Arabian Journal of Chemistry (2013) xxx, xxx–xxx King Saud University Arabian Journal of Chemistry www.ksu.edu.sa www.sciencedirect.com ORIGINAL ARTICLE Synthesis, anti-inflammatory, analgesic and anticonvulsant activities of some new 4,6-dimethoxy-5-(heterocycles)benzofuran starting from naturally occurring visnagin E.R. El-Sawy a, M.S. Ebaid a, H.M. Abo-Salem a, A.G. Al-Sehemi b, A.H. Mandour a,* a Chemistry Department of Natural Compounds, National Research Centre, Cairo, Egypt b Chemistry Department, Faculty of Science, King Khalid University, Abha, Saudi Arabia Received 5 August 2012; accepted 31 December 2012 KEYWORDS Abstract Novel 3-(4,6-dimethoxybenzofuran-5-yl)-1-phenyl-1H-pyrazole-4-carboxaldehyde (3) Benzofuran; and 3-chloro-3-(4,6-dimethoxybenzofuran-5-yl)propenal (4) were prepared via Vilsmeier–Haack Heterocycle; reaction of 1-(4,6-dimethoxybenzofuran-5-yl)ethanone (1) and its hydrazone derivative 2. Reaction Vilsmeier–Haack reaction; of compound 4 with some hydrazine derivatives, namely hydrazine hydrate, phenylhydrazine and Anti-inflammatory; benzylhydrazine hydrochloride led to the formation of pyrazole derivatives 5–8, respectively. On Analgesic; the other hand, reaction of compound 4 with thiourea, urea or guanidine gave the pyrimidine deriv- Anticonvulsant activities atives 9–11, respectively. Reaction of amino compound 11 with acetic anhydride, benzoyl chloride and benzenesulphonyl chloride yielded N-substituted pyrimidine derivatives 12–14, respectively. Reaction of diazonium salt of compound 11 with sodium azide afforded azidopyrimidine derivative 15, which upon reaction with ethyl acetoacetate gave 1,2,3-triazole derivative 16. Acid catalyzed reaction of 11 with p-nitrobenzaldehyde gave Schiff base 17, which cyclized upon reaction with thio- glycolic acid or chloroacetyl chloride to give thiazolidin-4-one 18 and azetidin-2-one 19, respec- tively. The newly synthesized compounds were tested for their anti-inflammatory, analgesic and anticonvulsant activities. Depending on the obtained results, the newly synthesized compounds pos- sess significant anti-inflammatory, analgesic and anticonvulsant activities. ª 2013 King Saud University. Production and hosting by Elsevier B.V. All rights reserved. * Corresponding author. Tel.: +20 222604756; mobile: +20 1. Introduction 123369722; fax: +20 233370931. E-mail address: [email protected] (A.H. Mandour). Vilsmeier–Haack reaction is a widely used method for the Peer review under responsibility of King Saud University. formylation of activated aromatic and heteroaromatic com- pounds (Vilsmeier and Haack, 1927). The reactions of ali- phatic substrates, particularly carbonyl compounds (Thomas Production and hosting by Elsevier et al., 2004) and their hydrazones (Kira et al., 1969) with 1878-5352 ª 2013 King Saud University. Production and hosting by Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.arabjc.2012.12.041 Please cite this article in press as: El-Sawy, E.R. et al., Synthesis, anti-inflammatory, analgesic and anticonvulsant activities of some new 4,6-dimethoxy-5- (heterocycles)benzofuran starting from naturally occurring visnagin. Arabian Journal of Chemistry (2013), http://dx.doi.org/10.1016/j.arabjc.2012.12.041 2 E.R. El-Sawy et al. 1 13 chloromethyleneiminium salts are highly versatile. They lead 8.15 ppm (s, H, NH). C NMR (125 MHz, DMSO-d6, to multiple iminoalkylations in the presence of excess reagent 25 °C, TMS): d = 18.2 (CH3), 59.4 & 60.5 (2OCH3), 89.9 (C- and the resulting intermediates undergo cyclization to afford 7), 104.9–157.2 ppm (Ar–C). Anal. For C18H18N2O3 (310.35) aromatic or heterocyclic compounds (El-Sawy et al., 2007; calcd: C 69.66, H 5.56, N 9.03. Found: C 69.45, H 5.32, N 8.99. Quiroga et al., 2008; Damjanovic et al., 2009; Prakash et al., 2011). Furthermore, the reactions of methylene active com- 2.1.2. 3-(4,6-Dimethoxybenzofuran-5-yl)-1-phenyl-1H- pounds with chloromethyleneiminium salts lead mainly to pyrazole-4-carboxaldehyde (3) the formation of b-haloencarboxaldehyde derivatives (Meesala To a solution of compounds 2 (0.93 g, 0.003 mol) in dimethyl- and Nagarajan, 2006; Herbivo et al., 2009) which are useful formamide (15 mL), phosphorus oxychloride (1.17 mL, precursors in the construction of different heterocyclic com- 0.01 mol) was added dropwise at 0 °C while stirring. After pounds (Meesala and Nagarajan, 2006; Herbivo et al., 2009; complete addition of POCl3, the reaction mixture was left to Paul et al., 2001; Park et al., 2005; Hegab and Abdulla, stir for 15 h, and then poured onto ice-water (20 mL). The so- 2006; Hegab et al., 2008). On the other hand, benzofuran lid that formed was filtered off, air dried and recrystallized derivatives occupy a position of considerable significance for from absolute ethanol. Yield 84 %, m.p. 59–61 °C. IR widespread occurrence in plants and their potential as impor- (KBr): m 1705 (C‚O), 1640 (C‚N), 1569 (C‚C), 1102, tant pharmaceuticals (Mandour et al., 1996; El-Shihi et al., À1 1 1084, 1055 cm (C–O–C). H NMR (500 MHz, DMSO-d6, 2005; Banskota et al., 2000; Choi et al., 2008; Liu et al., 25 °C, TMS): d = 3.69 & 3.89 (2s, 6H, 2OCH3), 7.01 (m, 2011). Literature revealed that pyrazole and pyrimidine are 5H, Ar–H), 7.50 (s, 1H, H-7), 7.53 (d, 1H, H-3), 7.91 (d, 1H, known for their pronounced pharmaceutical activities (Farag H-2), 9.02 (s, 1H, H-5 pyrazole), 9.55 ppm (s, 1H, CHO). et al., 2008; Menozzi et al., 2003; El-Sawy et al., 2012). So, 13 C NMR (125 MHz, DMSO-d6,25°C, TMS): d = 56.1 & the goal of this work is the synthesis of some new benzofurans 60.5 (2OCH3), 89.7 (C-7), 104.9–157.2 (Ar–C), 201.1 ppm containing substituted pyrazole and pyrimidine moieties at (C‚O). MS, m/z (%): 348 (M+, 2), 77 (100). Anal. For their 5-position and evaluating their anti-inflammatory, anal- C20H16N2O4 (348.35) calcd: C 68.96, H 4.63, N 8.03. Found: gesic and anticonvulsant activities. C 69.00, H 4.44, N 7.89. 2. Experimental 2.1.3. 3-Chloro-3-(4,6-dimethoxybenzofuran-5-yl)propenal (4) To a solution of compound (1) (1 g, 0.0042 mol) in dimethyl- 2.1. Chemistry formamide (15 mL), phosphorus oxychloride (1.17 mL, 0.012 mol) was added dropwise at 0 °C while stirring. After Melting points were determined in open capillary tubes on an complete addition of POCl3, the reaction mixture was warmed Electrothermal 9100 digital melting point apparatus (Mount to room temperature and then heated at 60 °C for 3 h. After Holly, New Jersey, USA) and are uncorrected. Elemental anal- cooling, the reaction mixture was poured onto crushed ice and yses were performed on a Perkin–Elmer 2400 analyzer (Perkin- then neutralized with 10% aqueous sodium hydroxide solution. Elmer, USA) and were found within ±0.4 % of the theoretical The precipitate that formed was filtered off, washed with water, values. IR spectra were recorded on a Perkin–Elmer 1600 air dried and recrystallized from methanol. Yield 30 %, m.p. FTIR (Perkin–Elmer, USA) in KBr discs. The 1H and 13C 118–120 °C. IR (KBr): m 1722 (C‚O), 1585 (C‚C), 1085, NMR spectra were recorded on Bruker spectrometer (500 1054, 1005 (C–O–C), 739 cmÀ1 (Cl). 1H NMR (500 MHz, and 125 MHz) (Bruker, Germany) in DMSO-d6, and chemical DMSO-d6,25°C, TMS): d = 3.89 & 4.11 (2s, 6H, 2OCH3), shifts were recorded in d ppm relative to the internal standard 6.82 (d, 1H, CH‚), 7.05 (s, 1H, H-7), 7.18 (d, 1H, H-3) 7.90 solvent TMS. Mass spectra (EI) were run at Gas Chromato- (d, 1H, H-2), 9.51 ppm (d, 1H, CHO). 13C NMR (125 MHz, graph Mass Spectrometer, single phase, 200 V, 50/60 Hz, DMSO-d6,25°C, TMS): d = 56.2 & 59.9 (2OCH3), 89.7 (C- 30 A (Jeol Ltd., Japan). 7), 105.3–156.7 (Ar–C), 201.1 ppm (C‚O). MS, m/z (%): 268 + + Visnagin was purchased from Chemical Industrial Develop- (M +2, 20), 266 (M , 7), 238 (100). Anal. For C13H11ClO4 ing Company (CID), Giza, Egypt. The starting 1-(4,6-dime- (266.68) calcd: C 58.55, H 4.16. Found: C 58.33, H 4.44. thoxy benzofuran-5-yl) ethanone (1) was prepared via the alkaline hydrolysis of visnagin followed by methylation with 2.1.4. 5-(4,6-Dimethoxybenzofuran-5-yl)-1H-pyrazole (5) dimethyl sulphate (Schonberg et al., 1953). A mixture of compound 4 (0.53 g, 0.002 mol) and hydrazine hydrate 99% (0.1 g, 0.002 mol) in absolute ethanol (15 mL) 2.1.1. 1-(1-(4,6-Dimethoxybenzofuran-5-yl)ethylidene)-2- containing few drops of glacial acetic acid was refluxed for phenylhydrazine (2) 3 h. After cooling, the reaction mixture was poured onto water A mixture of 1-(4,6-dimethoxybenzofuran-5-yl)ethanone (1) (20 mL) and the solid that formed was filtered off, air dried (1 g, 0.0042 mol) and phenylhydrazine (0.45 g, 0.0042 mol) in and recrystallized from methanol. Yield 77 %, m.p. 69– glacial acetic acid (20 mL) was refluxed for 2 h. After cooling, 72 °C. IR (KBr): m 3100 (NH), 1637 (C‚N), 1606 (C‚C), À1 1 the reaction mixture was poured onto water (50 mL) and the 1062, 1020 cm (C–O–C). H NMR (500 MHz, DMSO-d6, solid that formed was filtered off, washed with water, air dried 25 °C, TMS): d = 3.89 & 4.11 (2s, 6H, 2OCH3), 6.81 (d, 1H, and recrystallized from absolute ethanol.