered ring compounds having two nitrogen atoms located adjacent to each other [1]. Several pyrazoline derivatives possess important biological activities such as anti‐inflammatory [2‐4], antidepressant [5‐6], antipyretic [7], antibacterial [8‐13], antifungal [8,11,14] and antitumoral [15]. Over the years, the structure of pyrazoline [1,16] has received considerable attention. Of particular interest is the use of pyrazolines as synthetic intermediates for preparing cyclopropane [17‐19] and pyrazole [1,20‐23] derivatives. Moreover pyrazolines have played a crucial role in the development of theory in heterocyclic chemistry and also are extensively useful synthons in organic chemistry [1]. 1,3‐Dipolar cycloadditions is a general methodology that has been applied both to the synthesis of five‐membered heterocyclic compounds such as 2‐pyrazolines using α,β‐ unsaturated ketones as starting materials [1]. The α,β‐unsaturated ketones have been attracting much more attention, particularly the α,β‐unsaturated derivatives of cyclohexanone, not only due to their intriguing biological activities such as antiangiogenic [24,25], cytotoxicity [26,27], cholesterol‐lowering activity [28], use in agrochemicals, pharmaceuticals and perfumes [29], and as liquid crystalline polymer units [30], but also as important precursors for the synthesis of heterocyclic compounds such as pyrazolines. Generally, these compounds are prepared by Claisen‐Schmidt condensation from aromatic aldehydes and ketons [31‐39]. In this study, we have synthesized a series of pyrazoline derivatives 3a‐d using α,β‐unsaturated cyclohexanone derivatives 2a‐c as starting materials (Scheme 1 and 2). The structures of the newly synthesized compounds 2c, 3a and 3d were confirmed by IR and their spectroscopic analyses. Compounds 3b and 3c, were synthesized by Kok et. al. [40], using another method which was reported in the cited reference. We report also in this paper, reaction of the new α,β‐ unsaturated ketone 2c with hydrazine hydrate in hot acetic acid, this reaction produced complex mixture of unidentified products. Bioactivities studies of all synthesized compounds will be the subject of future publication. 2. Experimental 2.1. Instrumentation Melting points were determined with a (Bransted/ ‐Electrothermal) apparatus and are uncorrected. IR spectra were recorded in KBr pellets on (a Perkin‐Elmer FT‐IR‐01 and a Shimadzu FT‐IR‐8400S) spectrophotometers. Nuclear magnetic resonance (NMR) spectra were recorded using Bruker Advance DRX 400 spectrometer (400.13 MHz for 1H NMR and 100.62 MHz for 13C NMR) and Bruker Advance 250 spectrometer (250.13 MHz for 1H NMR and 62.89 MHz for 13C NMR). Chemical shift values are reported in ppm relative to TMS as internal reference in CDCl3. 