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

Authors: Yahia Nasser Mabkhot; Salah S. Aladdi; S. S. Al-Showiman; A. M. A. Al-Majid; Assem Barakat; Hazem A. Ghabbour; Mohamed R. Shaaban
Journal: Journal of Chemistry
 (2015)

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## 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, and8), 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.


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## Body

## 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 enaminone3 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 (δ) 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 (νmax): 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); MSm/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)diethanone2 (1.37 g, 0.5 mmol) and DMF-DMA (1.19 mL, 0.01 mol) was refluxed inm-xylene (15 mL) for 3 h. After cooling, the resulting solid product was collected by filtration to give the desired product3 used for the next step without any further purification.Yellow crystal; Yield: 63%; m.p. 235°C; IR (νmax): 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, CHa′) 5.39 (d, 1H, CHb′), 6.14 (d, 1H, CHa) 6.16 (d, 1H, CHb), 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 (-CHb′), 126.35, 128.58, 130.55 (Ph), 142.35 (-C-CH3), 115.14 (-CHa), 154.45 (-CHb), 154.54 (=CNS), 176.49, 180.51 (C=O); MSm/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 Compounds4a,b

Compounds4a,bwere prepared using the following general procedure.Compound3 (0.131 g, 0.5 mmol) was added to hydrazine hydrate (2 mL, 63 mmol) or phenylhydrazine (1 mL, 10 mmol) (to make compounds4a,b, resp.). The mixture of compound3 and the appropriate hydrazine was refluxed until compound3 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 (νmax): 1616 (C=N), 1637 (C=O), 3477 (NH); MSm/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 (νmax): 1602 (C=N), 1640 (C=O); 1H-NMR (DMSO-d6): δ, 2.29 (s, 3H, CH3), 6.14–6.16 (d, 1H, CHa), 6.72–6.74 (d, 1H, CHa′), 7.63–7.65 (d, 1H, CHb′), 7.67–7.78 (d, 1H, CHb), 7.61–7.69 (m, 5H, C6H5); 13C-NMR: δ, 15.09 (CH3), 113.23 (CHa), 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 (CHb), 175.74 (C=O); MSm/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 of3 (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 (νmax): 1618 (C=N), 1634 (C=O); MSm/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 Compounds6a–c

Compounds6a–cwere prepared using the following general procedure.Compound3 (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 compounds6a–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 (νmax): 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, CHa′), 5.83–5.91 (d, 1H, CHa), 7.02–7.00 (m, 1H, CHb′), 7.08–7.20 (d, 1H, CHb), 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 (CHa′), 137.45 (=CCO), 141.62 (S-CCO), 142.31 (-C-CH3), 143.28 (Ar-C-N), 153.19 (CHb), 155.15 (CHb′), 155.74 (CHa), 176.48 (C=O); MSm/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 (νmax): 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, CHa′), 6.17–6.20 (d, 1H, CHa), 7.64–7.43 (d, 1H, CHb′), 9.90–7.80 (d, 1H, CHb), 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 (CHa), 126.36, 129.18, 130.13 (Ar-C), 131.06 (CHa′), 136.05 (=CCO), 139.77(-C-CH3), 142.57 (CHb), 151.40 (CHb′), 175.74 (C=O); MSm/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 (νmax): 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, CHa), 6.19 (d, 1H, CHa′), 6.20 (d, 1H, CHb), 6.20 (d, 1H, CHb′), 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 (CHa), 126.36, 129.18, 130.13 (Ar-C), 131.06 (CHa′), 136.05 (=CCO), 139.77(-C-CH3), 142.57 (CHb), 151.40 (CHb′), 175.74 (C=O); MSm/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 Compounds7a–c

