Synthesis and Characterization of Novel Thieno-Fused Bicyclic Compounds through New Enaminone Containing Thieno[2,3-<i>b</i>]pyridine Scaffold

Mabkhot, Yahia Nasser; Aladdi, Salah S.; Al-Showiman, S. S.; Al-Majid, A. M. A.; Barakat, Assem; Ghabbour, Hazem A.; Shaaban, Mohamed R.

doi:https://doi.org/10.1155/2015/382381

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Research Article | Open Access

Volume 2015 | Article ID 382381 | https://doi.org/10.1155/2015/382381

Synthesis and Characterization of Novel Thieno-Fused Bicyclic Compounds through New Enaminone Containing Thieno[2,3-b]pyridine Scaffold

Yahia Nasser Mabkhot,¹Salah S. Aladdi,¹S. S. Al-Showiman,¹A. M. A. Al-Majid,¹Assem Barakat,^1,2Hazem A. Ghabbour,^3,4and Mohamed R. Shaaban^5,6

Academic Editor: Josefina Pons

Received06 Oct 2015

Accepted02 Nov 2015

Published25 Nov 2015

Abstract

New substituted thieno-fused bicyclic compounds named (1H-pyrazol-3-yl)thieno[2,3-b]pyridin-4(7H)-one derivatives (4a,b), 2-([1,2,4]triazolo[1,5-a]pyrimidin-7-yl)-3-methyl-7-phenylthieno[2,3-b]pyridin-4(7H)-one (5), phenylthieno[2,3-b]pyridin-4(7H)-one derivatives (6a–c, 7a–c, and 8), and 3-(3-methyl-4-oxo-7-phenyl-4,7-dihydrothieno[2,3-b]pyridin-2-yl)-3-oxopropyl 4-chlorobenzoate (9) were synthesized by reacting the new enaminone (3) with different reagents. The chemical structure of the new molecules was determined by means of different spectroscopic methods such as NMR, IR, MS spectrometry, and by CHN analyses. The molecular structure of the 1,1′-(3-methyl-5-(phenylamino)thiophene-2,4-diyl)diethanone (2) was successfully solved by X-ray single crystal.

1. Introduction

E naminones are a precursor for the synthesis of heterocycles which have been devoted in the last decade. These synthons were reacted with several nucleophilic and electrophilic reagents to construct new heterocyclic systems of pharmaceutical targets such as pyrazolo[3,4-d]pyrimidin-4-one, pyrazolo[1,5-a]pyrimidine derivatives [1], pyrido[2,3-d] [1,2,4]triazolino[4,3-a]pyrimidin-4-one, pyridino[2,3-d]pyrimidin-4-one, and pyrido[2,3-d] [1,2,4]triazolino[4,5-a]pyrimidin-5-one [2]. Thieno-fused bicyclic compounds incorporate pyrimidine, pyrazoles, benzo[4,5]imidazo[1,2-a]pyrimidine and [1,2,4]triazolo[1,5-a]pyrimidine rings [3], isoquinoline [4], and natural products and their analogues [5, 6].

Additionally, the thieno[2,3-b]pyridine core structure and its substituents are scaffold possessing potential biological activities including estrogenic, antihypertensive anti-inflammatory, antiviral, anticancer, and antimicrobial activities [7–15]; indeed, many substituted thieno[2,3-b]pyridine building blocks were synthesized and recognized for the selectivity of these bioisosteres of the antibacterial quinolones such as ofloxacin, ciprofloxacin, and norfloxacin [16, 17]. In continuation of our interest in the chemistry of thieno-fused bicyclic compounds [18–21] to develop new library of pharmaceutical targets we started from new enaminone 3 as precursor for synthesis of new thieno-fused bicyclic compounds containing thieno[2,3-b]pyridine core.

2. Experimental Section

2.1. General

All the chemical products were purchased from various suppliers, including Sigma-Aldrich and Fluka, and were used without further purification, unless otherwise stated. All melting points were measured on a Gallenkamp melting point apparatus in open glass capillaries and are uncorrected. IR spectra were recorded as KBr pellets on a Nicolet 6700 FT-IR spectrophotometer. The NMR spectra were recorded on a Varian Mercury Jeol-400 NMR spectrometer. ¹HNMR (400 MHz) and ¹³C-NMR (100 MHz) were run in deuterated dimethyl sulphoxide (DMSO-d₆). Chemical shifts () are referred to in ppm while J-coupling constants were represented in Hz. Mass spectra were recorded on a Jeol of JMS-600 H. Elemental analysis was carried out on Elmer 2400 Elemental Analyzer, CHN mode.

