untitled European Journal of Chemistry 4 (3) (2013) 216‐219 European Journal of Chemistry ISSN 2153‐2249 (Print) / ISSN 2153‐2257 (Online)  2013 EURJCHEM DOI:10.5155/eurjchem.4.3.216‐219.788 European Journal of Chemistry Journal homepage: www.eurjchem.com Activated bentonite promoted Friedländer condensation reactions: Synthesis of thieno[2,3‐b]quinolinones and tacrines analogues derivatives Khaireddine Mohamed Dridi a,b,*, Ridha Ben Said a,c, Youssef Arfaoui a,c and Abdullah Sulaiman Al‐Ayed a a Department of Chemistry, College of Sciences and Arts, Qassim University, Al‐Rass, 53, Kingdom of Saudi Arabia b Laboratory of Organic Chemistry, Department of Chemistry, Faculty of Sciences, El Manar University, El Manar II, Tunis 1060, Tunisia c Unité Physico‐Chimie des Matériaux Condensés, Département de Chimie, Faculté des Sciences, Université Tunis El Manar, El Manar II, Tunis 1060, Tunisia *Corresponding author at: Department of Chemistry, College of Sciences and Arts, Qassim University, Al‐Rass, 53, Kingdom of Saudi Arabia. Tel.: +966.05.59928442; fax: +966.06.3335160. E‐mail address: khairydridi@yahoo.fr (K.M. Dridi). ARTICLE INFORMATION ABSTRACT Received: 01 April 2013 Received in revised form: 25 April 2013 Accepted: 08 May 2013 Online: 30 September 2013 KEYWORDS Some new aminothieno[2,3‐b]quinolinones and tacrine analogues derivatives were synthesized in high yield with acid activated bentonite as a catalyst via the Friedländer condensation reactions between 2‐aminothiophene‐3‐carbonitrile and ketones. The structure elucidation of compounds was done by FT‐IR, NMR spectroscopy and microanalytical elemental data. Ketones Bentonite Tacrine analogues Friedlander reaction 2‐Aminothiophene‐3‐carbonitrile 4‐Aminothieno[2,3‐b]quinolinones 1. Introduction Tacrine (Figure 1) sold under the name Gognex has been the first drug that proved to have a beneficial effect on cognition in patients with Alzheimer's disease (AD) [1,2]. However this drug is not used anymore due to its side effects such as hepatotoxicity [3,4]. In order to investigate the biological effects of structurally modified tacrine and as an extension of our efforts towards the facile synthesis of heterocycles containing thiophene ring moiety [5,6]. We report here the synthesis of series of thiophene analogues, since it is widely recognized that thiophene ring is a bioisostere of benzene. 2‐Aminothiophene‐3‐carbonitrile, 1, which were found to possess an extensive spectrum of pharmacological activities [7,8‐10], were chosen as synthon for the synthesis of 4‐aminothienoquinolinones 2 and thienotacrine, 3. 