Compounds7a–cwere prepared using the following general procedure.Compound3 (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), orp-toluidine (0.05 g, 0.5 mmol) (to make compounds6a–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 (νmax): 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, CHa′), 6.55–6.57 (d, 1H, CHa), 6.97 (d, 1H, CHa), 6.97–6.99 (t, 1H, CHb′), 7.01–7.03 (t, 1H, CHb), 7.78–7.82 (m, 4H, C6H4); 13C-NMR: δ 115.70, 119.21, 129.03 (Ar-C), 148.25 (Ar-C-N); MSm/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 (νmax): 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, CHa′), 6.62–6.65 (d, 1H, CHa), 6.95–6.98 (t, 1H, CHb′), 7.69–7.82 (t, 1H, CHb), 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). MSm/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 (νmax): 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, CHa′), 4.29–4.31 (d, 1H, CHa), 6.90 (t, 1H, CHb′), 7.00–7.05 (t, 1H, CHb), 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 (Cha), 129.77 (Chb), 143.23 (SCCO), 143.23 (Ar-C-N), 159.92 (S-C-N); MSm/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 of3 (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 (νmax): 1588 (C=N), 1628 (C=O); 1H-NMR (DMSO-d6): δ 2.75 (s, 3H, CH3), 5.48–5.51 (d, 1H, CHa′), 6.24–6.26 (d, 1H, CHa), 7.10–7.27 (t, 1H, CHb′), 7.87–8.02 (t, 1H, CHb),7.71–7.79 (m, 9H, C6H5). 13C-NMR: δ, 15.47 (CH3), 114.83 (CHa), 121.17, 125.80, 126.16, 130.19, 130.58, 140.62, 142.50 (Ar-C), 125.80 (CHa′), 126.16 (CHb), 130.68 (S-C=CH3), 162.50 (N-C=N(pyrazole)), 162.21 (CHb′), 162.50 (N-C=CCH3), 176.50 (S-C-N), 189.64 (C=O). MSm/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 of3 (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 (νmax): 1594 (C=C), 1610–1630 (3C=O). 1H-NMR (DMSO-d6): δ 3.12 (s, 3H, CH3), 5.36–5.39 (d, 1H, CHa′), 6.15–6.17 (d, 1H, CHa), 7.66–7.68 (t, 1H, CHb′), 7.70-7.80 (t, 1H, CHb), 7.66–7.68 (m, 5H, C6H5); 13C-NMR: δ, 16.11 (CH3), 115.13 (CHa), 126.33 (CH,a′), 128.58, 130.54, 130.95, 132.60, 137.24 (Ar-C), 141.03 (S-CCO), 142.34 (-C-CH3), 153.16 (CHb′), 154.52 (S-C-N), 176.51 (COO), 180.51 (C=O); MSm/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.


## 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 (δ) 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 (νmax): 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); MSm/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)diethanone2 (1.37 g, 0.5 mmol) and DMF-DMA (1.19 mL, 0.01 mol) was refluxed inm-xylene (15 mL) for 3 h. After cooling, the resulting solid product was collected by filtration to give the desired product3 used for the next step without any further purification.Yellow crystal; Yield: 63%; m.p. 235°C; IR (νmax): 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, CHa′) 5.39 (d, 1H, CHb′), 6.14 (d, 1H, CHa) 6.16 (d, 1H, CHb), 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 (-CHb′), 126.35, 128.58, 130.55 (Ph), 142.35 (-C-CH3), 115.14 (-CHa), 154.45 (-CHb), 154.54 (=CNS), 176.49, 180.51 (C=O); MSm/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 Compounds4a,b

Compounds4a,bwere prepared using the following general procedure.Compound3 (0.131 g, 0.5 mmol) was added to hydrazine hydrate (2 mL, 63 mmol) or phenylhydrazine (1 mL, 10 mmol) (to make compounds4a,b, resp.). The mixture of compound3 and the appropriate hydrazine was refluxed until compound3 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 (νmax): 1616 (C=N), 1637 (C=O), 3477 (NH); MSm/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 (νmax): 1602 (C=N), 1640 (C=O); 1H-NMR (DMSO-d6): δ, 2.29 (s, 3H, CH3), 6.14–6.16 (d, 1H, CHa), 6.72–6.74 (d, 1H, CHa′), 7.63–7.65 (d, 1H, CHb′), 7.67–7.78 (d, 1H, CHb), 7.61–7.69 (m, 5H, C6H5); 13C-NMR: δ, 15.09 (CH3), 113.23 (CHa), 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 (CHb), 175.74 (C=O); MSm/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 of3 (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 (νmax): 1618 (C=N), 1634 (C=O); MSm/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 Compounds6a–c

