untitled ISSN 2 Utility o pyrimid pyridaz Mohamed Department of C * Corresponding Tel.: +2.0122.22 ARTICLE IN DOI: 10.5155/e Received: 10 M Accepted: 11 Ju Published onlin Printed: 30 Sep KEYWORDS Pyrazole Thiophene β‐Diketones Dihydropyridin Antimicrobial a Tetrahydropyri 1. Introduct Among explored for such as py pyranes have Various bio pyrazoles su antifungal, a gesic, antihy hypnotictivit Cyanopyridin tion as they a antibacterial cardiovascul thiones hav antitumor [1 fused 4H‐py owing to th influenza, vi viral [24], an antitumor [2 pyrane deriv 2153‐2249 (Prin of β‐diketo dinethione ine deriva d Ahmed Ma Chemistry, Faculty g author at: Depart 283357. Fax: +2.068 FORMATION eurjchem.7.3.298- ay 2016 une 2016 ne: 30 September 2 ptember 2016   S ne activity imidinethione tion a wide variety r developing ph razoles, cyano e played an imp ological applic uch as antican antimicrobial, yperglycemic, ty [1‐6], antid ne derivatives appeared of int l [10,11], antit lar [14] and ant ve been found 17] and hypogl yrane derivativ heir antimicrob rus sialidases ntiprol feraction 27] and anti‐in vatives are we E nt) / ISSN 2153‐ h Euro ones in he e, pyrazol atives and ahmoud Abd of Science, Arish Un tment of Chemistry, 8.3350065. E‐mail a -308.1447 2016 y of heterocyc harmaceutical i opyridines, pyr portant role in cations have ncer, antiviral, antihistaminic antipyretic, a depressant [7], have attracted terest to posses tumor [12], an tisoriasis [15] a d to possess lycemic [18] ac ves have attrac bial activity [1 [22], mutageni n agents [25], s flammatory ag ell known for uropean Journal Europ 2257 (Online)  http://dx.doi.org/1 pean Jo Journal we eterocycl le, thioph d investig del Reheim * niversity, Arish 455 y, Faculty of Science address: dr.moham ABSTRACT A series of m from the reac bifunctional n hydroxynapht by nucleophil analyses and antimicrobial Cite this: Eur. clic that have important mole rimidinethiones medicinal chem been reported , anti‐inflamm c, antiplatelet, nti‐tumor, sed anticonvulsan d considerable ss anticonvulasn ntihypertensive activities. Pyrim antitubercular ctivities. Pyran cted a great in 19‐21], inhibiti ic activity [23], ex‐pheromones ents [28]. More their antihista l of Chemistry 7 pean Journal of C 2016 Atlanta Pub 10.5155/eurjchem ournal ebpage: www ic synthes hene, dihy gation of t *, Ibrahim Sa 511, Egypt e, Arish University, A medabdelreheim@g any important d ction of 1‐(2‐hy nucleophiles, th thalen‐1‐yl)‐3‐ph ic attack. Struct spectral data. activity. J. Chem. 2016, 7 been ecules s and mistry. d for matory, anal‐ dative, nt [8]. atten‐ nt [9], e [13], midine [16], ne and nterest ion of , anti‐ s [26], eover, aminic acti acti anti obs hete effic hyd key wer 2. E 2.1. inst reco spe 400 met che usin (3) (2016) 298‐ Chemistry blishing House LL m.7.3.298-308.14 of Che w.eurjchem.co sis: Synth ydropyrid their antim aad Abdel H Arish 45511, Egypt gmail.com (M.A.M.A diverse number ydroxynaphthale hese reactions henylpropane‐1, tures of the ne Some of the pr 7(3), 298‐308 ivity [29]. Also, ive compounds i‐microbial and servations and erocyclic chem cient synthesi droxynaphthale y starting mate re investigated Experimental . Instrumentat All melting p trument and orded on a FTI ectra were reco 0 MHz on a Va ter at 70 eV. T ecked by thin la ng n‐hexane, eth ‐308 LC ‐ All rights rese 447 emistry om hesis of ne dine, dihyd microbial afiz and Saf t. A. Reheim). r of fused heter en‐1‐yl)‐3‐pheny mainly procee ,3‐dione with th w compounds w roducts were al , naphthalene is s such as anti d anti‐cancer [ in continuatio mistry, we repo is of new he en‐1‐yl)‐3‐phen erial. A selected for their antim tion oints were me are uncorrect IR 5300 spectro rded in DMSO‐ arian Gemini N The purity of yer chromatog hyl acetate (9: 1 erved ‐ Printed in y ew tetrah dropyran l activity faa Mohame ocyclic systems ylpropane‐1,3‐di ed via condens he aldehydic fu were establishe lso screened in s important ary ‐inflammatory, 30,31]. In view on of our prev ort herein a c eterocycles ba nylpropane‐1,3‐ d series of the icrobial activiti easured using ted. IR spectra ometer (ν, cm‐1 ‐d6 and CDCl3 a NMR. 1000 EX synthesized co raphy TLC (alu 1, v: v) eluent. n the USA hydro‐ e, d were prepared ione with some sation of 1‐(2‐ nction followed ed by elemental n vitro for their yl ring in many anti‐bacterial, w of the above vious works in convenient and ased on 1‐(2‐ ‐dione (1) as a ese compounds ies. Akofler Block a (KBr) were 1). The 1H NMR t 300 MHz and mass spectro‐ ompounds was uminum sheets) d e ‐ d l r y , e n d ‐ a s k e R d ‐ s ) Reheim et al. / European Journal of Chemistry 7 (3) (2016) 298‐308 299 Scheme 1 Elemental analyses were carried out by the Microanalytical Research Center, Faculty of Science, and Microanalytical Unit, Faculty of Pharmacy, Cairo University, Egypt. 2.2. Synthesis 2.2.1. Synthesis of 1‐(2‐hydroxynaphthalen‐1‐yl)‐3‐phenyl propane‐1,3‐dione (1) A mixture of ethyl benzoylacetate (0.01 mol) and β‐ naphthol (0.01 mol) was exposed to microwave irradiation for 4‐6 mins, the reaction mixture was allowed to reach room temperature, then diluted with ethanol with stirring and the solid product that formed, was filtrated and crystallized from ethanol (Scheme 1). Color: Brown. Yield: 91%. M.p.: 136‐138 °C. FT‐IR (KBr, , cm‐1): 3434 (OH), 3056 (CH‐Arom), 2967 (CH‐Aliph), 1727, 1637 (2CO). 1H NMR (400 MHz, DMSO‐d6, δ, ppm): 4.38 (s, 2H, CH2), 7.13‐8.29 (m, 11H, aromatic H), 9.92 (s, 1H, OH). MS (EI, m/z (%)): 290 (M+, 18). Anal. calcd. for C19H14O3: C, 78.61; H, 4.86; O, 16.53. Found: C, 78.62; H, 4.88; O, 16.54%. 