HETEROCYCLES

Short Paper | Regular issue | Vol. 91, No. 7, 2015, pp. 1455-1464
Received, 27th April, 2015, Accepted, 26th May, 2015, Published online, 8th June, 2015.
DOI: 10.3987/COM-15-13236

■ An Efficient Synthetic Route towards Novel 3N-Substituted Thieno[2,3-d]pyrimidin-4(3H)-ones

Monaem Balti,* Maha Hachicha, and Mohamed Lotfi El Efrit

Department of Chemistry, Faculty of Sciences of Tunis-Tunisia, El Manar-B.P. 94 Poste Romena, 1068, Tunisia

Abstract

During the last few years, condensed thienopyrimidine derivatives have received considerable attention. Herewith it has been reported the synthesis of some novel 3N-substituted thieno[2,3-d]pyrimidin-4(3H)-ones appended to different bio-potent moieties hopping to obtain new derivatives with dual biological activities.

Heterocycles containing the thienopyrimidine moiety (Figure 1) are of interest because of their interesting pharmacological and biological activities.1-6 Thus, over the last two decades many thienopyrimidines have been found to exhibit a variety of pronounced activities, for example, as antiinflammatory,3,7 antimicrobial,3,8 antiviral9 and analgesic7,10 agents. Some thienopyrimidine derivatives showed good antitumor activity,11 while compounds with the general structure designated by C (Figure 1) showed potent and specific cytotoxicity against several leukemia cell lines.4 Motivated by the aforementioned biological and pharmacological importance of the title compounds, and as continuation with our previous work on the synthesis of novel heterocyclic systems,12,13 we report herein the synthesis of some new heterocycles incorporating a thienopyrimidine moiety.

The routes to thieno[2,3-d]pyrimidin-4(3H)-ones mainly involve cyclocondensation of 2-amino-thiophenes with various electrophilic reagents such as α-substituted acetonitriles,14 formic acid,15 formamide,15 urea16 and guanidine.17 In this paper we wish to report the cyclocondensation of 2-aminothiophene-3-carboxylates with orthoester in combination with ethanolamine. The synthetic pathway was planned in such a way to synthesize the thieno[2,3-d]pyrimidin-4(3H)-one ring, in addition the 3-substituent was selected to incorporate well documented pharmacophoric moieties of interest such triazole, imidazole and indole. The target compounds were prepared as outlined in Scheme 1.

The starting materials 2-aminothiophene-3-carboxylate 1a,b derivatives were prepared following the method of Gewald18 via the reaction of cyclohexanone and sulfur with either ethyl cyanoacetate in the presence of diethylamine.
Initially condensation of 1a,b with orthoester in the presence of acetic acid under reflux gave product 2a,b which was further refluxed with ethanolamine to gave 3a,b through ring cyclization.
Compounds 3a,b upon reaction with methanesulphonyl chloride in the presence of pyridine gave the mesylate 4a,b. Finally the title compounds 5a-l were obtained by reacting mesylate 4a,b with various secondary amines and hydroxyl substituted heterocycles (Scheme 1) under mild basic condition. All the newly synthesized compounds were characterized by IR, 1H and 13C-NMR and mass spectra. In case of IR studies, all the compounds have shown a sharp intense band at 1664-1690 cm-1 which corresponds to carbonyl group of thieno[2,3-d]pyrimidin-4(3H)-one ring. A medium intense band appeared around 1543-1607 cm-1 was attributed to C=N stretching. In case of 1H-NMR, the C2 methyl of thieno[2,3-d]pyrimidin-4(3H)-one ring appeared at 2.08-2.75 ppm. The signals appeared at 6.21-8.20 ppm were attributed to aromatic protons. For 13C-NMR, the C2 methyl carbon of thieno[2,3-d]pyrimidin-4(3H)-one ring resonated in the range 21.28-23.66 ppm. The ethyl carbons showed signals at 30.63-66.16 ppm. A signal resonated at 154.46-159.51 ppm was attributed to C2 carbon of thieno[2,3-d]pyrimidin-4(3H)-one ring. The carbonyl carbon of thieno[2,3-d]pyrimidine ring was resonated in the range 159.42-162.17 ppm. The other rings attached to alkyl chain have shown signals at their respective positions.

