Synthesis, reactions and biological evaluation of some novel thienothiophene derivatives European Journal of Chemistry 10 (3) (2019) 209-217 European Journal of Chemistry View Journal Online View Article Online Synthesis, reactions and biological evaluation of some novel thienothiophene derivatives Mounir Abbas Ali Mohamed *, Hanan Salah and Ahmed Mohamed Mohamed El-Saghier Chemistry Department, Faculty of Science, Sohag University, Sohag 82524, Egypt mounir_abbas@yahoo.com (M.A.A.M.), hanansalah7396@gmail.com (H.S.), el_saghier@yahoo.com (A.M.M.E.) * Corresponding author at: Chemistry Department, Faculty of Science, Sohag University, Sohag 82524, Egypt. Tel: +20.1.016395449 Fax: +20.093.4601159 e-mail: mounir_abbas@yahoo.com (M.A.A. Mohamed). 10.5155/eurjchem.10.3.209-217.1850 Received: 18 March 2019 Received in revised form: 26 May 2019 Accepted: 28 May 2019 Published online: 30 September 2019 Printed: 30 September 2019 Synthesis of some new bis(chalcones)-based thienothiophene derivatives and study of their synthetic utilities as building blocks for new bis(thiazole), bis(dihydropyran), bis(dihydro pyridine), bis(isoxazoles), bis(pyrazoles), bis(hydropyrimidinethiones), bis(tetrahydro diazepines, oxazepines) and bis(dihydrobenzodiazepnies, benzoxazepines) each linked to a thienothiophene core, is reported. Biological evaluation of the obtained compounds as antibacterial agents was achieved. Compounds 4b, 4c, 7a, 6a, 9a and 11b were found to be very potent against P. aeruginosa, E. coli and K. pneumonia. Chalcone Isoxazole Diazepine Oxazepine Thienothiophene Antibacterial activity Cite this: Eur. J. Chem. 2019, 10(3), 209-217 Journal website: www.eurjchem.com 1. Introduction Chalcones are very interesting molecules due to their diverse applications in different fields. They display a wide range of pharmacological properties, including antimutagenic and antitumor-promoting activities, antibacterial, anti- inflammatory, antiulcerative, and hepatoprotective activities [1-5]. Chalcones also are useful intermediates for the synthesis of five-, six- and seven-membered heterocyclic compounds [6- 10]. In addition, considerable attention has been focused on thienothiophenes due to their interesting biological activities. They have been tested as potential antitumor, antiviral, antibiotic and antiglaucoma drugs or as inhibitors of platelet aggregation [11-15]. Recently, Mashraqui [16] had described the application of thieno[2,3-b]thiophene in the design of a novel nonlinear optics (NLO) system by incorporating this nucleus within an unsymmetrically functionalized cyclophane. Furthermore, attention has been increasingly paid in recent years to the synthesis of bis-heterocyclic for their numerous applications as electrical materials [17], chelating agents, and metal ligands [18]. They also exhibit various biological activities including antibacterial, fungicidal, tuberculostatic, antitumor and as antimicrobial [19-38] and plant growth regulative properties [39,40]. Moreover, compounds including bis-heterocyclic moieties were encountered in many bioactive natural product and recent reports showed that among libraries of derivatized heterocycles, the most active library compounds had a bis-heterocyclic structure [41-49]. 2. Experimental All melting points were determined on a Koffler melting point apparatus and are uncorrected. 1H NMR and 13C NMR spectra were recorded on a Bruker Avance 400 MHz spectrometer using TMS as internal reference (Chemical shifts in δ, ppm), and IR spectra were obtained on a Nicolet 710 FT- IR spectrometer (KBr, ν, cm-1). 2.1. Synthesis of 1,1'-(3,4-dimethylthieno[2,3-b]thiophene- 2,5-diyl)diethanone (1) To a solution of anhydrous potassium carbonate (~5 g) in dry benzene (30 mL), acetylacetone 1.03 mL (0.01 mol), TBAB (~50 mg), carbon disulfide 0.9 mL (0.015 mol) was added drop-wise with continuous stirring. After 30 min the reaction mixture was cooled to 0 °C and then treated with chloro acetone (0.190 mL, 0.02 mol). ABSTRACT RESEARCH ARTICLE KEYWORDS European Journal of Chemistry ISSN 2153-2249 (Print) / ISSN 2153-2257 (Online) – Copyright © 2019 The Authors – Atlanta Publishing House LLC – Printed in the USA. This work is published and licensed by Atlanta Publishing House LLC – CC BY NC – Some Rights Reserved. http://dx.doi.org/10.5155/eurjchem.10.3.209-217.1850 http://dx.doi.org/10.5155/eurjchem.10.3.209-217.1850 https://crossmark.crossref.org/dialog/?doi=10.5155/eurjchem.10.3.209-217.1850&domain=pdf&date_stamp=2019-09-30 http://www.eurjchem.com/ http://dx.doi.org/10.5155/eurjchem.10.3.209-217.1850 mailto:mounir_abbas@yahoo.com mailto:hanansalah7396@gmail.com mailto:el_saghier@yahoo.com mailto:mounir_abbas@yahoo.com http://www.eurjchem.com/ https://crossmark.crossref.org/dialog/?doi=10.5155/eurjchem.10.3.209-217.1850&domain=pdf&date_stamp=2019-09-30� 210 Mohamed et al. / European Journal of Chemistry 10 (3) (2019) 209-217 Scheme 1. Synthesis of 1,1'-(3,4-dimethylthieno[2,3-b]thiophene-2,5-diyl)diethanone 1 under phase transfer catalysis conditions. S NH2H2N I2/Oil-bath S S N S S NH2N NH2 2 S S OO 1 2 Scheme 2. Synthesis of 2,2'-(3,4-dimethylthieno[2,3-b]thiophene-2,5-diyl)dithiazol-5-amine (2). 2 CH2(CN)2 S S OO Ar Ar CN NH2H2N NC 3a-d S S HNNH Ar Ar CN OO NC 4a-d EtOH TEA a; Ar = Ph b; Ar = 4-Cl-C6H4 c; Ar = 4-CH3O-C6H4 d; Ar = 4-NO2-C6H4 S S OO 1 Ar O H 2 S S OO Ar Ar CN NH2H2N NC 3a-d AcOH/AcONH4 Scheme 3. Synthesis of 6,6'-(3,4-dimethylthieno[2,3-b]thiophene-2,5-diyl)-bis(2-oxo-4-aryl-1,2-dihydropyridine-3-carbonitrile) derivatives (4a-d). The reaction mixture was further stirred for 3 h, and then filtered off and benzene layer was washed thoroughly with water and dried over anhydrous magnesium sulphate and evaporated in vacuum to give compound 1 (Scheme 1). Color: Yellow. Yield: 92%. M.p.: 154-156 °C. Anal. calcd. for C12H12O2S2: C, 57.12; H, 4.79; S, 25.41. Found: C, 56.88; H, 4.50; S, 25.01%. FT-IR (KBr, ν, cm-1): 1699 (CO). 1H NMR (400 MHz, DMSO-d6, δ, ppm): 2.55 (s, 6H, 2COCH3), 2.81 (s, 6H, 2CH3). 13C NMR (100 MHz, DMSO-d6, δ, ppm): 19.3, 38.50, 131.7, 134.5, 143.4, 160.5, 191.2. MS (EI, m/z (%)): 252 (M+, 12%), 250 (100%), 164 (34%), 134 (18%). 2.2. Synthesis of 4,4'-(3,4-dimethylthieno[2,3-b]thiophene- 2,5-diyl)dithiazol-2-amine (2) A mixture of compound 1 (2.52 g, 0.01 mol), thiourea (1.52 g, 0.02 mol) and iodine (2.54 g, 0.02 mol) was fused on oil bath at 100 °C for 3 h. The formed slurry was treated with water (25 mL) and boiled then was neutralized with ammonia solution (pH = 7) and the formed solid was collected by filtration and recrystallized from ethanol into white needles (Scheme 2). Color: White. Yield: 77%. M.p.: 264-266 °C, Lit. 295 °C [50,51]. Anal. calcd. for C14H12N4S4: C, 46.13; H, 3.32; N, 15.37. Found: C, 45.76; H, 3.05; N, 15.20%. FT-IR (KBr, ν, cm-1): 3398, 3312 (NH2). 1H NMR (400 MHz, DMSO-d6, δ, ppm): 2.59 (s, 6H, 2CH3), 6.72 (s, 4H, 2NH2), 6.80-7.13 (dd, 2H, 2=CH). MS (EI, m/z (%)): 365 (M+1, 10), 364 (M+, 42), 331 (50), 207 (45), 79 (98). 2.3. Synthesis of 6,6'-(3,4-dimethylthieno[2,3-b]thiophene- 2,5-diyl)bis(2-amino-4-aryl- 4H-pyran-3-carbonitrile) (3a- d) A mixture of compound 1 (0.252 g, 0.001 mol), aromatic aldehyde (0.002 mol) and malononitrile (0.132 g, 0.002 mol) in absolute ethanol (25 mL) was treated with few drops of triethylamine as catalyst and then was heated under reflux for different periods of time (2-4 h). Solvent was removed under vacuum and the residual mass was triturated with light petroleum (40-60 °C). The formed solid was recrystallized from ethanol into compounds 3a-d (Scheme 3). 6, 6'-(3, 4-Dimethylthieno[2, 3-b]thiophene-2, 5-diyl)bis(2- amino-4-phenyl-4H-pyran-3-carbonitrile) (3a): Color: Pale yellow. Yield: 67%. M.p.: 166-168 °C. FT-IR (KBr, ν, cm-1): 3294, 3206 (NH2), 2212 (CN). 1H NMR (400 MHz, DMSO-d6, δ, ppm): 2.58 (s, 6H, 2CH3), 4.65 (d, J = 4.8 Hz, 2H, 2CHγ-pyran), 5.85 (d, J = 5.6 Hz, 2H, 2=CH), 6.87-6.98 (br, 4H, 2NH2), 7.23- 7.45 (m, 10H, CHarom). 13C NMR (100 MHz, DMSO-d6, δ, ppm): 15.03 (2CH3), 67.08 (CHγ-pyran), 113.18 (CN), 128.19, 136.02, 140.00, 143.65 (Thienothiophene ArC's), 129.16, 129.56, 144.78, 148.57 (pyran ArC's), 129.56, 130.49, 138.90, 139.49 (Ph ArC's). Anal. calcd. for C32H24N4O2S2: C, 68.55; H, 4.31; N, 9.99. Found: C, 68.20; H, 4.36; N, 10.16%. 6, 6'-(3, 4-Dimethylthieno[2, 3-b]thiophene-2, 5-diyl)bis(2- amino-4-(4-chlorophenyl)-4H-pyran-3-carbonitrile) (3b): Color: White. Yield: 75%. M.p.: 144-146 °C. Anal. calcd. for C32H22Cl2N4O2S2: C, 61.05; H, 3.52; N, 8.90. Found: C, 60.15; H, 3.25; N, 8.70%. 