2.2.2. General procedure for preparation of benzylidene derivatives (4a‐d) A mixture of compound 1 (0.01 mol), appropriate aryl aldehydes (0.01 mol) in ethanol (30 mL) with catalytic amount of piperidine was heated under reflux for 3 hrs. The reaction mixture was allowed to cool and poured into crushed ice then acidified with HCl. The separated solid was filtered, washed with water and crystallized from ethanol to give compound 4a‐d (Scheme 1). 2‐Benzylidene‐1‐(2‐hydroxynaphthalen‐1‐yl)‐3‐phenyl propane‐1,3‐dione (4a): Color: Pale green. Yield: 61%. M.p.: 145‐147 °C. FT‐IR (KBr, , cm‐1): 3453 (OH), 3057 (C‐H‐Arom), 1726, 1637 (2C=O). 1H NMR (400 MHz, DMSO‐d6, δ, ppm): 5.24 (s, 1H, CH‐olefinic), 7.06‐8.34 (m, 16H, Ar‐H), 9.95 (s, 1H, OH). MS (EI, m/z (%)): 378 (M+, 6). Anal. calcd. for C26H18O3: C, 82.52; H, 4.79; O, 12.68. Found: C, 82.51; H, 4.78; O, 12.69%. 2‐(4‐Chlorobenzylidene)‐ 1 ‐(2‐hydroxynaphthalen‐1‐yl) ‐ 3‐ phenylpropane‐1,3‐dione (4b): Color: Pale yellow. Yield: 72%. M.p.: 170‐172 °C. FT‐IR (KBr, , cm‐1): 3437 (OH), 3057 (C‐H, Ar), 1725, 1637 (2C=O). 1H NMR (400 MHz, DMSO‐d6, δ, ppm): 6.68 (s, 1H, CH‐olefinic), 7.20‐8.37 (m, 15H, Ar‐H), 9.96 (s, 1H, OH). MS (EI, m/z (%)): 414 (M++2, 80). Anal. calcd. for C26H17ClO3: C, 75.64; H, 4.15; O, 11.63. Found: C, 75.63; H, 4.14; O, 11.64%. 1‐(2‐Hydroxynaphthalen‐1‐yl)‐2‐(4‐methoxybenzylidene)‐3‐ phenylpropane‐1,3‐dione (4c): Color: Green. Yield: 69%. M.p.: 160‐162 °C. FT‐IR (KBr, , cm‐1): 3453 (OH), 3056 (C‐H, Arom.), 2922 (C‐H Aliph.), 1720, 1637 (2C=O). 1H NMR (400 MHz, DMSO‐d6, δ, ppm): 3.84 (s, 3H, OCH3), 5.20 (s, 1H, CH‐ olefinic), 7.54‐8.30 (m, 15H, Ar‐H), 9.94 (s, 1H, OH). MS (EI, 300 Reheim et al. / European Journal of Chemistry 7 (3) (2016) 298‐308 m/z (%)): 408 (M+, 20). Anal. calcd. for C27H20O4: C, 79.40; H, 4.94; O, 15.67. Found: C, 79.37; H, 4.91; O, 15.65%. 2‐(4‐Hydroxybenzylidene)‐1‐ (2‐hydroxynaphthalen‐1‐yl)‐3‐ phenylpropane‐1,3‐dione (4d): Color: Pale yellow. Yield: 70 %. M.p.: 176‐177 °C. FT‐IR (KBr, , cm‐1): 3453 (OH), 3046 (C‐H, Arom.), 1730, 1636 (2C=O). 1H NMR (400 MHz, DMSO‐d6, δ, ppm): 5.48 (s, 1H, CH‐olefinic), 7.59‐8.38 (m, 15H, Ar‐H), 9.95 (s, 1H, OH), 9.97 (s, 1H, OH). MS (EI, m/z (%)): 394 (M+, 60). Anal. calcd. for C26H18O4: C, 79.17; H, 4.60; O, 16.23. Found: C, 79.14; H, 4.55; O, 16.20%. 2.2.3. General procedure for preparation of tetrahydro pyrimidinethion derivatives (5a‐d) To boiling solution of compound 4a‐d (0.01 mol) and thiourea (0.01 mol) in ethanolic potassium hydroxide (30 mL, 10%), was added. The reaction mixture was refluxed for 20 h, then allowed to cool and poured into crushed ice then acidified with HCl. The separated solid was filtered, washed with water and crystallized from ethanol to give compound 5a‐d (Scheme 1). (4,6‐Diphenyl‐2‐thioxo‐1,2,3, 4‐tetrahydropyrimidin‐5‐yl)(2‐ hydroxynaphthalen‐1‐yl)methanone (5a): Color: Yellow. Yield: 73 %. M.p.: 150‐152 °C. FT‐IR (KBr, , cm‐1): 3447, 3400 (OH/NH), 3058 (C‐H, Arom.), 2964 (C‐H, Aliph.), 1637 (C=O). 1H NMR (400 MHz, DMSO‐d6, δ, ppm): 4.35 (s, 1H, CH‐ pyrimidine), 7.11‐8.37 (m, 18H, Ar‐H + 2NH), 9.97 (s, 1H, OH). MS (EI, m/z (%)): 436 (M+, 5). Anal. calcd. for C27H20N2O2S: C, 74.29; H, 4.62; N, 6.42. Found: C, 74.30; H, 4.63; N, 6.41%. (4‐(4‐Chlorophenyl)‐6‐phenyl‐2‐thioxo‐1, 2, 3, 4‐tetrahydro pyrimidin‐5‐yl)(2‐hydroxynaphthalen‐1‐yl)methanone (5b): Color: Yellow. Yield: 77 %. M.p.: 177‐179 °C. FT‐IR (KBr, , cm‐ 1): 3400, 3374 (OH/NH), 3061 (C‐H, Arom.), 2934 (CH Aliph.), 1685 (C=O). 1H NMR (400 MHz, DMSO‐d6, δ, ppm): 4.35 (s, 1H, CH‐pyrimidine), 7.21‐8.38 (m, 17H, Ar‐H + 2NH), 9.97 (s, 1H, OH). MS (EI, m/z (%)): 470 (M+, 22). Anal. calcd. for C27H19ClN2O2S: C, 68.86; H, 4.07; N, 5.95. Found: C, 68.85; H, 4.06; N, 5.96%. (2‐Hydroxynaphthalen‐1‐yl)(4‐(4‐methoxyphenyl)‐6‐phenyl‐ 2‐thioxo‐1,2,3, 4‐tetrahydropyrimidin‐5‐yl)methanone (5c): Color: Pale yellow. Yield: 81 %. M.p.: 157‐159 °C. FT‐IR (KBr, , cm‐1): 3444, 3400 (OH/NH), 3057 (C‐H, Arom.), 2965 (C‐H, Aliph.), 1637 (C=O). 1H NMR (400 MHz, DMSO‐d6, δ, ppm): 3.80 (s, 3H, OCH3), 4.40 (s, 1H, CH‐pyrimidine), 7.11‐8.35 (m, 17H, Ar‐H + 2NH), 9.96 (s, 1H, OH). MS (EI, m/z (%)): 466 (M+, 20). Anal. calcd. for C28H22N2O3S: C, 72.08; H, 4.75; N, 6.00. Found: C, 72.02; H, 4.70; N, 6.06%. (2‐Hydroxynaphthalen‐1‐yl)(4‐(4‐hydroxyphenyl)‐6‐phenyl‐ 2‐thioxo‐1,2,3, 4‐tetrahydropyrimidin‐5‐yl)methanone (5d): Color: Yellow. Yield: 80 %. M.p.: 170‐172 °C. FT‐IR (KBr, , cm‐ 1): 3443, 3400 (OH/NH), 3057 (C‐H Arom.), 2965 (C‐H Aliph.), 1637 (C=O). 1H NMR (400 MHz, DMSO‐d6, δ, ppm): 4.36 (s, 1H, CH‐pyrimidine), 7.21‐8.38 (m, 17H, Ar‐H + 2NH), 9.95 (s, 1H, OH), 9.97 (s, 1H, OH). MS (EI, m/z (%)): 452 (M+, 17). Anal. calcd. for C27H20N2O3S: C, 71.66; H, 4.45; N, 6.19. Found: C, 71.63; H, 4.41; N, 6.15%. 2.2.4. General procedure for preparation of compounds (7a,b) A mixture of compound 1 (0.01 mol) and hydrazine hydrate or phenyl hydrazine in ethanol (30 mL) was heated under reflux for 12 hrs. The reaction mixture was allowed to cool and poured into crushed ice. The separated solid was filtered, washed with water and crystallized from ethanol to give compound 7a,b (Scheme 1). 1‐(3‐Phenyl‐1H‐pyrazol‐5‐yl)naphthalen‐2‐ol (7a): Color: Pale brown. Yield: 55 %. M.p.: 182‐184 °C. FT‐IR (KBr, , cm‐1): 3417 (OH), 3202 (NH), 3050 (C‐H Arom.). 1H NMR (400 MHz, DMSO‐d6, δ, ppm): 6.85 (s, 1H, CH‐pyrazole), 6.96‐8.10 (m, 11H, Ar‐H), 10.10 (hump, 1H, OH),12.95 (s, 1H, NH). MS (EI, m/z (%)): 286 (M+, 50). Anal. calcd. for C19H14N2O: C, 79.70; H, 4.93; N, 9.78. Found: C, 79.73; H, 4.95; N, 9.80%. 1‐(1, 3‐Diphenyl‐1H‐pyrazol‐5‐yl)naphthalen‐2‐ol (7b): Color: Brown. Yield: 62 %. M.p.: 202‐204 °C. FT‐IR (KBr, , cm‐ 1): 3417 (OH), 3065 (C‐H Arom.). 