In summary, the results of the study described above have led to the development of a simple approach for the synthesis of a novel class of thieno[2,3-d]pyrimidin-4(3H)-one derivatives. Further studies on the bioactivity of the synthesized compounds are currently under way in our laboratory.

EXPERIMENTAL

Melting points were determined on a Büchi B-545 melting point apparatus and are uncorrected. All reactions were monitored by thin layer chromatography (TLC). IR spectra were recorded in the range 4000-600 cm-1 using KBr disks on a Perkin Elmer 1600 series FTIR spectrometer. 1H and 13C-NMR spectra were recorded with CDCl3 as the solvent, on a Bruker-300 spectrometer. The chemical shifts are reported in ppm relative to TMS (internal reference). Mass spectra were determined on an Agilent 5975B spectrometer, under electronicimpact (EI) conditions. Purification of products was performed by column chromatography using silica gel 60 (Fluka).

General synthetic procedure for thienoiminoethers (2a,b).

A mixture of compound 1a or 1b (20 mmol), triethylorthoacetate (28 mmol) and catalytic amount of acetic acid was heated under reflux for 3 h. After the completion of the reaction, monitored by TLC, reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure. The residue was chromatographed on a silica gel column, eluting with EtOAc/cyclohexane (1:8) to provide products 2a,b.

Ethyl (E)-2-((1-ethoxyethylidene)amino)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (2a): Yield: 89%, mp 68 °C. IR (KBr, cm-1): 1656 (C=N), 1692 (C=O). 1H-NMR (CDCl3): 1.25 (t, J = 7.2 Hz, 3H), 1.31 (t, J = 7.2 Hz, 3H), 4.15 (q, J = 7.2 Hz, 2H), 4.24 (q, J = 7.2 Hz, 2H), 1.89 (s, 3H), 1.75 (m, 4H), 2.73 (m, 2H), 2.57 (m, 2H). 13C-NMR (CDCl3): 14.55 (CH3CH2O), 17.02 (CH3CH2O), 19.57 (CH3), 22.81, 23.34, 26.59, 26.98 (4CH2 cyclohexane), 59.39 (CH3CH2O), 62.52 (CH3CH2O), 115.84, 126.69, 134.40, 157.65 (Cthiophene), 163.83 (C=O), 164.25 (C=N).

Ethyl (E)-2-((1-ethoxyethylidene)amino)-6-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (2b): Yield: 86%, mp 77 °C. IR (KBr, cm-1): 1576 (C=N), 1659 (C=O). 1H-NMR (CDCl3): 1.29 (t, J = 7.2 Hz, 3H), 1.35 (t, J = 7.2 Hz, 3H), 4.19 (q, J = 7.2 Hz, 2H), 4.27 (q, J = 7.2 Hz, 2H), 1.93 (s, 3H), 2.70-2.91 (m, 4H), 3.01 (m, 1H), 2.09 (m, 2H), 7.21-7.33 (m, 5H, CHarom). 13C-NMR(CDCl3): 14.35 (CH3CH2O), 17.09 (CH3CH2O), 20.23 (CH3), 27.03, 30.11, 32.75, 40.78 (CH and 3CH2 cyclohexane), 59.73 (CH3CH2O), 62.62 (CH3CH2O), 115.66, 126.15, 126.41, 126.98, 128.57, 134.20, 146.11, 158.19 (Carom and Cthiophene), 163.81(C=O), 164.43 (C=N).

General procedure for the preparation of thieno[2,3-d]pyrimidin-4(3H)-ones (3a,b).

An equimolar mixture of the compounds, ethanolamineand catalytic amount of acetic acid in EtOH (15 mL) was heated under reflux for 8 h, then left to cool and the solvent was removed under reduced pressure. Purification of the residue was carried out by flash silica gel chromatography using EtOAc/cyclohexane (3:1) as eluent to afford products 3a,b.