2019 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.10.3.209-217.1850 Mohamed et al. / European Journal of Chemistry 10 (3) (2019) 209-217 211 S S OO Ar Ar EtONa/EtOH 5a-d CH2(CN)2 EtOH/TEA S S OO Ar Ar CN NH2H2N NC 3a-d a; Ar = Ph b; Ar = 4-Cl-C6H4 c; Ar = 4-CH3O-C6H4 d; Ar = 4-NO2-C6H4 S S OO 1 Ar O H2 Scheme 4. Synthesis of chalcone derivatives 5a-d. FT-IR (KBr, ν, cm-1): 3312, 3232 (NH2), 2209 (CN). 1H NMR (400 MHz, DMSO-d6, δ, ppm): 2.60 (s, 6H, 2CH3), 4.75 (d, J = 4.8 Hz, 2H, 2CHγ-pyran), 5.80 (d, J = 5.6 Hz, 2H, 2=CH), 6.81-6.96 (br, 4H, 2NH2), 7.35-7.56 (m, 8H, CHarom). 6,6'-(3, 4-Dimethylthieno[2, 3-b]thiophene-2, 5-diyl)bis(2- amino-4-(4-methoxyphenyl)-4H-pyran-3-carbonitrile) (3c): Color: Yellow. Yield: 82%. M.p.: 176-178 °C. Anal. calcd. for C34H28N4O4S2: C, 65.79; H, 4.55; N, 9.03. Found: C, 65.40, H, 4.25, N, 9.18%. FT-IR (KBr, ν, cm-1): 3303, 3225 (NH2), 2210 (CN). 1H NMR (400 MHz, DMSO-d6, δ, ppm): 2.59 (s, 6H, 2CH3), 3.88 (s, 6H, 2OCH3), 4.66 (d, J = 4.6 Hz, 2H, 2CHγ-pyran), 5.65 (d, J = 5.6 Hz, 2H, 2=CH), 6.88-7.06 (br, 4H, 2NH2), 7.32-7.50 (m, 8H, CHarom). 6,6'-(3, 4-Dimethylthieno[2, 3-b]thiophene-2, 5-diyl)bis(2- amino-4-(4-nitrophenyl)-4H-pyran-3-carbonitrile) (3d): Color: Brown. Yield: 77%. M.p.: 156-158 °C. Anal. calcd. for C32H22N6O6S2: C, 59.07; H, 3.41; N, 12.92. Found: C, 58.72; H, 3.01; N, 12.66%. FT-IR (KBr, ν, cm-1): 3315, 3238 (NH2), 2213 (CN). 1H NMR (400 MHz, DMSO-d6, δ, ppm): 2.58 (s, 6H, 2CH3), 4.60 (d, J = 4.8 Hz, 2H, 2CHγ-pyran), 5.68 (d, J = 5.8 Hz 2H, 2=CH), 6.78-6.86 (br, 4H, 2NH2), 7.33-7.55 (m, 8H, CHarom). 2.4. Synthesis of 6,6'-(3,4-dimethylthieno[2,3-b]thiophene- 2,5-diyl)bis(4-aryl-2-oxo-1,2-dihydropyridine-3- carbonitrile) (4a-d) Compound 3a-d (0.001 mol) was dissolved in glacial acetic acid (20 mL) and then was treated with ammonium acetate (0.12 g, 0.0015 mol). The reaction mixture was heated under reflux for 3 h. Solvent was removed under vacuum; ice-cold water was then added to the residual mass and left overnight. The formed soled was filtered off and recrystallized from ethanol to give compound 4a-d (Scheme 3). 6,6'-(3, 4-Dimethylthieno[2, 3-b]thiophene-2,5-diyl)bis(2- oxo-4-phenyl-1,2-dihydropyridine-3-carbonitrile) (4a): Color: Yellow. Yield: 68%. M.p.: 138-140 °C. Anal. calcd. for C32H20N4O2S2: C, 69.05; H, 3.62; N, 10.07. Found: C, 68.66; H, 3.22; N, 9.78%. FT-IR (KBr, ν, cm-1): 3234 (NH), 2210 (CN), 1688 (CO). 1H NMR (400 MHz, DMSO-d6, δ, ppm): 2.58 (s, 6H, 2CH3), 5.58 (s, 2H, 2CHolefenic), 7.33-7.55 (m, 10H, CHarom), 12.03 (br, 2H, 2NH). 6,6'-(3, 4-Dimethylthieno[2, 3-b]thiophene-2, 5-diyl)bis(4-(4- chlorophenyl)-2-oxo-1,2-dihydropyridine-3-carbonitrile) (4b): Color: Pale yellow. Yield: 72 %. M.p.: 155-157 °C. Anal. calcd. for C32H18Cl2N4O2S2: C, 61.44; H, 2.90; N, 8.96. Found: C, 61.02; H, 2.65; N, 8.68%. FT-IR (KBr, ν, cm-1): 3224 (NH), 2214 (CN), 1698 (CO). 1H NMR (400 MHz, DMSO-d6, δ, ppm): 2.59 (s, 6H, 2CH3), 5.62 (s, 2H, 2CHolefenic), 7.30-7.52 (m, 8H, CHarom), 9.22 (s, 2H, 2NH). 6,6'-(3, 4-Dimethylthieno[2, 3-b]thiophene-2, 5-diyl)bis(4-(4- methoxyphenyl)-2-oxo-1,2-dihydropyridine-3-carbonitrile) (4c): Color: White. Yield: 70%. M.p.: 180-182 °C. Anal. calcd. for C34H24N4O4S2: C, 66.22; H, 3.92; N, 9.08. Found: C, 65.90; H, 3.66; N, 8.75%. FT-IR (KBr, ν, cm-1): 3209 (NH), 2206 (CN), 1690 (CO). 1H NMR (400 MHz, DMSO-d6, δ, ppm): 2.60 (s, 6H, 2CH3), 3.96 (s, 6H, 2OCH3), 5.59 (s, 2H, 2CHolefenic), 7.28-7.50 (m, 8H, CHarom), 9.20 (br, 2H, 2NH). 6, 6'-(3, 4-Dimethylthieno[2, 3-b]thiophene-2, 5-diyl)bis(4- (4-nitrophenyl)-2-oxo-1,2-dihydropyridine-3-carbonitrile) (4d): Color: Brown. Yield: 66%. M.p.: 208-210 °C. Anal. calcd. for C32H18N6O6S2: C, 59.44; H, 2.81; N, 13.00. Found: C, 59.05; H, 2.66; N, 12.70%. FT-IR (KBr, ν, cm-1): 3222 (NH), 2212 (CN), 1687 (CO). 1H NMR (400 MHz, DMSO-d6, δ, ppm): 2.62 (s, 6H, 2CH3), 5.56 (s, 2H, 2CHolefenic), 7.38-7.56 (m, 8H, CHarom), 9.24 (br, 2H, 2NH). 2.5. Synthesis of 1,1'-(3,4-dimethylthieno[2,3-b]thiophene- 2,5-diyl)bis(3-arylprop-2-en-1-one) (5a-d) A mixture of compound 1 (0.252 g, 0.001 mol), aromatic aldehyde (0.002 mol) in absolute ethanol (25 mL) and sodium ethoxide (0.2 g, 0.003 mol) was refluxed for 1 h. Solvent was removed under vacuum and the solid mass was recrystallized from methanol into chalcone derivatives 5a-d (Scheme 4). 