1H NMR (400 MHz, DMSO‐d6, δ, ppm): 7.11 (s, 1H, CH‐pyrazole), 7.21‐8.38 (m, 16H, Ar‐H), 9.97 (s, 1H, OH). MS (EI, m/z (%)): 362 (M+, 56). Anal. calcd. for C25H18N2O: C, 82.85; H, 5.01; N, 7.73. Found: C, 82.83; H, 5.09; N, 7.76%. 2.2.5. Synthesis of 2‐amino‐5‐(2‐hydroxy‐1‐naphthoyl)‐4‐ phenylthiophene‐3‐carbonitrile (10) Equimolar amounts of compound 1 (0.01 mol), malono‐ nitrile and elemental sulfur (0.01 mol) in ethanol (30 mL) containing piperidine (1.2 mL) were refluxed for 15 hrs, poured onto cold water (30 mL) and acidified with HCl (pH = 3). The solid product thus formed was filtered and crystallized from dioxane (Scheme 1). Color: Yellow. Yield: 86 %. M.p.: 178‐ 180 °C. FT‐IR (KBr, , cm‐1): 3440 (OH), 3331, 3202 (NH2), 3058 (C‐H Arom.), 2212 (C≡N), 1638 (C=O). 1H NMR (400 MHz, DMSO‐d6, δ, ppm): 7.20‐8.38 (m, 11H, Ar‐H), 9.97 (s, 1H, OH), 12.02 (s, 2H, NH2). MS (EI, m/z (%)): 372 (M++2, 22). Anal. calcd. for C22H14N2O2S: C, 71.33; H, 3.81; N, 7.56. Found: C, 71.35; H, 3.84; N, 7.59%. 2.2.6. Synthesis of 6‐(2‐hydroxynaphthalen‐1‐yl)‐2‐oxo‐4‐ phenyl‐1,2‐dihydropyridine‐3‐carbonitrile (12) A mixture of compound 1 (0.01 mol), malononitrile (0.01 mol) in ethanol (30 mL) containing catalytic amount of piperidine was heated under reflux for 24 hrs. The reaction mixture was allowed to cool and poured into crushed ice then acidified with HCl. The separated solid was filtered, washed with water and crystallized from ethanol (Scheme 2). Color: Pale yellow. Yield: 76 %. M.p.: 146‐148 °C. FT‐IR (KBr, , cm‐1): 3408 (OH), 3400 (NH), 3060 (C‐H Arom.), 2192 (C≡N), 1636 (C=O). 1H NMR (300 MHz, DMSO‐d6, δ, ppm): 7.09 (s, 1H, =CH), 7.20‐8.39 (m, 11H, Ar‐H), 9.70 (s, 1H, NH), 9.98 (s, 1H, OH). MS (EI, m/z (%)): 338 (M+, 17). Anal. calcd. for C22H14N2O2: C, 78.09; H, 4.17; N, 8.28. Found: C, 78.04; H, 4.13; N, 8.25%. 2.2.7. Synthesis of 6‐(2‐hydroxynaphthalen‐1‐yl)‐2‐oxo‐4‐ phenyl‐2H‐pyran‐3‐carbonitrile (14) A mixture of compound 1 (0.01 mol), ethylcyanoacetate in ethanol (30 mL) containing catalytic amount of piperidine was heated under reflux for 24 hrs. The reaction mixture was allowed to cool and poured into crushed ice then acidified with HCl. The separated solid was filtered, washed with water and crystallized from the ethanol (Scheme 2). Color: Pale yellow. Yield: 83 %. M.p.: 160‐162 °C. FT‐IR (KBr, , cm‐1): 3450 (OH), 3062 (C‐H Arom.), 2196 (C≡N), 1658 (C=O). 1H NMR (400 MHz, DMSO‐d6, δ, ppm): 6.92‐8.38 (m, 12H, Ar‐H), 9.20 (s, 1H, OH). MS (EI, m/z (%)): 339 (M+, 27). Anal. calcd. for C22H13NO3: C, 77.87; H, 3.86; N, 4.13. Found: C, 77.83; H, 3.83; N, 4.10%. 2.2.8. General procedure for preparation of pyrano‐3‐ carbonitrile derivatives (19a‐d) A mixture of compound 1 (0.01 mol) and arylidine malononitrile 15a‐d (0.01 mol) in ethanol (40 mL) containing catalytic amount of piperidine (1.2 mL) was refluxed for 6 hrs, The reaction mixture was allowed to cool and poured in to cold water (30 mL) and acidified with HCl (pH = 3). The solid product was collected and crystallized from ethanol to give compound 19a‐d (Scheme 3). Reheim et al. / European Journal of Chemistry 7 (3) (2016) 298‐308 301 1 CNCH2COOEt O O Ar' CN Ph 8, 11-14 Ar' = OH O NH Ar' CN Ph Dimruth HN O Ar' CN Ph 11 12 14 CH2(CN)2 8 Ar' O Ph CNCN 13 Ar' O Ph CN EtOOC - H2O - H2O - C2H5OH O O Ph HO Scheme 2 2‐Amino‐5‐(2‐hydroxy‐1‐naphthoyl)‐4,6‐diphenyl‐4H‐pyran‐ 3‐carbonitrile (19a): Color: Brown. Yield: 81 %. M.p.: 168‐170 °C. FT‐IR (KBr, , cm‐1): 3448 (OH), 3420, 3400 (NH2), 3064 (C‐ H Arom.), 2932 (CH Aliph.), 2197 (C≡N), 1640 (C=O). 1H NMR (400 MHz, DMSO‐d6, δ, ppm): 4.35 (hump, 1H, 4H‐pyrane), 7.20‐8.37 (m, 18H, Ar‐H + NH2), 9.97 (s, 1H, OH). MS (EI, m/z (%)): 444 (M+, 40). Anal. calcd. for C29H20N2O3: C, 78.36; H, 4.54; N, 6.30. Found: C, 78.37; H, 4.55; N, 6.32%. 2‐Amino‐4‐(4‐chlorophenyl)‐5‐ (2‐hydroxy‐1‐naphthoyl)‐6‐ phenyl‐4H‐pyran‐3‐carbonitrile (19b): Color: Pale yellow. Yield: 77 %. M.p.: 160‐162 °C. FT‐IR (KBr, , cm‐1): 3447 (OH), 3420, 3400 (NH2), 3058 (C‐H Arom.), 2191 (C≡N), 1639 (C=O). 1H NMR (400 MHz, DMSO‐d6, δ, ppm): 4.36 (hump, 1H, 4H‐ pyrane), 7.17‐8.34 (m, 17H, Ar‐H + NH2), 9.95 (s, 1H, OH). MS (EI, m/z (%)): 480 ((M++2), 8). Anal. calcd. for C29H19ClN2O3: C, 72.73; H, 4.00; N, 5.85. Found: C, 72.75; H, 4.05; N, 5.88%. 2‐Amino‐5‐(2‐hydroxy‐1‐naphthoyl)‐4‐ (4‐methoxyphenyl)‐ 6‐phenyl‐4H‐pyran‐3‐carbonitrile (19c): Color: Pale yellow. Yield: 85 %. M.p.: 216‐218 °C. FT‐IR (KBr, , cm‐1): 3450 (OH), 3345, 3210 (NH2), 2924 (C‐H Aliph.), 2193 (C≡N), 1624 (C=O). 1H NMR (400 MHz, DMSO‐d6, δ, ppm): 3.83 (s, 3H, OCH3), 4.40 (hump, 1H, 4H‐pyrane), 7.07‐8.29 (m, 17H, Ar‐H+NH2), 9.93 (s, 1H, OH). MS (EI, m/z (%)): 474 ((M+), 20). Anal. calcd. for C30H22N2O4: C, 75.94; H, 4.67; N, 5.90. Found: C, 75.90; H, 4.63; N, 5.88%. 2‐Amino‐5‐(2‐hydroxy‐1‐naphthoyl)‐4‐ (4‐hydroxyphenyl)‐ 6‐phenyl‐4H‐pyran‐3‐carbonitrile (19d): Color: Brown. Yield: 79 %. M.p.: 163‐165 °C. FT‐IR (KBr, , cm‐1): 3347 (OH), 3300, 3222 (NH2), 3063 (CH Arom.), 2934 (C‐H Aliph.), 2199 (C≡N), 1624 (C=O). 1H NMR (400 MHz, DMSO‐d6, δ, ppm): 4.50 (s, 1H, 4H‐pyrane), 6.92 (s, 2H, NH2), 6.94‐8.38 (m, 15H, Ar‐H), 9.98 (s, 1H, OH), 10.02 (s, 1H, OH). MS (EI, m/z (%)): 460 ((M+), 37). Anal. calcd. for C29H20N2O4: C, 75.64; H, 4.38; N, 6.08. Found: C, 75.17; H, 4.39; N, 6.09%. 2.2.9. General procedure for preparation of dihydropyridine thion derivatives (24a‐c) A mixture of compound 1 (0.01 mol) and arylidene cyanothioacetamide derivatives 20a‐c (0.01 mol) in ethanol with catalytic amount of piperidine was heated under reflux for 10 hrs. The reaction mixture was allowed to cool and poured into crushed ice then acidified with HCl. The separated solid was filtered, washed with water and crystallized from ethanol to give compound 24a‐c (Scheme 3). 