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An efficient, clean, and catalyst-free synthesis of fused pyrimidines using sonochemistry.

1. Introduction

Pyrimidine structural moiety constitutes a major class of heterocyclic compounds which have various pharmaceutical applications. For example, they are found to possess antineoplastic [1-3], antiviral [4-6], antibiotic [7], and anti-inflammatory properties [8]. Pyrimidines also exhibit a range of pharmacological activities such as antibacterial [911], antifungal [12, 13], anticancer [14, 15], and cardioprotective effects [16]. Bicyclic and tricyclic fused pyrimidine derivatives have received much attention in connection with biologically significant systems such as pyrido[2, 3d]pyrimidines. Pyrido[2, 3-d]pyrimidine structural motif is present in pirenperone (tranquilizer) [17] and ramastine (antiallergic) [18], as well as in some antiulcerative and antiasthmatic agents [19]. In addition, quinolines have pharmacological properties which include wide applications in medicinal chemistry; for example, this scaffold structure is present in anti-inflammatory agents, antimalarial drugs, and antihypertensive, antiasthmatic, antibacterial, and tyrosine kinase inhibiting agents [20-25].

Moreover the importance of uracil and its annulated derivatives is well recognized by synthetic [26, 27] as well as biological [28, 29] chemists. The 6-amino-uracil derivatives represent very important classes of functionalized uracils; also 6-amino-uracils find wide applications as starting materials for the synthesis of a number of fused uracils of biological significance, for example, pyrano-, pyrido-, pyrazolo-, pyrimido-, and pyridazinopyrimidines [30, 31].

On the other hand, ultrasonic reactions have been increasingly used as clean, green, and environmentally benign routes for the preparation of organic compounds of synthetic and biological values [32-37]. A large number of organic reactions can be carried out in higher yield, shorter reaction time, and under milder conditions, by using ultrasonic irradiation [38-41].

These observations led us to attempt the synthesis of some new fused pyrimidine derivatives using 6-aminoalkyltiouracil as starting material under sonochemical conditions. The present work describes our approach for the synthesis of polyfunctional pyrimidines using green chemistry.

2. Experimental

2.1. Chemicals and Apparatus. Melting points were measured on an electrothermal 9100 apparatus. IR spectra were determined on a Shimadzo IR-470 spectrometer. [sup.1]H NMR and [sup.13]CNMR spectra were recorded on a 400 MHz Bruker DRX-400 in DMSO-[d.sub.6] as solvent and TMS as an internal standard. Chemical shifts on [sup.1]H and [sup.13]C NMR were expressed in ppm downfield from tetramethylsilane. Sonication was performed in Elmasonic S 40H ultrasonic cleaning unit. Elemental analyses were carried out on a Carlo-Erba EA1110CNNO-S analyser and agreed with the calculated values. All the chemicals were purchased from Merck and used without further purification. All solvents used were dried and distilled according to standard procedures.

2.2. General Procedure for the Synthesis of (4a-r). A mixture of equimolar amounts of 6-amino-2-(alkylthio)pyrimidin-4(3H)-one 1 (1mmol), 1, 3-indanedione 2 (1mmol), or 1, 3-cyclohexadione 5 and aldehydes 3 (1 mmol) in ethylene glycol (5 mL) was placed in a Pyrex-glass open vessel and irradiated at 65[degrees]C by ultrasonic irradiations (40 kHz) (for conventional conditions, the reaction mixture was heated under reflux conditions). The progress of the reaction was monitored by TLC (EtOAc/petroleum ether 8:4). After completion of reaction, the mixture was concentrated and cooled. The solid obtained was filtered off and recrystallized from EtOH/[H.sub.2]O (1/1) to furnish the desired pure product.

2.3. Spectral Data for the Products

2.3.1. 5-(4-Chlorophenyl)-2-(methylthio)-3H-indeno[5, 6:1', 2'] pyrido[2, 3-d]pyrimidine-4, 6(5H, 11H)-dione (4a). Red Powder; M.p.: > 300[degrees]C; IR (KBr) [v.sub.max] = 3448, 3410, 3271, 3062, 2932, 1680, 1653, 1585, 1541, 1502, 1452, 1350, 1271, 1078, 899, 742, 707[cm.sup.-1]. [sup.1]HNMR (400 MHz, DMSO-[d.sub.6]): [delta] = 2.60 (s, 3H, C[H.sub.3]), 4.82 (s, 1H, CH), 7.30-7.25 (m, 5H, Ar-H), 7.36 (t, 1H, J = 7.40 Hz, Ar-H), 7.45 (t, 1H, J = 7.40 Hz, Ar-H), 7.79 (d, 1H, J = 7.20 Hz, Ar-H), 11.13 (br s, 1H, NH), 12.60 (br s, 1H, CO-NH) ppm. [sup.13]C NMR (100 MHz, DMSO-[d.sub.6]): [delta] = 13.3 (Me), 34.2 (CH), 99.9,107.9,120.4,120.9,128.4,130.1, 130.8, 131.2, 132.4, 133.6, 136.6, 137.5, 144.8, 153.5, 155.8, 161.5 (CONH), 191.1 (C = O) ppm. Anal. Cald. for [C.sub.21][H.sub.14]Cl[N.sub.3][O.sub.2]S (407.87): C, 61.84; H, 3.46; N, 10.30%; Found: C, 61.95; H, 3.31; N, 10.43%.

2.3.2. 2-(Methylthio)-5-phenyl-3H-indeno[5, 6:1', 2']pyrido[2, 3-d]pyrimidine-4, 6 (5H, 11H)-dione (4b). Red Powder; M.p.: > 300[degrees]C; IR (KBr) [v.sub.max] = 3448, 3040, 2922, 2851, 1685, 1647, 1582, 1537, 1500, 1456, 1358, 1273, 742, 702 [cm.sup.-1]. [sup.1]HNMR (400 MHz, DMSO-[d.sub.6]): [delta] = 2.60 (s, 3H, C[H.sub.3]), 4.82 (s, 1H, CH), 7.15-7.11 (m, 1H, Ar-H), 7.26-7.21 (m, 4H, Ar-H), 7.34 (t, 2H, J = 7.40 Hz, Ar-H), 7.44 (t, 1H, J = 7.60 Hz, Ar-H), 7.78 (d, 1H, J = 7.20 Hz, Ar-H), 11.07 (br s, 1H, NH), 12.55 (br s, 1H, CO-NH) ppm. [sup.13]C NMR (100 MHz, DMSO-[d.sub.6]): [delta] = 13.3 (Me), 34.5 (CH), 100.0, 108.5, 120.3, 120.8, 126.6, 127.4, 128.2. 128.5, 130.6, 132.3, 133.7, 136.7, 146.0, 153.3, 155.7, 162.5 (CONH), 191.1 (C = O) ppm. Anal. Cald. for [C.sub.21][H.sub.15][N.sub.3][O.sub.2]S: (373.43); C, 67.54; H, 4.05; N, 11.25%; Found: C, 67.39; H, 4.12; N, 11.12%.