1,1′-(3-Methyl-5-(phenylamino)thiophene-2,4-diyl)diethanone (2). In a round bottom flask (100 mL) acetylacetone (10 mL, 100 mmol) was dissolved in DMF (45 mL); then the reaction mixture was kept at RT for 5 mins; subsequently, phenyl isocyanate (13.5 mL, 100 mmol) was added and stirred for further 30 mins. the reaction mixture was then cooled by using ice bath, and chloroacetone (9.25 mL, 100 mmol) was added and stirred for 15 mins. The reaction mixture was allowed to warm to rt and continued stirring for 30 mins. The precipitated product was filtered off and washed by H₂O and dried. The crude product was purified by crystallization from glacial acetic acid to afford the pure compound in yellow crystals.

Yield: 95%; m.p. 115°C; IR (): 1492, 1602–1646 (C=O), 3415 (NH); ¹H-NMR (DMSO-d₆): δ 2.85 (s, 3H, CH₃), 3.38 (s, 6H, 2CH₃), 5.85 (s, 1H, NH), 7.63–7.84 (m, 5H, C₆H₅); ¹³C-NMR: δ, 16.08 (CH₃), 40, 46 (COCH₃), 120.19, 122.46, 130.55, (Ar-C), 137.04 (CH₃COC), 140.95 (Ar-C-N), 142.34 (CH₃-C); MS m/z (%): 274 [M+, 100]; Anal. calcd. for C₁₅H₁₅NO₂S: C, 65.91; H, 5.53; N, 5.12; S, 11.73; Found: C, 65.92; H, 5.55; N, 5.10; S, 11.70.

2-(3-(Dimethylamino)acryloyl)-3-methyl-7-phenylthieno[2,3-b]pyridin-4(7H)-one (3). A mixture of 1,1′-(3-methyl-5-(phenylamino)thiophene-2,4-diyl)diethanone 2 (1.37 g, 0.5 mmol) and DMF-DMA (1.19 mL, 0.01 mol) was refluxed in m-xylene (15 mL) for 3 h. After cooling, the resulting solid product was collected by filtration to give the desired product 3 used for the next step without any further purification.

Yellow crystal; Yield: 63%; m.p. 235°C; IR (): 1593 (C=C), 1613–1640 (C=O).; ¹H-NMR (DMSO-d₆): δ, 2.85 (s, 3H, CH₃), 3.16 (s, 6H, N(CH₃)₂), 5.36 (d, 1H, ) 5.39 (d, 1H, ), 6.14 (d, 1H, ) 6.16 (d, 1H, ), 7.63–7.68 (m, 5H, C₆H₅); ¹³C-NMR: δ, 16.12 (-CH₃), 45.15 (-N=(CH₃)₂), 94.03 (-CH=CH-N=), 153.15 (-), 126.35, 128.58, 130.55 (Ph), 142.35 (-C-CH₃), 115.14 (-), 154.45 (-), 154.54 (=CNS), 176.49, 180.51 (C=O); MS m/z (%): 325 [M+, 30%]; Anal. calcd. for C₁₈H₁₇N₂O₂S: C, 67.43; H, 5.36; N, 8.28; S, 9.47; Found: C, 67.45; H, 5.40; N, 8.31; S, 9.50.

2.2. General Procedure for the Preparation of Compounds 4a,b

Compounds 4a,b were prepared using the following general procedure.

Compound 3 (0.131 g, 0.5 mmol) was added to hydrazine hydrate (2 mL, 63 mmol) or phenylhydrazine (1 mL, 10 mmol) (to make compounds 4a,b, resp.). The mixture of compound 3 and the appropriate hydrazine was refluxed until compound 3 is completely dissolved, followed by addition of the mixed solvent EtOH/DMF. The reaction mixture was then refluxed for 6-7 h and the product was filtered after cooling. The desired product was obtained in a pure form by recrystallization from MeOH. Using the general procedure, the following compounds were prepared.

3-Methyl-7-phenyl-2-(1H-pyrazol-3-yl)thieno[2,3-b]pyridin-4(7H)-one (4a). Red crystal; Yield: 67%; m.p. 285°C; IR (): 1616 (C=N), 1637 (C=O), 3477 (NH); MS m/z (%): 322 [M+, 30%]; Anal. calcd. for C₁₈H₁₆N₃OS: C, 66.43; H, 4.26; N, 13.67; S, 10.43; Found: C, 66.41; H, 4.25; N, 13.66; S, 10.41.