5‐(2‐Hydroxy‐1‐naphthoyl)‐4, 6‐diphenyl‐2‐thioxo‐1, 2‐di hydropyridine‐3‐carbonitrile (24a): Color: Yellow. Yield: 76 %. M.p.: 173‐175 °C. FT‐IR (KBr, , cm‐1): 3434 (OH), 3400 (NH), 3071 (C‐H Arom.), 2189 (C≡N), 1634 (C=O). 1H NMR (300 MHz, DMSO‐d6, δ, ppm): 7.58‐8.36 (m, 17H, Ar‐H + NH), 9.96 (s, 1H, OH). MS (EI, m/z (%)): 459 ((M+ +1), 50). Anal. calcd. for C29H18N2O2S: C, 75.96; H, 3.96; N, 6.11. Found: C, 75.93; H, 3.90; N, 6.10%. 4‐(4‐Chlorophenyl)‐5‐ (2‐hydroxy‐1‐naphthoyl)‐6‐phenyl‐2‐ thioxo‐1,2‐dihydropyridine‐3‐carbonitrile (24b): Color: Yellow. Yield: 70 %. M.p.: 173‐175 °C. FT‐IR (KBr, , cm‐1): 3464 (OH), 3433 (NH), 3070 (C‐H Arom.), 2193 (C≡N), 1634 (C=O). 1H NMR (400 MHz, DMSO‐d6, δ, ppm): 7.15‐8.32 (m, 16H, Ar‐H + NH), 9.94 (s, 1H, OH). MS (EI, m/z (%)): 494 ((M++2), 5). Anal. calcd. for C29H17ClN2O2S: C, 70.66; H, 3.48; N, 5.68. Found: C, 70.60; H, 3.44; N, 5.69%. 302 Reheim et al. / European Journal of Chemistry 7 (3) (2016) 298‐308 Scheme 3 5‐(2‐Hydroxy‐1‐naphthoyl)‐4‐ (4‐methoxyphenyl)‐6‐phenyl‐ 2‐thioxo‐1,2‐dihydropyridine‐3‐carbonitrile (24c): Color: Yellow. Yield: 69 %. M.p.: 178‐180 °C. FT‐IR (KBr, , cm‐1): 3408 (OH), 3400 (NH), 3072 (C‐H Arom.), 2924 (CH Aliph.), 2190 (C≡N), 1634 (C=O). 1H NMR (400 MHz, DMSO‐d6, δ, ppm): 3.90 (s, 3H, OCH3), 7.16‐8.33 (m, 16H, Ar‐H + NH), 9.95 (s, 1H, OH). MS (EI, m/z (%)): 488 ((M+), 12). Anal. calcd. for C30H20N2O3S: C, 73.75; H, 4.13; N, 5.73. Found: C, 73.77; H, 4.15; N, 5.77%. 2.2.10. General procedure for preparation of compounds (27a‐d) To a stirred cold solution of aryldiazonium chlorides 25a‐ d (0.01 mol, prepared by treating aniline derivatives (0.01 mol) with sodium nitrite (0.01 mol) in HCl, ethanol (30 mL) and catalytic sodium acetate, the active methylene reagent 1 was added gradually. The stirring was continued for two hrs. The solid product so formed was filtered off, washed with water several times, dried and crystallized from ethanol to give compound 27a‐d (Scheme 4). 1‐(2‐Hydroxynaphthalen‐1‐yl)‐3‐phenyl‐2‐ (2‐phenylhydra zono)propane‐1, 3‐dione (27a): Color: Red. Yield: 88 %. M.p.: 156‐158 °C. FT‐IR (KBr, , cm‐1): 3387 (OH), 3300 (NH), 3063 (C‐H Arom.), 1743, 1634 (2C=O). 1H NMR (300 MHz, DMSO‐d6, δ, ppm): 7.60‐8.37 (m, 17H, Ar‐H + NH), 9.97 (s, 1H, OH). MS (EI, m/z (%)): 394 ((M+), 55). Anal. calcd. for C25H18N2O3: C, 76.13; H, 4.60; N, 7.10. Found: C, 76.15; H, 4.63; N, 7.13%. 2‐(2‐(4‐Chlorophenyl)hydrazono)‐1‐(2‐hydroxynaphthalen‐ 1‐yl)‐3‐phenylpropane‐1,3‐dione (27b): Color: Orange. Reheim et al. / European Journal of Chemistry 7 (3) (2016) 298‐308 303 Scheme 4 Yield: 80 %. M.p.: 152‐154 °C. FT‐IR (KBr, , cm‐1): 3384 (OH), 3300 (NH), 3061 (C‐H Arom.), 1743, 1635 (2C=O). 1H NMR (300 MHz, DMSO‐d6, δ, ppm): 6.90‐8.36 (m, 16H, Ar‐H + NH), 9.96 (s, 1H, OH). MS (EI, m/z (%)): 430 ((M++2 ), 35). Anal. calcd. for C25H17ClN2O3: C, 70.02; H, 4.00; N, 6.53. Found: C, 70.09; H, 4.07; N, 6.55%. 1‐(2‐Hydroxynaphthalen‐1‐yl)‐2‐ (2‐(4‐methoxyphenyl) hydrazono)‐3‐phenylpropane‐1,3‐dione (27c): Color: Red. Yield: 79 %. M.p.: 158‐160 °C. FT‐IR (KBr, , cm‐1): 3387 (OH), 3300 (NH), 3061 (C‐H Arom.), 2923 (CH Aliph.), 1743, 1634 (2C=O). 1H NMR (400 MHz, DMSO‐d6, δ, ppm): 3.86 (s, 3H, OCH3), 7.12‐8.70 (m, 16H, Ar‐H + NH), 9.97 (s, 1H, OH). MS (EI, m/z (%)): 424 (M+, 8). Anal. calcd. for C26H20N2O4: C, 73.57; H, 4.75; N, 6.60. Found: C, 73.58; H, 4.74; N, 6.61%. 1‐(2‐Hydroxynaphthalen‐1‐yl)‐3‐phenyl‐2‐(2‐p‐tolylhydrazo no)propane‐1,3‐dione (27d): Color: Red. Yield: 73 %. M.p.: 170‐ 172 °C. FT‐IR (KBr, , cm‐1): 3437 (OH), 3400 (NH), 3072 (C‐H Arom.), 2921 (CH Aliph.), 1743, 1634 (2C=O). 1H NMR (400 MHz, DMSO‐d6, δ, ppm): 1.06 (s, 3H, CH3), 7.17‐8.33 (m, 16H, Ar‐H + NH), 9.95 (s, 1H, OH). MS (EI, m/z (%)): 409 ((M++1), 17). Anal. calcd. for C26H20N2O3: C, 76.46; H, 4.94; N, 6.86. Found: C, 76.44; H, 4.95; N, 6.87%. 2.2.11. General procedure for preparation of dihydro pyridazine derivatives (30a‐d) A mixture of compounds 27a‐d (0.001 mole), ammonium acetate (1 g) and malononitrile (0.001 mole) was fused in domestic microwave oven for 3 minutes. The solid precipitate so formed was treated with ethanol and filtered out and crystallized from ethanol to give compound 30a‐d (Scheme 4). 6‐(2‐Hydroxy‐1‐naphthoyl)‐3‐imino‐2, 5‐diphenyl‐2, 3‐di hydropyridazine‐4‐carbonitrile (30a): Color: Brown. Yield: 87 %. M.p.: 185‐187 °C. FT‐IR (KBr, , cm‐1): 3419 (OH), 3350 (NH), 2203 (C≡N), 1680 (C=O). 1H NMR (400 MHz, DMSO‐d6, δ, ppm): 7.14‐8.31 (m, 17H, Ar‐H + NH), 9.94 (s, 1H, OH). MS (EI, m/z (%)): 442 (M+, 35). Anal. calcd. for C28H18N4O2: C, 76.01; H, 4.10; N, 12.66. Found: C, 76.07; H, 4.11; N, 12.67%. 2‐(4‐Chlorophenyl)‐6‐ (2‐hydroxy‐1‐naphthoyl)‐3‐imino‐5‐ phenyl‐2,3‐dihydropyridazine‐4‐carbonitrile (30b): Color: Pale yellow. Yield: 75 %. M.p.: 192‐194 °C. FT‐IR (KBr, , cm‐1): 3417 (OH), 3213 (NH), 2203 (C≡N), 1680 (C=O). 1H NMR (400 MHz, DMSO‐d6, δ, ppm): 7.19‐8.36 (m, 15H, Ar‐H), 9.96 (s, 1H, OH), 10.00 (s, 1H, NH). MS (EI, m/z (%)): 478 ((M++2), 13). Anal. calcd. for C28H17ClN4O2: C, 70.52; H, 3.59; N, 11.75. Found: C, 70.50; H, 3.58; N, 11.73%. 6‐(2‐Hydroxy‐1‐naphthoyl)‐3‐imino‐2‐(4‐methoxyphenyl)‐5‐ phenyl‐2, 3‐dihydropyridazine‐4‐carbonitrile (30c): Color: Brown. Yield: 74 %. M.p.: 186‐188 °C. FT‐IR (KBr, , cm‐1): 3382 (OH), 3300 (NH), 3070 (CH Arom.), 2929 (CH Aliph.), 2193 (C≡N), 1634 (C=O). 1H NMR (400 MHz, DMSO‐d6, δ, ppm): 3.83 (s, 3H, OCH3), 7.13‐8.30 (m, 16H, Ar‐H + NH), 9.93 (s, 1H, OH). MS (EI, m/z (%)): 472 (M+, 5). Anal. calcd. for C29H20N4O3: C, 73.72; H, 4.27; N, 11.86. Found: C, 73.70; H, 4.23; N, 11.84%. 