2. Experimental 2.1. Instrumentation Melting points were taken with a Kofler hot staged apparatus and are uncorrected. All reactions were monitored by thin layer chromatography (TLC). IR spectra were determined with a Perkin Elmer 1600 series FT‐IR spectrometer. 1H and 13C NMR spectra were recorded on a Varian‐Unity spectrometer at 300 MHz using TMS as an internal standard. Elemental analyses were determined using a Elementar Vario EI III Elemental Analyser 2.2. Synthesis 2.2.1. General procedure for the synthesis of starting material substituted 2‐aminothiophene‐3‐carbonitrile (1) In a typical experiment, ketone (0.10 mol) and malononitrile (0.10 mol) were dissolved in 200 mL of absolute ethanol. Sulphur powder (0.11 mol) and morpholine (20 mL) were added. The mixture was heated at 50 °C during 3 hours and then was cooled at room temperature. The mixture poured into 300 mL ice‐water. The filtered precipitate was washed with cold water, dried and then recrystallized in suitable solvent (Scheme 1). 2‐Amino‐4,5,6,7‐tetrahydrobenzo[b]thiophene‐3‐carbonitrile (1a): Color: Ocher needles. Yield: 92 %. M.p.: 145‐147 °C. FT‐IR (CHCl3, ν, cm‐1): 3433, 3326 ν(NH) (NH2), 2198 ν(CN), 1615 δ(NH). 1H NMR (300 MHz, DMSO‐d6 + CDCl3, δ, ppm): 4.62 (s, br, 2H, NH2), 2.53 (m, 4H, CH2), 1.76 (m, 4H, CH2). 13C NMR (75 MHz, DMSO‐d6 + CDCl3, δ, ppm): 158.1 (1C, thienyl‐C), 133.2 (1C, thienyl‐C), 120.4 (1C, thienyl‐C), 116.1 (1C, CN), 113.2 (1C, thienyl‐C), 24.3 (1C, ‐CH2‐), 23.8 (1C, ‐CH2‐), 22.7 (1C, ‐CH2‐), 21.8 (1C, ‐CH2‐). 2‐Amino‐4,5‐dimethylthiophene‐3‐carbonitrile (1b): Color: Red‐brownish. Yield: 67 %. M.p.: 140‐142 °C. FT‐IR (CHCl3, ν, cm‐1): 3421, 3309 (NH2) (NH2), 2212 (CN), 1632 (NH) (NH2). 1H NMR (300 MHz, DMSO‐d6 + CDCl3, δ, ppm): 4.62 (s, br, 2H, NH2), 2.16 (s, 3H, CH3), 2.07 (s, 3H, CH3). 13C NMR (75 MHz, DMSO‐d6 + CDCl3, δ, ppm): 159.1 (1C, thienyl‐C), 129.6 (1C, thienyl‐C), 120.2 (1C, thienyl‐C), 115.9 (1C, CN), 112.5 (1C, thienyl‐C), 12.7 (1C, CH3), 12.3 (1C, CH3). 2‐Amino‐4‐(4‐chlorophenyl)thiophene‐3‐carbonitrile (1c): Color: Orange. Yield: 88 %. M.p.: 162‐164 °C. FT‐IR (CHCl3, ν, cm‐1): 3421, 3309 (NH) (NH2), 2212 (CN), 1638 (NH) (NH2), 816 (C‐Cl), 766 (disubstituted phenyl). Dridi et al. / European Journal of Chemistry 4 (3) (2013) 216‐219 217 S R2 R1 N NH2 S R2 R1 N NH2 R4 R3 O 32 N NH2 Tacrine S R2 R1 CN NH2 1 Figure 1. Chemical structures of tacrine, starting material 1 and the synthesized compounds 2 and 3. Scheme 1 1H NMR (300 MHz, DMSO‐d6 + CDCl3, δ, ppm): 7.32 (d, 2H, J = 8.5 Hz, Ar‐H), 7.04 (d, 2H, J = 8.5 Hz, Ar‐H), 6.87 (s, 1H, thienyl‐ H), 5.38 (s, br, 2H, NH2). 