3-(2-Hydroxyethyl)-2-methyl-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4(3H)-one (3a): Yield: 84%, mp 145 °C. IR (KBr, cm-1): 3468 (OH), 1607 (C=N), 1690 (C=O). 1H-NMR (CDCl3): 1.82 (m, 4H), 2.66 (s, 3H), 3.97 (t, J = 5.2 Hz, 2H), 4.23 (t, J = 5.2 Hz, 2H), 2.73 (m, 2H), 2.91 (m, 2H). 13C-NMR (CDCl3): 22.29, 22.98, 23.41, 25.21, 25.54 (4CH2 cyclohexane, CH3), 46.95 (CH2CH2OH), 61.14 (CH2CH2OH), 120.66, 131.33, 133.21, 146.85 (Cthiophene), 154.46 (C=N), 159.42 (C=O).

3-(2-Hydroxyethyl)-2-methyl-7-phenyl-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4(3H)-one (3b): Yield: 82%, mp 169°C. IR (KBr, cm-1): 3409 (OH), 1596 (C=N), 1667 (C=O). 1H-NMR (CDCl3): 3.98 (t, J = 5.2 Hz, 2H); 4.26 (t, J = 5.2 Hz, 2H); 2.67 (s, 3H), 2.83-3.00 (m, 4H), 3.08 (m, 1H) 1.96 (m, 2H), 7.21-7.43 (m, 5H, CHarom). 13C-NMR (CDCl3): 23.39, 25.89, 29.65, 32.98, 40.61 (CH and 3CH2 cyclohexane, CH3), 46.95 (CH2CH2OH), 61.12 (CH2CH2OH), 120.53, 126.61, 126.95, 128.68, 131.07, 132.76, 145.51 (Carom and Cthiophene), 154.72 (C=N), 159.47 (C=O).

General procedure for the tosylation of compounds (3a,b).

A mixture of compounds (10 mmol), pyridine (20 mmol), and CHCl3 (20 mL) was placed in a 3-neck round flask and cooled to 0 °C in an ice bath. Methanesulfonylchloride (15 mmol) was added to the mixture. The reaction was finished within 2 h. After adding water (10 mL), the resulting mixture was extracted with Et2O (70 mL). The ethereal layer was washed with 2 M aqueous HCl, aqueous NaHCO3, and brine. The solvent was removed by evaporation at reduced pressure, and the residue was chromatographed on a silica gel column, eluting with EtOAc/cyclohexane (2:5) to give the mesylate 4a,b.

2-(2-Methyl-4-oxo-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-3(4H)-yl)ethylmethanesulfonate (4a): Yield: 80%, mp 116 °C. IR (KBr, cm-1): 1664 (C=O), 1567 (C=N), 1377 and 1155 (O=S=O). 1H-NMR (CDCl3): 1.84 (m, 4H), 2.67 (s, 3H), 3.86 (t, J = 6.4 Hz, 2H), 4.36 (t, J = 6.4 Hz, 2H), 2.74 (m, 2H), 2.97 (m, 2H), 3.66 (s, 3H). 13C-NMR (CDCl3): 22.30, 22.98, 23.59, 25.20, 25.55 (4CH2 cyclohexane, CH3), 40.93 (CH3-S), 46.01 (CH2CH2O SO2CH3), 52.61(CH2CH2OSO2CH3), 120.61, 131.37, 133.21, 153.70 (Cthiophene), 158.42 (C=N), 161.74 (C=O).

2-(2-Methyl-4-oxo-7-phenyl-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-3(4H)-yl)ethylmethane-sulfonate (4b): Yield: 78%, mp 146 °C. IR (KBr, cm-1): 1666 (C=O), 1543 (C=N), 1378 and 1157 (O=S=O). 1H-NMR (CDCl3): 3.88 (t, J = 6.4 Hz, 2H), 4.38 (t, J = 6.4 Hz, 2H), 2.68 (s, 3H), 3.69 (s, 3H), 2.91-3.02 (m, 4H), 3.06 (m, 1H), 1.98 (m, 2H), 7.21-7.34 (m, 5H, CHarom). 13C-NMR (CDCl3): 23.66, 25.91, 29.67, 33.00, 40.63 (CH and 3CH2 cyclohexane, CH3), 40.97 (CH3-S), 46.12 (CH2CH2OSO2CH3), 54.82 (CH2CH2OSO2CH3), 120.51, 126.60, 126.96, 128.67, 131.15, 132.77, 145.57, 154.02 (Carom and Cthiophene), 158.53 (C=N), 162.08 (C=O).