1, 1'-(3, 4-Dimethylthieno[2, 3-b]thiophene-2, 5-diyl)bis(3- phenylprop-2-en-1-one) (5a): Color: White. Yield: 85%. M.p.: 208-210 °C. Anal. calcd. for C26H20O2S2: C, 72.87; H, 4.70. Found: C, 72.57; H, 4.40%. FT-IR (KBr, ν, cm-1): 1696 (CO). 1H NMR (400 MHz, DMSO-d6, δ, ppm): 2.25 (s, 6H, 2CH3), 7.32- 7.56 (m, 10H, CHarom), 8.18 (d, 2H, J = 12.8 Hz, 2CHethylenic), 8.68 (d, 2H, J = 12.6 Hz, 2CHethylenic). 13C NMR (100 MHz, DMSO-d6, δ, ppm): 15.5, 113.5, 129.6, 129.9, 132.32, 133.2, 138.8, 141.5, 145.3, 147.5, 148.6, 186.5. MS (EI, m/z (%)): 428 (M+, 80), 427 (M+-1, 72), 413 (21), 274 (100). 1, 1'-(3, 4-Dimethylthieno[2, 3-b]thiophene-2, 5-diyl)bis(3- (4-chlorophenyl)prop-2-en-1-one) (5b): Color: Yellow. Yield: 87%. M.p.: 262-264 °C. Anal. calcd. for C26H18Cl2O2S2: C, 62.78; H, 3.65. Found: C, 62.45; H, 3.38%. FT-IR (KBr, ν, cm-1): 1720 (CO). 1H NMR (400 MHz, DMSO-d6, δ, ppm): 2.32 (s, 6H, 2CH3), 7.35-7.56 (m, 8H, CHarom), 7.72 (d, 2H, J = 12.42, 2CHethylenic), 8.66 (d, 2H, J = 12.6, 2CHethylenic). 13C NMR (100 MHz, DMSO-d6, δ, ppm): 14.9, 112.5, 125.5, 129.2, 131.2, 133.05, 134.6, 137.2, 142.2, 145.5, 148.7, 185.5. MS (EI, m/z (%)): 498 (M+, 12), 496 (M+-2, 18), 426 (100). 1, 1'-(3, 4-Dimethylthieno[2, 3-b]thiophene-2, 5-diyl)bis(3- (4-methoxyphenyl)prop-2-en-1-one) (5c): Color: Pale yellow. Yield: 64%. M.p.: 238-240 °C. Anal. calcd. for C28H24O4S2: C, 68.83; H, 4.95. Found: C, 68.65; H, 4.78%. FT-IR (KBr, ν, cm-1): 1720 (CO). 1H NMR (400 MHz, DMSO-d6, δ, ppm): 2.29 (s, 6H, 2CH3), 3.89 (s, 6H, 2OCH3), 7.32-7.50 (m, 8H, CHarom), 7.96 (d, 2H, J = 12.6 Hz, 2CHethylenic), 8.65 (d, 2H, J = 12.8 Hz, 2CHethylenic). 1, 1'-(3, 4-Dimethylthieno[2, 3-b]thiophene-2, 5-diyl)bis(3- (4-nitrophenyl)prop-2-en-1-one) (5d): Color: Brown. Yield: 78%. M.p.: 268-270 °C. Anal. calcd. for C26H18N2O6S2: C, 60.22; H, 3.50; N, 5.40. Found: C, 59.88; H, 3.22; N, 5.15%. FT-IR (KBr, ν, cm-1): 1695 (CO). 1H NMR (400 MHz, DMSO-d6, δ, ppm): 2.36 (s, 6H, 2CH3), 7.55-7.75 (m, 8H, CHarom), 8.12 (d, 2H, J = 12.8 Hz, 2CHethylenic), 8.80 (d, 2H, J = 12.6, 2CHethylenic). 2.6. Synthesis of compounds 6a, 7a and 8a A mixture of compound 5a (0.43 g, 0.001 mol) and hydroxylamine, hydrazine and/or phenylhydrazine (0.0025 mol) was dissolved in ethanol (25 mL). 2019 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.10.3.209-217.1850 212 Mohamed et al. / European Journal of Chemistry 10 (3) (2019) 209-217 NH2OH NH2NH2 PhNHNH2 EtOH EtOH EtOH S S O N N O PhPh S S H N N N H N PhPh S S N N N N PhPh PhPh 6a 7a 8a S S OO Ph Ph5a Scheme 5. Synthesis of bis-heterocycles 6a-8a. S S NN Ph Ph Dioxan/TEA HN NH SS 9a S H2N NH2 S S OO Ph Ph5a Scheme 6. Synthesis of 4,4'-(3,4-dimethylthieno[2,3-b]thiophene-2,5-diyl)bis(6-phenylpyrimidine-2(1H)-thione), 9a. The reaction mixture was heated under reflux for 3 h. Solvent was removed under vacuum and water was added to the residual slurry and then left 2h. The formed solid was collected by filtration and recrystallized from ethanol to give compounds 6a, 7a and 8a, respectively (Scheme 5). 5, 5'-(3, 4-Dimethylthieno[2, 3-b]thiophene-2, 5-diyl)bis(3- phenylisoxazole) (6a): Color: Yellow. Yield: 58%. M.p.: 108-110 °C. Anal. calcd. for C26H18N2O2S2: C, 68.70; H, 3.99; N, 6.16. Found: C, 68.40; H, 3.66; N, 6.02%. 1H NMR (400 MHz, DMSO- d6, δ, ppm): 2.28 (s, 6H, 2CH3), 6.68 (s, 2H, 2=CH), 7.26-7.50 (m, 10H, CHarom). 13C NMR (100 MHz, DMSO-d6, δ, ppm): 15.2, 118.2, 122.5, 128.4, 132.1, 133.7, 138.2, 142.4, 147.1, 148.3, 153.1, 159.2. 5, 5'-(3, 4-Dimethylthieno[2, 3-b]thiophene-2, 5-diyl)bis(3- phenyl-1H-pyrazole) (7a): Color: White. Yield: 77%. M.p.: 143- 145 °C. Anal. calcd. for C26H20N4S2: C, 69.00; H, 4.45; N, 12.38. Found: C, 68.70; H, 4.15; N, 12.12%. FT-IR (KBr, ν, cm-1): 3195 (NH). 1H NMR (400 MHz, DMSO-d6, δ, ppm): 2.58 (s, 6H, 2CH3), 4.85 (s, 2H, 2=CH), 7.25-7.55 (m, 10H, CHarom), 10.12 (br, 2H, 2NH). 13C NMR (100 MHz, DMSO-d6, δ, ppm): 15.5, 112.5, 121.5, 127.5, 132.6, 133.4, 138.7, 142.3, 147.2, 148.5, 153.5, 156.8. 5, 5'-(3, 4-Dimethylthieno[2, 3-b]thiophene-2, 5-diyl)bis(1,3- diphenyl-1H-pyrazole) (8a): Color: Pale yellow. Yield: 75%. M.p.: 212-214 °C. Anal. calcd. for C38H28N4S2: C, 75.47; H, 4.67; N, 9.26. Found: C, 75.10; H, 4.38; N, 9.01%. 