13C NMR (75 MHz, DMSO‐d6 + CDCl3, δ, ppm): 165.2 (1C, thienyl‐C), 137.6 (1C, thienyl‐C), 134.7 (1C, Ar‐C), 132.1 (1C, Ar‐C), 128.1 (2C, Ar‐C), 127.8 (2C, Ar‐C), 121.2 (1C, thienyl‐C), 115.6 (1C, CN), 104.0 (1C, thienyl‐C). 2.2.2. General method for the Friedländer reaction 2.2.2.1. Preparation of the activated bentonite In a reactor equipped with a condenser, a stirrer magnetic and a thermometer was charged a dry bentonite and then concentrated sulfuric acid was added (Mass of H2SO4/Mass of Bentonite = 0.3). The mixture was then heated at about 100 °C, the temperature is kept constant during the entire process activation, by means of a water bath. The contact time is determined from the moment when the temperature of the suspension reaches 100 °C. Activated bentonite is then filtered and then washed with distilled water until all traces acid. The wash cycle is completed when the filtrate no longer gives the reaction of sulphates with barium chloride. Bentonite, free of sulphates ions is then dried at 105 to 110 °C, then ground and sieved. 2.2.2.2. Procedure for the synthesis of compounds 2 and 3 To a suspension of catalyst (AlCl3 or activated bentonite) in dry 1,2‐dichloroethane at room temperature under nitrogen, the corresponding aminothiophene 1 (5 mmol) and ketone (10 mmol) were added. The mixture was refluxed until the reaction was complete (monitoring by TLC). When AlCl3 was used: a solution of NaOH (10 %) was added until pH = 9 and then, a mixture of water:THF (v:v, 1:2) was added and the mixture was extracted with dichloromethane. The organic layer was dried, filtered and evaporated. The collected solid was submitted to chromatography (CH2Cl2:MeOH, 9:1, v:v) to give the desired compound. When activated bentonite was used as support catalyst: The mixture was filtered, a solution of water:THF (1:2, v:v) was added and usually work‐up provided the product (Scheme 2). 11‐Amino‐2,3,4,7,8,9‐hexahydro[1]benzothieno[2,3‐b] quinolin‐10(1H)‐one (2a): Following the general method for the Friedländer reaction, AlCl3 ( 800 mg) or Activated bentonite (1000 mg) in dry 1,2‐dichloroethane (50 mL) was reacted with cyclohexane‐1,3‐dione (10 mmol) and aminothiophene 1a (5 mmol). The mixture was refluxed for 24 h. Work‐up and chromatography provided compound 2a. Color: Brown. Yield: 67 %. M.p.: 219‐221 °C. FT‐IR (KBr, ν, cm‐1): 3382, 3215 (NH) (NH2), 1638 (CO), 1589 (NH) (NH2), 1328 (NH2). 1H NMR (300 MHz, DMSO‐d6 , δ, ppm): 5.08 (s, br, 1H, NH2), 3.1‐2.8 (m, 4H, 2*CH2), 2.66 (m, 2H, ‐CH2‐CO‐), 2.53 (m, 2H, =C‐CH2), 2.12 (m, 2H, ‐CH2‐CH2‐CH2‐CO‐), 1.74 (m, 4H, 2*CH2), 1.33 (s, br, 1H, NH2 linked H‐bonding to CO). 