Compounds6a–cwere prepared using the following general procedure.Compound3 (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 compounds6a–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 (νmax): 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, CHa′), 5.83–5.91 (d, 1H, CHa), 7.02–7.00 (m, 1H, CHb′), 7.08–7.20 (d, 1H, CHb), 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 (CHa′), 137.45 (=CCO), 141.62 (S-CCO), 142.31 (-C-CH3), 143.28 (Ar-C-N), 153.19 (CHb), 155.15 (CHb′), 155.74 (CHa), 176.48 (C=O); MSm/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 (νmax): 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, CHa′), 6.17–6.20 (d, 1H, CHa), 7.64–7.43 (d, 1H, CHb′), 9.90–7.80 (d, 1H, CHb), 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 (CHa), 126.36, 129.18, 130.13 (Ar-C), 131.06 (CHa′), 136.05 (=CCO), 139.77(-C-CH3), 142.57 (CHb), 151.40 (CHb′), 175.74 (C=O); MSm/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 (νmax): 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, CHa), 6.19 (d, 1H, CHa′), 6.20 (d, 1H, CHb), 6.20 (d, 1H, CHb′), 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 (CHa), 126.36, 129.18, 130.13 (Ar-C), 131.06 (CHa′), 136.05 (=CCO), 139.77(-C-CH3), 142.57 (CHb), 151.40 (CHb′), 175.74 (C=O); MSm/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 Compounds7a–c

Compounds7a–cwere prepared using the following general procedure.Compound3 (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), orp-toluidine (0.05 g, 0.5 mmol) (to make compounds6a–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 (νmax): 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, CHa′), 6.55–6.57 (d, 1H, CHa), 6.97 (d, 1H, CHa), 6.97–6.99 (t, 1H, CHb′), 7.01–7.03 (t, 1H, CHb), 7.78–7.82 (m, 4H, C6H4); 13C-NMR: δ 115.70, 119.21, 129.03 (Ar-C), 148.25 (Ar-C-N); MSm/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 (νmax): 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, CHa′), 6.62–6.65 (d, 1H, CHa), 6.95–6.98 (t, 1H, CHb′), 7.69–7.82 (t, 1H, CHb), 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). MSm/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 (νmax): 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, CHa′), 4.29–4.31 (d, 1H, CHa), 6.90 (t, 1H, CHb′), 7.00–7.05 (t, 1H, CHb), 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 (Cha), 129.77 (Chb), 143.23 (SCCO), 143.23 (Ar-C-N), 159.92 (S-C-N); MSm/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 of3 (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 (νmax): 1588 (C=N), 1628 (C=O); 1H-NMR (DMSO-d6): δ 2.75 (s, 3H, CH3), 5.48–5.51 (d, 1H, CHa′), 6.24–6.26 (d, 1H, CHa), 7.10–7.27 (t, 1H, CHb′), 7.87–8.02 (t, 1H, CHb),7.71–7.79 (m, 9H, C6H5). 13C-NMR: δ, 15.47 (CH3), 114.83 (CHa), 121.17, 125.80, 126.16, 130.19, 130.58, 140.62, 142.50 (Ar-C), 125.80 (CHa′), 126.16 (CHb), 130.68 (S-C=CH3), 162.50 (N-C=N(pyrazole)), 162.21 (CHb′), 162.50 (N-C=CCH3), 176.50 (S-C-N), 189.64 (C=O). MSm/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 of3 (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 (νmax): 1594 (C=C), 1610–1630 (3C=O). 1H-NMR (DMSO-d6): δ 3.12 (s, 3H, CH3), 5.36–5.39 (d, 1H, CHa′), 6.15–6.17 (d, 1H, CHa), 7.66–7.68 (t, 1H, CHb′), 7.70-7.80 (t, 1H, CHb), 7.66–7.68 (m, 5H, C6H5); 13C-NMR: δ, 16.11 (CH3), 115.13 (CHa), 126.33 (CH,a′), 128.58, 130.54, 130.95, 132.60, 137.24 (Ar-C), 141.03 (S-CCO), 142.34 (-C-CH3), 153.16 (CHb′), 154.52 (S-C-N), 176.51 (COO), 180.51 (C=O); MSm/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 compounds4a,b,5,6a–c,7a–c,8, and9 were synthesized as shown in Schemes 2 and 3 starting from the new enaminone3 (Scheme 1). The new synthesized molecules1–9 were characterized by CHN analyses, NMR, and MS spectral data.Scheme 1
Synthesis of compound3.Scheme 2
Synthesis of compounds4a,b and5.Scheme 3
Synthesis of compounds6–9.The starting intermediate2 needed for this research proposal was synthesized by reported method by Mabkhot et al. [22]. The new enaminone3 was synthesizedvia the reaction of acetyl thiophene2 with DMF-DMA in xylene as solvent as shown in Scheme 1. The final product3 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 product3 as depicted in Scheme 1.The IR spectrum of the new enaminone3 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 enaminone3 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 (J=11.6 Hz) and 5.39 (J=11.6 Hz) were observed. On the other hand, two doublets for the CH=CH protons at 6.14 (J=8.0 Hz) and 6.16 (J=8.0 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 (-CHb′), 126.35, 128.58, 130.55 (Ph), 142.35 (-C-CH3), 115.14 (-CHa), 154.45 (-CHb), 154.54 (=CNS), and 176.49, 180.51 (2C=O). The GC-MS showed the molecular ion [M]+ atm/z 325 corresponding to the molecular formula C18H17N2O2S.