2.3.3. 5-(4-Bromophenyl)-2-(methylthio)-3H-indeno[5, 6:1', 2'] pyrido[2, 3-d]pyrimidine-4, 6 (5H, 11H)-dione (4c). Red Powder; M.p.: > 300[degrees]C; IR (KBr): [v.sub.max] = 3380, 3300, 3100, 3080, 2920, 2820, 1690, 1640, 1618, 1558, 1498, 1440, 1348, 1270, 1070, 850,800,760 [cm.sup.-1]. [sup.1]H NMR (400 MHz, DMSO-[d.sub.6]): [delta] = 2.60 (s, 3H, C[H.sub.3]), 4.80 (s, 1H, CH), 7.21 (d, 2H, J = 760 Hz, Ar-H), 7.26 (d, 1H, J = 6.80 Hz, Ar-H), 7.35 (t, 1H, J = 720 Hz, Ar-H), 7.42 (m, 3H, Ar-H), 7.79 (d, 1H, J = 6.80 Hz, Ar-H), 11.12 (br s, 1H, NH), 12.58 (br s, 1H, CO-NH) ppm. [sup.13]CNMR (100 MHz, DMSO-[d.sub.6]): [delta]; 13.3 (Me), 34.3 (CH), 99.9, 107.8, 119.7, 120.4, 120.9, 129.6, 130.5, 130.8, 131.3, 132.4, 133.6, 136.6, 145.2, 155.8, 162.1 (CONH), 191.1 (C = O) ppm. Anal. Cald. for [C.sub.21][H.sub.14]Br[N.sub.3][O.sub.2]S (452.32): C, 55.76; H, 3.12; N, 9.29%; Found: C, 55.63; H, 3.01; N, 9.38%.

2.3.4. 5-(4-Fluorophenyl)-2-(methylthio)-3H-indeno[5, 6: 1',2'] pyrido[2, 3-d]pyrimidine-4, 6 (5H, 11H)-dione (4d). Red Powder; M.p.: > 300[degrees]C; IR (KBr): [v.sub.max] = 3440, 3400, 3026, 2921, 2840, 1677, 1641, 1602, 1578, 1539, 1493, 1458, 1357, 1275, 1149, 843, 798, 748, 709 [cm.sup.-1]. [sup.1]H NMR (400 MHz, DMSO-[d.sub.6]): [delta] = 2.60 (s, 3H, C[H.sub.3]), 4.83 (s, 1H, CH), 7.07-7.01 (m, 4H, Ar-H), 7.26 (d, 2H, J = 6.40 Hz, Ar-H), 7.35 (t, 1H, J = 740 Hz, Ar-H), 7.45 (t, 1H, J = 7.20 Hz, Ar-H), 7.79 (d, 1H, J = 720 Hz, Ar-H), 11.10 (br s, 1H, NH), 12.56 (br s, 1H, CO-NH) ppm. [sup.13]C NMR (100 MHz, DMSO-[d.sub.6]): [delta] = 13.3 (Me), 34.0 (CH), 99.6, 108.1, 114.9 (d, [sup.2][J.sub.C-F] = 21.0 Hz), 120.3, 120.7, 129.9 (d, [sup.3][J.sub.C-F] = 8.0 Hz), 130.6, 132.1, 133.9, 136.8, 142.6, 153.3, 156.1, 158.9, 160.6 (d, [sup.1][J.sub.C-F] = 240.0 Hz), 191.0 (C = O) ppm. Anal. Cald. for [C.sub.21][H.sub.14]F[N.sub.3][O.sub.2]S (391.42): C, 64.44; H, 3.61; N, 10.74%; Found: C, 64.38; H, 3.62; N, 10.85%.

2.3.5. 5-(2-Bromophenyl)-2-(methylthio)-3H-indeno[5, 6:1', 2'] pyrido[2, 3-d]pyrimidine-4, 6 (5H, 11H)-dione (4e). Red Powder; M.p.: > 300[degrees]C; IR (KBr): [v.sub.max] = 3350, 3300, 3110, 3080, 2920, 2820, 1690, 1645, 1618, 1558, 1498, 1440, 1347, 1270, 1070, 895, 845, 800, 760, 710 [cm.sup.-1]. [sup.1]H NMR (400 MHz, DMSO-[d.sub.6]): [delta] = 2.60 (s, 3H, C[H.sub.3]), 5.24 (s, 1H, CH), 7.06 (dt, 1H, J = 8.40 Hz, 2.2 Hz, Ar-H), 728-721 (m, 3H, Ar-H), 735 (t, 1H, J = 7.40 Hz, Ar-H), 7.48-7.43 (m, 2H, Ar-H), 7.80 (d, 1H, J = 7.20 Hz, Ar-H), 11.11 (br s, 1H, NH), 12.26 (br s, 1H, CO-NH), ppm. [sup.13]C NMR (100 MHz, DMSO-[d.sub.6]): [delta] = 13.3 (Me), 35.7 (CH), 100.0, 107.8, 120.4, 120.7, 123.4, 128.1, 128.4, 130.7, 132.0, 132.2, 132.8, 133.6, 136.6, 136.7, 144.9, 153.7, 155.6, 162.1 (CONH), 190.7 (C = O) ppm. Anal. Cald. for [C.sub.21][H.sub.14]Br[N.sub.3][O.sub.2]S (452.32): C, 55.76; H, 3.12; N, 9.29%. Found: C, 55.83; H, 3.08; N, 9.45%.

2.3.6. 5-(2-Chlorophenyl)-2-(methylthio)-3H-indeno[5, 6:1', 2'] pyrido[2, 3-d]pyrimidine-4, 6 (5H, 11H)-dione (4f). Red Powder; M.p.: > 300[degrees]C; IR (KBr): [v.sub.max] = 3460, 3385, 3120, 3060, 2930, 2854, 1685, 1649, 1616, 1580, 1541, 1502, 1445, 1345, 1277, 1078, 893, 764 [cm.sup.-1]. [sup.1]H NMR (400 MHz, DMSO-[d.sub.6]): [delta] = 2.60 (s, 3H, C[H.sub.3]), 5.24 (s, 1H, CH), 7.15 (d, 1H, J = 720 Hz, Ar-H), 7.21 (t, 2H, J = 7.40 Hz, Ar-H), 7.29 (d, 2H, J = 720 Hz, Ar-H), 7.35 (t, 1H, J = 7.20 Hz, Ar-H), 7.44 (t, 1H, J = 720 Hz, Ar-H), 7.79 (d, 1H, J = 7.20 Hz, Ar-H), 11.10 (br s, 1H, NH), 12.49 (br s, 1H, CO-NH) ppm. [sup.13]CNMR (100 MHz, DMSO-[d.sub.6]): [delta] = 13.3 (Me), 33.3 (CH), 99.9, 107.6, 120.4, 120.7, 127.4, 128.1, 129.5, 130.7. 131.9, 132.2, 132.9, 133.6, 136.6, 143.1, 153.7, 155.9, 162.1 (CONH), 190.7 (C = O) ppm. Anal. Cald. for [C.sub.21][H.sub.14]Cl[N.sub.3][O.sub.2]S (407.87): C, 61.84; H, 3.46; N, 10.30; Found: C, 61.72; H, 3.31; N, 10.18%.