13C NMR (75 MHz, DMSO‐d6, δ, ppm): 199.7 (1C, CO), 162.9 (1C, ‐S‐C=C(N)‐), 161.8 (1C, ‐N=C‐ CH2‐), 153.1 (1C, =C‐NH2), 132.7 (1C, ‐C=C‐S), 128.6 (1C, ‐C=C‐ S), 118.2 (1C, thienyl‐C=C‐C‐NH2), 112.3 (1C, pyridinyl‐C‐CO), 40.1 (1C, ‐CH2‐CO), 30.8 (1C, ‐CH2‐CH2‐CO), 28.4 (1C, thienyl‐ CH2‐CH2‐CH2‐CH2‐), 26.9 (1C, thienyl‐CH2‐CH2‐CH2‐CH2‐), 22.7 (1C, thienyl‐CH2‐CH2‐CH2‐CH2‐), 21.4 (1C, thienyl‐CH2‐CH2‐CH2‐ CH2‐), 20.9 (1C, pyridinyl‐CH2‐CH2‐). Anal. calcd. for C15H16N2OS: C, 66.15; H, 5.92; N, 10.29. Found: C, 66.08; H, 5.85; N, 10.34%. 4‐Amino‐2,3‐dimethyl‐7,8‐dihydro‐6H‐thieno[2,3‐b]quinolin‐ 5‐one (2b): Following the general method for the Friedländer reaction, AlCl3 ( 800 mg) or Activated bentonite (1000 mg) in dry 1,2‐dichloroethane (50 mL) was reacted with cyclohexane‐ 1,3‐dione (10 mmol) and aminothiophene 1b (5 mmol). The mixture was refluxed for 24 h. Work‐up and chromatography provided compound 2b. Color: Brown. Yield: 71 %. M.p.: 202‐ 204 °C. FT‐IR (KBr, ν, cm‐1): 3397, 3216 (NH) (NH2), 1638 (CO), 1587 (NH) (NH2), 1422 (CH) (CH2). 1H NMR (300 MHz, DMSO‐d6, δ, ppm): 5.33 (s, br, 1H, NH2), 2.97 (m, 2H, ‐CH2‐CO‐), 2.72 (m, 2H, =C‐CH2), 2.53 (m, 3H, CH3), 2.37 (m, 3H, CH3), 2.11 (m, 2H, ‐CH2‐CH2‐CH2‐CO‐), 1.63 (s, br, 1H, NH2 linked H‐ bonding to CO). 13C NMR (75 MHz, DMSO‐d6, δ, ppm): 201.2 (1C, CO), 162.1 (1C, ‐S‐C=C(N)‐), 161.6 (1C, ‐N=C‐CH2‐), 152.6 (1C, =C‐NH2), 138.2 (1C, ‐C=C‐S), 125.6 (1C, ‐C=C‐S), 121.9 (1C, thienyl‐C=C‐C‐NH2), 112.5 (1C, pyridinyl‐C‐CO), 39.9 (1C, ‐CH2‐ CO), 29.8 (1C, ‐CH2‐CH2‐CO), 21.4 (1C, pyridinyl‐CH2‐CH2‐), 14.8 (1C, CH3), 13.1 (1C, CH3). Anal. calcd. for C13H14N2OS: C, 63.39; H, 5.73; N, 11.37. Found: C, 63.43; H, 5.68; N, 10.41%. 4‐Amino‐3‐(4‐chlorophenyl)‐7,8‐dihydro‐6H‐thieno[2,3‐b] quinolin‐5‐one (2c): Following the general method for the Friedländer reaction, AlCl3 ( 800 mg) or Activated bentonite (1000 mg) in dry 1,2‐dichloroethane (50 mL) was reacted with cyclohexane‐1,3‐dione (10 mmol) and aminothiophene 1c (5 mmol). The mixture was refluxed for 24 h. Work‐up and chromatography provided compound 2c. Color: Brown. Yield: 64 %. M.p.: 234‐236 °C. FT‐IR (KBr, ν, cm‐1): 3396, 3212 (NH) (NH2), 1636 (CO), 1587 (NH) (NH2), 831 (C‐Cl), 765 (disubstituted phenyl). 1H NMR (300 MHz, DMSO‐d6, δ, ppm): 7.36 (m, 4H, Ar‐H), 6.86 (s, 1H, thienyl‐H), 5.28 (s, br, 1H, NH2), 2.91 (m, 2H, N=C‐CH2), 2.63 (m, 2H, ‐CH2‐CO‐), 2.07 (m, 2H, ‐ CH2‐CH2‐CH2‐CO‐), 1.42 (s, br, 1H, NH2 linked H‐bonding to CO). 