Table of Contents
Organic Chemistry International
Volume 2014, Article ID 406869, 9 pages
http://dx.doi.org/10.1155/2014/406869
Research Article

An Efficient, Clean, and Catalyst-Free Synthesis of Fused Pyrimidines Using Sonochemistry

1Department of Chemistry, Faculty of Sciences, University of Guilan, P.O. Box 41335-1914, Rasht, Iran
2Department of Chemistry, Faculty of Sciences, Islamic Azad University, Rasht Branch, P.O. Box 41335-3516, Rasht, Iran

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

Academic Editor: Jonathan White

Copyright © 2014 M. Mamaghani et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

In this report, synthesis of indenopyrido[2,3-d]pyrimidine and pyrimido[4,5-b]quinoline derivatives was investigated via one-pot three-component reaction between 6-amino-2-(alkylthio)-pyrimidin-4(3H)one, 1,3-indanedione, or 1,3-cyclohexadione and arylaldehyde under ultrasonic irradiation in ethylene glycol as solvent at 65°C. In these reactions fused pyrimidine derivatives were synthesized with high to excellent yields (82–97%) and short reaction times (10–33 min).

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 [13], antiviral [46], 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[2,3-d]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 [2025].

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 [3237]. A large number of organic reactions can be carried out in higher yield, shorter reaction time, and under milder conditions, by using ultrasonic irradiation [3841].