2.3.7. 5-(2-Hydroxyphenyl)-2-(methylthio)-3H-indeno[5, 6:1', 2]pyrido[2, 3-d]pyrimidine-4, 6 (5H, 11H)-dione (4g). Orang Powder; M.p.: > 300[degrees]C; IR (KBr): [v.sub.max] = 3450, 3270, 3050, 2920 2820 1700 1645 1620 1600 1560 1500 1440 1347 1280, 1180, 868, 800, 760, 700 [cm.sup.-1]. [sup.1]H NMR (400 MHz, DMSO-[d.sub.6]): [delta] = 2.59 (s, 3H, C[H.sub.3]), 4.98 (s, 1H, CH), 6.72-6.69 (m, 2H, Ar-H), 7.03-7.0 (m, 2H, Ar-H), 7.25 (d, 1H, J = 6.80 Hz, Ar-H), 7.35 (t, 1H, J = 7.40 Hz, Ar-H), 7.45 (t, 1H, J = 7.40 Hz, Ar-H), 7.79 (d, 1H, J = 7.20 Hz, Ar-H), 9.58 (br s, 1H, NH), 11.12 (s, 1H, OH), 12.73 (br s, 1H, CO-NH) ppm. [sup.13]C NMR (100 MHz, DMSO-[d.sub.6]): [delta] = 13.3 (Me), 29.6 (CH), 100.0, 107.9, 117.5, 120.0, 120.2, 120.8, 127.9, 130.0, 130.6, 132.3, 133.8, 136.8, 136.9, 154.8, 155.0, 156.4, 156.5, 163.9 (CONH), 191.1 (C = O) ppm. Anal. Cald. for [C.sub.21][H.sub.15][N.sub.3][O.sub.3]S (389.43): C, 64.77; H, 3.88; N, 10.79%; Found: C, 64.70; H, 3.98; N, 10.88%.

2.3.8. 5-(2, 4-Dichlorophenyl)-2-(methylthio)-3H-indeno[5, 6:1, 2]pyrido[2, 3-d]pyrimidine-4, 6 (5H, 11H)-dione (4h). Red Powder; M.p.: > 300[degrees]C; IR (KBr): [v.sub.max] = 3448, 3228, 3066, 2940, 2854, 1683, 1649, 1580, 1539, 1506, 1460, 1352, 1275, 1103, 1060, 858, 764, 704 [cm.sup.-1]. [sup.1]H NMR (400 MHz, DMSO-[d.sub.6]): [delta] = 2.60 (s, 3H, CH3), 5.22 (s, 1H, CH), 7.23 (d, 1H, J = 6.40 Hz, Ar-H), 7.37-7.27 (m, 3H, Ar-H), 7.47-7.44 (m, 2H, Ar-H), 7.80 (d, 1H, J = 7.20 Hz, Ar-H), 11.13 (br s, 1H, NH), 12.52 (br s, 1H, CO-NH) ppm. [sup.13]C NMR (100 MHz, DMSO-[d.sub.6]): [delta] = 13.3 (Me), 33.0 (CH), 99.4, 107.1, 120.5, 120.7, 127.6, 128.7, 130.8, 131.7, 132.2, 133.0, 133.5, 133.9, 142.3, 136.6, 153.8. 156.0, 162.0 (CONH), 190.7 (C = O) ppm. Anal. Cald. for [C.sub.21][H.sub.13][Cl.sub.2][N.sub.3][O.sub.2]S: (442.32) C, 57.02; H, 2.96; N, 9.50%; Found: C, 56.88; H, 2.83; N, 9.35%.

2.3.9. 5-(2-Nitrophenyl)-2-(methylthio)-3H-indeno[5, 6:1', 2'] pyrido[2, 3-d]pyrimidine-4, 6 (5H, 11H)-dione (4i). Red Powder; M.p.: > 300[degrees]C; IR (KBr): [v.sub.max] = 3350, 3060, 2923, 1685, 1649, 1578, 1540, 1504, 1450, 1539, 1342, 1277, 770, 708 [cm.sup.-1]. [sup.1]HNMR (400 MHz, DMSO-[d.sub.6]): [delta] = 2.60 (s, 3H, C[H.sub.3]), 4.83 (s, 1H, CH), 7.05 (t, 2H, J = 8.80 Hz, Ar-H), 7.29-7.25 (m, 3H, Ar-H), 7.35 (t, 1H, J = 7.40 Hz, Ar-H), 7.45 (t, 1H, J = 7.40 Hz, Ar-H), 7.79 (d, 1H, J = 7.20 Hz, Ar-H), 11.10 (br s, 1H, NH), 12.57 (br s, 1H, CO-NH) ppm. [sup.13]C NMR (100 MHz, DMSO-[d.sub.6]): [delta] = 13.3 (Me), 33.9 (CH), 97.0, 108.2, 115.0, 115.2, 120.4, 120.9, 126.3, 129.9, 130.0, 130.8, 132.4, 133.6, 136.7, 142.1, 155.7, 160.0, 162.4 (CONH), 191.1 (C = O) ppm. Anal. Cald. for [C.sub.21][H.sub.14][N.sub.4][O.sub.4]S (418.43) C, 60.28; H, 3.37; N, 13.39%; Found: C, 60.10; H, 3.48; N, 13.51%.

2.3.10. 5-(4-Methoxyphenyl)-2-(methylthio)-3H-indeno[5, 6:1, 2']pyrido[2, 3-d]pyrimidine-4, 6 (5H, 11H)-dione (4j). Red Powder; M.p.: > 300[degrees]C; IR (KBr): [v.sub.max] = 3211, 3040, 2920, 2851, 1674, 1645, 1606, 1554, 1500, 1442, 1352, 1261, 1219, 1020, 898, 835, 766, 706 [cm.sup.-1]. [sup.1]H NMR (400 MHz, DMSO-[d.sub.6]): [delta] = 2.59 (s, 3H, C[H.sub.3]), 3.68 (s, 3H, OC[H.sub.3]), 4.76 (s, 1H, CH), 6.79 (d, 2H, J = 8.20 Hz, Ar-H), 7.14 (d, 2H, J = 8.20 Hz, Ar-H), 7.26 (d, 1H, J = 7.20 Hz, Ar-H), 7.35 (t, 1H, J = 720 Hz, Ar-H), 7.44 (t, 1H, J = 7.40 Hz, Ar-H), 7.78 (d, 1H, J = 6.80 Hz, Ar-H), 11.03 (br s, 1H, NH), 12.53 (br s, 1H, CO-NH) ppm. [sup.13]CNMR (100 MHz, DMSO-[d.sub.6]): [delta] = 13.3 (Me), 33.6 (CH), 55.4 (MeO), 95.0, 108.7, 112.8, 113.9, 120.2, 120.8, 129.1, 130.6, 132.3, 133.7, 136.8, 138.2, 155.4, 158.1, 161.5 (CONH), 191.2 (C = O) ppm. Anal. Cald. for [C.sub.22][H.sub.17][N.sub.3][O.sub.3]S: (403.45) C, 65.49; H, 4.25; N, 10.42%; Found: C, 65.30; H, 4.35; N, 10.28%.