### 3.1. X-Ray Crystal Structure of2

The compound, C15H15NO2S, CCDC: 141975, crystallizes in triclinic, P-1 system with the following unit cell a = 10.3859 (3) Å, b = 13.8790 (6) Å, c = 18.8006 (6) Å, α = 86.920 (1)°, β = 82.081 (1)°, and γ = 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 linkedvia 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].Table 1
Crystal data
C15H15NO2S
γ = 79.233 (1)°
M
r = 273.35
V = 2635.84 (16) Å3
Triclinic,P-1
Z = 8
a = 10.3859 (3) Å
MoKα radiation
b = 13.8790 (6) Å
µ = 0.24 mm−1
c = 18.8006 (6) Å
T = 100 K
α = 86.920 (1)°
0.59 × 0.23 × 0.20 mm
β = 82.081 (1)°
Data collection
Bruker APEX-II D8 venture diffractometer
R
i
n
t = 0.069
66528 measured reflections
θ
m
a
x = 30.0°
15378 independent reflections
Standard reflections: 0
9027 reflections withI>2σ(I)
Refinement
R
F
2
>
2
σ
F
2
=
0.069
0 restraints
w
R
F
2
=
0.203
H atoms treated by a mixture of independent and constrained refinement
S = 1.09
Δ
ρ
m
a
x = 1.45 e Å-3
15378 reflections
Δ
ρ
m
i
n = −0.43 e Å-3
713 parametersTable 2
Bond lengths and bond angles of compound2 (Å, °).
S1A–C3A
1.749 (3)
O1C–C2C
1.226 (3)
S1A–C6A
1.724 (2)
O2C–C8C
1.237 (3)
S1B–C6B
1.720 (2)
O1D–C2D
1.228 (3)
S1B–C3B
1.751 (3)
O2D–C8D
1.234 (3)
S1C–C6C
1.722 (2)
N1A–C10A
1.422 (3)
S1C–C3C
1.749 (3)
N1A–C6A
1.349 (3)
S1D–C6D
1.721 (2)
N1B–C10B
1.419 (3)
S1D–C3D
1.752 (3)
N1B–C6B
1.346 (3)
O1A–C2A
1.229 (3)
N1C–C6C
1.351 (3)
O2A–C8A
1.235 (3)
N1C–C10C
1.420 (3)
O1B–C2B
1.228 (3)
N1D–C10D
1.420 (3)
O2B–C8B
1.235 (3)
N1D–C6D
1.348 (3)
C3A–S1A–C6A
91.88 (11)
O2B–C8B–C5B
120.7 (2)
C3B–S1B–C6B
91.85 (12)
O2B–C8B–C9B
118.5 (2)
C3C–S1C–C6C
91.81 (12)
N1B–C10B–C15B
118.1 (3)
C3D–S1D–C6D
91.82 (12)
N1B–C10B–C11B
121.2 (3)
C6A–N1A–C10A
123.7 (2)
O1C–C2C–C3C
122.8 (2)
C6B–N1B–C10B
125.1 (2)
O1C–C2C–C1C
120.1 (2)
C6C–N1C–C10C
124.6 (2)
S1C–C3C–C4C
111.79 (18)
C6D–N1D–C10D
123.6 (2)
S1C–C3C–C2C
117.51 (17)
O1A–C2A–C1A
120.6 (2)
S1C–C6C–C5C
112.18 (18)
O1A–C2A–C3A
122.4 (2)
S1C–C6C–N1C
121.02 (18)
S1A–C3A–C2A
117.20 (18)
N1C–C6C–C5C
126.8 (2)
S1A–C3A–C4A
111.67 (18)
O2C–C8C–C9C
118.3 (3)
S1A–C6A–C5A
112.22 (18)
O2C–C8C–C5C
120.7 (2)
N1A–C6A–C5A
127.6 (2)
N1C–C10C–C15C
118.0 (2)
S1A–C6A–N1A
120.15 (18)
N1C–C10C–C11C
121.0 (2)
O2A–C8A–C9A
117.7 (2)
O1D–C2D–C1D
120.6 (2)
O2A–C8A–C5A
120.2 (2)
O1D–C2D–C3D
122.5 (2)
N1A–C10A–C11A
120.3 (2)
S1D–C3D–C2D
117.06 (18)
N1A–C10A–C15A
120.6 (2)
S1D–C3D–C4D
111.96 (18)