3-Methyl-7-phenyl-2-(1-phenyl-1H-pyrazol-3-yl)thieno[2,3-b]pyridin-4(7H)-one (4b). Green crystal; Yield: 68%; m.p. 275°C; IR (): 1602 (C=N), 1640 (C=O); ¹H-NMR (DMSO-d₆): δ, 2.29 (s, 3H, CH₃), 6.14–6.16 (d, 1H, ), 6.72–6.74 (d, 1H, ), 7.63–7.65 (d, 1H, ), 7.67–7.78 (d, 1H, ), 7.61–7.69 (m, 5H, C₆H₅); ¹³C-NMR: δ, 15.09 (CH₃), 113.23 (), 119.70, 126.31, 129.49 (Ar-C), 130.49 (-C-CH₃), 130.93 (N-CHCS), 131.04 (-C-S), 140.39 (C-CO), 142.42 (Ar-C-N), 145.95 (), 175.74 (C=O); MS m/z (%): 307 [M+, 30%]; Anal. calcd. for C₁₇H₁₃N₃OS: C, 72.04; H, 4.47; N, 10.96; S, 8.36; Found: C, 72.04; H, 4.49; N, 11.0; S, 8.37.

2-([1,2,4]Triazolo[1,5-a]pyrimidin-7-yl)-3-methyl-7-phenylthieno[2,3-b]pyridin-4(7H)-one (5). It is a mixture of 3 (0.131 g, 0.5 mmol) and 3-amine-1H-1,2,4-triazole (0.042 g, 0.5 mmol) in dioxane. Catalytic amount of TEA (triethyl amine) and ZnCl₂ was added into the reaction mixture. The reaction mixture was then refluxed for 6 h and the product was filtered after cooling.

Yellow crystal; Yield: 72%; m.p. >300°C; IR (): 1618 (C=N), 1634 (C=O); MS m/z (%): 359 [M+, 30%]; Anal. calcd. for C₁₉H₁₃N₅OS: C, 63.50; H, 3.65; N, 19.49; S, 8.92; Found: C, 63.51; H, 3.65; N, 19.50; S, 8.93.

2.3. General Procedure for the Preparation of Compounds 6a–c

Compounds 6a–c were prepared using the following general procedure.

Compound 3 (0.131 g, 0.5 mmol) was added to ethane-1,2-diamine (0.03 g, 0.5 mmol), propane-1,3-diamine (0.04 g, 0.5 mmol), or hexane-1,2-diamine (0.06 g, 0.5 mmol) (to make compounds 6a–c, resp.) in AcOH (0.1 mmol) as solvent and NH₄OAc (0.1 mmol) as catalyst. The reaction mixture was then refluxed for 3 h and the product was filtered after cooling. The desired product was obtained in a pure form by recrystallization from EtOH. Using the general procedure, the following compounds were prepared.

2-(3-((2-Aminoethyl)amino)acryloyl)-3-methyl-7-phenylthieno[2,3-b]pyridin-4(7H)-one (6a). Yellow powder; Yield: 62%; m.p. 142°C; IR (): 1593 (C=C), 1616–1637 (2C=O), 2931 (CH₂), 3238 (NH₂) 3415 (NH); ¹H-NMR (DMSO-d₆): δ 2.63 (s, 3H, CH₃), 2.93 (q, 2H, CH₂NH), 3.48 (m, 2H, CH₂NH₂), 6.16 (s, 2H, NH₂), 5.24–5.40 (d, 1H, ), 5.83–5.91 (d, 1H, ), 7.02–7.00 (m, 1H, ), 7.08–7.20 (d, 1H, ), 7.64–7.67 (m, 5H, C₆H₅); ¹³C-NMR: δ 115.20 (CH₂NH₂), 115.52 (CH₂-CH=CH), 129.31, 130.91, 130.94, 143.28, (Ar-C), 131.04 (), 137.45 (=CCO), 141.62 (S-CCO), 142.31 (-C-CH₃), 143.28 (Ar-C-N), 153.19 (), 155.15 (), 155.74 (), 176.48 (C=O); MS m/z (%): 353 [M+, 30%]; Anal. calcd. for C₁₈H₁₄N₂O₂S: C, 64.57; H, 5.42; N, 11.89; S, 9.07; Found: C, 64.56; H, 5.40; N, 11.91; S, 9.10.

2-(3-((3-Aminopropyl)amino)acryloyl)-3-methyl-7-phenylthieno[2,3-b]pyridin-4(7H)-one (6b). Yellow powder; Yield: 64%; m.p. 145°C; IR (): 1593 (C=C), 1616–1637 (2C=O), 2931 (CH₂), 3238 (NH₂) 3415 (NH); ¹H-NMR (DMSO-d₆): δ 2.74 (s, 3H, CH₃), 3.16 (t, 2H, NH₂), 1.30–2.95 (m, 6H, CH₂), 6.08–6.20 (m, 1H, ), 6.17–6.20 (d, 1H, ), 7.64–7.43 (d, 1H, ), 9.90–7.80 (d, 1H, ), 7.62–7.72 (m, 5H, C₆H₅); ¹³C-NMR: δ, 13.93 (CH₃), 28.50 (-CH₂), 33.00 (-CH₂NH₂), 69.92 (-CH₂-NH) 114.60 (), 126.36, 129.18, 130.13 (Ar-C), 131.06 (), 136.05 (=CCO), 139.77(-C-CH₃), 142.57 (), 151.40 (), 175.74 (C=O); MS m/z (%): 367 [M+, 30%]; Anal. calcd. for C₂₈H₂₆N₂O₂S₂: C, 65.37; H, 5.76; N, 11.44; S, 8.72; Found: C, 65.35; H, 5.77; N, 11.45; S, 8.74.