2.3.11. 2-(Methylthio)-5-(p-tolyl)-3H-indeno[5, 6:1, 2]pyrido [2, 3-d]pyrimidine-4, 6 (5H, 11H)-dione (4k). Red Powder; M.p.: > 300[degrees]C; IR (KBr): [v.sub.max] = 3490, 3227, 3059, 2940, 2854, 1681, 1645, 1585, 1539, 1504, 1456, 1350, 1275, 897, 773 [cm.sup.-1]. [sup.1]H NMR (400 MHz, DMSO-[d.sub.6]): [delta] = 2.21 (s, 3H, C[H.sub.3]), 2.59 (s, 3H, C[H.sub.3]), 4.77 (s, 1H, CH), 7.03 (d, 2H, J = 720 Hz, Ar-H), 7.12 (d, 2H, J = 7.20 Hz, Ar-H), 7.25 (d, 1H, J = 6.40 Hz, Ar-H), 7.34 (t, 1H, J = 7.20 Hz, Ar-H), 7.44 (t, 1H, J = 720 Hz, Ar-H), 7.77 (d, 1H, J = 6.80 Hz, Ar-H), 11.04 (br s, 1H, NH), 12.54 (br s, 1H, CO-NH) ppm. [sup.13]CNMR (100 MHz, DMSO-[d.sub.6]): [delta] = 13.3 (Me), 21.0 (Me), 34.1 (CH), 100.2,108.7,120.2,120.8, 128.0, 128.4, 129.0, 130.6, 132.3, 133.7, 135.6, 136.8, 143.1, 153.2, 155.5, 162.4 (CONH), 191.1 (C = O) ppm. Anal. Cald. for [C.sub.22][H.sub.17][N.sub.3][O.sub.2]S: (387.45) C, 68.20; H, 4.42; N, 10.85%; Found: C, 68.38; H, 4.25; N, 10.78%.

2.3.12. 5-(3, 4-Dimethoxyphenyl)-2-(methylthio)-3H-indeno[5, 6:1', 2']pyrido[2, 3-d]pyrimidine-4, 6 (5H, 11H)-dione (4l). Red Powder; M.p.: > 300[degrees]C; IR (KBr): [v.sub.max] = 3389, 3223, 3130, 3063, 2933, 2839, 1691, 1653, 1554, 1504, 1450, 1340, 1226, 1024, 897, 798, 764, 710 [cm.sup.-1]. [sup.1]H NMR (400 MHz, DMSO-[d.sub.6]): [delta] = 2.60 (s, 3H, SC[H.sub.3]), 3.67 (s, 3H, OC[H.sub.3]), 3.71 (s, 3H, OC[H.sub.3]), 4.79 (s, 1H, CH), 6.64 (d, 1H, J = 8.40 Hz, Ar-H), 6.74 (d, 1H, J = 8.40 Hz, Ar-H), 6.95 (s, 1H, Ar-H), 7.27 (d, 1H, J = 6.80 Hz, Ar-H), 7.34 (t, 1H, J = 7.20 Hz, Ar-H), 7.43 (t, 1H, J = 720 Hz, Ar-H), 7.77 (d, 1H, J = 7.20 Hz, Ar-H), 11.01 (br s, 1H, NH), 12.54 (br s, 1H, CO-NH) ppm. [sup.13]CNMR (100 MHz, DMSO-[d.sub.6]): : [delta] = 13.3 (Me), 33.9 (CH), 55.9 (MeO), 56.0 (MeO), 100, 108.5, 112.3, 112.6, 119.8, 120.2, 120.8, 130.6, 132.3, 133.7, 136.7, 138.6, 147.8, 148.6, 155.4, 162.5 (CONH), 191.2 (C = O) ppm. Anal. Cald. for [C.sub.23][H.sub.19][N.sub.3][O.sub.4]S: (433.48) C, 63.73; H, 4.42; N, 9.69%; Found: C, 63.88; H, 4.33; N, 9.86%.

2.3.13. 5-(2, 4-Dichlorophenyl)-2-(ethylthio)-5, 11-dihydro-3H-indeno [2', 1':5, 6]pyrido[2, 3-d]pyrimidine-4, 6-dione (4m). Red Powder; M.p.: 282-284[degrees]C; IR (KBr): [v.sub.max] = 3203, 3136, 3059, 2966, 2926, 1649, 1607, 1550, 1502, 1450 1350, 1190, 1101, 1070, 858, 764, 700 [cm.sup.-1]. [sup.1]H NMR (400 MHz, DMSO-[d.sub.6]): [delta] = 1.36 (t, 3H, J = 71 Hz, C[H.sub.3]), 3.22 (q, 2H, J = 71 Hz, C[H.sub.2]), 5.22 (s, 1H, CH), 7.22 (d, 1H, J = 6.8 Hz, Ar-H), 746-726 (m, 5H, Ar-H), 7.80 (d, 1H, J = 7.2 Hz, Ar-H), 11.09 (s, 1H, NH), 12.48 (br s, 1H, NH-C = O) ppm. [sup.13]CNMR (100 MHz, DMSO-[d.sub.6]): [delta] = 15.0 (Me), 24.7 (C[H.sub.2]), 33.0 (CH), 99.4, 107.1, 120.5,127.5, 127.6, 128.7, 130.8, 131.7, 132.2, 133.0, 133.5, 133.9, 136.6, 142.3, 153.8, 156.0, 162.0 (CONH), 190.7 (C = O) ppm. Anal. Cald. for [C.sub.22][H.sub.15][Cl.sub.2][N.sub.3][O.sub.2]S (456.34): C, 57.90; H, 3.31; N, 9.21%; Found: C, 57.74; H, 3.23; N, 9.05%.

2.3.14. 5-(4-Chlorophenyl)-2-(ethylthio)-5, 11-dihydro-3H-in-deno[2', 1':5, 6]pyrido[2, 3-d]pyrimidine-4, 6-dione (4n). Red Powder; M.p.: 268-270[degrees]C, IR (KBr): [v.sub.max] = 3209, 3140, 3063, 2876, 1649, 1545, 1504, 1452, 1350, 1188, 1146, 860, 764, 704 [cm.sup.-1]. [sup.1]HNMR (400 MHz, DMSO-[d.sub.6]): [delta] = 1.36 (t, 3H, J = 7.2 Hz, C[H.sub.3]), 3.23 (q, 2H, J = 7.2 Hz, C[H.sub.2]), 4.82 (s, 1H, CH), 7.26 (m, 5H, Ar-H), 7.35 (t, 1H, J = 7.2 Hz, Ar-H), 7.45 (t, 1H, J = 7.4 Hz, Ar-H), 7.79 (d, 1H, J = 7.2 Hz, Ar-H), 11.08 (s, 1H, NH), 12.56 (br s, 1H, NH-C = O) ppm. [sup.13]CNMR (100 MHz, DMSO-[d.sub.6]): [delta] = 15.1 (Me), 24.6 (C[H.sub.2]), 34.2 (CH), 99.9, 112.0, 107.9, 120.4, 120.9, 128.4, 130.1, 130.8, 131.2, 132.3, 133.5, 136.6, 144.8, 155.8, 191.1 (C = O) ppm. Anal. Cald. for [C.sub.22][H.sub.16]Cl[N.sub.3][O.sub.2]S (421.90): C, 62.63; H, 3.82; N, 9.96%; Found: C, 62.38; H, 3.95; N, 9.76%.