O1B–C2B–C3B
122.6 (2)
N1D–C6D–C5D
127.3 (2)
O1B–C2B–C1B
120.4 (2)
S1D–C6D–C5D
112.21 (18)
S1B–C3B–C4B
111.87 (18)
S1D–C6D–N1D
120.51 (18)
S1B–C3B–C2B
117.38 (17)
O2D–C8D–C5D
120.0 (2)
N1B–C6B–C5B
126.5 (2)
O2D–C8D–C9D
117.7 (3)
S1B–C6B–C5B
112.20 (18)
N1D–C10D–C11D
120.9 (2)
S1B–C6B–N1B
121.26 (19)
N1D–C10D–C15D
120.4 (2)Table 3
Hydrogen-bond geometry for compound2 (Å, °).
D–H⋯A
D–H
H⋯A
D⋯A
D–H⋯A
N1D–H1ND⋯O2C
0.81 (3)
2.37 (3)
3.069 (3)
145 (3)
N1A–H1NA⋯O2B
0.78 (3)
2.37 (3)
3.057 (3)
149 (3)
N1C–H1NC⋯O2C
0.85 (4)
1.98 (3)
2.651 (3)
135 (3)
N1C–H1NC⋯O2D
0.85 (4)
2.31 (4)
2.968 (3)
135 (3)
N1B–H1NB⋯O2A
0.80 (3)
2.36 (3)
2.987 (3)
136 (3)
N1B–H1NB⋯O2B
0.80 (3)
2.04 (3)
2.647 (3)
133 (3)
C1A–H1AA⋯O1Bi
0.980
2.590
3.512 (4)
156.00
C7A–H7AA⋯O1A
0.980
2.230
2.985 (4)
133.00
C7B–H7BA⋯O1B
0.980
2.210
2.974 (4)
134.00
C13A–H13A⋯O1Dii
0.950
2.550
3.329 (3)
140.00
C13B–H13B⋯O1Ciii
0.950
2.470
3.340 (3)
153.00
C13D–H13D⋯O1B
0.950
2.490
3.291 (3)
141.00
C1C–H1CA⋯O1Civ
0.980
2.490
3.427 (4)
159.00
C7C–H7CA⋯O1C
0.980
2.20
2.970 (4)
135.00
C7C–H7CB⋯O1Dv
0.980
2.560
3.408 (4)
145.00
C7D–H7DA⋯O1D
0.980
2.230
2.992 (4)
134.00
Symmetry codes: (i)x+1, y+1, z; (ii) -x+2, -y, -z+1; (iii) -x, -y+1, -z+2; (iv) −x-1, -y+1, -z+1; (v) -x+1, -y, -z+1.Figure 1
ORTEP of the synthesized compound2.Figure 2
Molecular packing of the synthesized compound2.Having the new enaminone3 available in our hands encourage us to use it for the synthesis of the thieno-fused bicyclic compounds. Compounds4a,b were synthesized by refluxing a mixture of enaminone3 andN-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, enaminone3 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, compounds6a–c,7a–c, and8 were synthesized by refluxing a mixture of3 and aliphatic diamines, aromatic amines, and 2-aminobenzimidazole, respectively (Scheme 3).Interestingly, enaminone3 treated withp-chlorobenzoic acid to afford the corresponding ester9. 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 (J=12.0 Hz) and 5.36 (J=12.0 Hz) and the pyridinone CH protons at δ 6.15 (J=8.0 Hz) and 6.16 (J=8.0 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 (CHa), 126.33 (CH,a′), 128.58, 130.54, 130.95, 132.60, 137.24 (Ar-C), 141.03 (S-CCO), 142.34 (-C-CH3), 153.16 (CHb′), 154.52 (S-C-N), 176.51 (COO), and 180.51 (C=O). GC-MS exhibited the correct molecular ion peak [M]+ atm/z = 449 corresponding to the molecular formula C24H14ClNO4S.