2-(3-((4-Aminobutyl)amino)acryloyl)-3-methyl-7-phenylthieno[2,3-b]pyridin-4(7H)-one (6c). Yellow powder; Yield: 67%; m.p. 282°C; IR (): 1593 (C=C), 1616–1637 (2C=O), 2931 (CH₂), 3238 (NH₂) 3415 (NH); ¹H-NMR (DMSO-d₆): δ 2.74 (s, 3H, CH₃), 1.15–2.87 (m, 6H, CH₂), 3.80 (t, 2H, NH₂), 6.18 (q, 1H, ), 6.19 (d, 1H, ), 6.20 (d, 1H, ), 6.20 (d, 1H, ), 7.58–7.67 (m, 5H, C₆H₅); ¹³C-NMR: δ 13.93 (CH₃), 28.50 (-CH₂), 33.00 (-CH₂NH₂), 69.92 (-CH₂-NH) 114.60 (), 126.36, 129.18, 130.13 (Ar-C), 131.06 (), 136.05 (=CCO), 139.77(-C-CH₃), 142.57 (), 151.40 (), 175.74 (C=O); MS m/z (%): 409 [M+, 30%]; Anal. calcd. for C₂₃H₂₄N₂O₂S: C, 66.12; H, 6.08; N, 11.01; S, 8.40; Found: C, 66.12; H, 6.11; N, 11.04; S, 8.41.

2.4. General Procedure for the Preparation of Compounds 7a–c

Compounds 7a–c were prepared using the following general procedure.

Compound 3 (0.131 g, 0.5 mmol) was added to 4-chloroaniline (0.06 g, 0.5 mmol), 4-methoxyaniline (0.06 g, 0.5 mmol), or p-toluidine (0.05 g, 0.5 mmol) (to make compounds 6a–c, resp.) in dioxane as solvent and TEA (triethyl amine) (0.1 mmol) as catalyst. The reaction mixture was then refluxed for 4 h and the product was filtered after cooling. The desired product was obtained in a pure form by recrystallization from EtOH.

2-(3-((4Chlorohphenyl)amino)acryloyl)-3-methyl-7-phenylthieno[2,3-b]pyridin-4(7H)-one (7a). Yellow powder; Yield: 58%; m.p. >300°C; IR (): 1578 (C=C), 1636 (C=O), 3415 (NH); ¹H-NMR (DMSO-d₆): δ 2.49 (s, 3H, CH₃), 5.21 (d, 1H, NH), 6.51–6.53 (d, 1H, ), 6.55–6.57 (d, 1H, ), 6.97 (d, 1H, ), 6.97–6.99 (t, 1H, ), 7.01–7.03 (t, 1H, ), 7.78–7.82 (m, 4H, C₆H₄); ¹³C-NMR: δ 115.70, 119.21, 129.03 (Ar-C), 148.25 (Ar-C-N); MS m/z (%): 420.5 [M+, 30%]; Anal. calcd. for C₂₃H₁₅ClN₂O₂S: C, 65.63; H, 4.07; Cl, 8.42; N, 6.66; S, 7.62.; Found: C, 65.64; H, 4.09; Cl, 8.40; N, 6.67; S, 7.63.

2-(3-((4-Methoxyphenyl)amino)acryloyl)-3-methyl-7-phenylthieno[2,3-b]pyridin-4(7H)-one (7b). Yellow powder; Yield: 47%; m.p. >300°C; IR (): 1578 (C=C), 1636 (C=O), 3415 (NH); ¹H-NMR (DMSO-d₆): δ, 2.50 (s, 3H, CH₃), 3.61 (s, 3H, OCH₃), 4.62 (d, 1H, NH), 6.50–6.52 (d, 1H, ), 6.62–6.65 (d, 1H, ), 6.95–6.98 (t, 1H, ), 7.69–7.82 (t, 1H, ), 7.78–7.82 (m, 9H, C₆H₄); ¹³C-NMR: δ, 56.00 (OCH₃), 115.02, 115.57 (Ar-C), 142.76 (SCCO), 151.24 (Ar-C-N). MS m/z (%): 417 [M+, 30%]; Anal. calcd. for C₂₄H₁₈N₂O₃S: C, 69.21; H, 4.84; N, 6.73; S, 7.70.; Found: C, 69.20; H, 4.84; N, 6.74; S, 7.70.