2.3.15. 2-(Ethylthio)-5-(2-fluorophenyl)-5, 11-dihydro-3H-inde no[2', 1':5, 6]pyrido[2, 3-d]pyrimidine-4, 6-dione (4o). Red Powder; M.p.: 257-259[degrees]C; IR (KBr): [v.sub.max] = 3221, 3132, 3057, 2932, 1684, 1647, 1583, 1539, 1491, 1350, 1263, 1182, 760, 706 [cm.sup.-1]. [sup.1]HNMR (400 MHz, DMSO-[d.sub.6]): [delta] = 1.37 (t, 3H, J = 7.2 Hz, C[H.sub.3]), 3.23 (q, 2H, J = 7.2 Hz, C[H.sub.2]), 5.04 (s, 1H, CH), 7.03 (m, 2H, Ar-H), 7.18 (m, 1H, Ar-H), 7.25 (t, 2H, Ar-H), 7.34 (t, 1H, J = 7.2 Hz, Ar-H), 7.44 (t, 1H, J = 7.2 Hz, Ar-H), 7.80 (d, 1H, J = 6.8 Hz, Ar-H), 11.06 (s, 1H, NH), 12.48 (br s, 1H, NH--C = O) ppm. [sup.13]CNMR (100 MHz, DMSO-[d.sub.6]): [delta] = 15.1 (Me), 24.6 (C[H.sub.2]), 29.0 (CH), 99.4, 107.4, 115.5 ([sup.2]J = 22.0 Hz), 120.4 ([sup.3]J = 10.0 Hz), 120.8, 124.6, 128.4, 128.5, 130.7, 131.1, 132.2, 132.8, 132.9, 133.6, 136.7, 153.6, 155.8 (CONH), 160.3 ([sup.1][J.sub.C-F] = 245.0 Hz), 191.0 (C = O) ppm. Anal. Cald. for [C.sub.22][H.sub.16]F[N.sub.3][O.sub.2]S (405.44): C, 65.17; H, 3.98; N, 10.36%; Found: C, 65.06; H, 3.81; N, 10.22%.

2.3.16. 5-(4-Bromophenyl)-2-(ethylthio)-5, 11-dihydro-3H-indeno[2', 1:5, 6]pyrido[2, 3-d]pyrimidine-4, 6-dione (4p). Red Powder; M.p.: 255-257[degrees]C, IR (KBr): [v.sub.max] = 3230, 2858, 1645, 1578, 1539, 1499, 1450, 1352, 1182, 1016, 797, 708 [cm.sup.-1]. [sup.1]HNMR (400 MHz, DMSO-[d.sub.6]): [delta] = 1.36 (t, 3H, J = 7.2 Hz, C[H.sub.3]), 3.23 (q, 2H, J = 72 Hz, C[H.sub.2]), 4.81 (s, 1H, CH), 7.21 (d, 2H, J = 8.0 Hz, Ar-H), 7.26 (d, 1H, J = 7.2 Hz, Ar-H), 7.35 (t, 1H, J = 7.2 Hz, Ar-H), 7.44 (m, 3H, Ar-H), 7.79 (d, 1H, J = 7.2 Hz, Ar-H), 11.07 (s, 1H, NH), 12.55 (br s, 1H, NH-C = O) ppm; [sup.13]CNMR (100 MHz, DMSO-[d.sub.6]): [delta] = 15.1 (Me), 24.6 (C[H.sub.2]), 34.4 (CH), 99.7, 107.8, 119.7, 120.4, 120.9, 130.5, 130.7, 131.3, 132.3, 133.6, 136.6, 145.2, 155.8, 161.8 (CONH), 191.0 (C = O) ppm. Anal. Cald. for [C.sub.22][H.sub.16]Br[N.sub.3][O.sub.2]S (466.35): C, 56.66; H, 3.46; N, 9.01%; Found: C, 56.53; H, 3.27; N, 9.16%.

2.3.17. 2-(Ethylthio)-5-(4-methylthiophenyl)-5, 11-dihydro-3H-indeno[2', 1:5, 6]pyrido[2, 3-d]pyrimidine-4, 6-dione (4q). Red Powder; M.p.: 250-252[degrees]C; IR (KBr) [v.sub.max] = 3219, 3138, 3057, 2964, 2922, 1645, 1551, 1499, 1450, 1354, 1184, 835, 768, 712 [cm.sup.-1]. [sup.1]HNMR (400 MHz, DMSO-[d.sub.6]): [delta] = 1.36 (t, 3H, J = 7.2 Hz, C[H.sub.3]), 2.41 (s, 3H, C[H.sub.3]), 3.22 (q, 2H, J = 7.2 Hz, C[H.sub.2]), 4.78 (s, 1H, CH), 7.13 (d, 2H, J = 8.0 Hz, Ar-H), 7.19 (d, 2H, J = 8.0 Hz, Ar-H), 7.26 (d, 1H, J = 7.2 Hz, Ar-H), 7.34 (t, 1H, J = 7.2 Hz, Ar-H), 7.44 (t, 1H, J = 7.4 Hz, Ar-H), 7.78 (d, 1H, J = 7.2 Hz, Ar-H), 11.03 (s, 1H, NH), 12.53 (br s, 1H, NH-C = O) ppm. [sup.13]C NMR (100 MHz, DMSO-[d.sub.6]): [delta] = 15.1 (Me), 15.4 (Me), 24.7 (C[H.sub.2]), 34.1 (CH), 100.0, 108.3, 120.3, 120.8, 126.4, 128.8, 130.6, 132.3, 133.7, 136.0, 136.7, 142.9, 153.8, 154.0, 155.5, 155.6, 191.1 (C = O) ppm. Anal. Cald. for [C.sub.23][H.sub.19][N.sub.3][O.sub.2][S.sub.2] (433.55): C, 63.72; H, 4.42; N, 9.69%; Found: C, 63.57; H, 4.59; N, 9.56%.

2.3.18. 2-(Ethylthio)-5-phenyl-5,11-dihydro-3H-indeno[2', 1':5, 6]pyrido[2, 3-d]pyrimidine-4, 6-dione (4r). Red Powder; M.p.: 273-276[degrees]C; IR (KBr): [v.sub.max] = 3119, 3026, 2922, 2849, 1716, 1645, 1541, 1495, 1452, 1352, 1184, 744, 710 [cm.sup.-1]. [sup.1]HNMR (400 MHz, DMSO-[d.sub.6]): [delta] = 1.36 (t, 3H, J = 72 Hz, C[H.sub.3]), 3.23 (q, 2H, J = 72 Hz, C[H.sub.2]), 4.82 (s, 1H, CH), 7.13 (m, 1H, Ar-H), 7.24 (m, 5H, Ar-H), 7.35 (t, 1H, J = 74 Hz, Ar-H), 744(t, 1H, J = 7.4 Hz, Ar-H), 7.79 (d, 1H, J = 7.2 Hz, Ar-H), 11.02 (s, 1H, NH), 12.52 (br s, 1H, NH-C = O) ppm. [sup.13]C NMR (100 MHz, DMSO-[d.sub.6]): [delta] = 15.1 (Me), 24.6 (C[H.sub.2]), 34.5 (CH), 108.5, 120.3, 120.9, 126.6, 128.2, 128.5, 130.7, 132.3, 133.6, 136.6, 145.9, 155.6, 162.5 (CONH), 191.2 (C = O) ppm. Anal. Cald. for [C.sub.22][H.sub.17][N.sub.3][O.sub.2]S (38710): C, 68.26; H, 4.42; N, 10.85%; Found: C, 68.08; H, 4.55; N, 10.97%.