General procedure for the preparation of title compounds (5a-l)

A mixture of compound 4 (10 mmol), appropriate secondary amine (10 mmol) or hydroxyl substituted compound (10 mmol) and anhydrous K2CO3 (20 mmol) in dry DMF (20 mL) was stirred at 100 °C. The completion of the reaction was checked by TLC using EtOAc and cyclohexane (20%) as eluent. The reaction mixture was then poured into ice cold water and neutralized with dil. HCl (few drops). The precipitate thus formed was filtered and dried. All the newly prepared compounds were purified by column chromatography using EtOAc and cyclohexane (10%) as eluent.

3-(2-(1H-1,2,4-Triazol-1-yl)ethyl)-2-methyl-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4(3H)-one (5a): Yield: 91%, mp 147 °C. IR (KBr, cm-1): 1668 (C=O), 1543 (C=N). 1H-NMR (CDCl3): 1.85 (m, 4H); 2.26 (s, 3H); 4.44 (t, J = 6.4 Hz, 2H), 4.60 (t, J = 6.4 Hz, 2H), 2.74 (m, 2H), 2.98 (m, 2H), 8.34 (s, 1H), 9.02 (s, 1H). 13C-NMR (CDCl3): 22.32, 22.66, 22.98, 25.23, 25.61 (4CH2 cyclohexane, CH3), 44.64 (-NCH2CH2-triazole), 47.11 (-NCH2CH2-triazole), 120.49, 131.31, 133.66, 143.99, 152.87, 153.27 (Cthiophene and Ctriazole), 158.75 (C=N), 162.17 (C=O). HRMS (EI): m/z calculated for C15H18N5OS (M+H)+: 316.12; found 316.18.

3-(2-(1H-Benzo[d]imidazol-1-yl)ethyl)-2-methyl-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4-(3H)-one (5b): Yield: 83%, mp 216 °C. IR (KBr, cm-1): 1666 (C=O), 1545 (C=N). 1H NMR (CDCl3): 1.88 (m, 4H), 2.08 (s, 3H), 4.45 (t, J = 6.4 Hz, 2H), 4.69 (t, J = 6.4 Hz, 2H), 2.77 (m, 2H), 3.03 (m, 2H), 8.20 (s, 1H), 7.37 (m, 2H), 7.53 (m, 1H), 7.82 (m, 1H). 13C-NMR (CDCl3): 22.33, 22.67, 23.00, 25.26, 25.66 (4CH2 cyclohexane, CH3), 42.69 (-NCH2CH2-imidazole), 44.61(-NCH2CH2-imidazole), 109.24, 120.72, 122.95, 123.86, 124.41, 131.35, 133.76, 152.83 (Cthiophene and Cimidazole), 158.72 (C=N), 161.92 (C=O). HRMS (EI): m/z calculated for C20H21N4OS (M+H)+: 365.14, found 365.21.

3-(2-(2-Methyl-4-oxo-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-3(4H)-yl)ethyl)-thiazolidine-2,4-dione (5c): Yield: 68%, mp 176 °C. IR (KBr, cm-1): 1739, 1701 and 1660 (C=O), 1546 (C=N). 1H-NMR (CDCl3): 1.82 (m, 4H), 2.56 (s, 3H), 4.39 (t, J = 6.4 Hz, 2H), 4.57 (t, J = 6.4 Hz, 2H), 2.72 (m, 2H), 2.93 (m, 2H), 3.63 (s, 2H). 13C-NMR (CDCl3): 22.29, 22.71, 22.96, 25.21, 25.69 (4CH2 cyclohexane, CH3), 36.59 (CH2 thiazolidine), 42.37 (-NCH2CH2-thiazoline), 46.84 (-NCH2CH2-thiazoline), 119.92, 131.17, 133.46, 153.28 (Cthiophene) 158.34 (C=N), 161.51 (C=O), 166.37, 167.90 (2C=O thiazoline). HRMS (EI): m/z calculated for C16H18N3O3S2 (M+H)+: 364.08; found 364.13.