1H NMR (400 MHz, DMSO-d6, δ, ppm): 2.59 (s, 6H, 2CH3), 4.80 (s, 2H, 2=CH), 7.28- 7.55 (m, 20H, CHarom). 2.7. Synthesis of 4,4'-(3,4-dimethylthieno[2,3-b]thiophene- 2,5-diyl)bis(6-phenylpyrimidine-2(1H)-thione) (9a) A mixture of compound 5a (0.43 g, 0.001 mol) and thiourea (0.19 g, 0.0025 mol) in dioxane (25 mL) was treated with a catalytic amount of triethylamine. The reaction mixture was heated under reflux for 4 h, after the completion of the reaction (as monitored by TLC), solvent was removed under reduced pressure and the residual slurry was then triturated with light petroleum (40-60 °C) and the formed solid was collected and recrystallized from acetonitrile (Scheme 6). Color: Pale yellow. Yield: 65%. M.p.: 178-180 °C. Anal. calcd. for C28H20N4S2: 62.19; H, 3.73; N, 10.36. Found: C, 61.88; H, 3.50; N, 10.20%. FT-IR (KBr, ν, cm-1): 3211 (NH). 1H NMR (400 MHz, DMSO-d6, δ, ppm): 2.59 (s, 6H, 2CH3), 5.35 (s, 2H, 2=CH), 7.33-7.58 (m, 10H, CHarom), 10.15 (br, 2H, 2NH). 2.8. Synthesis of compounds 10a, 10b, 11a and 11b A mixture of compound 5a (0.43 g, 0.001 mol) and ethylenediamine, ethanolamine, o-phenylenediamine and/or o-aminophenol (0.002 mol) in dioxane (25 mL) was treated with few drops of triethylamine as catalyst. The reaction mixture was then heated under reflux for 4 h. Solvent was evaporated under vacuum, the solid mass was then triturated with light petroleum ether (40-60 °C) and the formed solid was collected, recrystallized from acetonitrile into compounds 10a,b and 11a,b, respectively (Scheme 7). 2019 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.10.3.209-217.1850 Mohamed et al. / European Journal of Chemistry 10 (3) (2019) 209-217 213 Dioxan/TEA 10a,b Dioxan/TEA NH2 XH XH NH2 a; X = NH b; X = O S S NH XX HN S S NH XX HN Ph Ph Ph Ph S S OO Ph Ph5a 11a,b Scheme 7. Synthesis of bis-heterocycles 10a,b and 11a,b. 7, 7'-(3, 4-Dimethylthieno[2, 3-b]thiophene-2, 5-diyl)bis(5- phenyl-2, 3, 4, 5-tetrahydro-1H-1, 4-diazepine) (10a): Color: Yellow. Yield: 75%. M.p.: 188-190 °C. Anal. calcd. for C30H32 N4S2: C, 70.28; H, 6.29; N, 10.93. Found: C, 69.95; H, 5.90; N, 10.61%. FT-IR (KBr, ν, cm-1): 3285, 3195 (2NH). 1H NMR (400 MHz, DMSO-d6, δ, ppm): 2.58 (s, 6H, 2CH3), 3.63 (br, 4H, 2CH2), 3.93 (br, 4H, 2CH2), 4.85 (d, J = 4.8 Hz, 2H, CH), 5.65 (d, J = 5.6 Hz, 2H, =CH), 7.25-7.55 (m, 10H, CHarom), 8.56 (br, 2H, 2NH), 10.12 (br, 2H, 2NH). 13C NMR (100 MHz, DMSO-d6, δ, ppm): 15.1, 53.8, 56.7, 66.5, 112.5, 118.6, 121.0, 123.1, 127.4, 128.5, 132.3, 138.1, 147.2, 148.4. 7, 7'-(3, 4-Dimethylthieno[2, 3-b]thiophene-2, 5-diyl)bis(5- phenyl-2, 3, 4, 5-tetrahydro-1,4-oxazepine) (10b): Color: Pale yellow. Yield: 78%. M.p.: 118-120 °C. Anal. calcd. for C30H30 N2O2S2: C, 70.01; H, 5.88; N, 5.44. Found: C, 70.12; H, 5.56; N, 5.20%. FT-IR (KBr, ν, cm-1): 3215 (NH). 1H NMR (400 MHz, DMSO-d6, δ, ppm): 2.59 (s, 6H, 2CH3), 3.62 (br, 4H, 2CH2), 3.96 (br, 4H, 2CH2), 4.88 (d, J = 4.8 Hz, 2H, 2CH), 5.60 (d, J = 5.8 Hz, 2H, 2=CH), 7.28-7.55 (m, 10H, CHarom), 8.33 (br, 2H, 2NH). 4,4'-(3, 4-Dimethylthieno[2, 3-b]thiophene-2, 5-diyl)bis(2- phenyl-2, 5-dihydro-1H-benzo[b][1, 4]diazepine) (11a): Color: Yellow. Yield: 78%. M.p.: 166-168 °C. Anal. calcd. for C38H32 N4S2: C, 74.97; H, 5.30; N, 9.20. Found: C, 74.56; H, 5.01; N, 8.87%. FT-IR (KBr, ν, cm-1): 3265, 3189 (2NH). 1H NMR (400 MHz, DMSO-d6, δ, ppm): 2.58 (s, 6H, 2CH3), 4.75 (d, J = 4.8 Hz, 2H, 2CH), 5.605 (d, J = 5.8 Hz, 2H, 2 =CH), 7.22-7.68 (m, 18H, CHarom), 8.45 (br, 2H, 2NH), 10.15 (br, 2H, 2NH). 2, 2'-(3, 4-Dimethylthieno[2, 3-b]thiophene-2, 5-diyl)bis(4- phenyl-4, 5-dihydrobenzo[b][1, 4]oxazepine) (11b): Color: Pale yellow. Yield: 78%. M.p.: 186-188 °C. Anal. calcd. for C38H30 N2O2S2: C, 74.73; H, 4.95; N, 4.59. Found: C, 74.25; H, 4.66; N, 4.30%. FT-IR (KBr, ν, cm-1): 3218 (NH). 1H NMR (400 MHz, DMSO-d6, δ, ppm): 2.59 (s, 6H, 2CH3), 4.85 (d, J = 4.6 Hz, 2H, 2CH), 5.66 (d, J = 5.6 Hz, 2H, 2=CH), 7.20-7.75 (m, 18H, CHarom), 8.53 (br, 2H, 2NH). 