2.3.19. 2-(Ethylthio)-5-(4-fluorophenyl)-5, 8, 9, 10-tetrahydro-3H, 7H-pyrimido[4, 5-b]quinoline-4, 6-dione (6a). White Powder; M.p.: 300-302[degrees]C; IR (KBr): [v.sub.max] = 3221, 3142, 3067, 3032, 2957, 2880, 1647, 1607, 1553, 1483, 1364, 1226, 1186, 837, 797 [cm.sup.-1]. [sup.1]H NMR (400 MHz, DMSO-[d.sub.6]): [delta] = 1.31 (t, 3H, J = 7.2Hz, C[H.sub.3]), 1.95-1.82 (m, 2H, C[H.sub.2] - [[CH.bar].sub.[2.bar]] - C[H.sub.2]), 2.29 - 2.18 (m, 2H, C[H.sub.2] - [[CH.bar].sub.[2.bar]]-), 2.66 - 2.56 (m, 2H, C[H.sub.2] - [[CH.bar].sub.[2.bar]] - C = O), 3.13 (q, 2H, J = 7.2Hz, [[CH.bar].sub.[2.bar]] - C[H.sub.3]), 4.95 (s, 1H, CH), 7.01 (t, 2H, J = 8.8 Hz, Ar-H), 7.22 (dd, 2H, J = 8.2, 5.8 Hz, Ar-H), 9.85 (s, 1H, NH), 12.33 (br s, 1H, NH-C = O) ppm. [sup.13]CNMR (100 MHz, DMSO-[d.sub.6]): [delta] = 15.1 (Me), 21.3 (C[H.sub.2]), 24.5 (C[H.sub.2]), 26.9 (C[H.sub.2]), 33.2 ([C.bar][H.sub.2] - C = O), 37.2 (CH), 98.4, 110.9, 115.0 ([sup.2][J.sub.CF] = 21.0 Hz), 129.6 ([sup.3][J.sub.CF] = 8.0 Hz), 143.3 ([sup.4][J.sub.CF] = 2.0 Hz), 152.4, 153.5, 153.6, 161.0 ([sup.1][J.sub.CF] = 240.0 Hz), 162.2 (CONH), 195.0 (C = O) ppm. Anal. Cald. for [C.sub.19][H.sub.18]F[N.sub.3][O.sub.2]S (371.43): C, 61.44; H, 4.88; N, 11.31%; Found: C, 61.32; H, 4.70; N, 11.18%.

2.3.20. 2-(Ethylthio)-5-(naphthalen-2-yl)-5, 8, 9, 10-tetrahydro 3H, 7H-pyrimido[4, 5-b]quinoline-4, 6-dione (6b). White Powder; M.p.: 310-312[degrees]C; IR (KBr): [v.sub.max] = 3221, 3138, 3063, 3028, 2953, 2874, 1647, 1607, 1554, 1479, 1450, 1366, 1186, 797, 752 [cm.sup.-1]. [sup.1]H NMR (400 MHz, DMSO-[d.sub.6]): [delta] = 1.31 (t, 3H, J = 7.2 Hz, C[H.sub.3]), 1.94 - 1.85 (2H, m, C[H.sub.2] - [[CH.bar].sub.[2.bar]] - C[H.sub.2]), 2.31 - 2.18 (m, 2H, [[CH.bar].sub.[2.bar]] - C[H.sub.2]-), 2.70 - 2.60 (m, 2H, C[H.sub.2] - [[CH.bar].sub.[2.bar]] - C = O), 3.15 (q, 2H, J = 7.2 Hz, [[CH.bar].sub.[2.bar]] - C[H.sub.3]), 5.12 (s, 1H, CH), 7.43 (3H, m, Ar-H), 7.62 (s, 1H, Ar-H), 7.84-7.74 (m, 3H, Ar-H), 9.88 (s, 1H, NH), 12.33 (br s, 1H, NH - C = O) ppm. [sup.13]C NMR (100 MHz, DMSO-[d.sub.6]): [delta] = 15.1 (Me), 21.3 (C[H.sub.2]), 24.5 (C[H.sub.2]), 26.9 (C[H.sub.2]), 27.0 ([C.bar][H.sub.2] - C = O), 34.2 (CH), 98.3, 111.0, 125.7, 125.8, 126.2, 127.7, 127.2, 127.9, 128.2, 132.2, 133.2, 144.6, 153.5, 153.6, 194.9 (C = O) ppm. Anal. Cald. for [C.sub.23][H.sub.21][N.sub.3][O.sub.2]S (403.50): C, 68.46; H, 5.25; N, 10.41%; Found: C, 68.60; H, 5.17; N, 10.55%.

2.3.21. 2-(Ethylthio)-5-(p-tolyl)-5, 8, 9, 10-tetrahydro-3H, 7H-pyrimido[4, 5-b]quinoline-4, 6-dione (6c). White Powder; M.p.: 292-294[degrees]C; IR (KBr): [v.sub.max] = 3225, 3142, 3067, 2878, 1649, 1614, 1556, 1475, 1366, 1186, 794 [cm.sup.-1]. [sup.1]H NMR (400 MHz, DMSO-[d.sub.6]): [delta] = 1.31 (t, 3H, J = 7.2 Hz, [[CH.bar].sub.[3.bar]] - C[H.sub.2]), 1.92-1.80 (m, 2H, C[H.sub.2] - [[CH.bar].sub.[2.bar]] - C[H.sub.2]), 2.3-2.1 (m, 5H, [[CH.bar].sub.[2.bar]] - C[H.sub.2]- and [[CH.bar].sub.[3.bar]] - Ar), 2.65-2.57 (m, 2H, C[H.sub.2] - [[CH.bar].sub.[2.bar]] - C = O), 3.14 (q, 2H, J = 72 Hz, [[CH.bar].sub.[2.bar]] - C[H.sub.3]), 4.90 (s, 1H, CH), 6.99 (d, 2H, J = 76 Hz, Ar-H), 708 (d, 2H, J = 76 Hz, Ar-H), 9.79 (s, 1H, NH), 12.31 (br s, 1H, NH - C = O) ppm. [sup.13]C NMR (100 MHz, DMSO-[d.sub.6]): [delta] = 15.1 (Me), 21.0 (Me), 21.3 (C[H.sub.2]), 24.5 (C[H.sub.2]), 26.8 (C[H.sub.2]), 26.9 ([C.bar][H.sub.2] - C = O), 33.3 (CH), 98.6, 111.2, 127.8, 128.9, 135.2, 144.2, 153.2, 153.3, 194.8 (C = O) ppm. Anal. Cald. for [C.sub.20][H.sub.21][N.sub.3][O.sub.2]S (367.46): C, 65.37; H, 5.76; N, 11.41%; Found: C, 65.21; H, 5.52; N, 11.25%.