13C NMR (75 MHz, DMSO‐d6, δ, ppm): 198.3 (1C, CO), 161.8 (1C, ‐S‐C=C(N)‐), 160.1 (1C, ‐N=C‐CH2‐), 154.3 (1C, =C‐NH2), 145.9 (1C, ‐C=C‐S), 136.2 (1C, C‐Ar), 135.6 (1C, Cl‐C‐Ar), 134.2 (2C, 218 Dridi et al. / European Journal of Chemistry 4 (3) (2013) 216‐219 Scheme 2 CH‐Ar), 129.3 (2C, CH‐Ar), 128.7 (1C, ‐C=C‐S), 121.2 (1C, thienyl‐C=C‐C‐NH2), 115.2 (1C, pyridinyl‐C‐CO), 33.8 (1C, ‐CH2‐ CO), 25.4 (1C, ‐CH2‐CH2‐CO), 22.7 (1C, pyridinyl‐CH2‐CH2‐). Anal. Calcd. For C17H13ClN2OS: C, 62.10 ; H, 3.98 ; N, 8.52 . Found: C, 62.14 ; H, 4.01; N, 8.47%. 1‐[4‐Amino‐3‐(4‐chlorophenyl)‐6‐methylthieno[2,3‐b] pyridin‐5‐yl]ethanone (2d): Following the general method for the Friedländer reaction, AlCl3 (800 mg) or Activated bentonite (1000 mg) in dry 1,2‐dichloroethane (50 mL) was reacted with cyclohexane‐1,3‐dione (10 mmol) and aminothiophene 1c (5 mmol). The mixture was refluxed for 24 h. Work‐up and chromatography provided compound 2d. Color: Brown. Yield: 73 %. M.p.: 208‐210 °C. FT‐IR (KBr, ν, cm‐1): 3349, 3224 (NH) (NH2), 1635 (CO), 1589 (NH) (NH2), 831 (C‐Cl), 766 (disubstituted phenyl). 1H NMR (300 MHz, DMSO‐d6, δ, ppm): 7.41 (m, 4H, ArH), 6.89 (s, 1H, thienyl‐H), 5.17 (s, br, 1H, NH2), 2.66 (m, 3H, N=C‐CH3), 2.52 (m, 3H, CH3‐CO‐), 1.68 (s, br, 1H, NH2 linked H‐bonding to CO). 13C NMR (75 MHz, DMSO‐d6, δ, ppm): 197.4 (1C, CO), 161.3 (1C, ‐S‐C=C(N)‐), 158.6 (1C, ‐N=C‐ CH3), 154.7 (1C, =C‐NH2), 145.9 (1C, ‐C=C‐S), 135.9 (1C, C‐Ar), 135.2 (1C, Cl‐C‐Ar), 134.2 (2C, CH‐Ar), 128.7 (2C, CH‐Ar), 127.2 (1C, ‐C=C‐S), 121.4 (1C, thienyl‐C=C‐C‐NH2), 115.5 (1C, pyridinyl‐C‐CO), 17.1 (1C, CH3), 14.2 (1C, CH3). Anal. Calcd. For C16H13ClN2OS: C, 60.66; H, 4.14; N, 8.85 . Found: C, 60.61; H, 4.17; N, 8.91%. (4‐Amino‐2‐trifluoromethyl‐5,6,7,8‐tetrahydrobenzo[4,5] thieno[2,3‐b]pyridin‐3‐yl)thiophen‐2‐yl‐methanone (2e): Following the general method for the Friedländer reaction, AlCl3 ( 800 mg) or Activated bentonite (1000 mg) in dry 1,2‐ dichloroethane (50 mL) was reacted with 1‐thiophen‐2‐ ylbutane‐1,3‐dione (10 mmol) and aminothiophene 1a (5 mmol). The mixture was refluxed for 24 h. Work‐up and chromatography provided compound 2e. Color: Yelllow‐Brown. Yield: 68 %. M.p.: 183‐185 °C. FT‐IR (KBr, ν, cm‐1): 3376, 3253 (NH) (NH2), 1672 (CO), 1583 (NH2) (NH2). 1H NMR (300 MHz, DMSO‐d6 + CDCl3, δ, ppm): 7.2 (d, J = 5.2 Hz, 1H, ‐ thiophene‐H), 6.8‐6.5 (m, 2H, ‐thienyl‐H), 5.82 (s, br, 1H, NH2), 2.83 (m, 2H, ‐CH2), 2.58 (m, 2H, ‐CH2), 2.08 (m, 4H, 2*‐CH2), 1.72 (s, br, 1H, NH2 linked H‐bonding to CO). 13C NMR (75 MHz, DMSO‐d6, δ, ppm): 196.5 (1C, CO), 163.7 (1C, ‐S‐C=C(N)‐), 159.2 (1C, ‐N=C‐CF3), 151.7 (1C, =C‐NH2), 146.8 (1C, ‐C=C‐S), 136.2, (1C, thienyl‐C), 131.2 (1C, thienyl‐C), 130.1 (1C, thienyl‐C), 128.5 (1C, thienyl‐C), 126.3 (1C, ‐C=C‐S), 125.7 (1C, thienyl‐ C=C‐C‐NH2), 118.2 (1C, pyridinyl‐C‐CO), 114.2 (1C, CF3), 28.3 (1C, ‐CH2‐CH2‐CH2‐CH2‐), 28.1 (1C, ‐CH2‐CH2‐CH2‐CH2‐), 25.3 (1C, ‐CH2‐CH2‐CH2‐CH2‐), 24.8 (1C, ‐CH2‐CH2‐CH2‐CH2‐). Anal. calcd. for C17H13F3N2OS: C, 58.28; H, 3.74; N, 8.00. Found: C, 58.19; H, 3.82; N, 8.07%. 