2.9. Biological evaluation The antibacterial activity of different compounds 2, 3a-d, 4a-d, 6a, 7a, 9a, 10a,b and 11a,b was determined by agar well diffusion method as described by Pandey [52]. Petri plates containing 20 mL of sterilized nutrient agar (NA) medium were seeded with 50 μL of 24 hr culture of the pathogenic bacterial strains (Bacillus cereus, Bacillus subtilis, Klebsiella pneumonia, Escherichia coli, Serratia sp. and Pseudomonas aerugenosa) and allowed to solidify. Sterile cork borer (6 mm diameter) was used to bore wells in the plates, compounds solutions (100 ppm) were carefully dispensed into the bored holes as well as solvent control. The plates were then incubated at 37 °C for 48 hours. The antibacterial activity was assayed by measuring the diameter of the inhibition zone formed around the well (NCCLS) [53-55]. 3. Results and discussion 3.1. Synthesis In continuation of our work on the synthesis of thienothiophene derivatives [56-58], the starting compound 1,1'-(3,4-dimethylthieno[2,3-b]thiophene-2,5-diyl)diethanone (1) was obtained via the one-pot reaction of acetylacetone, carbon disulfide and two equivalents of chloroacetone under phase transfer catalysis conditions [benzene/K2CO3/TBAB], Scheme 1. The structure of compound 1 was established on the basis of its elemental analyses and spectral data. Its IR spectrum revealed absorption bands at 1669 cm-1 due to carbonyl functions. The 1H NMR spectrum displayed a singlet at δ 2.55 ppm, characteristic of acetyl protons as well as another singlet at δ 2.81 ppm characteristic for methyl protons, whereas its 13C NMR δ 19.3 (2CH3), 38.50 (2CH3- acetyl), 131.7, 134.5, 143.4, 160.5 (thienothiophene), 191.2 ppm (2 C=O) and MS data 252 (M+, 12%), 250 (100%), 164 (34%), 134 (18%). The reaction of compound 1 with thiourea and iodine under solvent-free conditions afforded after working up 2, 2'- (3, 4-dimethylthieno[2, 3-b]thiophene-2, 5-diyl)dithiazol-5- amine (2) in good yield. Compound 2 was previously obtained [10] by treatment of bis-2-bromoacetylthieno[2,3-b]thiophene with thiourea in refluxing EtOH/TEA. The IR spectrum of compound 2 showed absorption maxima at 3398 and 3312 cm-1 characteristic for NH2 group, where the 1H NMR spectrum of compound 2 revealed a doublet of doublets at δ 6.80-7.13 ppm (2H, =CH thiazole), a singlet at δ 6.72 ppm for (4H, 2NH2) protons and a singlet at 2.59 ppm for (6H, CH3 protons), Scheme 2. The reaction mechanism of this reaction was assumed to proceed via a preliminary nucleophilic attack of the primary amine group of thiourea into the acetyl carbonyl group followed by oxidation using iodine to give the thiazole derivative, Scheme 8. 2019 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.10.3.209-217.1850 214 Mohamed et al. / European Journal of Chemistry 10 (3) (2019) 209-217 CH3 O H2N S NH2 CH3 H N OH NH2 S CH3 N NH2 S -H2O H2C N NH S I2 -2HI H H N NH S N NH2 S = S S Scheme 8. The suggested reaction mechanism of compound 2. The one-pot reaction of compound 1, aromatic aldehydes (two equivalents) and malononitrile (two equivalents) in ethanol in the presence of a catalytic amount of triethylamine as a catalyst afforded 6,6'-(3,4-dimethylthieno[2,3-b]thiophe ne-2,5-diyl)bis(2-amino-4-aryl-4H-pyran-3-carbonitrile) (3a- d) in good yield. The reaction of compounds 3a-d with ammonium acetate in acetic acid afforded the expected 6,6'-(3, 4-dimethylthieno[2,3-b]thiophene-2, 5-diyl) bis(2-oxo-4-aryl- 1,2-dihydropyridine-3-carbonitrile) derivatives (4a-d), Scheme 3. The IR spectrum of compound 3a revealed charac- terristic bands at 3294, 3206 and 2212 cm-1 corresponding to NH2 and CN groups respectively, whereas its 1H NMR spectrum showed a broad band at δ 6.98-6.87 ppm for NH2 proton. Where the IR spectrum of compound 4a showed absorption bands at 3234, 2210 and 1688 cm-1 for NH, CN and C=O groups respectively, while its 1H NMR spectrum revealed a broad band at δ 12.03 ppm for 2NH protons. The reaction mechanism was proposed to proceed through a preliminary chalcone formation followed by a Michael addition of malononitrile and subsequent cyclisation, Scheme 9. This aforementioned mechanism was supported by treatment of compound 1 with two equivalents of aromatic aldehyde in absolute ethanol in the presence of sodium ethoxide as a catalyst to give the corresponding chalcone derivatives 5a-d then treatment of chalcone derivatives with malononitrile under alkaline conditions afforded the corresponding pyrane derivatives 3a-d, Scheme 4. Encouraged by the aforementioned results compound 5a was allowed to react