3-Methyl-7-phenyl-2-(3-(p-tolylamino)acryloyl)thieno[2,3-b]pyridin-4(7H)-one (7c). Gray powder; Yield: 59%; m.p. 250°C; IR (): 1578 (C=C), 1636 (C=O), 3415 (NH); ¹H-NMR (DMSO-d₆): δ 1.28–3.37 (s, 6H, CH₃), 4.29 (d, 1H, NH), 4.26–4.28 (d, 1H, ), 4.29–4.31 (d, 1H, ), 6.90 (t, 1H, ), 7.00–7.05 (t, 1H, ), 7.78–7.826.98-7.12 (m, 4H, C₆H₄). ¹³C-NMR: δ 14.66 (CH₃), 114.06, 115.11, 122.96, (Ar-C), 114.06 (), 129.77 (), 143.23 (SCCO), 143.23 (Ar-C-N), 159.92 (S-C-N); MS m/z (%): 400 [M+, 30%]; Anal. calcd. for C₂₄H₁₈N₂O₂S: C, 71.98; H, 5.03; N, 6.99; S, 8.01.; Found: C, 72.00; H, 5.01; N, 7.00; S, 8.00.

2-(Benzo[4,5]imidazo[1,2-a]pyrimidin-4-yl)-3-methyl-7-phenylthino[2,3-b]pyridin-4(7H)-one (8). It is a mixture of 3 (0.131 g, 0.5 mmol) and 2-aminobenzimidazole (0.07 g, 0.5 mmol) in EtOH as solvent and TEA (triethyl amine)/ZnCl₂ as catalyst. The reaction mixture was then refluxed for 8 h and the product was filtered after cooling. The desired product was obtained in a pure form.

Red crystal, Yield: 62%; m.p. 210°C; IR (): 1588 (C=N), 1628 (C=O); ¹H-NMR (DMSO-d₆): δ 2.75 (s, 3H, CH₃), 5.48–5.51 (d, 1H, ), 6.24–6.26 (d, 1H, ), 7.10–7.27 (t, 1H, ), 7.87–8.02 (t, 1H, ),7.71–7.79 (m, 9H, C₆H₅). ¹³C-NMR: δ, 15.47 (CH₃), 114.83 (), 121.17, 125.80, 126.16, 130.19, 130.58, 140.62, 142.50 (Ar-C), 125.80 (), 126.16 (), 130.68 (S-C=CH₃), 162.50 (N-C=N(pyrazole)), 162.21 (), 162.50 (N-C=CCH₃), 176.50 (S-C-N), 189.64 (C=O). MS m/z (%): 422 [M+, 30%]; Anal. calcd. for C₂₅H₁₉N₄OS: C, 65.88; H, 4.07; N, 16.17; S, 9.25; Found: C, 65.85; H, 4.06; N, 16.18; S, 9.25.

3-(3-Methyl-4-oxo-7-phenyl-4,7-dihydrothieno[2,3-b]pyridin-2-yl)-3-oxoprop-1-en-1-yl 4-chlorobenzoate (9). It is a mixture of 3 (0.131 g, 0.5 mmol) and 4-chlorobenzoic acid (0.08 g, 0.5 mmol) in dioxane as solvent and TEA (triethyl amine) (0.1 mmol) as catalyst. The reaction mixture was then refluxed for 4 h and the product was filtered after cooling. The desired product was obtained in a pure form by recrystallization from EtOH.

Yellow powder, Yield: 67%; m.p. 265°C; IR (): 1594 (C=C), 1610–1630 (3C=O). ¹H-NMR (DMSO-d₆): δ 3.12 (s, 3H, CH₃), 5.36–5.39 (d, 1H, ), 6.15–6.17 (d, 1H, ), 7.66–7.68 (t, 1H, ), 7.70-7.80 (t, 1H, ), 7.66–7.68 (m, 5H, C₆H₅); ¹³C-NMR: δ, 16.11 (CH₃), 115.13 (), 126.33 (), 128.58, 130.54, 130.95, 132.60, 137.24 (Ar-C), 141.03 (S-CCO), 142.34 (-C-CH₃), 153.16 (), 154.52 (S-C-N), 176.51 (COO), 180.51 (C=O); MS m/z (%): 444 [M+, 30%]; Anal. calcd. for C₂₄H₁₄ClNO₄S: C, 64.36; H, 3.15; Cl, 7.91; N, 3.13; S, 7.16; Found: C, 64.37; H, 3.14; Cl, 7.91; N, 3.15; S, 7.18.