These observations led us to attempt the synthesis of some new fused pyrimidine derivatives using 6-amino-alkyltiouracil 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. 1H NMR and 13C NMR spectra were recorded on a 400 MHz Bruker DRX-400 in DMSO-d6 as solvent and TMS as an internal standard. Chemical shifts on 1H and 13C 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 (1 mmol), 1,3-indanedione 2 (1 mmol), 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°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/H2O (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°C; IR (KBr) , 3410, 3271, 3062, 2932, 1680, 1653, 1585, 1541, 1502, 1452, 1350, 1271, 1078, 899, 742, 707 cm−1. 1H NMR (400 MHz, DMSO-d6): δ = 2.60 (s, 3H, CH3), 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. 13C NMR (100 MHz, DMSO-d6): δ = 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 C21H14ClN3O2S (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°C; IR (KBr) , 3040, 2922, 2851, 1685, 1647, 1582, 1537, 1500, 1456, 1358, 1273, 742, 702 cm−1. 1H NMR (400 MHz, DMSO-d6): δ = 2.60 (s, 3H, CH3), 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. 13C NMR (100 MHz, DMSO-d6): δ = 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 C21H15N3O2S: (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°C; IR (KBr): , 3300, 3100, 3080, 2920, 2820, 1690, 1640, 1618, 1558, 1498, 1440, 1348, 1270, 1070, 850, 800, 760 cm−1. 1H NMR (400 MHz, DMSO-d6): δ = 2.60 (s, 3H, CH3), 4.80 (s, 1H, CH), 7.21 (d, 2H, J = 7.60 Hz, Ar-H), 7.26 (d, 1H, J = 6.80 Hz, Ar-H), 7.35 (t, 1H, J = 7.20 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. 13C NMR (100 MHz, DMSO-d6): δ; 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 C21H14BrN3O2S (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°C; IR (KBr): , 3400, 3026, 2921, 2840, 1677, 1641, 1602, 1578, 1539, 1493, 1458, 1357, 1275, 1149, 843, 798, 748, 709 cm−1. 1H NMR (400 MHz, DMSO-d6): δ = 2.60 (s, 3H, CH3), 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 = 7.40 Hz, Ar-H), 7.45 (t, 1H, J = 7.20 Hz, Ar-H), 7.79 (d, 1H, J = 7.20 Hz, Ar-H), 11.10 (br s, 1H, NH), 12.56 (br s, 1H, CO–NH) ppm. 13C NMR (100 MHz, DMSO-d6): δ = 13.3 (Me), 34.0 (CH), 99.6, 108.1, 114.9 (d,  Hz), 120.3, 120.7, 129.9 (d,  Hz), 130.6, 132.1, 133.9, 136.8, 142.6, 153.3, 156.1, 158.9, 160.6 (d,  Hz), 191.0 (C=O) ppm. Anal. Cald. for C21H14FN3O2S (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°C; IR (KBr): , 3300, 3110, 3080, 2920, 2820, 1690, 1645, 1618, 1558, 1498, 1440, 1347, 1270, 1070, 895, 845, 800, 760, 710 cm−1. 1H NMR (400 MHz, DMSO-d6): δ = 2.60 (s, 3H, CH3), 5.24 (s, 1H, CH), 7.06 (dt, 1H, J = 8.40 Hz, 2.2 Hz, Ar-H), 7.28–7.21 (m, 3H, Ar-H), 7.35 (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. 13C NMR (100 MHz, DMSO-d6): δ = 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 C21H14BrN3O2S (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°C; IR (KBr): , 3385, 3120, 3060, 2930, 2854, 1685, 1649, 1616, 1580, 1541, 1502, 1445, 1345, 1277, 1078, 893, 764 cm−1. 1H NMR (400 MHz, DMSO-d6): δ = 2.60 (s, 3H, CH3), 5.24 (s, 1H, CH), 7.15 (d, 1H, J = 7.20 Hz, Ar-H), 7.21 (t, 2H, J = 7.40 Hz, Ar-H), 7.29 (d, 2H, J = 7.20 Hz, Ar-H), 7.35 (t, 1H, J = 7.20 Hz, Ar-H), 7.44 (t, 1H, J = 7.20 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. 13C NMR (100 MHz, DMSO-d6): δ = 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 C21H14ClN3O2S (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°C; IR (KBr): , 3270, 3050, 2920, 2820, 1700, 1645, 1620, 1600, 1560, 1500, 1440, 1347, 1280, 1180, 868, 800, 760, 700 cm−1. 1H NMR (400 MHz, DMSO-d6): δ = 2.59 (s, 3H, CH3), 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. 13C NMR (100 MHz, DMSO-d6): δ = 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 C21H15N3O3S (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°C; IR (KBr): , 3228, 3066, 2940, 2854, 1683, 1649, 1580, 1539, 1506, 1460, 1352, 1275, 1103, 1060, 858, 764, 704 cm−1. 1H NMR (400 MHz, DMSO-d6): δ = 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. 13C NMR (100 MHz, DMSO-d6): δ = 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 C21H13Cl2N3O2S: (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°C; IR (KBr): , 3060, 2923, 1685, 1649, 1578, 1540, 1504, 1450, 1539, 1342, 1277, 770, 708 cm−1. 1H NMR (400 MHz, DMSO-d6): δ = 2.60 (s, 3H, CH3), 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. 13C NMR (100 MHz, DMSO-d6): δ = 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 C21H14N4O4S (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°C; IR (KBr): , 3040, 2920, 2851, 1674, 1645, 1606, 1554, 1500, 1442, 1352, 1261, 1219, 1020, 898, 835, 766, 706 cm−1. 1H NMR (400 MHz, DMSO-d6): δ = 2.59 (s, 3H, CH3), 3.68 (s, 3H, OCH3), 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 = 7.20 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. 13C NMR (100 MHz, DMSO-d6): δ = 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 C22H17N3O3S: (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°C; IR (KBr): , 3227, 3059, 2940, 2854, 1681, 1645, 1585, 1539, 1504, 1456, 1350, 1275, 897, 773 cm−1. 1H NMR (400 MHz, DMSO-d6): δ = 2.21 (s, 3H, CH3), 2.59 (s, 3H, CH3), 4.77 (s, 1H, CH), 7.03 (d, 2H, J = 7.20 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 = 7.20 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. 13C NMR (100 MHz, DMSO-d6): δ = 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 C22H17N3O2S: (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°C; IR (KBr): , 3223, 3130, 3063, 2933, 2839, 1691, 1653, 1554, 1504, 1450, 1340, 1226, 1024, 897, 798, 764, 710 cm−1. 1H NMR (400 MHz, DMSO-d6): δ = 2.60 (s, 3H, SCH3), 3.67 (s, 3H, OCH3), 3.71 (s, 3H, OCH3), 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 = 7.20 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. 13C NMR (100 MHz, DMSO-d6): δ = 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 C23H19N3O4S: (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°C; IR (KBr): , 3136, 3059, 2966, 2926, 1649, 1607, 1550, 1502, 1450 1350, 1190, 1101, 1070, 858, 764, 700 cm−1. 1H NMR (400 MHz, DMSO-d6): δ = 1.36 (t, 3H, J = 7.1 Hz, CH3), 3.22 (q, 2H, J = 7.1 Hz, CH2), 5.22 (s, 1H, CH), 7.22 (d, 1H, J = 6.8 Hz, Ar-H), 7.46–7.26 (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. 13C NMR (100 MHz, DMSO-d6): δ = 15.0 (Me), 24.7 (CH2), 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 C22H15Cl2N3O2S (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-indeno[2′,1′:5,6]pyrido[2,3-d]pyrimidine-4,6-dione (4n)

Red Powder; M.p.: 268–270°C, IR (KBr): , 3140, 3063, 2876, 1649, 1545, 1504, 1452, 1350, 1188, 1146, 860, 764, 704 cm−1. 1H NMR (400 MHz, DMSO-d6): δ = 1.36 (t, 3H, J = 7.2 Hz, CH3), 3.23 (q, 2H, J = 7.2 Hz, CH2), 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. 13C NMR (100 MHz, DMSO-d6): δ = 15.1 (Me), 24.6 (CH2), 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 C22H16ClN3O2S (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-indeno[2′,1′:5,6]pyrido[2,3-d]pyrimidine-4,6-dione (4o)