6‐(2‐Hydroxy‐1‐naphthoyl)‐3‐imino‐5‐phenyl‐2‐p‐tolyl‐2, 3‐ dihydropyridazine‐4‐carbonitrile (30d): Color: Brown. Yield: 87 %. M.p.: 184‐186 °C. FT‐IR (KBr, , cm‐1): 3385 (OH), 3300 (NH), 3071 (CH Arom.), 2924 (CH Aliph.), 2193 (C≡N), 1635 (C=O). 1H NMR (400 MHz, DMSO‐d6, δ, ppm): 1.76 (s, 3H, CH3), 6.67‐8.37 (m, 16H, Ar‐H + NH), 9.96 (hump, 1H, OH). MS (EI, m/z (%)): 456 (M+, 7). Anal. calcd. for C29H20N4O2: C, 76.30; H, 4.42; N, 12.27. Found: C, 76.33; H, 4.45; N, 12.29%. 2.2.12. General procedure for preparation of pyrazol derivatives (33a‐d) A mixture of compound 4b,d (0.01 mol) and hydrazine hydrate or phenyl hydrazine (0.01 mol) in ethanol (30 mL) was heated under reflux for 12 hrs. The reaction mixture was allowed to cool and poured into crushed ice. The separated solid was filtered, washed with water and crystallized from dioxane to give compound 33a‐d (Scheme 5). (5‐(4‐Chlorophenyl)‐3‐phenyl‐1H‐pyrazol‐4‐yl) (2‐hydroxy naphthalen‐1‐yl)methanone (33a): Color: Pale yellow. Yield: 68 %. M.p.: 188‐190 °C. FT‐IR (KBr, , cm‐1): 3418 (OH), 3204 (NH), 3051 (C‐H Arom.), 1618 (C=O). 1H NMR (400 MHz, DMSO‐d6, δ, ppm): 6.83‐8.08 (m, 15H, Ar‐H), 9.97 (s, 1H, OH), 12.93 (s, 1H, NH). MS (EI, m/z (%)): 426 (M++2, 15). Anal. calcd. for C26H17ClN2O2: C, 73.50; H, 4.03; N, 6.59. Found: C, 73.52; H, 4.08; N, 6.60%. (2‐Hydroxynaphthalen‐1‐yl) (5‐(4‐hydroxyphenyl)‐3‐phenyl‐ 1H‐pyrazol‐4‐yl)methanone (33b): Color: Brown. Yield: 72 %. M.p.: 182‐184 °C. FT‐IR (KBr, , cm‐1): 3446 (OH), 3205 (NH), 3051 (C‐H Arom.), 1618 (C=O). 1H NMR (400 MHz, DMSO‐d6, δ, ppm): 6.88‐8.11 (m, 15H, Ar‐H), 10.03 (s, 1H, OH), 12.92 (s, 1H, NH), 13.58 (s, 1H, OH). MS (EI, m/z (%)): 408 (M++2, 10). Anal. calcd. for C26H18N2O3: C, 76.83; H, 4.46; N, 6.89. Found: C, 76.85; H, 4.49; N, 6.91%. (5‐(4‐Chlorophenyl)‐1, 3‐diphenyl‐1H‐pyrazol‐4‐yl)(2‐hydro xynaphthalen‐1‐yl)methanone (33c): Color: Pale yellow. Yield: 80 %. M.p.: 190‐192 °C. 304 Reheim et al. / European Journal of Chemistry 7 (3) (2016) 298‐308 31-33 a, R = H, Ar = C6H4Cl-p b, R = H, Ar = C6H4OH-p c, R = C6H5, Ar = C6H4Cl-p d, R = C6H5, Ar = C6H4OH-p 31 NH2NHR 31-34, Ar' = OH NH2OH.HCl 4b,d Ar' O O Ph Ar 34 34 a, Ar = C6H4Cl-p b, Ar = C6H4OH-p NO Ar Ph Ar' O -H2O 32 (O) NH N Ar' Ar O OH Ph R N N Ar' Ar O Ph R NN Ar' Ar O Ph R 33 Scheme 5 FT‐IR (KBr, , cm‐1): 3386 (OH), 3063 (C‐H Arom.), 1635 (C=O). 1H NMR (400 MHz, DMSO‐d6, δ, ppm): 7.18‐8.35 (m, 20H, Ar‐H), 9.96 (s, 1H, OH). MS (EI, m/z (%)): 502 (M++2, 4). Anal. calcd. for C32H21ClN2O2: C, 76.72; H, 4.23; N, 5.59. Found: C, 76.74; H, 4.25; N, 5.61%. (2‐Hydroxynaphthalen‐1‐yl) (5‐(4‐hydroxyphenyl)‐1, 3‐di phenyl‐1H‐pyrazol‐4‐yl)methanone (33d): Color: Brown. Yield: 72 %. M.p.: 184‐186 °C. FT‐IR (KBr, , cm‐1): 3450 (OH), 3056 (C‐H Arom.), 1638 (C=O). 1H NMR (400 MHz, DMSO‐d6, δ, ppm): 6.67‐8.39 (m, 20H, Ar‐H), 9.96 (s, 1H, OH), 9.98 (s, 1H, OH). MS (EI, m/z (%)): 482 (M+, 18). Anal. calcd. for C32H22N2O3: C, 79.65; H, 4.60; N, 5.81. Found: C, 79.64; H, 4.58; N, 5.80%. 2.2.13. General procedure for preparation of isoxazole derivatives (34a,b) A mixture of compound 4b,d (0.01 mol), hydroxylamine hydrochloride in glacial acetic acid (30 mL) containing anhydrous sodium acetate (1 g) was heated under reflux for 24 hrs. The reaction mixture was allowed to cool and poured into cold water (60 mL). The separated solid was filtered and crystallized from ethanol to give compound 34a,b (Scheme 5). (5‐(4‐Chlorophenyl)‐3‐phenylisoxazol‐4‐yl)(2‐hydroxy naphthalen‐1‐yl)methanone (34a): Color: Pale yellow. Yield: 71 %. M.p.: 158‐160 °C. FT‐IR (KBr, , cm‐1): 3447 (OH), 3058 (C‐ H Arom.), 1640 (C=O). 1H NMR (400 MHz, DMSO‐d6, δ, ppm): 7.16‐8.33 (m, 15H, Ar‐H), 9.95 (s, 1H, OH). MS (EI, m/z (%)): 427 (M++2, 11). Anal. calcd. for C26H16ClNO3: C, 73.33; H, 3.79; N, 3.29. Found: C, 73.30; H, 3.74; N, 3.27%. (2‐Hydroxynaphthalen‐1‐yl) (5‐(4‐hydroxyphenyl)‐3‐phenyl isoxazol‐4‐yl)methanone (34b): Color: Pale yellow. Yield: 69 %. M.p.: 163‐165 °C. FT‐IR (KBr, , cm‐1): 3446 (OH), 3060 (C‐H Arom.), 1640 (C=O). 1H NMR (300 MHz, DMSO‐d6, δ, ppm): 7.58‐8.36 (m, 15H, Ar‐H), 9.94 (s, 1H, OH), 9.97 (s, 1H, OH). MS (EI, m/z (%)): 407 (M+, 3). Anal. calcd. for C26H17NO4: C, 76.65; H, 4.21; N, 3.44. Found: C, 76.64; H, 4.23; N, 3.45%. 2.2.14. Synthesis of 2‐(ethoxymethylene)‐1‐(2‐hydroxy naphthalen‐1‐yl)‐3‐phenylpropane‐1,3‐dione (35) A mixture of compound 1 (0.01 mol) and triethoxy‐ methane (3 mL) in acetic anhydride (10 mL) was heated under reflux for 6 hrs. The reaction mixture was allowed to cool. The separated solid was filtered, washed with ethanol and crystallized from ethanol (Scheme 6). Color: Brown. Yield: 53 %. M.p.: 164‐166 °C. FT‐IR (KBr, , cm‐1): 3383 (OH), 3068 (CH, Arom.), 2932‐2852 (CH, Aliph.), 1738, 1635 (2CO). 1H NMR (400 MHz, DMSO‐d6, δ, ppm): 1.11 (t, 3H, CH3), 4.35 (q, 2H, CH2), 6.90 (s, 1H, CH‐olefinic), 7.17‐8.04 (m, 11H, Ar‐H), 9.97 (s, 1H, OH). MS (EI, m/z (%)): 347 (M++1, 13). Anal. calcd. for C22H18O4: C, 76.29; H, 5.24; O, 18.48. Found: C, 76.28; H, 5.20; O, 18.43%. 2.2.15. Synthesis of 2‐((dimethylamino)methylene)‐1‐(2‐ hydroxynaphthalen‐1‐yl)‐3‐phenylpropane‐1,3‐dione (36) A mixture of compound 1 (0.01 mol) and DMF‐DMA (0.01 mol) in dioxane (30 mL) was heated under reflux for 6 hrs. The reaction mixture was allowed to cool. The separated solid was filtered, washed with ethanol and crystallized from ethanol (Scheme 6). Color: Pale yellow. Yield: 57 %. M.p.: 158‐160 °C. FT‐IR (KBr, , cm‐1): 3437 (OH), 3058 (CH, Arom.), 2960‐2852 (CH, Aliph.), 1638 (CO). 1H NMR (300 MHz, DMSO‐d6, δ, ppm): 3.56 (s, 6H, 2CH3), 7.17 (s, 1H, CH‐olefinic), 7.58‐8.35 (m, 11H, Ar‐H), 9.96 (s, 1H, OH). MS (EI, m/z (%)): 345 (M+, 20). Anal. calcd. for C22H19NO3: C, 76.50; H, 5.54; N, 4.06. Found: C, 76.51; H, 5.56; N, 4.11%. 