3. Results and Discussion

Novel thieno-fused bicyclic compounds 4a,b, 5, 6a–c, 7a–c, 8, and 9 were synthesized as shown in Schemes 2 and 3 starting from the new enaminone 3 (Scheme 1). The new synthesized molecules 1–9 were characterized by CHN analyses, NMR, and MS spectral data.

The starting intermediate 2 needed for this research proposal was synthesized by reported method by Mabkhot et al. [22]. The new enaminone 3 was synthesized via the reaction of acetyl thiophene 2 with DMF-DMA in xylene as solvent as shown in Scheme 1. The final product 3 was presumably formed as a result of intramolecular conjugate addition of the nucleophilic nitrogen onto the further end of the double bond (β-carbon) of the intermediate bis-enaminone with elimination of a dimethylamine molecule resulting in formation of Michael product 3 as depicted in Scheme 1.

The IR spectrum of the new enaminone 3 has shown an absorption band at 1613–1640 cm⁻¹ ascribed to the carbonyl group ν(C=O) and an abruption band at 1593 cm⁻¹ ascribed to the alkene group ν(C=C).

¹H-NMR spectrum of the new enaminone 3 exhibited a singlet at δ 2.85 and 3.15 ppm, due to the methyl of the N(CH₃)₂ groups. In addition, two doublets for the CH=CH protons at 5.36 ( Hz) and 5.39 ( Hz) were observed. On the other hand, two doublets for the CH=CH protons at 6.14 ( Hz) and 6.16 ( Hz) due to pyridinone ring in addition to a multiplet at δ 7.63–7.68 belong to phenyl ring protons. ¹³C-NMR spectrum agrees well with the suggested structure and showed the following signals: δ16.12 (-CH₃), 45.15 (-N=(CH₃)₂), 94.03 (-CH=CH-N=), 153.15 (-), 126.35, 128.58, 130.55 (Ph), 142.35 (-C-CH₃), 115.14 (-), 154.45 (-), 154.54 (=CNS), and 176.49, 180.51 (2C=O). The GC-MS showed the molecular ion [M]⁺ at m/z 325 corresponding to the molecular formula C₁₈H₁₇N₂O₂S.

3.1. X-Ray Crystal Structure of 2

The compound, C₁₅H₁₅NO₂S, CCDC: 141975, crystallizes in triclinic, P-1 system with the following unit cell = 10.3859 (3) Å, = 13.8790 (6) Å, = 18.8006 (6) Å, = 86.920 (1)°, = 82.081 (1)°, and = 79.233 (1)°. The unit cell contains four molecules. The molecule consists of tetrasubstituted thiophene ring, in the C3 and C5 two acetyl groups with different orientation. On the other hand, C4 has methyl group and C6 has amine derivative (Figure 1). In the crystal packing the molecules linked via five nonclassical hydrogen bonds were shown in Figure 2 and Table 3. The selected data collection, handling, and bond lengths and angles for the crystal were shown in Tables 1 and 2, respectively [23, 24].

Having the new enaminone 3 available in our hands encourage us to use it for the synthesis of the thieno-fused bicyclic compounds. Compounds 4a,b were synthesized by refluxing a mixture of enaminone 3 and N-nucleophile, for example, hydrazine analogous and subsequently heated under reflux in EtOH/DMF as solvent. (Scheme 2). The IR spectrum of the synthesized molecules exhibited absorption bands at 3416, 1640, and 1602 cm⁻¹ due to ν(N-H), ν(C=O), and ν(C=N), respectively.

Next, enaminone 3 reacted with 3-amino-1H-1,2,4-triazole in dioxane in the presence of TEA (triethyl amine) and ZnCl₂ as catalyst to afford the final product 2-([1,2,4]triazolo[1,5-a]pyrimidin-7-yl)-3-methyl-7-phenylthieno[2,3-b]pyridin-4(7H)-one (5). The suggested chemical structure agreed with experimental spectral data.

In addition, compounds 6a–c, 7a–c, and 8 were synthesized by refluxing a mixture of 3 and aliphatic diamines, aromatic amines, and 2-aminobenzimidazole, respectively (Scheme 3).

Interestingly, enaminone 3 treated with p-chlorobenzoic acid to afford the corresponding ester 9. The IR spectrum is consistent with the expected absorption bands. ¹H-NMR spectrum in DMSO-d₆ showed singlet at 3.12 related to the CH₃ group and two doublets corresponding to the CH=CH protons at δ 5.36 ( Hz) and 5.36 ( Hz) and the pyridinone CH protons at δ 6.15 ( Hz) and 6.16 ( Hz), in addition to a multiplet corresponding to the phenyl rings in the range δ 7.68–7.62. ¹³C-NMR spectrum is also in agreement with the suggested structure; it showed signals corresponding to the different carbon atoms in the compound as follows: δ 16.11 (CH₃), 115.13 (), 126.33 (), 128.58, 130.54, 130.95, 132.60, 137.24 (Ar-C), 141.03 (S-CCO), 142.34 (-C-CH₃), 153.16 (), 154.52 (S-C-N), 176.51 (COO), and 180.51 (C=O). GC-MS exhibited the correct molecular ion peak [M]⁺ at m/z = 449 corresponding to the molecular formula C₂₄H₁₄ClNO₄S.