2-Methyl-3-(2-((2-oxo-2H-chromen-7-yl)oxy)ethyl)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4(3H)-one (5d): Yield: 94%, mp 224 °C. IR (KBr, cm-1): 1716 and 1660 (C=O), 1544 (C=N). 1H-NMR (CDCl3): 1.82 (m, 4H), 2.74 (s, 3H), 4.35 (t, J = 5.2 Hz, 2H), 4.50 (t, J = 5.2 Hz, 2H), 2.70 (m, 2H), 2.95 (m, 2H), 6.21 (d, J = 9.2 Hz, 1H), 7.33 (d, J = 12 Hz, 1H), 7.60 (d, J = 9.6 Hz, 1H), 6.76 (s, 1H), 6.78 (d, J = 2.8 Hz, 1H). 13C-NMR (CDCl3): 22.33, 23.00, 23.52, 25.23, 25.59 (4CH2 cyclohexane, CH3), 44.00 (-NCH2CH2O), 66.16 (-NCH2CH2O), 101.65, 112.46, 113.12, 113.67, 120.65, 129.00, 131.40, 133.22, 143.26, 154.16, 155.80 (Cthiophene and Cchromenone), 158.72 (C=N), 161.21 (C=O), 161.90 (C=O). HRMS (EI): m/z calculated for C22H21N2O4S (M+H)+: 409.12; found 409.20.

3-(2-(2-(1H-Indol-3-yl)ethoxy)ethyl)-2-methyl-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4(3H)-one (5e): Yield: 77%, mp 203 °C. IR (KBr, cm-1): 3312 (NH), 1658 (C=O), 1541 (C=N). 1H-NMR (CDCl3): 1.81 (m, 4H), 2.62 (s, 3H), 4.43 (t, J = 5.2 Hz, 2H), 4.60 (t, J = 5.2 Hz, 2H), 3.17 (t, J = 6.4 Hz, 2H), 4.33 (t, J = 6.4 Hz, 2H), 2.73 (m, 2H), 2.91 (m, 2H), 7.60 (d, J = 7.6 Hz, 1H), 7.34 (d, J = 8.4 Hz, 1H), 7.18 (m, 1H), 7.10 (m, 1H), 7.05 (s, 1H), 8.25 (br s, 1H). 13C-NMR (CDCl3): 22.30, 22.98, 23.53, 25.21, 25.57 (4CH2 cyclohexane, CH3), 28.80 (indole-CH2CH2O), 46.86 (-NCH2CH2O), 60.92 (-NCH2CH2O), 62.66 (indole-CH2CH2O), 111.32, 112.27, 118.86, 119.45, 120.59, 122.17, 122.65, 127.48, 131.25, 133.07, 136.52, 154.41 (Cthiophene and Cindole), 159.51 (C=N), 161.86 (C=O). HRMS (EI): m/z calculated for C23H26N3O2S (M+H)+: 408.17; found 408.22.

2-(2-(2-(2-Methyl-4-oxo-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-3(4H)-yl)ethoxy)ethyl)iso-indoline-1,3-dione (5f): Yield: 79%, mp 133 °C. IR (KBr, cm-1): 1694 and 1660 (C=O), 1545 (C=N). 1H-NMR (CDCl3): 1.85 (m, 4H), 2.66 (s, 3H), 4.53 (t, J = 5.2 Hz, 2H), 4.60 (t, J = 5.2 Hz, 2H), 4.29 (t, J = 6.4 Hz, 2H), 4.33 (t, J =6.4 Hz, 2H), 2.74 (m, 2H), 2.90 (m, 2H), 7.84-7.92 (m, 2H), 7.72-7.79 (m, 2H). 13C-NMR (CDCl3): 22.27, 22.93, 23.33, 25.19, 25.76 (4CH2 cyclohexane, CH3), 43.64 (isoindoline-CH2CH2O), 46.71 (-NCH2CH2O), 61.02 (isoindoline-CH2CH2O), 62.46 (-NCH2CH2O), 120.42, 123.39, 131.43, 131.98, 133.12, 135.18, 154.37 (Cthiophene and Cisoindoline), 158.13 (C=N), 161.79 (C=O). 165.37 (2C=O). HRMS (EI): m/z calculated for C23H24N3O4S (M+H)+: 438.14; found 438.18.