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2.3.22. 2-(Ethylthio)-5-(4-methoxyphenyl)-5, 8, 9, 10-tetrahydro-3H, 7H-pyrimido[4, 5-b]quinoline-4, 6-dione(6d). White Powder; M.p.: 288-290[degrees]C; IR (KBr): [v.sub.max] = 3225, 3140, 3067, 3030, 2949, 1649, 1608, 1553, 1479, 1366, 1184, 1230, 1034, 835 [cm.sup.-1]. [sup.1]H NMR (400 MHz, DMSO-[d.sub.6]): [delta] = 1.31 (t, 3H, J = 7.2 Hz, C[H.sub.3]), 1.95-1.81 (m, 2H, C[H.sub.2] - [[CH.bar].sub.[2.bar]] - C[H.sub.2]), 2.23 (m, 2H, C[H.sub.2] - [[CH.bar].sub.[2.bar]]-), 2.60 - 2.55 (m, 2H, C[H.sub.2] - [[CH.bar].sub.[2.bar]] - C = O), 3.13 (q, 2H, J = 72 Hz, [[CH.bar].sub.[2.bar]] - C[H.sub.3]), 3.67 (s, 3H, OC[H.sub.3]), 4.89 (s, 1H, CH), 6.75 (d, 2H, J = 8.4 Hz, Ar-H), 7.10 (d, 2H, J = 8.4 Hz, Ar-H), 9.78 (s, 1H, NH), 12.30 (br s, 1H, NH - C = O) ppm. [sup.13]C NMR (100 MHz, DMSO-[d.sub.6]): [delta] = 15.1 (Me), 21.3 (MeO), 24.5 (C[H.sub.2]), 26.9 (C[H.sub.2]), 32.8 (C[H.sub.2]), 37.2 ([C.bar][H.sub.2] - C = O), 55.4 (CH), 98.8, 111.3, 113.7, 128.8, 139.5, 153.1, 153.2, 157.9, 162.0 (CONH), 194.8 (C = O) ppm. Anal. Cald. for [C.sub.22][H.sub.21][N.sub.3][O.sub.2]S (383.46): C, 62.64; H, 5.52; N, 10.96%; Found: C, 62.64; H, 5.58; N, 1085%.

2.3.23. 2-(Ethylthio)-5-(5-methylthiophen-2-yl)-5, 8, 9, 10-tetrahydro-3H, 7H-pyrimido[4, 5-b]quinoline-4, 6-dione (6e). White Powder; M.p.: 280-282[degrees]C; IR (KBr): [v.sub.max] = 3223, 3138, 3067, 3030, 2951, 2872, 1649, 1607, 1553, 1479, 1448, 1364, 1182, 798 [cm.sup.-1]. [sup.1]HNMR (400 MHz, DMSO-[d.sub.6]): [delta] = 1.32 (t, 3H, J = 7.2 Hz, C[H.sub.3]), 1.98-1.85 (m, 2H, C[H.sub.2] - [[CH.bar].sub.[2.bar]] - C[H.sub.2]-), 2.27 (m, 2H, C[H.sub.2] - [[CH.bar].sub.[2.bar]]-), 2.30 (s, 3H, C[H.sub.3]-Ar), 2.62-2.54 (m, 2H, C[H.sub.2] - [[CH.bar].sub.[2.bar]] - C = O), 3.13 (q, 2H, J = 7.2 Hz, [[CH.bar].sub.[2.bar]] - C[H.sub.3]), 5.15 (s, 1H, CH)76.48 (s, 2H, Ar-H), 9.90 (s, 1H, NH), 12.41 (br s, 1H, NH - C = O) ppm. [sup.13]C NMR (100 MHz, DMSO-[d.sub.6]): [delta] = 15.1 (Me), 15.4 (Me), 21.3 (C[H.sub.2]), 24.6 (C[H.sub.2]), 26.9 (C[H.sub.2]), 28.6 ([C.bar][H.sub.2] - C = O), 37.2 (CH), 98.0, 110.6, 123.0, 125.0, 137.0, 148.6, 152.5, 153.4, 162.0 (CONH), 194.7 (C = O) ppm. Anal. Cald. for [C.sub.18][H.sub.19][N.sub.3][O.sub.2][S.sub.2](373.09): C, 57.88; H, 5.13; N, 11.25%; Found: C, 57.95; H, 5.20; N, 11.10%.

2.3.24. 5-(4-Chlorophenyl)-2-(ethylthio)-5, 8, 9, 10-tetrahydro-3H, 7H-pyrimido[4, 5-b]quinoline-4, 6-dione (6f). White Powder; M.p.: 262-265[degrees]C; IR (KBr) [v.sub.max] = 3261, 3182, 3045, 2941, 2822, 1647, 1553, 1500, 1454, 1342, 1188, 1063, 825 [cm.sup.-1]. [sup.1]HNMR (400 MHz, DMSO-[d.sub.6]): [delta] = 1.31 (t, 3H, J = 7.2 Hz, C[H.sub.3]), 1.95-1.82 (m, 2H, C[H.sub.2] - [[CH.bar].sub.[2.bar]] - C[H.sub.2]), 2.25-2.21 (m, 2H, C[H.sub.2] - [[CH.bar].sub.[2.bar]]-), 2.65-2.55 (m, 2H, C[H.sub.2] - [[CH.bar].sub.[2.bar]] - C = O), 3.13 (q, 2H, J = 72 Hz, [[CH.bar].sub.[2.bar]] - C[H.sub.3]), 4.92 (s, 1H, CH), 7.21 (d, 2H, J = 8.4 Hz, Ar-H), 7.25 (d, 2H, J = 8.4 Hz, Ar-H), 9.86 (s, 1H, NH), 12.36 (br s, 1H, NH - C = O) ppm. [sup.13]CNMR (100 MHz, DMSO-[d.sub.6]): [delta] = 15.1 (Me), 21.2 (C[H.sub.2]), 24.6 (C[H.sub.2]), 26.8 (C[H.sub.2]), 33.6 ([C.bar][H.sub.2] - C = O), 37.1 (CH), 98.1, 110.7, 110.7, 128.2, 129.8, 130.8, 131.6, 146.0, 153.6, 153.7, 194.9 (C = O) ppm. Anal. Cald. for [C.sub.19][H.sub.18]Cl[N.sub.3][O.sub.2]S (387.89): C, 58.83; H, 4.68; N, 10.83%; Found: C, 58.70; H, 4.47; N, 10.68%.

3. Results and Discussion

As part of our continuing efforts on the development of new synthetic strategies for the preparation of heterocyclic compounds [42-48], herein we wish to report one-pot three-component synthesis of fused pyridopyrimidines under sonochemical conditions without the use of catalyst(Schemes 1 and 2).