## 3.1. X-Ray Crystal Structure of2

The compound, C15H15NO2S, CCDC: 141975, crystallizes in triclinic, P-1 system with the following unit cell a = 10.3859 (3) Å, b = 13.8790 (6) Å, c = 18.8006 (6) Å, α = 86.920 (1)°, β = 82.081 (1)°, and γ = 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 linkedvia 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].Table 1
Crystal data
C15H15NO2S
γ = 79.233 (1)°
M
r = 273.35
V = 2635.84 (16) Å3
Triclinic,P-1
Z = 8
a = 10.3859 (3) Å
MoKα radiation
b = 13.8790 (6) Å
µ = 0.24 mm−1
c = 18.8006 (6) Å
T = 100 K
α = 86.920 (1)°
0.59 × 0.23 × 0.20 mm
β = 82.081 (1)°
Data collection
Bruker APEX-II D8 venture diffractometer
R
i
n
t = 0.069
66528 measured reflections
θ
m
a
x = 30.0°
15378 independent reflections
Standard reflections: 0
9027 reflections withI>2σ(I)
Refinement
R
F
2
>
2
σ
F
2
=
0.069
0 restraints
w
R
F
2
=
0.203
H atoms treated by a mixture of independent and constrained refinement
S = 1.09
Δ
ρ
m
a
x = 1.45 e Å-3
15378 reflections
Δ
ρ
m
i
n = −0.43 e Å-3
713 parametersTable 2
Bond lengths and bond angles of compound2 (Å, °).
S1A–C3A
1.749 (3)
O1C–C2C
1.226 (3)
S1A–C6A
1.724 (2)
O2C–C8C
1.237 (3)
S1B–C6B
1.720 (2)
O1D–C2D
1.228 (3)
S1B–C3B
1.751 (3)
O2D–C8D
1.234 (3)
S1C–C6C
1.722 (2)
N1A–C10A
1.422 (3)
S1C–C3C
1.749 (3)
N1A–C6A
1.349 (3)
S1D–C6D
1.721 (2)
N1B–C10B
1.419 (3)
S1D–C3D
1.752 (3)
N1B–C6B
1.346 (3)
O1A–C2A
1.229 (3)
N1C–C6C
1.351 (3)
O2A–C8A
1.235 (3)
N1C–C10C
1.420 (3)
O1B–C2B
1.228 (3)
N1D–C10D
1.420 (3)
O2B–C8B
1.235 (3)
N1D–C6D
1.348 (3)
C3A–S1A–C6A
91.88 (11)
O2B–C8B–C5B
120.7 (2)
C3B–S1B–C6B
91.85 (12)
O2B–C8B–C9B
118.5 (2)
C3C–S1C–C6C
91.81 (12)
N1B–C10B–C15B
118.1 (3)
C3D–S1D–C6D
91.82 (12)
N1B–C10B–C11B
121.2 (3)
C6A–N1A–C10A
123.7 (2)
O1C–C2C–C3C
122.8 (2)
C6B–N1B–C10B
125.1 (2)
O1C–C2C–C1C
120.1 (2)
C6C–N1C–C10C
124.6 (2)
S1C–C3C–C4C
111.79 (18)
C6D–N1D–C10D
123.6 (2)
S1C–C3C–C2C
117.51 (17)
O1A–C2A–C1A
120.6 (2)
S1C–C6C–C5C
112.18 (18)
O1A–C2A–C3A
122.4 (2)
S1C–C6C–N1C
121.02 (18)
S1A–C3A–C2A
117.20 (18)
N1C–C6C–C5C
126.8 (2)
S1A–C3A–C4A
111.67 (18)
O2C–C8C–C9C
118.3 (3)
S1A–C6A–C5A
112.22 (18)
O2C–C8C–C5C
120.7 (2)
N1A–C6A–C5A
127.6 (2)
N1C–C10C–C15C
118.0 (2)
S1A–C6A–N1A
120.15 (18)
N1C–C10C–C11C
121.0 (2)
O2A–C8A–C9A
117.7 (2)
O1D–C2D–C1D
120.6 (2)
O2A–C8A–C5A
120.2 (2)
O1D–C2D–C3D
122.5 (2)
N1A–C10A–C11A
120.3 (2)
S1D–C3D–C2D
117.06 (18)
N1A–C10A–C15A
120.6 (2)
S1D–C3D–C4D
111.96 (18)
O1B–C2B–C3B
122.6 (2)
N1D–C6D–C5D
127.3 (2)