2.2. Synthesis 2.2.1. Synthesis of α,β‐unsaturated derivatives of cyclohexanone Ziani et al. / European Journal of Chemistry 4 (2) (2013) 176‐179 177 Scheme 1 A mixture of the aromatic aldehyde (20 mmol, 2 eq.) and cyclohexanone (10 mmol, 1 eq.) were dissolved in 15 mL of ethanol in a simple necked round bottomed flask and stirred for several minutes at 0 °C (ice bath). Into this solution, 10 mL of a 40% NaOH solution in water was then added drop wise over several minutes. The mixture is then allowed to stir at room temperature for approximately 4 h. The yellow solid obtained was filtered and washed with cold water and dried. The product, so‐obtained, was crystallized with ethanol to give the desired compounds in good yields (Scheme 1). 2,6‐Dibenzylidenecyclohexanone (2a): Color: Yellow crystals. Yield: 90% yield. M.p.: 118‐119 °C (117‐118 °C [41]). 1H NMR (400.13 MHz, CDCl3, δ, ppm): 1.66‐1.83 (m, 2H, CH2), 2.89‐2.95 (m, 4H, 2 CH2), 7.24‐7.48 (m, 10H, Ar‐H), 7.80 (s, 2H, 2 CH=C). 13C NMR (100.6 MHz, CDCl3, δ, ppm): 22.8 (CH2), 28.3 (2 CH2), 128.2 (4 CH of Ar‐H), 128.4 (2 Ar‐H), 130.2 (4 CH of Ar‐ H), 135.8 (2 CH), 135.9 (2 C‐Ar), 136.7 (2 C=C), 190.0 (C=O). 2,6‐Bis(4‐fluorobenzylidene)cyclohexanone (2b): Color: Yellow crystals. Yield: 86%. M.p.: 155‐156 °C (156‐158 °C [37]). 1H NMR (400.13 MHz, CDCl3, δ, ppm): 2.75‐1.82 (m, 2H, CH2), 2.86‐2.89 (m, 4H, 2 CH2), 7.05‐7.11 (m, 4H, Ar‐H), 7.42‐7.46 (m, 4H, Ar‐H), 7.74 (s, 2H, 2 CH=C). 13C NMR (100.6 MHz, CDCl3, δ, ppm): 22.9 (CH2), 28.3 (2 CH2), 115.5 (d, J = 22.1 Hz, 4 CH of Ar‐ H), 132.0 (d, J = 4.0 Hz, 2 Ar‐C), 132.3 (d, J = 9.0 Hz, 4 CH of Ar‐ H), 135.7 (d, J = 2.0 Hz, 2 CH), 135.8 (2 C=C), 189.9 (C=O). 2,6‐Bis(4‐(methylthio)benzylidene)cyclohexanone (2c). Color: Yellow powder. Yield: 87%. M.p.: 184‐185 °C. IR (KBr, ν, cm‐1): 2922 (C‐H), 1658 (C=O), 1599 (C=C). 1H NMR (400.13 MHz, CD2Cl2, δ, ppm): 1.77‐1.83 (m, 2H, CH2), 2.51 (s, 6H, 2 S‐ CH3), 2.91‐2.94 (m, 4H, 2 CH2), 7.27 (d, J = 8.0 Hz, 4H, Ar H), 7.43 (d, J = 8.0 Hz, 4 H, Ar H), 7.69 (s, 2H, 2 CH=C). 13C NMR (100.6 MHz, CDCl3, δ, ppm): 14.6 (2 CH3), 22.5 (CH2), 28.1 (2 CH2), 125.1 (4 CH of Ar H), 130.4 (4 CH of Ar‐H), 132.1 (2 Ar‐C), 135.3 (2 CH), 135.4 (2 C=C), 139.6 (2 Ar‐C), 189.0 (C=O). 2.2.2. Synthesis of pyrazolines Compound 2a (3 mmol) was treated with 4‐ nitrophenylhydrazine (3 mmol) in ethanol (15 mL). The mixture was refluxed for 12 h. A precipitation of a yellow powder 3a was separated by filtration, and crystallized from ethanol. Compounds 3b and 3d were prepared from compound 2b and 2c (1.5 mmol), respectively, and hydrazine hydrate (1.5 mmol) in ethanol (12 mL) using the same procedure given for compound 3a. The products 3b and 3d were obtained as yellow and white crystals respectively. Pyrazoline 3c, a white powder, was prepared from compound 2b (3 mmol) and hydrazine hydrate (3 mmol) using the same procedure given for compound 3a but with acid acetic as solvent (Scheme 2). 7‐Benzylidene‐2‐(4‐nitrophenyl)‐3‐phenyl‐3,3a,4,5,6,7‐hexa hydro‐2H‐indazole (3a): Color: Yellow crystals. Yield: 92%. M.p.: 182 °C. IR (KBr, ν, cm‐1): 2949 (C‐H), 1595 (C=N), 1500 (C=C), 1560 (N‐O), 1382 (N‐O), 1045 (C‐N). 1H NMR (250.13 MHz, CDCl3, δ, ppm): 1.45‐1.55 (m, 1H, C‐H), 1.72‐1.77 (m, 1H, C‐H), 1.95‐2.00 (m, 1H, C‐H), 2.25 (m, 1H, C‐H), 2.45 (m, 1H, C‐H), 3.05‐3.10 (m, 2H,CH), 4.75 (d, J = 10.5 Hz, 1H, N‐CH), 7.01 (d, J = 9.25 Hz, 2H, ArH), 7.30‐7.41 (m, 11H, Ar + =CH). 8.02 (d, J = 9.25 Hz, 2H, ArH). 13C NMR (62.9 MHz, CDCl3, δ, ppm): 24.2 (CH2), 28.9 (CH2), 29.6 (CH2), 57.9 (CH), 72.2 (CH), 113.1 (2 CH of Ar‐H), 125.4 (2 CH of Ar‐H), 125.6 (2 CH of Ar‐H), 127.4 (CH of Ar‐H), 127.9 (CH of Ar‐H ), 128.0 (CH=C), 128.3 (2 CH of Ar‐ H), 129.5 (2 CH of Ar‐H), 129.6 (2 CH of Ar‐H), 130.1 (Ar‐C), 136.2 (C=C), 139.5 (Ar‐C), 140.8 (Ar‐C), 150.3 (Ar‐C), 156.6 (C=N). 7‐(4‐Fluorobenzylidene)‐3‐(4‐fluorophenyl)‐3,3a,4,5,6,7‐ hexahydro‐2H‐ indazole [40] (3b): Color: Pale yellow powder. Yield: 70%. M.p.: 179‐181 °C. 1H NMR (400.13 MHz, CDCl3, δ, ppm): 1.36‐1.58 (m, 2H, CH), 1.91‐2.06 (m, 2H, CH), 2.40‐2.33 (m, 1H, CH), 2.70‐2.98 (m, 2H, CH), 4.48 (d, J= 12.0 Hz, CH), 7.01‐7.47 (m, 10H, 8 Ar‐H+ CH=C + N‐H). 1‐(7‐(4‐fluorobenzylidene)‐3‐(4‐fluorophenyl)‐3,3a,4,5,6,7‐ hexahydro‐2H‐indazol‐2‐yl) ethanone [40] (3c): Color: White powder. Yield: 91%. 1H NMR (400.13 MHz, CDCl3, δ, ppm): 1.48‐ 1.51 (m, 1H, CH), 1.68‐1.72 (m, 1H, CH), 1.94‐2.20 (m, 2H, CH), 2.38 (s, 3H, CH3), 2.38‐2.43 (m, 1H, CH), 2.95‐3.04 (m, 2H, 2 CH), 4.92 (d, J= 8.0 Hz, 1H, CH), 7.03‐7.36 (m, 9H, 8 Ar‐H + CH=C). 7‐(4‐(Methylthio)benzylidene)‐3‐(4‐(methylthio)phenyl)‐3, 3a,4,5,6,7‐hexahydro‐2H‐indazole (3d): Color: White crystals. Yield: 85%. M.p.: 150 °C. 1H NMR (400.13 MHz, CDCl3, δ, ppm ): 1.47‐1.54 (m, 2H, C‐H), 1.93‐2.06 (m, 2H, C‐H), 2.43 (m, 1H, C‐ H), 2.52 (s, 6H, 2 S‐CH3), 2.79 (m, 1H, C‐H), 3.02 (m, 1H, C‐H), 4.48 (d, J = 8.0 Hz, 1H, N‐CH), 5.95 (s, 1H, CH=C), 7.18 (s, 1H, N‐ H) 7.24 ‐7.44 (m, 8H, ArH). 13C NMR (100.6 MHz, CDCl3, δ, ppm ): 15.6 (S‐CH3), 15.9 (S‐CH3), 24.4 (CH2), 28.4 (CH2), 28.6 (CH2), 53.7 (CH), 72.8 (CH), 126.0 (2 CH of Ar‐H), 126.8 (2 CH of Ar‐H), 127.6 (2 CH of Ar‐H), 127.7 (Ar‐C),130.1 (2 CH of Ar‐H), 130.6 (CH=C), 133.5 (C=C), 137.2 (Ar‐C), 137.5 (Ar‐C), 137.8 (Ar‐C), 156.7 (C=N). 3. Results and discussion The α,β‐unsaturated cyclohexanone derivatives, 2a‐c, (Scheme 1) were obtained by condensation of cyclohexanone with substituted benzaldehydes, 1a‐c, with excellent yields due to the stability of α,β‐unsaturated cyclohexanone derivatives [41]. Compounds 2a [42] and 2b [37] were identified by comparing their 1H and13C NMR spectral data with those reported in the cited references. But the new compound 2c was elucidated by IR, 1H NMR and 13C NMR. In the IR spectrum, a strong band around 1658 cm‐1 indicates the presence of conjugated carbonyl and a band at 1599 cm‐1 for (C=C) group. In the 1H NMR spectra, the olefinic protons gave a singlet signal at (7.69 ppm). 