2.2.16. Synthesis of 3‐(hydroxyimino)‐1‐(2‐hydroxy naphthalen‐1‐yl)‐3‐phenylpropan‐1‐one (37) A mixture of compound 1 (0.01 mol), hydroxylamine hydrochloride in glacial acetic acid (30 mL) containing anhydrous sodium acetate (1 g) was heated under reflux for 24 hrs. The reaction mixture was allowed to cool and poured into cold water (60 mL). Reheim et al. / European Journal of Chemistry 7 (3) (2016) 298‐308 305 Scheme 6 % 100 (1) The separated solid was filtered and crystallized from ethanol (Scheme 6). Color: Pale brown. Yield: 76 %. M.p.: 145‐ 147 °C. FT‐IR (KBr, , cm‐1): 3427 (OH), 3079 (C‐H Arom.), 2925 (CH Aliph.), 1638 (C=O). 1H NMR (300 MHz, DMSO‐d6, δ, ppm): 4.40 (s, 2H, CH2), 7.18‐8.35 (m, 12H, Ar‐H + OH), 9.96 (s, 1H, OH). MS (EI, m/z (%)): 305 (M+, 45). Anal. calcd. for C19H15NO3: C, 74.74; H, 4.95; N, 4.59. Found: C, 74.75; H, 4.96; N, 4.61%. 2.3. Pharmacology 2.3.1. In‐vitro antimicrobial activity The newly synthesized compounds and its derivatives have been screened for antibacterial activity against some species of Gram‐positive bacteria (Staphylococcus aureus and Bacillus subtilis) and Gram‐negative bacteria (Escherichia coli and Pseudomonas aeruginosa). Anti‐fungal activities of the compounds were tested against yeast and mycelial fungi; Candida albicans and Aspergillus flavus, respectively. Each tested compound was dissolved in DMSO making a solution concentration of 1.00 mg/mL and loaded separately in paper discs of Whatman filter paper with equal diameter size (10 mm), Paper discs were sterilized in an autoclave. The paper discs loaded with the desired concentration of the complex solution, were placed aseptically in the petri dishes containing nutrient agar medium (agar 20 g + beef extract 3 g + peptone 5 g) inoculated with Staphylococcus aureus, Bacillus subtilis, Escherichia coli, Pseudomonas aeruginosa, Candida albicans and Aspergillus flavus. The petri dishes were incubated at 36 °C. The inhibition zones were recorded after 24 hrs of incubation in case of bacteria and yeast and after 5‐6 days in case of mycelial fungi. Each treatment was replicated three times [32]. Ampicillin and clotrimazole, were used as a common standard antibiotic and antifungal agents, respectively. They prepared using the same procedure as above at the same concentration and solvents. The % activity index was calculated for the tested compounds by using the given formula in equation (1). 2.3.2. Minimum inhibitory concentration measurement The minimum inhibitory concentration (MIC) was determined using the disc diffusion technique by preparing discs containing 1.9‐1000 µg/mL of each compound against Gram‐positive Staphylococcus aureus, Bacillus subtilis and Gram‐negative Escherichia coli, Pseudomonas aeuroginosa. The anti‐fungal activities of the compounds were tested against two fungi Candida albicans and Aspergillus flavus. The twofold dilutions of the solution were prepared. The microorganism suspensions at 10 CFU/mL (colony forming unit/mL) concent‐ rations were inoculated to the corresponding wells. The plates were incubated at 36 °C for 24 hrs for the bacteria. The standard antibiotic ampicillin and antifungal clotrimazole was also recorded using the same procedure as above at the same concentration and solvents. At the end of the incubation period, the minimum inhibitory concentrations (MIC) values were recorded as the lowest concentration of the substance that had no visible turbidity [33,34]. Control experiments with DMSO and uninoculated media were run parallel to the test compounds under the same condition. 3. Results and discussion 3.1. Synthesis In continuation of this work and as a part of our biological chemistry program [35‐38], we reported here the utility of 1‐ (2‐hydroxynaphthalen‐1‐yl)‐3‐phenylpropane‐1,3‐dione (1) in the synthesis of unique heterocyclic of expected biological interest. Thus, β‐diketone (1) is prepared in a quantitative yield in a demostic microwave oven from the reaction of 2‐ naphthol and ethylbenzoylacetate. β‐diketone (1) underwent several chemical transformations aiming at exploring its synthetic potentiality. Thus, β‐diketone (1) reacted with aryl aldehydes 3a‐d to afford the condensation products 4a‐d (Scheme 1). Structures of compounds 4a‐d were established using their elemental and spectral data. Compounds 4a‐d are allowed to react with thiourea to afford tetrahydropyrimidine thions 5a‐d [39] (Scheme 1). Structures of tetrahydro pyrimidinethions 5a‐d were established using their elemental and spectral data. For example, the IR spectrum of compound 5a revealed an absorption band at 3447 cm‐1 corresponding to OH group and a band at 3400 cm‐1 corresponding to NH group and a band at 1637 cm‐1 corresponding to carbonyl group. The 1H NMR of the same product revealed to the presence of a signal at  4.35 ppm corresponding to aliphatic proton at 306 Reheim et al. / European Journal of Chemistry 7 (3) (2016) 298‐308 pyrimidine ring, a multiplet signal at  7.11‐8.37 ppm corresponding to Ar‐Hand amino function and a signal at  9.97 ppm corresponding to OH function. The mass spectrum of the same product is in accordance with the proposed structure. Furthermore, the behavior of β‐diketone (1) toward nitrogen nucleophile was also investigated. Thus, β‐diketone (1) reacted with hydrazine and phenylhydrazine to afford substituted pyrazoles 7a,b. Establishing structure pyrazoles 7a,b was based on their elemental and spectral data [40,41] (Scheme 1). In addition to this the behaviour of β‐diketone (1) toward a mixture of