In the initial experiment, to optimize the reaction conditions, different solvents were screened for the synthesis of 5-(4-chlorophenyl)-2-(methylthio)-3H-indeno [5, 6:1', 2']pyrido[2, 3-d]pyrimidine-4, 6 (5H, 11H)-dione 4a as a model reaction. The reaction between equimolar amounts of 6-amino-2-(methylthio)pyrimidin-4(3H)-one 1 (prepared by the condensation of thiourea with ethylcyanoacetate in sodium ethoxide and followed by alkylation with alkyliodide [49]), 1, 3-indanedione 2, and 4-chlorobenzaldehyde were examined in various solvents and different temperatures (25, 50, 65, and 80[degrees]C) under sonochemical conditions. The results of this study are summarized in Table 1. It is evident from the results that ethylene glycol is the most effective solvent among the selected solvents, giving the highest yield (95%) and lower reaction time (25 min) under ultrasound irradiation (entry 1). For comparison, the preparation of 4a was carried out under conventional heating at reflux conditions which furnished

the desired product at lower yield and much higher reaction time (180 min) (Table 1, entry 1). The results revealed that the reaction induced by ultrasonic irradiations offered better result than the conventional condition (Figure 1).

Using the optimized reaction conditions various derivatives of indenopyrido[2,3-d]pyrimidines 4a-r (Scheme 1) were prepared in high to excellent yields (85-97%) and lower reaction times (Table 2).

Due to remarkable results from the above experiments, we decided to broaden the scope of this protocol for the synthesis of quinoline derivatives as another fused pyrimidine derivative. We investigated the reaction between 6-amino-2-(ethylthio)pyrimidin-4(3H)-one 1, 1, 3-cyclohexadione 5, and arylaldehydes 3 under the aforementioned optimized reaction conditions and obtained pyrimido[4, 5-b]quinoline-4, 6-diones 6a-f (Scheme 2) in high yields (82-95%) and short reaction times (10-25 min) (Table 3).

[FORMULA NOT REPRODUCIBLE IN ASCII]

The plausible mechanism of this MCRs involves Knoevenagel condensation between CH-acid (2 or 5) and aryl aldehydes (3) resulting in the arylidene intermediate 7, followed by Michael addition of enaminone 1, cyclization, and removal of [H.sub.2]O to form the desired products (4 or 6) (Scheme 3).

All the synthesized pyridopyrimidine derivatives were characterized on the basis of elemental and spectral ([sup.1]H NMR, [sup.13]CNMR, and IR) analyses.

4. Conclusion

In summary, we have developed a simple, green, and efficient protocol for the synthesis of novel fused derivatives of pyrimidine under ultrasonic irradiations. The easy work of the products, without the use of catalyst, mild reaction condition, high to excellent yields, short reaction times, and cleaner reaction profiles are the notable features of this protocol. The method is amenable for the iterative generation of combinatorial libraries.

http://dx.doi.org/10.1155/2014/406869

Conflict of Interests

The authors declare that there is no conflict of interests regarding the publication of this paper.

Acknowledgments

The authors are grateful to the Research Council of University of Guilan and Islamic Azad University, Rasht Branch, for financial support of this work.

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M. Mamaghani, (1) K. Tabatabaeian, (1) R. Araghi, (1) A. Fallah, (2) and R. Hossein Nia (1)

(1) Department of Chemistry, Faculty of Sciences, University of Guilan, P.O. Box 41335-1914, Rasht, Iran

(2) Department of Chemistry, Faculty of Sciences, Islamic Azad University, Rasht Branch, P.O. Box 41335-3516, Rasht, Iran

Correspondence should be addressed to M. Mamaghani; mchem41@gmail.com

Received 26 August 2014; Accepted 27 October 2014; Published 16 November 2014

Academic Editor: Jonathan White

TABLE 1: Effect of various solvents in the synthesis of 4a under
conventional conditions and ultrasonic irradiations.

Entry       SOLVENT         Conventional method    Sonochemical method

                           Time (min)    Yield    Time (min)    Yield
                                        (%) (a)                (%) (a)

1       ETHYLENE GLYCOL       180       90 (b)        25       95 (c)
2             ACOH            180         86          29         90
3             DMF             210         82          29         88
4             ETOH            220         84          30         88
5          [H.SUB.2]O         240         78          41         83
6           ACETONE           240         70          42         76
7         CH[CL.SUB.3]        270         66          47         70
8         C[H.SUB.3]CN        300         60          50         65

(a) Isolated yield.

(b) Reflux temperature.

(c) 65[degrees]C.

TABLE 2: Synthesis of indenopyrido[2,3-d]pyrimidine 4a-r.

Entry   Product   R               Ar                Time (min)

1         4a      Me    4-Cl[C.sub.6][H.sub.4]          25

2         4b      Me      [C.sub.6][H.sub.5]            33

3         4c      Me    4-Br[C.sub.6][H.sub.4]     28 (220) (b)

4         4d      Me     4-F[C.sub.6][H.sub.4]     20 (160) (b)

5         4e      Me    2-Br[C.sub.6][H.sub.4]     30 (220) (b)

6         4f      Me    2-Cl[C.sub.6][H.sub.4]     27 (210) (b)

7         4g      Me    2-OH[C.sub.6][H.sub.4]     32 (240) (b)

8         4h      Me        2,4-[Cl.sub.2]         20 (160) (b)
                          [C.sub.6][H.sub.3]

9         4i      Me         2-N[O.sub.2]          22 (170) (b)
                          [C.sub.6][H.sub.4]

10        4g      Me         4-OC[H.sub.3]              35
                          [C.sub.6][H.sub.4]

11        4k      Me         4-C[H.sub.3]               35
                          [C.sub.6][H.sub.4]

12        4l      Me   3,4-[(OC[H.sub.3]).sub.2]   35 (280) (b)
                          [C.sub.6][H.sub.3]

13        4m      Et        2,4-[Cl.sub.2]         15 (180) (b)
                          [C.sub.6][H.sub.3]

14        4n      Et    4-Cl[C.sub.6][H.sub.4]     20 (185) (b)

15        4o      Et     2-F[C.sub.6][H.sub.4]          18

16        4p      Et    4-Br[C.sub.6][H.sub.4]          25

17        4q      Et    4-MeS[C.sub.6][H.sub.4]         22

18        4r      Et      [C.sub.6][H.sub.5]            27

Entry      Yield
          (%) (a)

1           95

2           92

3       95 (91) (b)

4       97 (85) (b)

5       94 (88) (b)

6       96 (89) (b)

7       90 (90) (b)

8       96 (90) (b)

9       97 (90) (b)

10          90

11          93

12      90 (85) (b)

13      95 (90) (b)

14      89 (80) (b)

15          86

16          85

17          85

18          87

(a) Isolated yield.

(b) Conventional conditions.

TABLE 3: Synthesis of pyrimido[4,5-fo]quinoline 6a-f.

Entry   Product                  Ar                    Time (min)

1         6a            4-F[C.sub.6][H.sub.4]         10 (180) (b)
2         6b                  1-naphtyl               15 (230) (b)
3         6c       4-C[H.sub.3][C.sub.6][H.sub.4]     20 (270) (b)
4         6d      4-C[H.sub.3]O[C.sub.6] [H.sub.4]         23
5         6e            5-methylthiophen-2-yl              25
6         6f           4-Cl[C.sub.6][H.sub.4]              17

Entry   Yield (%) (a)

1        95 (90) (b)
2        93 (87) (b)
3        89 (82) (b)
4            87
5            82
6            90

(a) Isolated yields.

(b) Conventional conditions.
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Author:Mamaghani, M.; Tabatabaeian, K.; Araghi, R.; Fallah, A.; Nia, R. Hossein
Publication:Organic Chemistry International
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Date:Jan 1, 2014
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