4. Conclusions

In summary, we have succeeded in the synthesis of a number of novel thieno-fused bicyclic compounds via novel enaminone containing thieno[2,3-b]pyridine core by classical method. The structures of the new compounds were confirmed by means of different spectroscopic methods and by elemental analyses. The biological activity of the synthesized product is underway in our laboratory.

Supplementary Material

Supplementary Material will be available online at http://dx.doi.org/10.1155/2015/382381.

Conflict of Interests

The authors have declared that there is no conflict of interests.

Authors’ Contribution

The authors contributed equally to this work.

Acknowledgment

The authors would like to extend their sincere appreciation to the Deanship of Scientific Research at king Saud University for funding this research group (no. RG -007-2015).

Supplementary Materials

Copies of the spectra (¹H-NMR; ¹³C-NMR; MS and IR) of synthesized compounds were included in the supplementary material.

Supplementary Material

References

S. Bondock, W. Fadaly, and M. A. Metwally, “Synthesis and antimicrobial activity of some new thiazole, thiophene and pyrazole derivatives containing benzothiazole moiety,” European Journal of Medicinal Chemistry, vol. 45, no. 9, pp. 3692–3701, 2010.
View at: Publisher Site | Google Scholar
H. M. Hassneen and T. A. Abdallah, “New routes to pyridino[2,3-d]pyrimidin-4-one and pyridino-[2,3-d]triazolino[4,5-a]pyrimidin-5-one derivatives,” Molecules, vol. 8, no. 3, pp. 333–341, 2003.
View at: Publisher Site | Google Scholar
Y. N. Mabkhot, A. M. Al-Majid, and A. S. Alamary, “Synthesis and chemical characterisation of some new diheteroaryl thienothiophene derivatives,” Molecules, vol. 16, no. 9, pp. 7706–7714, 2011.
View at: Publisher Site | Google Scholar
K. M. Dawood, A. M. Farag, and Z. E. Kanddeel, “Heterocyclic synthesis via enaminonitriles: one-pot synthesis of some new pyrazole, isoxazole, pyrimidine, pyrazolo [1,5-a]pyrimidine, pyrimido[1,2-a]benzimidazole and pyrido[1,2-a]benzimidazole derivatives,” Journal of Chemical Research, Synopses, no. 2, pp. 88–89, 1999.
View at: Publisher Site | Google Scholar
L. U. E. Ping and J. V. Greenhill, “Enaminones in heterocyclic synthesis,” Advances in Heterocyclic Chemistry, no. 67, pp. 207–343, 1997.
View at: Google Scholar
P. G. Baraldi, A. Barco, S. Benetti, G. P. Pollini, and D. Simoni, “Synthesis of natural products via isoxazoles,” Synthesis, no. 10, pp. 857–869, 1987.
View at: Google Scholar
K. Saito, A. Nakao, T. Shinozuka et al., “Discovery and structure-activity relationship of thienopyridine derivatives as bone anabolic agents,” Bioorganic and Medicinal Chemistry, vol. 21, no. 7, pp. 1628–1642, 2013.
View at: Publisher Site | Google Scholar
L. C. S. Pinheiro, J. C. Borges, C. D. Oliveira et al., “Synthesis of new 4-(phenylamino)thieno[2,3-b]pyridines and derivatives of the novel benzo[b]thieno[3,2-h][1,6]naphthyridine tetracyclic system,” Arkivoc, vol. 2008, no. 14, pp. 77–87, 2008.
View at: Publisher Site | Google Scholar
A. M. R. Bernardino, L. C. D. S. Pinheiro, C. R. Rodrigues et al., “Design, synthesis, SAR, and biological evaluation of new 4-(phenylamino)thieno[2,3-b]pyridine derivatives,” Bioorganic and Medicinal Chemistry, vol. 14, no. 16, pp. 5765–5770, 2006.
View at: Publisher Site | Google Scholar
S. A. Al-Trawneh, M. M. El-Abadelah, J. A. Zahra et al., “Synthesis and biological evaluation of tetracyclic thienopyridones as antibacterial and antitumor agents,” Bioorganic and Medicinal Chemistry, vol. 19, no. 8, pp. 2541–2548, 2011.
View at: Publisher Site | Google Scholar
