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One Pot Synthesis of Novel Cyanopyridones as an Intermediate of Bioactive Pyrido[2,3-d]Pyrimidines
One Pot Synthesis of Novel Cyanopyridones as an Intermediate of Bioactive Pyrido[2,3-d]Pyrimidines
Journal of the Korean Chemical Society. 2014. Aug, 58(4): 366-376
Copyright © 2014, Korea Chemical Society
  • Received : February 26, 2014
  • Accepted : May 29, 2014
  • Published : August 20, 2014
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About the Authors
Taslimahemad T. Khatri
Viresh H. Shah
Department of Chemistry, Saurashtra University, Kalawad road, Rajkot 360 005, Gujarat, India

Abstract
Synthesis, structural characterization, and biological activity studies of novel pyrido[2,3- d ]pyrimidines ( 10a–h, 11a–h ) are described. Cyclization of cynoacetamides ( 4, 5 ) with malonitrile ( 7 ) and aldehyde ( 6a–h ) via Hantzsch pyridine synthesis afforded cyanopyridones ( 8a–h, 9a–h ), which on cyclization with formic acid under microwave conditions led to the final product. All the reactions are significantly faster and the isolated yields are remarkably higher in microwave conditions compared to the conventionally heated reactions. The compounds were tested in vitro for their antibacterial activity against Escherichia coli, Pseudomonas aeruginosa, Bacillus subtillus, Staphylococcus aureus , and Micrococcus luteus and antifungal activity against Trichphyton longifusus, Candida albicans, Microsporum canis, Fusarium solani . Compounds 10b, 10e, 11b and 11e exhibited good antibacterial and antifungal activities compared with standards.
Keywords
INTRODUCTION
In the past few years, heating and driving chemical reactions by microwave energy has been an increasingly popular theme in the scientific community because it increases reaction rates and yields under milder conditions. 15 The combination of solvent-free reaction conditions and microwave irradiation leads to large reduction in reaction times, enhancement in conversion and sometimes in selectivity with several advantages of the eco-friendly approach, termed green chemistry. 6,7 Bicyclic nitrogen-containing heterocyclic compounds, such as purines 810 quinazolines 1113 and pyridopyrimidines 1417 are well-known pharmacophores in drug discovery. Pyrido[2,3- d ]pyrimidines have been the most thoroughly investigated of the four possible pyrido pyrimidine ring systems and hence, this scaffold is associated with a wide range of biological activities, such as dihydrofolate reductase (DHFR) inhibitory activity, antitumor activity, 1821 adenosine kinase inhibition 22 and tyrosine kinase inhibition. 23
Keeping in mind our previous efforts 24 and the biomedical applications of pyrido[2,3- d ]pyrimidines, with a view to further assess the pharmacological profile of this class of compounds, it was thought worthwhile to synthesize some new congeners of this class. Herein, we report the solvent free approach to synthesis of 4,7-dioxo-5,8-diphenyl-3,4,7,8- tetrahydropyrido[2,3- d ]pyrimidine-6-carbonitriles ( 10, 11 ) under microwave irradiation with high yields. Results from assessment of the antimicrobial activity of these newly synthesized compounds are reported in this study.
EXPERIMENTAL
Melting points were determined in open capillary tubes and are uncorrected. Formation of the compounds was routinely checked by TLC (Kieselgel 60, F 254 ) of 0.5 mm thickness and spots were located by iodine and UV. The microwave-assisted reactions were realized in a QPro-M microwave synthesizer. IR spectra were recorded on Shimadzu FT-IR-8400 instrument using KBr pellet method. Mass spectra were recorded on Shimadzu GCMS-QP- 2010 model using Direct Injection Probe technique. 1 H NMR and 13 C NMR were determined in DMSO- d 6 solution on a Bruker Ac 400 MHz FT NMR spectrometer with TMS as internal standard. Elemental analysis of the all the synthesized compounds was carried out on Elemental Vario EL III Carlo Erba 1108 model and the results are in agreements with the structures assigned.
- General procedure for synthesis of 2-cyano-N-phenylacetamide (4, 5)
10 mmol of aromatic amines ( 1, 2 ) and 20mmol of cyanoacetic acid ester ( 3 ) were refluxed for 8–10 h on oil bath in solvent free condition (under TLC analysis). After completion of the reaction, the reaction mixture was cooled to room temperature; separated product was filtered, washed with methanol and crystallized from methanol to afford the desired products 4, 5 .
- General procedure for synthesis of 6-amino-1,2-dihydro-4-(aryl)-2-oxo-1-(aryl)pyridine-3,5-dicarbonitriles (8, 9)
10 mmol of 2-cyano- N -phenylacetamides ( 4, 5 ), 10 mmol of aromatic aldehyde ( 6a–h ) and malononitrile ( 7 ) were dissolved in 20 ml of methanol. The reaction mixture was heated on water bath for 8–16 h using piperidine as catalyst 24 (under TLC analysis). After completion of the reaction, the reaction mixture was cooled to room temperature; separated product was filtered, washed with methanol and crystallized from DMF to afford the desired products 8, 9 . The compound 9d is reported in literature. 25
6-amino-4-(4-methoxyphenyl)-2-oxo-1-phenyl-1,2-dihydropyridine-3,5-dicarbonitrile (8a)
White crystalline solid, IR (KBr): υ max 3350 & 3280 (NH 2 ), 2908 (C=C), 2815 (OCH 3 ), 2225 (CN), 1708 (CO), 1640 (C=C), 1563, 1213 (C−O), 841 cm −1 . MS: m/z 342, 311, 300, 265, 251, 235, 164, 158, 150, 142, 107, 77. Anal. Calcd. for C 20 H 14 N 4 O 2 : C, 70.17; H, 4.12; N, 16.37%. Found: C, 70.12; H, 4.07; N, 16.31%. 1 H NMR (DMSO d 6 , 400 MHz): δ 8.56 (s, −NH 2 , 2H), 7.56−7.58 (d, J = 8.0 Hz, 2CH), 7.44−7.51 (m, 3CH), 7.38−7.41 (d, J = 8.4 Hz, 2CH), 6.82−7.84 (d, J = 8.4 Hz, 2CH), 2.52 (s, −OCH 3 , 3H). 13 C NMR (DMSO- d 6 , 100 MHz): δ 172.8 (C−ArOMe), 169.4 (C−O), 158.1 (C=O), 157.4 (C−NH 2 ), 131.7 (C−N), 130.0 (2CH), 128.8 (C), 127.4 (2CH), 126.2 (CH), 125.3 (2CH), 123.1 (2CH), 116.8 (C), 115.3 (CN), 113.4 (CN), 72.1 (C), 55.2 (OCH 3 ).
6-amino-4-(4-chlorophenyl)-2-oxo-1-phenyl-1,2-dihydropyridine-3,5-dicarbonitrile (8b)
White crystalline solid, IR (KBr): υ max 3410 & 3315 (NH 2 ), 2968 (C=C), 2287 (CN), 1720 (CO), 1613 (C=C), 1539, 839 cm −1 . MS: m/z 347, 311, 304, 254, 202, 164, 142, 111, 77. Anal. Calcd. for C 19 H 11 ClN 4 O: C, 65.81; H, 3.20; N, 16.16%. Found: C, 65.78; H, 3.17; N, 16.12%. 1 H NMR (DMSO- d 6 , 400 MHz): δ 9.12 (s, −NH 2 , 2H), 7.77−7.80 (d, J = 8.4 Hz, 2CH), 7.48−7.51 (d, J = 7.8 Hz, 2CH), 7.41−7.43 (t, J = 7.8 Hz, CH), 7.28−7.30 (t, J = 8.0 Hz, 2CH), 6.99−7.02 (d, J = 8.0 Hz, 2CH). 13 C NMR (DMSO d 6 , 100 MHz): δ 177.2 (C−ArCl), 161.4 (CO), 153.5 (C−NH 2 ), 151.2 (C−Cl), 134.2 (C−N), 134.1 (2CH), 132.2 (C), 126.9 (2CH), 126.4 (CH), 126.2 (2CH), 124.3 (2CH), 117.2 (C), 116.1 (CN), 114.8 (CN), 74.4 (C).
6-amino-4-(3-chlorophenyl)-2-oxo-1-phenyl-1,2-dihydropyridine-3,5-dicarbonitrile (8c)
White crystalline solid, IR (KBr): υ max 3594 & 3267 (NH 2 ), 2953 (C=C), 2227 (CN), 1715 (CO), 1621 (C=C), 1602, 1549, 808 cm −1 . MS: m/z 347, 320, 311, 269, 304, 254, 202, 189, 164, 142, 111, 77. Anal. Calcd. for C 19 H 11 ClN 4 O: C, 65.81; H, 3.20; N, 16.16%. Found: C, 65.77; H, 3.18; N, 16.11%. 1 H NMR (DMSO- d 6 , 400 MHz): δ 8.69 (s, −NH 2 , 2H), 7.51−7.54 (t, J = 10.4 Hz, CH), 7.39−7.43 (d, J = 10.0 Hz, 2CH), 7.36−7.39 (t, J = 8.4 Hz, CH), 7.32−7.34 (t, J = 8.4 Hz, CH), 7.28 (s, CH), 7.12−7.14 (d, J = 8.4 Hz, CH), 7.06−7.09 (d, J = 10.0 Hz, 2CH). 13 C NMR (DMSO- d 6 , 100 MHz): δ 175.5 (C−ArCl), 165.4 (CO), 157.2 (C−NH 2 ), 156.1 (C−Cl), 136.5 (C), 135.4 (C−N), 133.3 (CH), 132.1 (CH), 128.4 (CH), 128.0 (CH), 127.4 (CH), 126.8 (2CH), 125.5 (2CH), 119.3 (C), 117.6 (CN), 114.2 (CN), 76.1 (C).
6-amino-4-(2-chlorophenyl)-2-oxo-1-phenyl-1,2-dihydropyridine-3,5-dicarbonitrile (8d)
White crystalline solid, IR (KBr): υ max 3339 & 3281 (NH 2 ), 3001 (C=C), 2270 (CN), 1680 (CO), 1676 (C=C), 1512, 780 cm −1 . MS: m/z 347, 311, 304, 254, 209, 202, 164, 142, 111, 77. Anal. Calcd. for C 19 H 11 ClN 4 O: C, 65.81; H, 3.20; N, 16.16%. Found: C, 65.79; H, 3.16; N, 16.13%. 1 H NMR (DMSO- d 6 , 400 MHz): δ 8.87 (s, −NH 2 , 2H), 7.62−7.58 (t, J = 11.2 Hz, 2CH), 7.52−7.55 (d, J = 11.2, 2CH), 7.30−7.27 (m, 3CH), 7.22−7.18 (d, J = 9.6, 2CH). 13 C NMR (DMSO- d 6 , 100 MHz): δ 170.0 (C−ArCl), 158.2 (CO), 155.2 (C−NH 2 ), 152.8 (C−Cl), 137.4 (CH), 136.2 (C), 135.2 (CH), 132.6 (C−N), 131.1 (CH), 130.0 (2CH), 129.2 (2CH), 129.0 (CH), 126.2 (CH), 118.9 (C), 117.1 (CN), 115.7 (CN), 72.1(C).
6-amino-4-(4-bromophenyl)-2-oxo-1-phenyl-1,2-dihydropyridine-3,5-dicarbonitrile (8e)
White crystalline solid, IR (KBr): υ max 3384 & 3260 (NH 2 ), 2921 (C=C), 2261 (CN), 1712 (CO), 1653 (C=C), 1551, 841 cm −1 . MS: m/z 391, 373, 347, 321, 312, 164, 154, 142, 77. Anal. Calcd. for C 19 H 11 BrN 4 O: C, 58.33; H, 2.83; N, 14.32%. Found: C, 58.28; H, 2.78; N, 14.27%. 1 H NMR (DMSO- d 6 , 400 MHz): δ 8.91 (s, −NH 2 , 2H), 7.89−7.92 (d, J = 8.0 Hz, 2CH), 7.69−7.73 (d, J = 8.0 Hz, 2CH), 7.31−7.33 (t, J = 8.4 Hz, CH), 7.22−7.25 (t, J = 8.4 Hz, 2CH), 7.19−7.22 (d, J = 8.4 Hz, 2CH). 13 C NMR (DMSO- d 6 , 100 MHz): δ 170.6 (C−ArBr), 162.1 (CO), 155.8 (C−NH 2 ), 153.1 (C−Br), 136.6 (2CH), 136.2 (C−N), 130.6 (2CH), 127.5 (C), 126.8 (2CH), 126.1 (CH), 126.0 (2CH), 118.5 (C), 116.7 (CN), 114.2 (CN), 73.0 (C).
6-amino-4-(4-nitrophenyl)-2-oxo-1-phenyl-1,2-dihydropyridine-3,5-dicarbonitrile (8f)
Yellow crystalline solid, IR (KBr): υ max 3410 & 3313 (−NH 2 ), 2893 (C=C), 2312 (CN), 1680 (CO), 1620 (C=C), 1555 (−NO 2 ), 1456, 1350 (NO 2 ), 839 cm −1 . MS: m/z 357, 341, 315, 311, 280, 235, 164, 122, 77. Anal. Calcd. for C 19 H 11 N 5 O 3 : C, 63.86; H, 3.10; N, 19.60%. Found: C, 63.81; H, 3.07; N, 19.57%. 1 H NMR (DMSO- d 6 , 400 MHz): δ 8.84 (s, −NH 2 , 2H), 8.32−8.35 (d, J = 10.4 Hz, 2CH), 7.70−7.73 (d, J = 10.0 Hz, 2CH), 7.48−7.51 (d, J = 8.4 Hz, 2CH), 7.41−7.44 (t, J = 8.4 Hz, 2CH), 7.19−7.22 (t, J = 8.4 Hz, CH). 13 C NMR (DMSO- d 6 , 100 MHz): δ 173.4 (C−ArNO 2 ), 160.5 (CO), 158.2 (C−NH 2 ), 154.6 (C−NO 2 ), 140.1 (2CH), 139.2 (2CH), 132.7 (C-N), 126.4 (C), 126.1 (2CH), 125.4 (CH), 125.1 (2CH), 117.9 (C), 115.5 (CN), 114.2 (CN), 72.5 (C).
6-amino-4-(3-nitrophenyl)-2-oxo-1-phenyl-1,2-dihydropyridine-3,5-dicarbonitrile (8g)
Yellow crystalline solid, IR (KBr): υ max 3420 & 3250 (NH 2 ), 2961 (C=C), 2222 (CN), 1721 (CO), 1641 (C=C), 1597, 1550 (NO 2 ), 1429, 1346 (NO 2 ), 814 cm −1 . MS: m/z 357, 331, 311, 280, 238, 235, 164, 122, 77. Anal. Calcd. for C 19 H 11 N 5 O 3 : C, 63.86; H, 3.10; N, 19.60%. Found: C, 63.80; H, 3.07; N, 19.55%. 1 H NMR (DMSO- d 6 , 400 MHz): δ 8.72 (s, −NH 2 , 2H), 8.22−8.25 (d, J = 11.2 Hz, CH), 8.01 (s, CH), 7.77−7.80 (t, J = 10.0 Hz, CH), 7.59−7.61 (d, J = 10.0 Hz, CH), 7.42−7.44 (d, J = 8.0 Hz, 2CH), 7.38−7.41 (t, J = 8.0 Hz, 2CH), 7.19−7.22 (t, J = 8.4 Hz, CH). 13 C NMR (DMSO- d 6 , 100 MHz): δ 174.0 (C−ArNO 2 ), 166.1 (CO), 158.0 (C−NH 2 ), 154.0 (C−NO 2 ), 143.8 (CH), 134.4 (CH), 133.1 (C−N), 132.0 (CH), 129.2 (C), 128.0 (CH), 124.2 (2CH), 123.8 (2CH), 123.2 (CH), 118.7 (C), 116.4 (CN), 115.0 (CN), 74.5 (C).
6-amino-2-oxo-1-phenyl-4-(p-tolyl)-1,2-dihydropyridine-3,5-dicarbonitrile (8h)
White crystalline solid, IR (KBr): υ max 3436 & 3320 (NH 2 ), 3089 (C=C), 2949 (CH 3 ), 2307 (CN), 1706 (CO), 1620 (C=C), 1540, 1430, 840 cm −1 . MS: m/z 326, 311, 284, 249, 164, 91, 77. Anal. Calcd. for C 20 H 14 N 4 O: C, 73.61; H, 4.32; N, 17.17%. Found: C, 73.57; H, 4.28; N, 17.13%. 1 H NMR (DMSO- d 6 , 400 MHz): δ 8.71 (s, −NH 2 , 2H), 7.31−7.33 (d, J = 10.4 Hz, 2CH), 7.24−7.26 (d, J = 8.0 Hz, 2CH), 7.22−7.24 (d, J = 10.4 Hz, 2CH), 7.12−7.17 (m, 3CH), 2.23 (s, CH 3 , 3H). 13 C NMR (DMSO- d 6 , 100 MHz): δ 170.8 (C−ArMe), 164.1 (CO), 155.8 (C−NH 2 ), 138.2 (C−Me), 137.7 (2CH), 134.6 (C−N), 131.6 (CH), 128.1 (C), 126.0 (2CH), 125.2 (2CH), 124.4 (2CH), 116.0 (C), 114.2 (CN), 114.0 (CN), 75.7 (C), 20.3 (CH 3 ).
6-amino-1-(4-chlorophenyl)-4-(4-methoxyphenyl)-2-oxo-1,2-dihydropyridine-3,5-dicarbonitrile (9a)
White crystalline solid, IR (KBr): υ max 3387 & 3325 (NH 2 ), 3011 (C=C), 2974 (CH 3 ), 2231 (CN), 1712 (CO), 1610 (C=C), 1540, 1204 (C−O), 1108, 837 cm −1 . MS: m/z 376, 345, 341, 334, 269, 265, 158, 111, 107. Anal. Calcd. for C 20 H 13 ClN 4 O 2 : C, 63.75; H, 3.48; N, 14.87%. Found: C, 63.70; H, 3.46; N, 14.84%. 1 H NMR (DMSO- d 6 , 400 MHz): δ 9.10 (s, −NH 2 , 2H), 7.68−7.70 (d, J = 8.4 Hz, 2CH), 7.56−7.58 (d, J = 8.0 Hz, 2CH), 7.48−7.51 (d, J = 8.0 Hz, 2CH), 7.02−7.05 (d, J = 8.4 Hz, 2CH), 2.88 (s, CH 3 , 3H). 13 C NMR (DMSO- d 6 , 100 MHz): δ 174.4 (C−ArCl), 170.2 (C−O), 158.6 (CO), 157.2 (C−NH 2 ), 138.3 (C−Cl), 137.6 (C), 134.8 (C−N), 130.2 (2CH), 128.0 (2CH), 127.0 (2CH), 125.4 (2CH), 116.4 (C), 115.1 (CN), 114.8 (CN), 75.0 (C), 58.2 (OCH 3 ).
6-amino-1,4-bis(4-chlorophenyl)-2-oxo-1,2-dihydropyridine-3,5-dicarbonitrile (9b)
White crystalline solid, IR (KBr): υ max 3495 & 3331 (NH 2 ), 3101 (C=C), 2239 (CN), 1715 (CO), 1641 (C=C), 1515, 842 cm −1 . MS: m/z 381,364, 345, 338, 303, 269, 158, 111. Anal. Calcd. for C 19 H 10 C l2 N 4 O: C, 59.86; H, 2.64; N, 14.70%. Found: C, 59.81; H, 2.63; N, 14.66%. 1H NMR (DMSO- d 6 , 400 MHz): δ 9.00 (s, −NH 2 , 2H), 7.59–7.63 (d, J = 10.4 Hz, 2CH), 7.45–7.48 (d, J = 8.4 Hz, 2CH), 7.40–7.42 (d, J = 8.4 Hz, 2CH), 7.26–7.29 (d, J = 10.4 Hz, 2CH). 13 C NMR (DMSO- d 6 , 100 MHz): δ 176.6 (C–ArCl), 169.8 (CO) 156.8 (C–NH 2 ), 140.0 (C–Cl), 136.1 (C–N), 136.0 (C–Cl), 135.4 (2CH), 134.6 (2CH), 134.0 (C), 129.0 (2CH), 128.4 (2CH), 117.2 (C), 115.1 (CN), 114.7 (CN), 75.1 (C).
6-amino-4-(3-chlorophenyl)-1-(4-chlorophenyl)-2-oxo-1,2-dihydropyridine-3,5-dicarbonitrile (9c)
White crystalline solid, IR (KBr): υ max 3412 & 3325 (NH 2 ), 3008 (C=C), 2301 (CN), 1720 (CO), 1646 (C=C), 1550, 812 cm −1 . MS: m/z 381, 364, 338, 303, 158, 111. Anal. Calcd. for C 19 H 10 Cl 2 N 4 O: C, 59.86; H, 2.64; N, 14.70%. Found: C, 59.83; H, 2.62; N, 14.64%. 1H NMR (DMSO- d 6 , 400 MHz): δ 8.88 (s, −NH 2 , 2H), 7.59–7.61 (d, J = 7.8 Hz, 2CH), 7.50–7.52 (d, J = 7.8 Hz, 2CH), 7.39–7.41 (d, J = 8.4 Hz, CH), 7.34–7.38 (t, J = 8.4 Hz, CH), 7.28 (s, CH), 7.10–7.13 (d, J = 8.4 Hz, CH). 13 C NMR (DMSO- d 6 , 100 MHz): δ 177.8 (C–ArCl), 170.4 (CO), 160.2 (C–NH 2 ), 148.4 (C–Cl), 135.4 (2CH), 134.8 (C–Cl), 132.2 (C–N), 130.8 (2CH), 129.6 (CH), 129.0 (CH), 128.6 (C), 128.0 (CH), 127.7 (CH), 116.5 (C), 115.2 (CN), 115.0 (CN), 75.4 (C).
6-amino-4-(4-bromophenyl)-1-(4-chlorophenyl)-2-oxo-1,2-dihydropyridine-3,5-dicarbonitrile (9e)
White crystalline solid, IR (KBr): υ max 3462 & 3345 (NH 2 ), 3014 (C=C), 2312 (CN), 1714 (CO), 1640 (C=C), 1561, 838 cm −1 . MS: m/z 426, 389, 372, 345, 329, 312, 269, 158, 155, 111. Anal. Calcd. for C 19 H 10 BrClN 4 O: C, 53.61; H, 2.37; N, 13.16%. Found: C, 53.58; H, 2.35; N, 13.14%. 1H NMR (DMSO- d 6 , 400 MHz): δ 8.95 (s, −NH 2 , 2H), 7.71– 7.73 (d, J = 8.4 Hz, 2CH), 7.52–7.56 (d, J = 10.4 Hz, 2CH), 7.44–7.46 (d, J = 10.4 Hz, 2CH), 7.29–7.32 (d, J = 8.4 Hz, 2CH). 13 C NMR (DMSO- d 6 , 100 MHz): δ 173.0 (C–ArBr), 162.5 (CO), 156.7 (C–NH 2 ), 155.8 (C–Br), 136.4 (C–Cl), 135.2 (2CH), 133.6 (2CH), 131.4 (C–N), 130.2 (C), 129.6 (2CH), 128.8 (2CH), 119.2 (C), 116.4 (CN), 115.8 (CN), 72.7 (C).
6-amino-1-(4-chlorophenyl)-4-(4-nitrophenyl)-2-oxo-1,2-dihydropyridine-3,5-dicarbonitrile (9f)
Yellow crystalline solid, IR (KBr): υ max 3436 & 3354 (NH 2 ), 3011 (C=C), 2249 (CN), 1713 (CO), 1634 (C=C), 1558, 1343, 848 cm −1 . MS: m/z 392, 356, 345, 340, 329, 280, 269, 158, 122, 111. Anal. Calcd. for C 19 H 10 ClN 5 O 3 : C, 58.25; H, 2.57; N, 17.88%. Found: C, 58.22; H, 2.54; N, 17.82%. 1H NMR (DMSO- d 6 , 400 MHz): δ 8.75 (s, −NH 2 , 2H), 8.28–8.31 (d, J = 8.0 Hz, 2CH), 7.70–7.73 (d, J = 8.0 Hz, 2CH), 7.55–7.58 (d, J = 8.4 Hz, 2CH), 7.41–7.44 (d, J = 8.4 Hz, 2CH). 13 C NMR (DMSO- d 6 , 100 MHz): δ 171.6 (C–ArNO 2 ), 162.2 (CO), 155.2 (C–NH 2 ), 155.0 (C–NO 2 ), 149.2 (2CH), 135.2 (C–Cl), 133.8 (C–N), 131.5 (C), 130.6 (2CH), 128.4 (2CH), 127.0 (2CH), 117.5 (C), 115.2 (CN), 115.0 (CN), 77.1 (C).
6-amino-1-(4-chlorophenyl)-4-(3-nitrophenyl)-2-oxo-1,2-dihydropyridine-3,5-dicarbonitrile (9g)
Yellow crystalline solid, IR (KBr): υ max 3446 & 3349 (NH 2 ), 3082 (C=C), 2280 (CN), 1704 (CO), 1614 (C=C), 1559, 754 cm −1 . MS: m/z 392, 356, 345, 340, 280, 158, 122, 111. Anal. Calcd. for C 19 H 10 ClN 5 O 3 : C, 58.25; H, 2.57; N, 17.88%. Found: C, 58.21; H, 2.55; N, 17.83%. 1 H NMR (DMSO- d 6 , 400 MHz): δ 9.04 (s, −NH 2 , 2H), 8.19–8.22 (d, J =11.2 Hz, CH), 7.99 (s, CH), 7.74–7.78. (t, J = 11.2 Hz, CH), 7.64–7.67 (d, J = 11.2 Hz, CH), 7.48–7.51 (d, J = 8.4 Hz, 2CH), 7.37–7.40 (d, J = 8.4 Hz, 2CH). 13 C NMR (DMSO- d 6 , 100 MHz): δ 170.4 (C–ArNO 2 ), 165.6 (CO), 158.2 (C–NH 2 ), 156.7 (C–NO 2 ), 148.0 (CH), 137.2 (CH), 136.4 (C–Cl), 133.3 (C–N), 132.6 (CH), 130.2 (2CH), 129.8 (C), 129.2 (CH), 128.6 (2CH), 117.9 (C), 116.6 (CN), 114.4 (CN), 75.0 (C).
6-amino-1-(4-chlorophenyl)-2-oxo-4-(p-tolyl)-1,2-dihydropyridine-3,5-dicarbonitrile (9h)
White crystalline solid, IR (KBr): υ max 3434 & 3347 (NH 2 ), 3109 (C=C), 2984 (CH 3 ), 2307 (CN), 1715 (CO), 1640 (C=C), 1555, 1419, 839 cm −1 . MS: m/z 360, 345, 325, 309, 269, 233, 158, 111, 91. Anal. Calcd. for C 20 H 13 ClN 4 O: C, 66.58; H, 3.63; N, 15.53%. Found: C, 66.54; H, 3.60; N, 15.50%. 1 H NMR (DMSO- d 6 , 400 MHz): δ 8.88 (s, −NH 2 , 2H), 7.44–7.48 (d, J = 8.4 Hz, 2CH), 7.38–7.41 (d, J = 8.0 Hz, 2CH), 7.30–7.34 (d, J = 8.4 Hz, 2CH), 7.12–7.17 (d, J = 8.0 Hz, 2CH), 2.34 (s, CH 3 , 3H). 13 C NMR (DMSO- d 6 , 100 MHz): δ 174.5 (C–ArMe), 165.4 (CO), 158.6 (C–NH 2 ), 135.4 (C–Cl), 134.4 (2CH), 134.0 (2CH), 132.8 (C–Me), 130.4 (C–N), 128.0 (C), 127.7 (2CH), 127.5 (2CH), 116.2 (C), 115.5 (CN), 115.0 (CN), 76.3 (C), 22.9 (CH3).
- General procedure for synthesis of 4,7-dioxo-8-(aryl)-5-(substituted phenyl)-3,4,7,8-tetrahydropyrido[2,3-d] pyrimidine-6-carbonitrile (10, 11)
10 mmol of 6-amino-1,2-dihydro-4-(aryl)-2-oxo-1-(aryl) pyridine-3,5-dicarbonitriles ( 8 , 9 ) was dissolved in 20 ml of formic acid which was used as self solvent. Catalytic amount of conc. Sulphuric acid was added to promote the reaction. The reaction mixture was irradiated at 100 MW in microwave under TLC analysis. After completion of the reaction, the reaction mixture was cooled to room temperature; separated product was filtered, washed with methanol and crystallized from DMF to afford the desired products 10 , 11 .
5-(4-methoxyphenyl)-4,7-dioxo-8-phenyl-3,4,7,8-tetrahydropyrido[2,3-d]pyrimidine-6-carbonitrile (10a)
White solid, IR (KBr): υ max 3269 (NH), 2927 (C=C), 2366 (CN), 1771 (CO–NH), 1659 (CO–N), 1603 (C=C), 1164 (C–O), 1102, 1036, 836 cm −1 . MS: m/z 370, 355, 339, 327, 293, 278, 252, 224, 186, 143, 77. Anal. Calcd. for C 21 H 14 N 4 O 3 : C, 68.10; H, 3.81; N, 15.13%. Found: C, 67.80; H, 3.36; N, 15.05%. 1 H NMR (DMSO- d 6 , 400 MHz): δ 10.28 (s, −NH pyrimidine , 1H), 8.20 (s, =CH pyrimidine , 1H), 8.01–8.03 (d, J = 11.6 Hz, 2CH), 7.65–7.68 (d, J = 10.4 Hz, 2CH), 7.33–7.39 (t, J = 10.8 Hz, 2CH), 7.10–7.17 (m, 3CH), 3.867 (s, OCH 3 , 3H). 13 C NMR (DMSO- d 6 , 100 MHz): δ 176.5 (C–ArOMe), 172.2 (CO–NH), 168.2 (C–OMe), 160.8 (CO–N), 155.4 (C=N), 150.8 (=C–N=), 133.2 (C–N), 132.8 (2CH), 130.4 (2CH), 129.4 (C), 128.0 (CH), 126.7 (2CH), 118.4 (2CH), 115.8 (C–CN), 115.0 (CN), 105.2 (C–CONH), 56.7 (OCH 3 ).
5-(4-chlorophenyl)-4,7-dioxo-8-phenyl-3,4,7,8-tetrahydropyrido[2,3-d]pyrimidine-6-carbonitrile (10b)
White crystalline solid, IR (KBr): υ max 3198 (NH), 2363 (CN), 1672 (CO), 1588 (C=C), 1556 (C=N), 1144 (C–N), 752 cm −1 . MS: m/z 374, 359, 339, 331, 313, 305, 297, 269, 258, 228, 210, 196, 186, 143, 127, 111, 77. Anal. Calcd. for C 20 H 11 ClN 4 O 2 : C, 64.09; H, 2.96 N, 14.95%. Found: C, 63.92; H, 2.85; N, 14.84%. 1 H NMR (DMSO- d 6 , 400 MHz): δ 11.19 (s, −NH pyrimidine , 1H), 7.99 (s, =CH pyrimidine , 1H), 7.80–7.83 (d, J = 8.4 Hz, 2CH), 7.54–7.63 (m, 3CH), 7.50–7.53 (m, 2CH), 7.37–7.39 (m, 2CH). 13 C NMR (DMSO d 6 , 100 MHz): δ 174.4 (C–ArCl), 170.0 (CO–NH), 166.6 (CO–N), 155.8 (C=N), 153.4 (=C–N=), 144.2 (C–Cl), 134.0 (2CH), 132.7 (C–N), 131.5 (C), 130.3 (2CH), 129.4 (CH), 127.4 (2CH), 126.8 (2CH), 115.0 (C–CN), 114.6 (CN), 106.8 (C–CONH).
5-(3-chlorophenyl)-4,7-dioxo-8-phenyl-3,4,7,8-tetrahydropyrido[2,3-d]pyrimidine-6-carbonitrile (10c)
White crystalline solid, IR (KBr): υ max 3218 (NH), 2213 (CN), 1689 (CO–NH), 1682 (CO–N), 1508 (C=C), 1500 (C=N), 1201 (C–N), 788 cm −1 . MS: m/z 374, 359, 339, 331, 305, 258, 210, 196, 186, 143, 111, 77. Anal. Calcd. for C 20 H 11 ClN 4 O 2 : C, 64.09; H, 2.96 N, 14.95%. Found: C, 63.89; H, 2.90; N, 14.87%. 1 H NMR (DMSO- d 6 , 400 MHz): δ 11.56 (s, −NH pyrimidine , 1H), 8.02 (s, =CH pyrimidine , 1H), 7.54–7.55 (d, J = 8.0 Hz, 2CH), 7.43–7.46 (m, 3CH), 7.37–7.39 (d, J = 8.0 Hz, 2CH), 7.34 (s, CH), 7.30–7.32 (t, J = 7.6 Hz, CH). 13 C NMR (DMSO- d 6 , 100 MHz): δ 175.8 (C–ArCl), 173.3 (CO–NH), 164.5 (CO–N), 156.8 (C=N), 153.0 (=C–N=), 145.4 (C–Cl), 134.4 (CH), 133.0 (C–N), 132.8 (CH), 132.4 (CH), 130.7 (C), 129.6 (2CH), 128.8 (CH), 127.0 (CH), 126.2 (2CH), 116.4 (C–CN), 115.8 (CN), 105.5 (C–CONH).
5-(2-chlorophenyl)-4,7-dioxo-8-phenyl-3,4,7,8-tetrahydropyrido[2,3-d]pyrimidine-6-carbonitrile (10d)
White crystalline solid, IR (KBr): υ max 3233 (NH), 2323 (CN), 1652 (CO–NH), 1603 (CO–N), 1587 (C=C), 1511 (C=N), 734 cm −1 . MS: m/z 374, 359, 339, 331, 313, 269, 258, 186, 143, 111, 77. Anal. Calcd. for C 20 H 11 ClN 4 O 2 : C, 64.09; H, 2.96 N, 14.95%. Found: C, 63.99; H, 2.88; N, 14.90%. 1H NMR (DMSO- d 6 , 400 MHz): δ 12.06 (s, −NH pyrimidine , 1H), 7.88 (s, =CH pyrimidine , 1H), 7.71–7.73 (d, J = 11.6 Hz, 2CH), 7.57–7.61 (m, 3CH), 7.44–7.45 (t, 2CH), 7.12–7.14 (d, 2CH). 13 C NMR (DMSO- d 6 , 100 MHz): δ 178.6 (C–ArCl), 174.2 (CO–NH), 162.8 (CO–N), 158.2 (C=N), 151.4 (=C–N=), 146.2 (C–Cl), 135.2 (CH), 134.8 (CH), 133.2 (C–N), 131.8 (C), 130.4 (CH), 129.2 (2CH), 129.0 (CH), 128.4 (2CH), 126.6 (CH), 115.1 (C–CN), 114.7 (CN), 103.4 (C–CONH).
5-(4-bromophenyl)-4,7-dioxo-8-phenyl-3,4,7,8-tetrahydropyrido[2,3-d]pyrimidine-6-carbonitrile (10e)
White crystalline solid, IR (KBr): υ max 3189 (NH), 2311 (CN), 1743 (CO–NH), 1689 (CO–N), 1579 (C=C), 1556 (C=N), 1230 (C–N), 1120, 821 cm −1 . MS: m/z 418, 375, 347, 339, 263, 186, 154, 77. Anal. Calcd. for C 20 H 11 ClN 4 O 2 : Calculated: C, 64.09; H, 2.96 N, 14.95%. Found: C, 63.99; H, 2.88; N, 14.90%. 1 H NMR (DMSO- d 6 , 400 MHz): δ 11.80 (s, −NH pyrimidine , 1H), 8.23 (s, =CH pyrimidine , 1H), 7.99–8.02 (d, J = 11.6 Hz, 2CH), 7.87–7.88 (d, J = 10.4 Hz, 2CH), 7.51–7.53 (d, J = 8.4 Hz, 2CH), 7.40–7.47 (m, 3CH). 13 C NMR (DMSO- d 6 , 100 MHz): δ 178.4 (C–ArBr), 172.0 (CO–NH), 164.5 (CO–N), 152.1 (C=N), 149.0 (=C–N=), 147.4 (C–Br), 133.8 (2CH), 131.6 (C–N), 130.4 (C), 129.7 (2CH), 128.8 (CH), 126.4 (2CH), 122.3 (2CH), 117.2 (C–CN), 116.0 (CN), 104.8 (C–CONH).
5-(4-nitrophenyl)-4,7-dioxo-8-phenyl-3,4,7,8-tetrahydropyrido[2,3-d]pyrimidine-6-carbonitrile (10f)
Yellow crystalline solid, IR (KBr): υ max 3247 (NH), 2924 (C=C), 2362 (CN), 1694 (CO), 1511 (C=N), 1104 cm −1 . MS: m/z 385, 370, 342, 316, 308, 295, 266, 239, 143, 122, 77. Anal. Calcd. for C 20 H 11 N 5 O 4 : Calculated: C, 62.34; H, 2.88; N, 18.17%. Found: C, 62.24; H, 2.79; N, 18.06%. 1 H NMR (DMSO- d 6 , 400 MHz): δ 11.38 (s, −NH pyrimidine , 1H), 7.78 (s, =CH pyrimidine , 1H), 7.60–7.62 (m, 2CH), 7.54–7.60 (m, CH), 7.50–7.53 (dd, J = 7.6 Hz, 2CH), 7.38–7.40 (dd, J = 7.6 Hz, 2CH). 13 C NMR (DMSO- d 6 , 100 MHz): δ176.4 (C–ArNO 2 ), 170.2 (CO–NH), 163.8 (CO–N), 150.6 (C=N), 149.2 (=C–N=), 148.4 (C–NO 2 ), 134.0 (2CH), 132.6 (C–N), 131.4 (2CH), 130.8 (2CH), 128.9 (C), 128.3 (CH), 122.8 (2CH), 116.0 (C–CN), 115.7 (CN), 106.5 (C–CONH).
5-(3-nitrophenyl)-4,7-dioxo-8-phenyl-3,4,7,8-tetrahydropyrido[2,3-d]pyrimidine-6-carbonitrile (10g)
Yellow crystalline solid, IR (KBr): υ max 3221 (NH), 2952 (C=C), 2212 (CN), 1714 (CO–NH), 1651 (CO–NH), 1581 (C=C), 1104, 788 cm −1 . MS: m/z 385, 370, 342, 316, 295, 239, 122, 77. Anal. Calcd. for C 20 H 11 N 5 O 4 : C, 62.34; H, 2.88; N, 18.17%. Found: C, 62.27; H, 2.74; N, 18.00%. 1 H NMR (DMSO- d 6 , 400 MHz): δ 11.78 (s, −NH pyrimidine , 1H), 7.88 (s, =CH pyrimidine , 1H), 7.79–7.81 (d, 2CH), 7.56–7.58 (t, CH), 7.45–7.50 (m, 3CH), 7.34 (s, CH), 7.18–7.20 (d, 2CH). 13 C NMR (DMSO- d 6 , 100 MHz): δ 177.2 (C–ArNO 2 ), 170.6 (CO–NH), 163.2 (CO–N), 155.5 (C=N), 154.2 (=C–N=), 148.0 (C–NO 2 ), 132.8 (CH), 132.2 (CH), 131.4 (C–N), 130.6 (2CH), 129.9 (2CH), 129.2 (CH), 128.4 (C), 122.2 (CH), 121.0 (CH), 115.5 (C–CN), 114.9 (CN), 109.7 (C–CONH).