active methylene and elemental sulfur was also investigated. Thus, β‐diketone (1) reacted with malononitrile and elemental sulfur to afford the thiophene derivative 10 (Scheme 1). The formation of thiophene 10 from the reaction of diketone (1) and malononitrile is beleived to be formed via initial addition of malononitrile on the double bond system of carbonyl group of diketone 1 and subsequent elimination of water to afford the non‐isolable intermediate 8. The intermediate 8 reacted with elemental sulfur to afford thiophene 10 via intermediacy of compound 9 (Scheme 1). Establishing structure thiophene 10 was based on its elemental analysis and spectral data. The IR spectrum of compound 10 revealed an absorption band at 3440 cm‐1 corresponding to OH group and a band at 2212 cm‐1 corres‐ ponding to CN group and a band at 1638 cm‐1 corresponding to carbonyl group. The mass spectrum of the same product is in accordance with the proposed structure. The behaviour of β‐diketone (1) toward active methylene reagent was also investigated. Thus, β‐diketone reacted with malononitrile to afford the dihydropyridine derivative 12 (Scheme 2). The formation of dihydropyridine derivative 12 from the reaction of diketone (1) and malononitrile is beleived to be formed via initial addition of malononitrile on the double bond system of carbonyl group of diketone and subsequent elimination of water to afford the non‐isolable intermediate 8. The intermediate 8 tautomerizes and cyclizes under the same reaction condition to afford the non‐isolable intermediate 11 which underwent Dimruth rearrangement to afford compound 12 (Scheme 2). Establishing structure 12 was based on its elemental analysis and spectral data. The IR spectrum of compound 12 revealed an absorption band at 2192 cm‐1 corresponding to CN group and a band at 1636 cm‐1 corresponding to carbonyl group. The mass spectrum of the same product is in accordance with the proposed structure. Thus, it revealed a molecular ion peak at 338 m/z (M+) and a number of fragments corresponding to the proposed structure. The product obtained from the reaction of β‐diketone with malononitrile prompted us to investigate further the behaviour of β‐diketone with ethylcyanoacetate. Thus, when compound 1 is allowed to react with ethylcyanoacetate under the same reaction condition afforded the pyranone derivative 14 whose structure was based on its spectral analysis. The formation of pyranone derivative 14 is beleived to be formed via initial addition of ethylcyanoacetate on the double bond system of compound 1 and subsequent elimination of water to afford the non‐isolable intermediate 13. The intermediate 13 tautomerizes and cyclizes under the same reaction condition to afford the pyranone derivative 14 (Scheme 2). On the other hand the behaviour of β‐diketone (1) toward some electrophilic reagents was also investigated. Thus, β‐ diketone reacted with arylidenemalononitrile 15a‐d under reflux to afford the pyrane derivatives 19a‐d (Scheme 3). The formation of pyrane derivatives is beleived to be formed via intial addition of active methylene of compound 1 on the double bond system of arylidenemalononitrile to afford the acyclic intermediate 16 which tautomerizes into compound 17 that cyclizes under the same reaction condition to afford compound 18 that tautomerizes into pyrane derivative 19 (Scheme 3). Establishing structure 19a‐d were based on their elemental and spectral analysis. Similarly, β‐diketone reacted with arylidene cyanothioacetamide 20a‐c to afford the dihydropyridinethione derivatives 24a‐c (Scheme 3). Establishing structure 24a‐c were based on their elemental analysis and spectral data. Coupling of β‐diketone (1) with aryl diazonium salts 25a‐d in ethanol containing sodium acetate afforded the hydrazo form compound 27a‐d based on spectral data. Compounds 27a‐d reacted with malononitrile to afford pyridazine derivatives 30a‐d. Establishing structure 30 was based on its elemental and spectral data. For example, the IR spectrum of compound 30c revealed the presence of a band at 3382 cm‐1 corresponding to OH group, a band at 3300 cm‐1 corres‐ ponding to NH group, a band at 2193 cm‐1 corresponding to C≡N group and a band at 1634 cm‐1 corresponding to C=O group. 1H NMR of the same product revealed the presence of a signal at  3.83 ppm corresponding to OCH3, a multiplet signal at  7.13‐8.30 ppm corresponding to Ar‐Hand amino function and a singlet signal at  9.93 ppm corresponding to OH group. The mass spectrum of the same product is in accordance with the proposed structure. Thus, it revealed a molecular ion peak at 472 m/z (M+) beside a number of fragments agree with the proposed structure. Formation of pyridazine derivatives from the reaction of malononitrile and the hydrazo compounds 27 is beleived to be formed via initial addition of malononitrile on the double bond of carbonyl group of compound 27 to afford the acyclic intermediate 28, that cyclizes and loses water to give compound 30 under the same reaction condition (Scheme 4). Once more the behaviour of nitrogen nucleophile toward β‐diketones 4b,d was also investigated. Thus, when β‐ diketones 4b,d are allowed to react with hydrazine and phenyl hydrazine pyrazoles derivative 33a‐d were obtained via intermediacy of compound 31 and 32 (Scheme 5). Establishing structures of compound 33a‐d were based on their elemental and spectral data. Similarly, β‐diketones 4b,d reacted with hydroxyl amine hydrochloride to afford isoxazole derivative 34 (Scheme 5). Establishing structures of compound 34a,b were based on their elemental and spectral data. Refluxing of compound 1 with