Red Powder; M.p.: 257–259°C; IR (KBr): , 3132, 3057, 2932, 1684, 1647, 1583, 1539, 1491, 1350, 1263, 1182, 760, 706 cm−1. 1H NMR (400 MHz, DMSO-d6): δ = 1.37 (t, 3H, J = 7.2 Hz, CH3), 3.23 (q, 2H, J = 7.2 Hz, CH2), 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. 13C NMR (100 MHz, DMSO-d6): δ = 15.1 (Me), 24.6 (CH2), 29.0 (CH), 99.4, 107.4, 115.5 ( = 22.0 Hz), 120.4 ( = 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 ( Hz), 191.0 (C=O) ppm. Anal. Cald. for C22H16FN3O2S (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°C, IR (KBr): , 2858, 1645, 1578, 1539, 1499, 1450, 1352, 1182, 1016, 797, 708 cm−1. 1H NMR (400 MHz, DMSO-d6): δ = 1.36 (t, 3H, J = 7.2 Hz, CH3), 3.23 (q, 2H, J = 7.2 Hz, CH2), 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; 13C NMR (100 MHz, DMSO-d6): δ = 15.1 (Me), 24.6 (CH2), 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 C22H16BrN3O2S (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°C; IR (KBr) , 3138, 3057, 2964, 2922, 1645, 1551, 1499, 1450, 1354, 1184, 835, 768, 712 cm−1. 1H NMR (400 MHz, DMSO-d6): δ = 1.36 (t, 3H, J = 7.2 Hz, CH3), 2.41 (s, 3H, CH3), 3.22 (q, 2H, J = 7.2 Hz, CH2), 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. 13C NMR (100 MHz, DMSO-d6): δ = 15.1 (Me), 15.4 (Me), 24.7 (CH2), 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 C23H19N3O2S2(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°C; IR (KBr): , 3026, 2922, 2849, 1716, 1645, 1541, 1495, 1452, 1352, 1184, 744, 710 cm−1. 1H NMR (400 MHz, DMSO-d6): δ = 1.36 (t, 3H, J = 7.2 Hz, CH3), 3.23 (q, 2H, J = 7.2 Hz, CH2), 4.82 (s, 1H, CH), 7.13 (m, 1H, Ar-H), 7.24 (m, 5H, Ar-H), 7.35 (t, 1H, J = 7.4 Hz, Ar-H), 7.44 (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. 13C NMR (100 MHz, DMSO-d6): δ = 15.1 (Me), 24.6 (CH2), 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 C22H17N3O2S (387.10): 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°C; IR (KBr): , 3142, 3067, 3032, 2957, 2880, 1647, 1607, 1553, 1483, 1364, 1226, 1186, 837, 797 cm−1. 1H NMR (400 MHz, DMSO-d6): δ = 1.31 (t, 3H, J = 7.2 Hz, CH3), 1.95–1.82 (m, 2H, CH2CH2–CH2), 2.29–2.18 (m, 2H, CH2CH2–), 2.66–2.56 (m, 2H, CH2CH2–C=O), 3.13 (q, 2H, J = 7.2 Hz,   CH2–CH3), 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. 13C NMR (100 MHz, DMSO-d6): δ = 15.1 (Me), 21.3 (CH2), 24.5 (CH2), 26.9 (CH2), 33.2 (CH2–C=O), 37.2 (CH), 98.4, 110.9, 115.0 ( = 21.0 Hz), 129.6 ( = 8.0 Hz), 143.3 ( = 2.0 Hz), 152.4, 153.5, 153.6, 161.0 ( = 240.0 Hz), 162.2 (CONH), 195.0 (C=O) ppm. Anal. Cald. for C19H18FN3O2S (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°C; IR (KBr): , 3138, 3063, 3028, 2953, 2874, 1647, 1607, 1554, 1479, 1450, 1366, 1186, 797, 752 cm−1. 1H NMR (400 MHz, DMSO-d6): δ = 1.31 (t, 3H, J = 7.2 Hz, CH3), 1.94–1.85 (2H, m, CH2CH2–CH2), 2.31–2.18 (m, 2H,   CH2–CH2–), 2.70–2.60 (m, 2H, CH2CH2–C=O), 3.15 (q, 2H, J = 7.2 Hz,  CH2–CH3), 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. 13C NMR (100 MHz, DMSO-d6): δ = 15.1 (Me), 21.3 (CH2), 24.5 (CH2), 26.9 (CH2), 27.0 (CH2–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 C23H21N3O2S (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°C; IR (KBr): , 3142, 3067, 2878, 1649, 1614, 1556, 1475, 1366, 1186, 794 cm−1. 1H NMR (400 MHz, DMSO-d6): δ = 1.31 (t, 3H, J = 7.2 Hz,    CH3–CH2), 1.92–1.80 (m, 2H, CH2CH2–CH2), 2.3–2.1 (m, 5H,    CH2–CH2– and   CH3-Ar), 2.65–2.57 (m, 2H, CH2CH2–C=O), 3.14 (q, 2H, J = 7.2 Hz,    CH2–CH3), 4.90 (s, 1H, CH), 6.99 (d, 2H, J = 7.6 Hz, Ar-H), 7.08 (d, 2H, J = 7.6 Hz, Ar-H), 9.79 (s, 1H, NH), 12.31 (br s, 1H, NH–C=O) ppm. 13C NMR (100 MHz, DMSO-d6): δ = 15.1 (Me), 21.0 (Me), 21.3 (CH2), 24.5 (CH2), 26.8 (CH2), 26.9 (CH2–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 C20H21N3O2S (367.46): C, 65.37; H, 5.76; N, 11.41%; Found: C, 65.21; H, 5.52; N, 11.25%.

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°C; IR (KBr): , 3140, 3067, 3030, 2949, 1649, 1608, 1553, 1479, 1366, 1184, 1230, 1034, 835 cm−1. 1H NMR (400 MHz, DMSO-d6): δ = 1.31 (t, 3H, J = 7.2 Hz, CH3), 1.95–1.81 (m, 2H, CH2CH2–CH2), 2.23 (m, 2H, CH2CH2–), 2.60–2.55 (m, 2H, CH2CH2–C=O), 3.13 (q, 2H, J = 7.2 Hz,    CH2–CH3), 3.67 (s, 3H, OCH3), 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. 13C NMR (100 MHz, DMSO-d6): δ = 15.1 (Me), 21.3 (MeO), 24.5 (CH2), 26.9 (CH2), 32.8 (CH2), 37.2 (CH2–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 C22H21N3O2S (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°C; IR (KBr): , 3138, 3067, 3030, 2951, 2872, 1649, 1607, 1553, 1479, 1448, 1364, 1182, 798 cm−1. 1H NMR (400 MHz, DMSO-d6): δ = 1.32 (t, 3H, J = 7.2 Hz, CH3), 1.98–1.85 (m, 2H, CH2CH2–CH2–), 2.27 (m, 2H, CH2CH2–), 2.30 (s, 3H, CH3-Ar), 2.62–2.54 (m, 2H, CH2CH2–C=O), 3.13 (q, 2H, J = 7.2 Hz,    CH2–CH3), 5.15 (s, 1H, CH), 6.48 (s, 2H, Ar-H), 9.90 (s, 1H, NH), 12.41 (br s, 1H, NH–C=O) ppm. 13C NMR (100 MHz, DMSO-d6): δ = 15.1 (Me), 15.4 (Me), 21.3 (CH2), 24.6 (CH2), 26.9 (CH2), 28.6 (CH2–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 C18H19N3O2S2(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°C; IR (KBr) , 3182, 3045, 2941, 2822, 1647, 1553, 1500, 1454, 1342, 1188, 1063, 825 cm−1. 1H NMR (400 MHz, DMSO-d6): δ = 1.31 (t, 3H, J = 7.2 Hz, CH3), 1.95–1.82 (m, 2H, CH2CH2–CH2), 2.25–2.21 (m, 2H, CH2CH2–), 2.65–2.55 (m, 2H, CH2CH2–C=O), 3.13 (q, 2H, J = 7.2 Hz,    CH2–CH3), 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. 13C NMR (100 MHz, DMSO-d6): δ = 15.1 (Me), 21.2 (CH2), 24.6 (CH2), 26.8 (CH2), 33.6 (CH2–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 C19H18ClN3O2S (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 [4248], 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).

406869.sch.001
Scheme 1: Synthesis of indenopyrido[2,3-d]pyrimidine (4a–r).
406869.sch.002
Scheme 2: Synthesis of of pyrimido[4,5-b]quinoline 6a–f.

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°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).

tab1
Table 1: Effect of various solvents in the synthesis of 4a under conventional conditions and ultrasonic irradiations.
406869.fig.001
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).

tab2
Table 2: Synthesis of indenopyrido[2,3-d]pyrimidine 4ar.

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).

tab3
Table 3: Synthesis of pyrimido[4,5-b]quinoline 6af.

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 H2O to form the desired products (4 or 6) (Scheme 3).

406869.sch.003
Scheme 3: The plausible mechanism of synthesis of fused pyrimidine derivatives 4a–r and 6a–f.

All the synthesized pyridopyrimidine derivatives were characterized on the basis of elemental and spectral (1H NMR, 13C NMR, 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.

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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