3-(2-(1H-1,2,4-Triazol-1-yl)ethyl)-2-methyl-7-phenyl-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4(3H)-one (5g): Yield: 89%, mp 94 °C. IR (KBr, cm-1): 3050 (CHarom), 1655 (C=O), 1545 (C=N). 1H-NMR (CDCl3): 4.65 (t, J = 5.6 Hz, 2H), 4.48 (t, J = 5.6 Hz, 2H), 2.67 (s, 3H), 2.83-2.96 (m, 4H), 3.14 (m, 1H) 1.95 (m, 2H), 7.98 (s, 1H), 8.48 (s, 1H), 7.18-7.30 (m, 5H, CHphenyl). 13C-NMR (CDCl3): 21.28, 25.55, 29.49, 32.30, 34.03 (CH and 3CH2 cyclohexane, CH3), 40.52 (-NCH2CH2-triazole), 43.68 (-NCH2CH2-triazole), 119.98, 126.19, 126.59, 128.28, 130.76, 132.88, 145.53, 148.27, 154.96 (Cthiophene, Ctriazole and Cphenyl), 158.69 (C=N), 161.67 (C=O). HRMS (EI): m/z calculated for C21H22N5OS (M+H)+: 392.15; found 392.41.

3-(2-(1H-Benzo[d]imidazol-1-yl)ethyl)-2-methyl-7-phenyl-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]-pyrimidin-4(3H)-one (5h): Yield: 77%, mp 163 °C. IR (KBr, cm-1): 3042 (CHarom), 1677 (C=O), 1556 (C=N). 1H-NMR (CDCl3): δ = 4.55 (t, J = 5.6 Hz, 2H), 4.47 (t, J = 5.6 Hz, 2H), 2.70 (s, 3H), 2.81-2.98 (m, 4H), 3.11 (m, 1H) 1.89 (m, 2H), 7.20-7.32 (m, 5H, CHphenyl), 8.12 (s, 1H), 7.41 (m, 2H), 7.52 (m, 1H), 7.78 (m, 1H). 13C-NMR (CDCl3): δ = 22.18, 24.97, 29.32, 31.98, 34.14 (CH and 3CH2 cyclohexane, CH3), 40.47 (-NCH2CH2-imidazole), 43.53 (-NCH2CH2-imidazole), 120.08, 122.87, 123.93, 124.67, 126.23, 126.74, 128.17, 130.41, 132.49, 144.83, 148.37, 155.04 (Cthiophene, Cimidazole and Cphenyl), 158.34 (C=N), 161.08 (C=O). HRMS (EI): m/z calculated for C26H25N4OS (M+H)+: 441.17; found 441.34.

3-(2-(2-Methyl-4-oxo-7-phenyl-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-3(4H)-yl)ethyl)-thiazolidine-2,4-dione (5i): Yield: 67%, mp 211 °C. IR (KBr, cm-1): 3047 (CHarom), 1730, 1706 and 1678 (C=O), 1547 (C=N). 1H-NMR (CDCl3): 4.41 (t, J = 6.4 Hz, 2H), 4.58 (t, J = 6.4 Hz, 2H), 2.73 (s, 3H), 2.80-2.93 (m, 4H), 3.07 (m, 1H), 1.90 (m, 2H), 7.22-7.31 (m, 5H, CHphenyl), 3.66 (s, 2H). 13C-NMR (CDCl3): 21.32, 25.47, 29.52, 32.27, 33.86 (CH and 3CH2 cyclohexane, CH3), 36.44 (CH2thiazolidine), 40.48 (-NCH2CH2-thiazolidine), 43.61 (-NCH2CH2-thiazolidine), 120.03, 126.33, 126.71, 129.04, 130.84, 132.82, 145.39, 148.19, 154.79 (Cthiophene and Cphenyl), 158.44 (C=N), 161.51 (C=O), 167.32 (2C=O). HRMS (EI): m/z calculated for C22H22N3O3S2 (M+H)+: 440.11; found 440.17.