triethylorthoformate in the presence of acetic anhydride yielded 2‐(ethoxymethylene)‐1‐ (2‐hydroxynaphthalen‐1‐yl)‐3‐phenylpropane‐1,3‐dione, 35. The IR spectrum of compound 35 showed bands at 3383 (OH), 3068 (CH‐arom), 2932‐2852 (CH‐aliph) and 1738, 1635 (2CO) cm‐1. The 1H NMR spectrum of compound 35 in DMSO‐d6 revealed signals at  1.11 (t, 3H, CH3), 4.35 (q, 2H, CH2), 6.90 (s, 1H, CH‐olefinic), 7.17‐8.04 (m, 11H, aromatic H), 9.97 (s, 1H, OH). β‐diketone (1) react with dimethylformamidedimethyl‐ acetal (DMF‐DMA) to yield 2‐(dimethylamino) methylene)‐1‐ (2‐hydroxynaphthalen‐1‐yl)‐3‐phenylpropane‐1,3‐dione, 36 in excellent yield. The structure of the latter product was established on the basis of its elemental analysis and spectral data. For example, its 1H NMR spectrum displayed three signals at δ 3.56, 7.17 and 9.96 ppm attributed to magnetically nonequivalent N(CH3)2 group, CH‐olefinic and OH proton respectively. In addition to this a multiplet signals at δ 7.58‐ 8.35 ppm corresponding to aromatic hydrogen atoms. Also hydroxylamine hydrochloride reacted with β‐diketone (1) in refluxing glacial acetic acid containing anhydrous sodium acetate to afford 3‐(hydroxyimino)‐1‐(2‐hydroxy naphthalen‐ 1‐yl)‐3‐phenylpropan‐1‐one, 37 in excellent yield (Scheme 6). 3.2. Pharmacology The newly synthesized compounds have been tested for antibacterial activity against Gram‐negative bacteria (Escheric‐ hia coli & Pseudomonas aeuroginosa) and Gram‐positive bacteria (Bacillus subtilis), and antifungal activity against yeast (Candida albicans) and myelial fungi (Aspergillus flavus) by the cup‐plate method and agar diffusion disc method for deter‐ mining MIC (Minimum inhibitory concentration). Reheim et al. / European Journal of Chemistry 7 (3) (2016) 298‐308 307 Table 1. Antibacterial and antifungal activities of synthesized compounds *. Compound Gram negative bacteria (‐ve) Gram positive bacteria (+ve) Fungal species E. coli P. aeruginosa S. aureus B. subtilis C. albicans A. flavus DIZ (mm) % Activity index DIZ (mm) % Activity index DIZ (mm) % Activity index DIZ (mm) % Activity index DIZ (mm) % Activity index DIZ (mm) % Activity index 5b 3 14.3 8 34.8 12 50.0 10 43.5 11 45.8 14 56.0 19b 4 19.0 10 43.5 14 58.3 12 52.2 13 54.2 16 64.0 27c NA ‐ NA ‐ 9 37.5 7 30.4 10 41.7 12 48.0 10 17 80.9 21 91.3 22 91.7 23 100.0 18 75.0 21 84.0 33a 13 61.9 17 73.9 20 83.3 20 86.9 17 70.8 20 80.0 19c 2 9.5 5 21.7 4 16.7 NA ‐ 3 12.5 5 20.0 33d 6 28.6 11 47.8 7 29.2 4 17.4 7 29.2 10 40.0 33c 11 52.4 16 69.6 18 75.0 19 82.6 14 58.3 17 68.0 1 7 33.3 13 56.5 11 45.8 9 39.1 5 20.8 8 32.0 5d 14 66.7 19 82.6 17 70.8 18 78.3 15 62.5 18 72.0 4b 9 42.8 14 60.9 16 66.7 16 69.6 12 50.0 15 60.0 34a NA ‐ 3 13.0 2 8.3 NA ‐ 2 8.3 3 12.0 4c 10 47.6 15 65.2 15 62.5 13 56.5 6 25.0 10 40.0 24b NA ‐ NA ‐ NA ‐ NA ‐ NA ‐ NA ‐ 34b 5 23.8 12 52.2 8 33.3 5 21.7 8 33.3 11 44.0 36 NA ‐ NA ‐ NA ‐ NA ‐ NA ‐ NA ‐ 33b 16 76.2 20 86.9 21 87.5 22 95.6 20 83.3 23 92.0 Ampicillin 21 100 23 100 24 100 23 100 NA ‐ NA ‐ Clotrimazole NA ‐ NA ‐ NA ‐ NA ‐ 24 100 25 100 * NA: No activity; DIZ: Diameter of inhibition zone. Table 2. Minimum inhibitory concentrations (MIC) for selected compounds *. Compounds Minimum inhibitory concentration (MIC) of the synthesized compounds (µg/mL) E. coli P. aeruginosa S. aureus B. subtilis C. albicans A. flavus 5b 750 500 250 500 62.5 46.9 19b 750 375 250 500 46.9 23.4 27c NA NA 500 750 93.7 62.5 10 93.7 62.5 62.5 125 15.6 5.8 33a 187.5 125 93.7 187.5 23.4 7.8 19c NA 750 NA NA 500 375 33d 500 250 750 NA 187.5 93.7 33c 187.5 125 125 187.5 31.2 15.6 1 375 187.5 375 750 250 187.5 5d 125 93.7 125 250 23.4 11.7 4b 375 187.5 187.5 250 62.5 31.2 34a NA NA NA NA 750 500 4c 250 125 187.5 375 250 125 24b NA NA NA NA 750 750 34b 500 250 500 NA 125 93.7 36 NA NA NA NA NA NA 33b 125 93.7 93.7 125 11.7 3.9 Ampicillin 125 187.5 93.7 187.5 NA NA Clotrimazole NA NA NA NA 7.8 5.8 * NA: No activity. Ampicillin and clotrimazole were used as standards for comparison of antibacterial and antifungal activity, respect‐ tively. Table 1 and 2 illustrated the results of antimicrobial and antifungal activity and it's MIC. The results which are illustrated in Table 1 showed that most of tasted compounds were active against most of micro‐ organisms used. Both of compound 24b and 36 showed no antibacterial or antifungal activity. On the other side each of compound 10 and 33b showed maximum antibacterial and antifungal activity. Compound 27c has no antibacterial activity against Gram‐negative bacteria only, although it has broad spectrum antibacterial activity against Gram‐positive bacteria and antifungal activity against C. albicans and A. flavus. On the other hands, compound 34a showed narrow spectrum antibacterial activity against P. aeruginosa (a Gram‐negative bacteria) and S. aureus (a Gram‐positive bacteria) and revealed no antibacterial activity against E. coli (a Gram negative bacteria) and B. subtilis (a Gram‐positive bacteria), but in case of compound 19c it has no antibacterial activity against B. subtilis only and has narrow range spectrum as antibacterial agent against S. aureus, E. coli and P. aeruginosa with also small rang spectrum antifungal activity. All the other compounds (1, 4b, 4c, 5b, 5d, 19b, 33a, 33c, 33d, 34b) indicated wide range spectrum antibacterial and antifungal activity. From Table 2, we observed that compounds 10, 5d, 33a, 33b and 33c showed the lowest minimum inhibitory concentrations (MIC) for most tested bacteria and fungi, while compounds 19b, 19c, 33c and 34b exhibited high concent‐ rations of MIC as compared with standard antimicrobial agents used. 4. 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