11‐Amino‐1,2,3,4,7,8,9,10‐octahydro[1]benzothieno[2,3‐b] quinoline (3a): Following the general method for the Friedländer reaction, AlCl3 ( 800 mg) or Activated bentonite (1000 mg) in dry 1,2‐dichloroethane (50 mL) was reacted with cyclohexanone (10 mmol) and aminothiophene 1a (5 mmol). The mixture was refluxed for 24 h. Work‐up and chromatography provided compound 3a. Color: Brown. Yield: 93 %. M.p.: 215‐217 °C. FT‐IR (KBr, ν, cm‐1): 3471, 3356 (NH) (NH2), 1602 (NH) (NH2), 1431 (CH2). 1H NMR (300 MHz, DMSO‐d6, δ, ppm): 4.62 (s, br, 2H, NH2), 2.93 (m, 2H, CH2), 2.81 (m, 2H, CH2), 2.51 (m, 4H, 2*CH2), 1.96‐1.91 (m, 8H, 4*CH2). 13C NMR (75 MHz, DMSO‐d6, δ, ppm): 159.1 (1C, ‐S‐C=C(N)‐), 153.9 (1C, ‐N=C‐CH2‐), 147.7 (1C, =C‐NH2), 132.8 (1C, ‐C=C‐S), 131.6 (1C, ‐C=C‐S), 126.1 (1C, thienyl‐C=C‐C‐NH2), 117.3 (1C, pyridinyl‐C‐CH2), 43.7 (1C, thienyl‐CH2‐CH2‐CH2‐CH2‐), 42.6 (1C, thienyl‐CH2‐CH2‐CH2‐CH2‐), 33.3 (1C, pyridinyl‐CH2‐CH2‐ CH2‐CH2‐), 31.0 (1C, pyridinyl‐CH2‐CH2‐CH2‐CH2‐), 25.7 (1C, pyridinyl‐CH2‐CH2‐CH2‐CH2‐), 23.4 (1C, thienyl‐CH2‐CH2‐CH2‐ CH2‐), 22.6 (1C, thienyl‐CH2‐CH2‐CH2‐CH2‐), 21.9 (1C, pyridinyl‐ CH2‐CH2‐CH2‐CH2‐). Anal. calcd. for C15H18N2S: C, 69.71; H, 7.02; N, 10.83. Found: C, 69.52; H, 7.08; N, 10.91%. 2,3‐Dimethyl‐5,6,7,8‐tetrahydrothieno[2,3‐b]quinolin‐4‐ amine (3b): Following the general method for the Friedländer reaction, AlCl3 ( 800 mg) or Activated bentonite (1000 mg) in dry 1,2‐dichloroethane (50 mL) was reacted with cyclohexanone (10 mmol) and aminothiophene 1b (5 mmol). The mixture was refluxed for 24 h. Work‐up and chromatography provided compound 3b. Color: Grey. Yield: 88 %. M.p.: 166‐168 °C. FT‐IR (KBr, ν, cm‐1): 3496, 3343 (NH) (NH2), 2922, 2857 (CH) (CH3), 1632 (NH) (NH2), 1279 (NH2). 1H NMR (300 MHz, DMSO‐d6 + CDCl3, δ, ppm): 4.58 (s, br, 2H, NH2), 2.91 (m, 2H, CH2), 2.53 (s, 3H, CH3), 2.41 (s, 3H, CH3), 1.96‐1.91 (m, 6H, 3*CH2). 13C NMR (75 MHz, DMSO‐d6, δ, ppm): 158.3 (1C, ‐S‐C=C(N)‐), 153.8 (1C, ‐N=C‐CH2‐), 147.2 (1C, =C‐ NH2), 133.1 (1C, ‐C=C‐S), 123.6 (1C, ‐C=C‐S), 126.3 (1C, thienyl‐ C=C‐C‐NH2), 113.5 (1C, pyridinyl‐C‐CH2), 34.3 (1C, ‐CH2‐CH2‐ CH2‐CH2‐) , 33.1 (1C, ‐CH2‐CH2‐CH2‐CH2‐), 27.3 (1C, ‐CH2‐CH2‐ CH2‐CH2‐), 23.5 (1C, ‐CH2‐CH2‐CH2‐CH2‐), 14.8 (1C, ‐CH3), 14.1 (1C, ‐CH3). Anal. calcd. for C13H16N2S: C, 67.20; H, 6.93; N, 12.07. Found: C, 67.13; H, 7.04; N, 12.26%. 