with different reagents viz. hydroxyl- amine, hydrazine and/or phenyl hydrazine, where the corres- ponding bis(five-membered ring heterocycles) namely: 5,5'-(3, 4-dimethylthieno[2, 3-b]thiophene-2, 5-diyl)bis(3-phenyliso xazole) (6a), 5,5'-(3,4-dimethylthieno[2,3-b]thiophene-2, 5- diyl)bis(3-phenyl-1H-pyrazole) (7a) and 5, 5'-(3, 4-dimethyl thieno[2, 3-b]thiophene-2, 5-diyl)bis(1, 3-diphenyl-1H-pyra- zole) (8a) were obtained respectively, Scheme 5. Treatment of compounds 5a with thiourea in dioxane in the presence of a catalytic amount of triethylamine as catalyst resulted in the formation of the corresponding six-membered ring heterocycles namely 4,4'-(3,4-dimethylthieno[2,3-b] thiophene-2,5-diyl)bis(6-phenylpyrimidine-2(1H)-thione) (9a), Scheme 6. Finally, compound 5a was allowed to react with ethylene diamine, ethanolamine, o-phenylenediamine, and/or o- aminophenol in dioxane in the presence of triethylamine as catalyst to give the corresponding seven-membered ring heterocycles 10a,b and 11a,b, respectively, Scheme 7. The reaction was thought to proceed via a preliminary nucleophilic attack of the amino group of the bifunctional reagent onto the chalcone ethylenic double bond followed by internal cyclisation by the other amino or hydroxyl group onto the carbonyl group followed by H2O elimination. All synthesized compounds were obtained as pure solid crystals or powder with high yield. The structures of the obtained compounds were established by their elemental analysis, IR, 1H NMR, 13C NMR and mass spectroscopy. 3.2. Biological evaluation The antibacterial activity of compounds 2, 3a-d, 4a-d, 6a, 7a, 9a, 10a,b and 11a,b is represented by the diameters (mm) of inhibition zones (Table 1 and Figure 1). All compounds were found to be active against three among the six tested strains. Compounds 4b, 4c, 6a, 9a and 11b was found to produce inhibition zones against E. coli and Pseudomonas aerugenosa; where compounds 7a, 9a and 10b were active against Pseudomonas aerugenosa and Klebsiella pneumonia. Although it’s known with its resistance to many antibiotics and antiseptics, remarkable activity towards Pseudomonas aerugenosa was recorded with the maximum inhibition zones (7 and 8 mm) for the synthesized compounds 2, 3a-d, 4a-d, 6a, 7a, 9a, 10a,b and 11a,b. Pseudomonas aeruginosa has a high degree of multidrug resistance related to the presence of antibiotic efflux systems providing resistance to multiple antimicrobial agents [54,55]. 2019 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.10.3.209-217.1850 Mohamed et al. / European Journal of Chemistry 10 (3) (2019) 209-217 215 Table 1. The antibacterial activity of the newly synthesized compounds against some bacterial pathogens. Compound Antibacterial data in MIC (µg/mL) Antifungal data in MIC (µg/mL) E. coli P. aerugenosa K. pneumonia A. niger A. fumigatus 2 6 7 3 5 - 3a 4 5 7 - - 3b 6 6 3 - - 3c 5 5 4 - - 3d 0 7 7 5 3 4a 8 7 5 - - 4b 7 8 6 - - 4c 8 6 8 - - 4d 5 5 6 6 5 6a 5 7 0 - - 7a 6 8 2 - - 9a 0 8 6 - - 10a 5 7 6 - - 10b 0 8 7 - - 11a 2 7 6 - - 11b 5 8 6 - - Streptomycin 10 12 10 - - Fluconazole - - - 20 22 CH3 O O -H2OAr O B- CH2 O H2C O Ar OH Ar O Ar CH2(CN)2 TEA CN CN OH Ar CN CN O Ar CN NH O Ar CN NH2 AcONH4 AcOH H N Ar CN O 3a-d 4a-d 1 Scheme 9. Suggested reaction pathway for the formation of compounds 4a-d. Figure 1. Antibacterial activity of compounds 6a, 9a and 10b against different pathogenic bacterial strains. 2019 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.10.3.209-217.1850 216 Mohamed et al. / European Journal of Chemistry 10 (3) (2019) 209-217 4. Conclusion We developed a direct and straightforward strategy for the synthesis of some new bis(chalcone) derivatives and studied the significance of this class of compounds as versatile synthons for new bis(thiazole), bis(pyran), bis(isoxazoles), bis(pyrazoles), bis(pyrimidines) and bis(diazepines, oxaze- pines, benzodiazepines and benzoxazepines). Due to the mild reaction conditions, good yields as well as easily accessible starting material, the synthetic approaches discussed here should provide access for new class of bis(functionalized) heterocycles. The new synthesized compounds were subjected for studying their pharmacological and biological activities. Compounds 4b, 