2-Methyl-3-(2-((2-oxo-2H-chromen-7-yl)oxy)ethyl)-7-phenyl-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]-pyrimidin-4(3H)-one (5j): Yield: 92%, mp 189 °C. IR (KBr, cm-1): 3055 (CHarom), 1703 and 1656 (C=O), 1547 (C=N). 1H-NMR (CDCl3): 4.57 (t, J = 5.6 Hz, 2H), 4.42 (t, J = 5.6 Hz, 2H), 2.73 (s, 3H), 2.77-2.92 (m, 4H), 3.05 (m, 1H) 1.92 (m, 2H), 7.19-7.31 (m, 5H, CHphenyl), 6.32 (d, J = 9.2 Hz, 1H), 7.37 (d, J = 12 Hz, 1H), 7.64 (d, J = 9.2 Hz, 1H), 6.80 (s, 1H), 6.83 (d, J = 3.2 Hz, 1H). 13C-NMR (CDCl3): 22.38, 25.06, 29.17, 32.03, 34.23 (CH and 3CH2 cyclohexane, CH3), 43.62 (-NCH2CH2O), 63.03 (-NCH2CH2O), 120.17, 123.81, 124.71, 126.21, 126.68, 128.88, 131.47, 132.56, 144.27, 150.12, 155.21 (Cthiophene, Cphenyle and Cchromenone), 158.37 (C=N), 161.18 (C=O), 162.24 (C=O). HRMS (EI): m/z calculated for C28H25N2O4S (M+H)+: 485.15; found 485.38.

3-(2-(2-(1H-Indol-3-yl)ethoxy)ethyl)-2-methyl-7-phenyl-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]-pyrimidin-4(3H)-one (5k): Yield: 69%, mp 266 °C. IR (KBr, cm-1): 3320 (NH), 3037 (CHarom), 1667 (C=O), 1551 (C=N). 1H-NMR (CDCl3): 4.41 (t, J = 5.6 Hz, 2H), 4.62 (t, J = 5.6 Hz, 2H), 3.23 (t, J = 6.4 Hz, 2H), 4.36 (t, J =6.4 Hz, 2H), 2.75 (s, 3H), 2.79-2.91 (m, 4H), 3.02 (m, 1H) 1.88 (m, 2H), 7.20-7.32 (m, 5H), 7.58 (d, J = 7.2 Hz, 1H), 7.37 (d, J = 8.4 Hz, 1H), 7.15 (m, 1H), 7.06 (m, 1H), 7.00 (s, 1H), 8.13 (br s, 1H). 13C-NMR (CDCl3): 22.35, 25.19, 29.21, 32.15, 34.13 (CH and 3CH2 cyclohexane, CH3), 30.63 (indole-CH2CH2O), 43.71 (-NCH2CH2O), 61.18 (-NCH2CH2O), 62.93 (indole-CH2CH2O), 120.33, 123.17, 124.91, 126.18, 126.73, 128.54, 131.52, 132.17, 136.32, 143.13, 152.23, 155.21 (Cthiophene, Cphenyl and Cindole), 158.22 (C=N), 160.83 (C=O). HRMS (EI); m/z calculated for C29H30N3O2S (M+H)+: 484.20; found 484.31.

2-(2-(2-(2-Methyl-4-oxo-7-phenyl-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4(3H)-yl)ethoxy)-ethyl)-isoindoline-1,3-dione (5l): Yield: 75%, mp 173 °C. IR (KBr, cm-1): 2966 and 2873 (CHarom), 1690 and 1668 (C=O), 1548 (C=N). 1H-NMR (CDCl3): 4.51 (t, J = 5.2 Hz, 2H), 4.58 (t, J = 5.2 Hz, 2H), 4.31 (t, J = 6.4 Hz, 2H), 4.37 (t, J =6.4 Hz, 2H), 2.67 (s, 3H), 2.86-2.94 (m, 4H), 3.17 (m, 1H), 1.97 (m, 2H), 7.20-7.34 (m, 5H), 7.80-7.88 (m, 2H), 7.71-7.77 (m, 2H). 13C-NMR (CDCl3): 23.50, 25.91, 29.67, 29.78, 32.98 (CH and 3CH2 cyclohexane, CH3), 40.62 (isoindoline-CH2CH2O), 46.91 (-NCH2CH2O), 59.12 (isoindoline-CH2CH2O), 61.22 (-NCH2CH2O), 120.49, 126.60, 126.95, 128.67, 131.04, 132.62, 145.55, 154.58 (Cthiophene, Cphenyl and Cisoindoline), 157.64 (C=N), 160.69 (C=O), 164.87 (2C=O). HRMS (EI): m/z calculated for C29H28N3O4S (M+H)+: 514.18; found 514.24.