4‐Amino‐3‐(4‐chlorophenyl)‐5,6,7,8‐tetrahydrothieno[2,3‐ b]quinoline (3c): Following the general method for the Friedländer reaction, AlCl3 ( 800 mg) or Activated bentonite (1000 mg) in dry 1,2‐dichloroethane (50 mL) was reacted with cyclohexanone (10 mmol) and aminothiophene 1c (5 mmol). Dridi et al. / European Journal of Chemistry 4 (3) (2013) 216‐219 219 Table 1. Percentage conversion of compound 2 and 3 in the presence of catalytic amount of AlCl3 and acid activated bentonite. Compound 2a 2b 2c 2d 2e 3a 3b 3c Yield (%) AlCl3 used as a support catalyst 52 58 55 62 53 78 83 77 Activated bentonite used as a support catalyst 67 71 64 73 68 93 88 86 Scheme 3 The mixture was refluxed for 24 h. Work‐up and chromatography provided compound 3c. Color: Orange. Yield: 86 %. M.p.: 177‐179 °C. FT‐IR (KBr, ν, cm‐1): 3481, 3346 (NH) (NH2), 1621 (NH) (NH2), 1447 (CH2), 831 (C‐Cl). 1H NMR (300 MHz, DMSO‐d6, δ, ppm): 7.37 (m, 4H, Ar‐H), 7.01 (s, 1H, thienyl‐ H), 4.54 (s, br, 2H, NH2), 2.97 (m, 2H, ‐N=C‐CH2), 2.51 (m, 2H, =C‐CH2), 1.93 (m, 4H, 2*CH2). 13C NMR (75 MHz, DMSO‐d6, δ, ppm): 159.1 (1C, ‐S‐C=C(N)‐), 155.9 (1C, ‐N=C‐CH2‐), 147.2 (1C, =C‐NH2), 135.8 (1C, ‐C=C‐S), 134.3 (1C, C‐Ar), 133.7 (1C, Cl‐C‐ Ar), 131.2 (2C, CH‐Ar), 129.1 (2C, CH‐Ar), 120.2 (1C, ‐C=C‐S), 115.9 (1C, thienyl‐C=C‐C‐NH2), 113.8 (1C, pyridinyl‐C‐CH2), 33.7 (1C, ‐CH2‐CH2‐CH2‐CH2‐), 23.2 (1C, ‐CH2‐CH2‐CH2‐CH2‐), 22.7 (1C, ‐CH2‐CH2‐CH2‐CH2‐), 22.4 (1C, ‐CH2‐CH2‐CH2‐CH2‐). Anal. calcd. for C17H15ClN2S: C, 64.84; H, 4.80; N, 8.90. Found: C, 64.79; H, 4.75; N, 8.97%. 3. Results and discussion Different synthetic approaches for the preparation of aminopyridine rings have been reported, the Friedländer reaction being one of the simplest and most efficient methods [11]. Friedländer reaction is a base or acid catalysed condensation of an aromatic 2‐amino substituted carbonyl compounds with carbonyl derivatives containing a reactive α‐ methylene group (Scheme 3). Many studies have been undertaken with the aim of developing new catalysts operating under milder conditions. The usual acid catalyst promoted Friedländer reaction was Lewis acid such as Al2O3, SiO2 and AlCl3. Clays such as acid activated bentonites have been used as solid catalyst supports for a number of organic synthesis [12‐ 15]. The advantages of using these catalysts reside in the association of Lewis and Bronsted site acids, the good absorptive capacity and the simple work‐up procedure as the separation of the spent catalyst is achieved by filtration. Otherwise, they have considerable potential as environmental friendly solid acid catalysts and they can be regenerated and reused. In this