J.-P. Wu, R. Fleck, J. Brickwood et al., “The discovery of thienopyridine analogues as potent IκB kinase β inhibitors. Part II,” Bioorganic & Medicinal Chemistry Letters, vol. 19, no. 19, pp. 5547–5551, 2009.
View at: Publisher Site | Google Scholar
J. W. Lockman, M. D. Reeder, K. Suzuki et al., “Inhibition of eEF2-K by thieno[2,3-b]pyridine analogues,” Bioorganic and Medicinal Chemistry Letters, vol. 20, no. 7, pp. 2283–2286, 2010.
View at: Publisher Site | Google Scholar
M. E. Schnute, D. J. Anderson, R. J. Brideau et al., “2-Aryl-2-hydroxyethylamine substituted 4-oxo-4,7-dihydrothieno[2,3-b]pyridines as broad-spectrum inhibitors of human herpesvirus polymerases,” Bioorganic and Medicinal Chemistry Letters, vol. 17, no. 12, pp. 3349–3353, 2007.
View at: Publisher Site | Google Scholar
H. Liu, Y. Li, X.-Y. Wang et al., “Synthesis, preliminary structure-activity relationships, and in vitro biological evaluation of 6-aryl-3-amino-thieno[2,3-b]pyridine derivatives as potential anti-inflammatory agents,” Bioorganic and Medicinal Chemistry Letters, vol. 23, no. 8, pp. 2349–2352, 2013.
View at: Publisher Site | Google Scholar
I. Adachi, T. Yamamori, Y. Hiramatsu et al., “Studies on dihydropyridines. III. Synthesis of 4,7-dihydrothieno[2,3-b]-pyridines with vasodilator and antihypertensive activities,” Chemical and Pharmaceutical Bulletin, vol. 36, no. 11, pp. 4389–4402, 1988.
View at: Publisher Site | Google Scholar
M. M. El-Abadelah, S. S. Sabri, H. A. Al-Ashqar, P. Mion, J. Bompart, and M. Calas, “Thienopyridinone antibacterials. Part II.¹ Synthesis and antibacterial activity of some 2-chloro-7-cyclopropyl-4,7-dihydro-4-oxothieno [2,3-b]pyridine-5-carboxylic acids,” Phosphorus, Sulfur, and Silicon and the Related Elements, vol. 134, no. 1, pp. 21–29, 1998.
View at: Publisher Site | Google Scholar
E. R. Bacon and S. J. Daun, “Synthesis of 7-ethyl-4,7-dihydro-4-oxo-2-(4-pyridinyl)thieno[2,3-b]pyridine-5-carboxylic acid,” Journal of Heterocyclic Chemistry, vol. 28, no. 8, pp. 1953–1955, 1991.
View at: Publisher Site | Google Scholar
Y. N. Mabkhoot, “Synthesis and analysis of some bis-heterocyclic compounds containing sulphur,” Molecules, vol. 14, no. 5, pp. 1904–1914, 2009.
View at: Publisher Site | Google Scholar
Y. N. Mabkhoot, “Synthesis and chemical characterisation of new bis-thieno [2,3-b]thiophene derivatives,” Molecules, vol. 15, no. 5, pp. 3329–3337, 2010.
View at: Publisher Site | Google Scholar
Y. N. Mabkhot, N. A. E. Kheder, and A. M. Al-Majid, “Facile and convenient synthesis of new thieno[2,3-b]-thiophene derivatives,” Molecules, vol. 15, no. 12, pp. 9418–9426, 2010.
View at: Publisher Site | Google Scholar
Y. N. Mabkhot, F. D. Aldawsari, S. S. Al-Showiman et al., “Synthesis, bioactivity, molecular docking and POM analyses of novel substituted thieno[2,3-b]thiophenes and related congeners,” Molecules, vol. 20, no. 2, pp. 1824–1841, 2015.
View at: Publisher Site | Google Scholar
Y. N. Mabkhot, N. N. E. El-sayed, F. Alatibi, A. Barakat, H. A. Ghabbour, and H.-K. Fun, “Synthesis, characterization and X-ray crystal structure of 3-methyl-4-oxo-7-phenyl-4,7-dihydrothieno[2,3-b]pyridine-2-carboxyxlic acid ethyl ester,” Asian Journal of Chemistry, vol. 26, no. 24, pp. 8596–8598, 2014.
View at: Publisher Site | Google Scholar
G. M. Sheldrick, “A short history of SHELX,” Acta Crystallographica Section A, vol. 64, no. 1, pp. 112–122, 2008.
View at: Publisher Site | Google Scholar
Brucker, APEX2, SAINT and SADABS, Bruker, Madison, Wis, USA, 2009.

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Copyright © 2015 Yahia Nasser Mabkhot et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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