O1B–C2B–C1B
120.4 (2)
S1D–C6D–C5D
112.21 (18)
S1B–C3B–C4B
111.87 (18)
S1D–C6D–N1D
120.51 (18)
S1B–C3B–C2B
117.38 (17)
O2D–C8D–C5D
120.0 (2)
N1B–C6B–C5B
126.5 (2)
O2D–C8D–C9D
117.7 (3)
S1B–C6B–C5B
112.20 (18)
N1D–C10D–C11D
120.9 (2)
S1B–C6B–N1B
121.26 (19)
N1D–C10D–C15D
120.4 (2)Table 3
Hydrogen-bond geometry for compound2 (Å, °).
D–H⋯A
D–H
H⋯A
D⋯A
D–H⋯A
N1D–H1ND⋯O2C
0.81 (3)
2.37 (3)
3.069 (3)
145 (3)
N1A–H1NA⋯O2B
0.78 (3)
2.37 (3)
3.057 (3)
149 (3)
N1C–H1NC⋯O2C
0.85 (4)
1.98 (3)
2.651 (3)
135 (3)
N1C–H1NC⋯O2D
0.85 (4)
2.31 (4)
2.968 (3)
135 (3)
N1B–H1NB⋯O2A
0.80 (3)
2.36 (3)
2.987 (3)
136 (3)
N1B–H1NB⋯O2B
0.80 (3)
2.04 (3)
2.647 (3)
133 (3)
C1A–H1AA⋯O1Bi
0.980
2.590
3.512 (4)
156.00
C7A–H7AA⋯O1A
0.980
2.230
2.985 (4)
133.00
C7B–H7BA⋯O1B
0.980
2.210
2.974 (4)
134.00
C13A–H13A⋯O1Dii
0.950
2.550
3.329 (3)
140.00
C13B–H13B⋯O1Ciii
0.950
2.470
3.340 (3)
153.00
C13D–H13D⋯O1B
0.950
2.490
3.291 (3)
141.00
C1C–H1CA⋯O1Civ
0.980
2.490
3.427 (4)
159.00
C7C–H7CA⋯O1C
0.980
2.20
2.970 (4)
135.00
C7C–H7CB⋯O1Dv
0.980
2.560
3.408 (4)
145.00
C7D–H7DA⋯O1D
0.980
2.230
2.992 (4)
134.00
Symmetry codes: (i)x+1, y+1, z; (ii) -x+2, -y, -z+1; (iii) -x, -y+1, -z+2; (iv) −x-1, -y+1, -z+1; (v) -x+1, -y, -z+1.Figure 1
ORTEP of the synthesized compound2.Figure 2
Molecular packing of the synthesized compound2.Having the new enaminone3 available in our hands encourage us to use it for the synthesis of the thieno-fused bicyclic compounds. Compounds4a,b were synthesized by refluxing a mixture of enaminone3 andN-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, enaminone3 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, compounds6a–c,7a–c, and8 were synthesized by refluxing a mixture of3 and aliphatic diamines, aromatic amines, and 2-aminobenzimidazole, respectively (Scheme 3).Interestingly, enaminone3 treated withp-chlorobenzoic acid to afford the corresponding ester9. 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 (J=12.0 Hz) and 5.36 (J=12.0 Hz) and the pyridinone CH protons at δ 6.15 (J=8.0 Hz) and 6.16 (J=8.0 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 (CHa), 126.33 (CH,a′), 128.58, 130.54, 130.95, 132.60, 137.24 (Ar-C), 141.03 (S-CCO), 142.34 (-C-CH3), 153.16 (CHb′), 154.52 (S-C-N), 176.51 (COO), and 180.51 (C=O). GC-MS exhibited the correct molecular ion peak [M]+ atm/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.



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*Source: 382381-2015-11-25.xml*