ACKNOWLEDGMENTS

The financial assistant from Tunisian Ministry of Higher Education and Scientific Research is acknowledgedwith thanks. Thanks are due to Dr. Ali Samarat (Department of Chemistry, Faculty of Sciences of Bizerta) for valuable discussions and his encouragement.

References

1. J. Quintela, C. Peinador, M. Moreira, A. Alfonso, L. Botana, and R. Riguera, Eur. J. Med. Chem., 2001, 36, 321. CrossRef
2. F. R. Heyman, P. Bousquer, G. Cunha, M. Moskey, A. Ahmed, N. Soni, P. Marcotte, P. Pease, K. Glaser, M. Yates, J. Bouska, D. Albert, D. P. Blak-Schaefer, K. Stewart, P. Rafferty, S. Davidsen, and M. Curtin, Bioorg. Med. Chem. Lett., 2007, 17, 1246. CrossRef
3. B. V. Ashalatha, B. Narayana, K. K. Vijayaraj, and S. Kumari, Eur. J. Med. Chem., 2007, 42, 719. CrossRef
4. J. Katada, K. lijima, M. Muramatsu, M. Takami, E. Yasuda, M. Hayashi, M. Hattori, and Y. Hayashi, Bioorg. Med. Chem. Lett., 1999, 9, 797. CrossRef
5. K. K. Jain, J. Bariwal, M. Kathiravan, M. Phoujdar, R. Sahne, B. Chauhan, A. Shah, and M. Yadav, Bioorg. Med. Chem. Lett., 2008, 16, 4759. CrossRef
6. K. Gewald, Chem. Ber., 1965, 98, 3571. CrossRef
7. V. Alagarsamy, S. Vijayakumar, and V. R. Solomon, Biomed. Pharmacol., 2007, 61, 285. CrossRef
8. M. Bhutyan, M. Rahman, K. Abdurrahim, M. Hossain, and M. Abunaser, Acta Pharm., 2006, 56, 411.
9. M. A. El-Sherbeny, M. B. El-Ashmawy, H. I. El-Subbagh, and A. A. El-Emam, Eur. J. Med. Chem., 1995, 30, 445. CrossRef
10. V. Alagarsamy, S. Meena, K. V. Ramseshu, V. R. Solomon, K. Thirumuruganb, K. Dhanabala, and M. Murugan, Eur. J. Med. Chem., 2006, 41, 1293. CrossRef
11. A. El-Shafei, A. A. Fadda, A. M. Khalil, T. A. E. Ameen, and F. A. Badria, Bioorg. Med. Chem., 2009, 17, 5096. CrossRef
12. B. Monaem, D. Khaireddine, and El E. M. Lotfi, Lett. Org. Chem., 2013, 10, 118.
13. B. Monaem, D. Khaireddine, and El E. M. Lotfi, Heterocycles, 2014, 89, 1483. CrossRef
14. C. J. Shishoo, M. B. Devani, U. S. Pathak, S. Ananthan, V. S. Bhadti, G. V. Ullas, K. S. Jain, I. S. Rathod, D. S. Talati, and N. H. Doshi, J. Heterocycl. Chem., 1984, 21, 375. CrossRef
15. Z. Csuros, R. Soos, J. Palinkas, and I. Bitter, Acta Chim. (Budapest), 1971, 68, 397.
16. M. Robba, J. M. Lecomte, and M. C. de Sevricourt, C. R. Acad. Sci. Paris Ser. C., 1968, 266, 128.
17. H. Link, Helv. Chim. Acta, 1990, 73, 797. CrossRef
18. K. Gewald, Chem. Abstr., 1963, 58, 6770.