5-(4-methylphenyl)-4,7-dioxo-8-phenyl-3,4,7,8-tetrahydropyrido[2,3-d]pyrimidine-6-carbonitrile (10h)
White solid, IR (KBr): υ max 3301 (NH), 2899 (CH 3 ), 2310 (CN), 1720 (CO–NH), 1691 (CO–N), 1519 (C=N), 1100, 820 cm −1 . MS: m/z 354, 329, 311, 286, 277, 263, 186, 91, 77. Anal. Calcd. for C 21 H 14 N 4 O 2 : C, 71.18; H, 3.98; N, 15.81%. Found: C, 71.11; H, 3.89; N, 15.78%. 1 H NMR (DMSO- d 6 , 400 MHz): δ 11.50 (s, −NH pyrimidine , 1H), 7.89 (s, =CH pyrimidine , 1H), 7.66–7.68 (m, 3CH), 7.54–7.58 (d, J = 10.4 Hz, 2CH), 7.51–7.52 (d, J = 8.0Hz, 2CH), 7.28–7.30 (d, J = 8.0Hz, 2CH), 2.18 (s, CH 3 , 3CH). 13 C NMR (DMSO- d 6 , 100 MHz): δ 172.4 (C–ArMe), 170.8 (CO–NH), 162.4 (CO–N), 153.0 (C=N), 151.8 (=C–N=), 137.2 (C–Me), 133.9 (2CH), 132.0 (C–N), 131.2 (2CH), 130.8 (C), 129.6 (CH), 128.2 (2CH), 126.8 (2CH), 116.6 (C–CN), 115.8 (CN), 104.0 (C–CONH), 22.8 (CH 3 ).
8-(4-chlorophenyl)-5-(4-methoxyphenyl)-4,7-dioxo-3,4,7,8-tetrahydropyrido[2,3-d]pyrimidine-6-carbonitrile (11a)
White crystalline solid, IR (KBr): υ max 3296 (NH), 3205 (C=C), 2924 (CH 3 ), 2216 (CN), 1683 (CO–NH), 1626 (CO–N), 1518 (C=N), 1288 (C–O), 1232, 1029, 840 cm −1 . MS: m/z 404, 389, 378, 362, 334, 293, 267, 252, 223, 186, 127, 111, 93, 75. Anal. Calcd. for C 21 H 13 ClN 4 O 3 : C, 62.31; H, 3.24; N, 13.84%. Found: C, 62.22; H, 3.12; N, 13.77%. 1 H NMR (DMSO- d 6 , 400 MHz): δ 12.66 (s, −NH pyrimidine , 1H), 7.52 (s, =CH pyrimidine , 1H), 7.29–7.38 (dd, 6CH), 7.01–7.03 (d, J = 11.2, 2CH), 3.83 (s, OCH 3 , 3CH). 13 C NMR (DMSO- d 6 , 100 MHz): δ 174.5 (C–ArOMe), 170.8 (CO–NH), 169.6 (CO–N), 161.4 (C=N), 156.2 (=C–N=), 147.3 (C–OMe), 144.0 (C–Cl), 133.4 (2CH), 131.3 (C–N), 129.8 (2CH), 128.2 (2CH), 127.9 (C), 123.1 (2CH), 115.8 (C–CN), 115.2 (CN), 107.4 (C–CONH), 55.7 (OCH 3 ).
5,8-bis(4-chlorophenyl)-4,7-dioxo-3,4,7,8-tetrahydropyrido[2,3-d]pyrimidine-6-carbonitrile (11b)
White crystalline solid, IR (KBr): υ max 3229 (NH), 2924 (C=C), 2214 (CN), 1641 (CO–N), 1527 (C=C), 1497 (C=N), 1245 (C–N), 1078, 843 cm −1 . MS: m/z 408, 373, 365, 338, 330, 314, 297, 254, 186, 111. Anal. Calcd. for C 20 H 10 C l2 N 4 O 2 : C, 58.70; H, 2.46; N, 13.69%. Found: C, 58.66; H, 2.39; N, 13.60%. 1H NMR (DMSO- d 6 , 400 MHz): δ 11.17 (s, −NH pyrimidine , 1H), 8.21 (s, =CH pyrimidine , 1H), 7.81–7.82 (d, J = 7.2 Hz, 2CH), 7.58–7.60 (d, J = 7.2 Hz, 2CH), 7.50–7.52 (d, J = 7.6 Hz, 2CH), 7.36–7.38(d, J = 6.4 Hz, 2CH). 13 C NMR (DMSO- d 6 , 100 MHz): δ 174.2 (C–ArCl), 172.8 (CO–NH), 165.4 (CO–N), 154.2 (C=N), 152.0 (=C–N=), 144.8 (C–Cl), 143.4 (C–Cl), 133.0 (2CH), 131.5 (C–N), 130.8 (2CH), 128.6 (C), 128.4 (2CH), 126.8 (2CH), 116.2 (C–CN), 115.4 (CN), 105.9 (C–CONH).
5-(3-chlorophenyl)-8-(4-chlorophenyl)-4,7-dioxo-3,4,7,8-tetrahydropyrido[2,3-d]pyrimidine-6-carbonitrile (11c)
White crystalline solid, IR (KBr): υ max 3189 (NH), 2928 (C=C), 2314 (CN), 1721 (CO–NH), 1664 (CO–N), 1521 (C=N), 1201 (C–N), 1078, 801 cm −1. MS: m/z 408, 373, 365, 331, 314, 297, 186, 111. Anal. Calcd. for C 20 H 10 Cl 2 N 4 O 2 : C, 58.70; H, 2.46; N, 13.69%. Found: C, 58.68; H, 2.37; N, 13.56%. 1 H NMR (DMSO- d 6 , 400 MHz): δ 12.01 (s, −NH pyrimidine , 1H), 8.00 (s, =CH pyrimidine , 1H), 7.88–7.89 (d, J = 8.0 Hz, 2CH), 7.65–7.62 (d, J = 8.0 Hz, 2CH), 7.50–7.57 (m, 3CH), 7.20 (s, CH). 13 C NMR (DMSO- d 6 , 100 MHz): δ 172.0 (C–ArCl), 170.7 (CO–NH), 166.2 (CO–N), 155.7 (C=N), 153.8 (=C–N=), 144.2 (C–Cl), 143.8 (C–Cl), 133.0 (2CH), 132.8 (C–N), 131.2 (CH), 130.3 (CH), 128.8 (C), 128.4 (2CH), 127.8 (CH), 126.4 (CH), 115.8 (C–CN), 115.2 (CN), 106.4 (C–CONH).