4c, 7a, 6a, 9a and 11b were found to be very potent against P. aeruginosa, E. coli and K. pneumonia. Acknowledgement The authors extend their appreciation to Dr. Rehab Mostafa Mohamed for achieving the biological assay; also, authors would be grateful for Chemistry Department, Faculty of Science, Sohag University for providing necessary facilities. Disclosure statement Conflict of interests: The authors declare that they have no conflict of interest. Author contributions: All authors contributed equally to this work. Ethical approval: All ethical guidelines have been adhered. Sample availability: Samples of the compounds are available from the author. ORCID Mounir Abbas Ali Mohamed http://orcid.org/0000-0001-7080-8505 Hanan Salah http://orcid.org/0000-0003-3645-0874 Ahmed Mohamed Mohamed El-Saghier http://orcid.org/0000-0002-4338-1486 References [1]. Bhat, B. A.; Dhar, K. L.; Saxena, A. K.; Shanmugavel, M.; Qazi, G. N. Bioorg. Med. Chem. 2005, 15, 3177-3180. [2]. Konieczny, M. T.; Konieczny, W.; Sabisz, M.; Skladanowski, A.; Wakiec, R.; Augustynowicz-Kopec, E.; Zwolska, Z. Eur. J. 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Phosphorus Sulfur Silicon Rel. Elem. 1992, 73(1-4), 15-25. 2019 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.10.3.209-217.1850 http://orcid.org/0000-0001-7080-8505 http://orcid.org/0000-0003-3645-0874 http://orcid.org/0000-0002-4338-1486 https://www.sciencedirect.com/science/article/pii/S0040402017300704%23! https://www.sciencedirect.com/science/article/pii/S0040402017300704%23! https://www.sciencedirect.com/science/article/pii/S0040402017300704%23! Mohamed et al. / European Journal of Chemistry 10 (3) (2019) 209-217 217 [57]. Moustafa, H. M.; Khodairy, A.; El-Saghier, A. M. M. Phosphorus Sulfur Silicon Rel. Elem. 2003, 178(6), 1211-1224. [58]. Khodairy, A.; El-Saghier, A. M. M. Acta Chim. Slov. 2011, 58, 360-366. Copyright © 2019 by Authors. This work is published and licensed by Atlanta Publishing House LLC, Atlanta, GA, USA. The full terms of this license are available at http://www.eurjchem.com/index.php/eurjchem/pages/view/terms and incorporate the Creative Commons Attribution-Non Commercial (CC BY NC) (International, v4.0) License (http://creativecommons.org/licenses/by-nc/4.0). By accessing the work, you hereby accept the Terms. This is an open access article distributed under the terms and conditions of the CC BY NC License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited without any further permission from Atlanta Publishing House LLC (European Journal of Chemistry). No use, distribution or reproduction is permitted which does not comply with these terms. Permissions for commercial use of this work beyond the scope of the License (http://www.eurjchem.com/index.php/eurjchem/pages/view/terms) are administered by Atlanta Publishing House LLC (European Journal of Chemistry). 2019 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.10.3.209-217.1850 http://www.eurjchem.com/index.php/eurjchem/pages/view/terms http://creativecommons.org/licenses/by-nc/4.0 http://www.eurjchem.com/index.php/eurjchem/pages/view/terms 1. Introduction 2. Experimental 2.1. Synthesis of 1,1'-(3,4-dimethylthieno[2,3-b]thiophene-2,5-diyl)diethanone (1) 2.2. Synthesis of 4,4'-(3,4-dimethylthieno[2,3-b]thiophene-2,5-diyl)dithiazol-2-amine (2) 2.3. Synthesis of 6,6'-(3,4-dimethylthieno[2,3-b]thiophene-2,5-diyl)bis(2-amino-4-aryl- 4H-pyran-3-carbonitrile) (3a-d) 2.4. Synthesis of 6,6'-(3,4-dimethylthieno[2,3-b]thiophene-2,5-diyl)bis(4-aryl-2-oxo-1,2-dihydropyridine-3-carbonitrile) (4a-d) 2.5. Synthesis of 1,1'-(3,4-dimethylthieno[2,3-b]thiophene-2,5-diyl)bis(3-arylprop-2-en-1-one) (5a-d) 2.6. Synthesis of compounds 6a, 7a and 8a 2.7. Synthesis of 4,4'-(3,4-dimethylthieno[2,3-b]thiophene-2,5-diyl)bis(6-phenylpyrimidine-2(1H)-thione) (9a) 2.8. Synthesis of compounds 10a, 10b, 11a and 11b 2.9. Biological evaluation 3. Results and discussion 3.1. Synthesis 3.2. Biological evaluation 4. Conclusion Disclosure statement ORCID References PrintField10: PrintField11: PrintField12: PrintField13: PrintField14: PrintField15: PrintField16: PrintField17: PrintField18: PrintField20: PrintField21: PrintField22: PrintField23: PrintField24: PrintField25: PrintField26: PrintField27: PrintField28: