untitled European Journal of Chemistry 4 (2) (2013) 146‐148 European Journal of Chemistry ISSN 2153‐2249 (Print) / ISSN 2153‐2257 (Online)  2013 EURJCHEM DOI:10.5155/eurjchem.4.2.146‐148.756 European Journal of Chemistry Journal homepage: www.eurjchem.com Synthesis of new curcumin analogues from Claisen‐Schmidt condensation Nouara Ziani a,*, Assia Sid b, Albert Demonceau c, Quentin Willem c, Benjamin Dassonneville c and Kaddour Lamara b a Département de Chimie, Faculté des Sciences, Université Ferhat Abbas, Sétif, 19000, Algérie b Laboratory of Applied Chemistry and Materials Technology, Chemistry Institute, University Larbi Ben M’hidi of Oum El Bouaghi, Rue de Constantine, 04000, Algeria c 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 new curcumin analogues were obtained by Claisen‐Schmidt condensation of substituted benzaldehydes with cyclohexanone derivatives using the ratio of 1:2 of ketone to aldehyde in dilute ethanolic solution under base catalyzed (NaOH) conditions at room temperature in good yields. The structures of the synthesized compounds were confirmed by data of IR, 1H NMR, and 13C NMR spectra. Curcumin Spectroscopy Benzaldehydes Curcumin analogues Cyclohexanone derivatives Claisen‐Schmidt condensation 1. Introduction Curcumin, 1,7‐bis‐(4‐hydroxy‐3‐methoxyphenyl)‐1,6‐ heptadiene‐3,5‐dione, (Figure 1), is a yellow compound isolated from the rhizome of the herb curcuma longa L., which has been used for centuries as a dietary pigment, spice, and traditional medicine in India and China [1,2]. This naturally occurring and synthetic compound is regarded as a promising drug and has received considerable attention due to its antioxidant, anticancer, anti‐inflammatory, anti‐HIV and antimalarial properties [3‐7]. Curcumin has a surprisingly wide range of chemo‐therapeutic activities and is under investigation for the treatment of various human cancers. However, the clinical application of curcumin has been significantly limited by its instability and poor metabolic property [8‐10]. Various curcumin analogues have been synthesized to overcome the poor metabolic property. These compounds have been attracting much more attention, not only due to their intriguing biological activities such as cyto‐toxicity [11], antimycotic [12], antitumor [13,14], antibacterial [15,16], anti‐inflammatory [17], and antileishmaniatic activities [18], 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 [19]. In the present work, we synthesized a series of new curcumin analogues 3a and 6a‐c (Scheme 1) by Claisen‐ Schmidt condensation from the reaction of benzaldehydes 2 and 5 with cyclohexanone derivatives 1 and 4 using NaOH as catalyst. Structures of the synthesized compounds were determined by IR and their spectroscopic analyses. These compounds are using as precursors to prepare a series of pyrazoline derivatives. This study and bioactivities of all synthesis compounds [20,21] 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 A mixture of the aromatic aldehyde (20 mmol, 2 eq.) and the appropriate cyclohexanone derivative (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 solid was separated and washed with cold water and dried. The product, so‐obtained, was crystallized from ethanol to obtain pure 3a and 6a‐c (Scheme 1). 2‐(2‐Fluorobenzylidene)‐5‐methylcyclohexanone (3a): Color: Yellow crystals. Yield: 86%. M.p.: 77‐78 °C. IR (KBr, ν, cm‐1): 2935 (C‐H), 1678 (C=O), 1610 (C=C). Ziani et al. / European Journal of Chemistry 4 (2) (2013) 146‐148 147 Figure 1. The keto‐enol tautomerization of curcumin. R O + R1 R2 O H O R1 R2 R1 R2 R NaOH / EtOH H2O , 0° C O + F O H O NaOH / EtOH H2O , 0° C F OF 3a 3b 6a-c (6a) R= CH3, R1= H, R2= F (6b) R= C2H5, R1= H, R2= F (6c) R= CH3, R1= CH3, R2= CH3 F 1 2 4 5 Scheme 1 1H NMR (250.13 MHz, CDCl3, δ, ppm): 1.05 (d, 3H, J = 5.7 Hz, CH3), 1.33‐1.37 (m, 1H, C‐H), 1.86‐1.93 (m, 1H, C‐H), 2.07‐2.17 (m, 2H, C‐H), 2.55‐2.70 (m, 2H, C‐H), 2.86‐2.92 (m, 1H, C‐H ), 7.05‐7.30 (m, 4H, Ar‐H), 7.46 (s, 1H, CH=C). 