present paper, we report our recent studies on the synthesis of 4‐aminothienoquinolinones 2 and their tacrine analogues derivatives 3 and we are interested in the development of environmentally friendly catalyst such as activated bentonite in the Friedländer reaction. The results of the Friedländer reaction of substituted 2‐aminothiophene‐3‐ carbonitrile with some carbonyl derivatives containing a reactive α‐methylene group were depicted outline. The starting material 2‐aminothiophene‐3‐carbonitrile 1 was prepared in one step from corresponding ketones by using versatile Gewald reaction [16,17] (Scheme 1). The synthesis of the 4‐aminothienoquinolinones 2 and thienotacrine 3 were performed by using Friedländer reaction. Precursor 1 reacted with β‐dicarbonyl compounds or cyclohexanone under conditions i) or ii) to give respectively products 2 and 3 (Scheme 2). The remarkable utility of clays in various reported organic transformations, motivated us to initially test the use of acid activated bentonite as catalyst in this field of reaction. In fact, we found that the use of 1000 mg activated bentonite for 10 mmol of cyclohexanone (or diketone) under dichloroethane reflux for 24 hours afforded thienotacrine 3 (or thienoquinolinone 2) in high to good yield as depicted in Table 1. However, attempts to use a superstoichiometric amount of Aluminium chloride (4 or 5 equiv.) led to lower yield. The excellent result achieved using acid activated bentonite could be probably explained by high absorptive capacity and the efficient coordination of catalyst and reactants. 4. Conclusion In order to investigate the biological effects of structural modification of tacrine, a simple and green one‐pot process was developed for the synthesis of 4‐aminothienoquinolinones 2 and thienotacrine 3 derivatives via Friedländer condensation reaction promoted by an environmentally friendly catalyst such as bentonite. Acknowledgements The authors extend their appreciation to The Deanship of Scientific Research at Qassim University for the financial support of this work (Project No: 1799). References [1]. Summers, W. K.; Majovsky, L. V.; Marsh, G. M.; Tachiki, K.; Kling, A. N. Engl. J. Med. 1986, 315, 1241‐1287 [2]. Sahakian, B. J.; Owen, A. M.; Morant, N. J.; Eagger, S. A.; Boddington, S.; Crayton, L.; Crockford, H. A.; Crooks, M.; Hill, K.; Levy, R. Psychopharmacology 1993, 110, 395‐401. [3]. Drukarch, B.; Kits, K. S.; Van der Meer, E. G.; Lodder, J. C.; Stoof, J. C. Eur. J. Pharmacol. 1987, 141, 153‐157. [4]. Augry, F.; Darch, A.; De Routou, J.; Guelfi, M. 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