13C NMR chemical shifts of the C=O group have been assigned at (189.0 ppm). Pyrazoline 3a was synthesized by reaction of compound 2a with 4‐nitrophenylhydrazine in the presence of glacial acetic acid in low yield (34%). When the reaction was repeated using ethanol as solvent rather glacial acetic acid, compound 3a was obtained in high yield (92%) (Scheme 2). Pyrazolines 3b and 3d were obtained by reaction of compounds 2b and 2c respectively with hydrazine hydrate in ethanol using the same procedure given for compound 3a [43]. 178 Ziani et al. / European Journal of Chemistry 4 (2) (2013) 176‐179 3a N N H F F H2NNH2.H2O EtOH, reflux 3b O 2a N N F F 3c O 4-Nitrophenylhydrazine EtOH, reflux, 92% 4-Nitrophenylhydrazine Acetic acid, reflux, 34% O FF H2NNH2.H2O Acetic acid, reflux N N H S S H2NNH2.H2O EtOH, reflux 3d O SS H2NNH2.H2O Acetic acid, reflux Unidentified prodects 2b 2c N N N+ O O- Scheme 2 Compound 2b was allowed to react with hydrazine hydrate in hot acetic acid to afford pyrazoline derivative 3c with good yields. Analogous synthesis using compound 2c with hydrazine hydrate in the presence of glacial acetic acid could not be achieved, formation of a complex mixture of unidentified products was observed. Pyrazolines 3b and 3c were synthesized by Kok et al. [40], using another method which was reported in the cited reference. For the synthesis of compound 7‐(4‐fluorobenzylidene)‐3‐(4‐fluorophenyl)‐3,3a,4,5,6,7‐hexa hydro‐2H‐indazole (3b), we have used Claisen‐Schmidt condensation [31‐39] (Yield: 70%), without catalyst. But Kok et al. have used few drops of acetic acid as catalyst (Yield: 72%). For the synthesis of compound 1‐(7‐(4‐fluorobenzylidene)‐3‐ (4‐fluorophenyl)‐3,3a,4,5,6,7‐hexahydro‐2H‐indazol‐2‐yl) ethanone (3c), Kok et al. was used a method [40] which contains two steps: Step 1, preparation of 7‐(4‐fluoro benzylidene)‐3‐(4‐fluorophenyl)‐3,3a,4,5,6,7‐hexahydro‐2H‐ indazole (3b); Step 2, Alkylation of compound 3b, using pyridine as a solvent, and benzoyl chloride as reagent. As against we have synthesized compound (3c) in a single step by the classical 1,3‐dipolar cycloadditions [1] using the compound, 6‐bis(4‐fluoro benzylidene)cyclohexanone (2b) as substrate, and ethanol as solvent. Compounds 3a and 3d were two new pyrazolines characterized by melting points, IR, 1H and 13C NMR spectra. The IR spectra showed a strong band for the (C=N) group at 1595 cm‐1 and a band at 1500 cm‐1 for C=C group. In the spectra 1H NMR, the olefinic protons gave a singlet signal at (5.95‐7.41 ppm). 13C NMR chemical shifts of the (C=N) group have been assigned at (156.6‐156.7 ppm). 4. Conclusion In conclusion, we have synthesized a series of 2‐ pyrazolines 3a‐d by 1,3‐dipolar cycloadditions using α,β‐ unsaturated cyclohexanone derivatives as starting materials. Pyrazolines 3a and 3c are very stable compounds, a property which may render them especially useful substances in drug research. Compounds 3b and 3d would be useful as synthetic precursors for preparing various pyrazoline derivatives due to the presence of reactive group (N‐H). Bioactivities studies of all synthesized compounds will be reported elsewhere in near future. 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