2,6‐Bis(4‐fluorobenzylidene)‐4‐methylcyclohexanone (6a): Color: Yellow powder. Yield: 96%. M.p.: 124‐125 °C. IR (KBr, ν, cm‐1): 2947 (C‐H), 1663 (C=O), 1595 (C=C). 1H NMR (400.13 MHz, CDCl3, δ, ppm): 1.09 (d, 3H, J = 8.0 Hz, CH3), 1.87‐1.89 (m, 1H, C‐H), 2.45‐2.51 (m, 2H, CH2), 2.99‐3.04 (m, 2H, CH2), 7.08‐ 7.12 (m, 4H, Ar‐H), 7.43‐7.46 (m, 4H, Ar‐H), 7.75 (s, 2H, 2 CH=C). 13C NMR (100.6 MHz, CDCl3, δ, ppm ): 21.6 (CH3), 29.3 (CH), 36.4 (2 CH2), 115.5 (d, J = 21.1 Hz, 4 CH of Ar‐H ), 132.0 (d, J = 3.0 Hz, 2 Ar‐C), 132.3 (d, J = 8.0 Hz, 4 CH of Ar‐H), 134.9 (d, J = 2.0 Hz, 2 CH), 136.1 ( 2 C=C), 162.6 (d, J = 249.5 Hz, 2 Ar‐C ), 189.8 (C=O). 4‐Ethyl‐2,6‐bis(4‐fluorobenzylidene)cyclohexanone (6b): Color: Yellow crystals. Yield: 95%. M.p.: 118‐119 °C. IR (KBr, ν, cm‐1): 2952 (C‐H), 1600 (C=O), 1508 (C=C). 1H NMR (250 MHz, CD2Cl2, δ, ppm ): 0.88 (t, 3H, J = 7.5 Hz, CH3), 1.42 (q, 2H, J = 7.5 Hz, CH2), 1.65 (m, 1H, C‐H), 2.45‐2.56 (m, 2H, CH), 3.03‐3.10 (m, 2H, CH), 7.09‐7.16 (m, 4H, Ar‐H), 7.45‐7.51 (m, 4H, Ar‐H), 7.71 (s, 2H, 2 CH=C). 13C NMR (100.6 MHz, CDCl3 , δ, ppm): 11.3 (CH3), 28.6 (CH2), 34.0 (2 CH2), 35.7 (CH), 115.5 (d, J = 21.1 Hz, 4 CH of Ar‐H ), 132.3 (d, J = 9.0 Hz, 4 CH of Ar‐H ), 132.4 (2 CH), 135.3 (d, J = 1.0 Hz, 2 Ar‐C), 135.6 (2 C=C), 162.7 (d, J = 249.5 Hz, 2 Ar‐C), 189.6 (C=O). 2,6‐Bis(2,4‐dimethylbenzylidene)‐4‐methylcyclohexanone (6c). Color: Yellow crystals. Yield: 91%. M.p.: 178‐179 °C. IR (KBr, ν, cm‐1): 2949 (C‐H), 1662 (C=O), 1599 (C=C). 1H NMR (400.13 MHz, CDCl3, δ, ppm): 0.98 (d, 3H, J = 4.0 Hz, CH3), 1.80‐ 1.82 (m, 1H, CH), 2.33 (s, 6H, 2 CH3), 2.37 (s, 6H, 2 CH3) 2.37‐ 2.41 (m, 2H, CH), 2.87‐2.92 (m, 2H, CH), 7.02–7.07 (m, 4H, Ar‐ H), 7.16–7.18 (m, 2H, Ar‐H), 7.89 (s, 2H, 2 CH=C). 13C NMR (100.6 MHz, CDCl3, δ, ppm): 20.0 (2 CH3), 21.3 (2 CH3), 21.4 (CH3), 29.9 (CH), 36.6 (2 CH2), 126.1 (2 CH of Ar‐H), 129.1 (2 CH of Ar‐H), 131.0 (2 CH of Ar‐H), 132.2 (2 Ar‐C), 135.4 (2 Ar‐C), 136.1 (2 Ar‐C), 138.1 (2 C=C), 138.4 (2 CH), 190.2 (C=O). 3. Results and discussion With a view to synthesize compound 3b, 3‐ methylcyclohexanone, 1, was allowed to react with 2‐fluoro benzaldehyde, 2, in ethanol, compound 3a were obtained rather than the compound 3b. Curcumin analogues, 6a‐c, were obtained by condensation of cyclohexanone derivatives, 4, with substituted benzaldehydes 5 in good yields. Compounds 3a and 6a‐c were four new Curcumin analogues characterized by melting points, IR and 1H NMR, 13C NMR spectra. Their spectra IR showed a strong band for the conjugated carbonyl at (1678‐1600 cm‐1) (1609‐1585 cm‐1 [22]) and a band at (1610‐1508 cm‐1) for C=C group (1515‐ 1446 cm‐1 [22]). In the 1H NMR spectra of new α,β‐unsaturated ketones, the olefinic proton gave a singlet signal at (7.89‐7.46 ppm) (7.82‐7.16 ppm, [22]). 13C NMR chemical shifts of the C=O group have been assigned at (190.2‐189.6 ppm) (191.3‐188.5 ppm [22]). 148 Ziani et al. / European Journal of Chemistry 4 (2) (2013) 146‐148 4. Conclusion Due to the importance of curcumin analogues, their wide range of biological activities, and applications in synthesis of pyrazolines, we have synthesized a series of new curcumin analogues 3a, 6a‐c by Claisen‐Schmidt condensation. These compounds can be as precursors to prepare a series of pyrazoline derivatives. 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