5-(2-chlorophenyl)-8-(4-chlorophenyl)-4,7-dioxo-3,4,7,8-tetrahydropyrido[2,3-d]pyrimidine-6-carbonitrile (11d)
White crystalline solid, IR (KBr): υ max 3301 (NH), 2987 (C=C), 2301 (CN), 1689 (CO–NH), 1519 (C=C), 1445 (C=N), 787 cm −1 . MS: m/z 408, 373, 366, 330, 315, 297, 186, 111. Anal. Calcd. for C 20 H 10 Cl 2 N 4 O 2 : C, 58.70; H, 2.46; N, 13.69%. Found: C, 58.60; H, 2.37; N, 13.59%. 1 H NMR (DMSO- d 6 , 400 MHz): δ 11.77 (s, −NH pyrimidine , 1H), 7.89 (s, =CH pyrimidine , 1H), 7.63–7.65 (d, J = 8.4 Hz, 2CH), 7.49–7.51 (d, J = 8.2Hz, 2CH), 7.34–7.33 (d, J = 7.6 Hz, 2CH), 7.15–7.16 (t, J = 7.0 Hz, CH), 7.01 (s, CH). 13 C NMR (DMSO- d 6 , 100 MHz): δ 174.8 (C–ArCl), 174.0 (CO–NH), 166.7 (CO–N), 159.4 (C=N), 150.6 (=C–N=), 146.8 (C–Cl), 145.0 (C–Cl), 133.8 (2CH), 133.0 (CH), 132.4 (C–N), 130.4 (CH), 128.6 (C), 128.2 (CH), 128.0 (2CH), 127.4 (CH), 116.8 (C–CN), 115.0 (CN), 104.8 (C–CONH).
5-(4-bromophenyl)-8-(4-chlorophenyl)-4,7-dioxo-3,4,7,8-tetrahydropyrido[2,3-d]pyrimidine-6-carbonitrile (11e)
White crystalline solid, IR (KBr): υ max 3222 (NH), 2936 (C=C), 2214 (CN), 1711 (CO–NH), 1641(CO–N), 1501 (C=N), 1225 (C–N), 851cm −1 . MS: m/z 453, 417, 408, 381, 373, 346, 340, 303, 297, 186, 155, 111. Anal. Calcd. for C 20 H 10 BrClN 4 O 2 : C, 52.95; H, 2.22; N, 12.35%. Found: C, 52.87; H, 2.11; N, 12.27%. 1 H NMR (DMSO- d 6 , 400 MHz): δ 12.16 (s, −NH pyrimidine , 1H), 8.04 (s, =CH pyrimidine , 1H), 7.91–7.93 (d, J = 8.0 Hz, 2CH), 7.76–7.78 (d, J = 8.2 Hz, 2CH), 7.61–7.63 (d, J = 7.8 Hz, 2CH), 7.43–7.45 (d, J = 7.4 Hz, 2CH). 13 C NMR (DMSO- d 6 , 100 MHz): δ 173.8 (C–ArBr), 172.4 (CO–NH), 165.0 (CO–N), 155.6 (C=N), 153.2 (=C–N=), 148.2 (C–Br), 144.0 (C–Cl), 131.6 (2CH), 131.2 (C–N), 130.4 (2CH), 129.4 (C), 128.2 (2CH), 123.4 (2CH), 116.4 (C–CN), 115.8 (CN), 105.4 (C–CONH).
8-(4-chlorophenyl)-5-(4-nitrophenyl)-4,7-dioxo-3,4,7,8-tetrahydropyrido[2,3-d]pyrimidine-6-carbonitrile (11f)
Yellow crystalline solid, IR (KBr): υ max 3119 (NH), 2894 (C=C), 2309 (NH), 1709 (CO–NH), 1627 (CO–N), 1481 (C=N), 1154, cm −1 . MS: m/z 419, 404, 394, 376, 373, 308, 297, 263, 194, 186, 153, 122, 111. Anal. Calcd. for C 20 H 10 ClN 5 O 4 : C, 57.22; H, 2.40; N, 16.68%. Found: C, 57.12; H, 2.32; N, 16.58%. 1 H NMR (DMSO- d 6 , 400 MHz): δ 11.86 (s, −NH pyrimidine , 1H), 7.88 (s, =CH pyrimidine , 1H), 7.67–7.69 (d, J = 7.2 Hz, 2CH), 7.59–7.61 (d, J = 7.2 Hz, 2CH), 7.48–7.50 (d, J = 8.0 Hz, 2CH), 7.44–7.47 (d, J = 8.0 Hz, 2CH). 13 C NMR (DMSO- d 6 , 100 MHz): δ 174.2 (C–ArNO 2 ), 170.8 (CO–NH), 166.0 (CO–N), 157.5 (C=N), 156.6 (=C–N=), 155.2 (C–NO 2 ), 144.4 (C–Cl), 133.4 (2CH), 132.5 (2CH), 132.0 (C–N), 129.2 (2CH), 128.4 (C), 123.6 (2CH), 115.4 (C–CN), 114.0 (CN), 105.8 (C–CONH).
8-(4-chlorophenyl)-5-(3-nitrophenyl)-4,7-dioxo-3,4,7,8-tetrahydropyrido[2,3-d]pyrimidine-6-carbonitrile (11g)
Yellow crystalline solid, IR (KBr): υ max 3233 (NH), 2974 (C=C), 2364 (CN), 1696 (CO–NH), 1618 (CO–N), 1584 (C=N), 1159, 1102, 846 cm −1 . MS: m/z 419, 404, 393, 376, 373, 349, 308, 297, 262, 195, 186, 153, 122, 111, 93, 75. Anal. Calcd. for C 20 H 10 ClN 5 O 4 : C, 57.22; H, 2.40; N, 16.68%. Found: C, 57.14; H, 2.29; N, 16.60%. 1 H NMR (DMSO- d 6 , 400 MHz): δ 10.60 (s, −NH pyrimidine , 1H), 8.14 (s, =CH pyrimidine , 1H), 7.64–7.67 (d, J = 8.4 Hz, 2CH), 7.44–7.47 (d, J = 8.8 Hz, 2CH), 7.35–7.39 (t, J = 8.0 Hz, CH), 6.87–6.96 (m, 3CH). 13 C NMR (DMSO- d 6 , 100 MHz): δ 174.0 (C–ArNO 2 ), 172.8 (CO–NH), 166.4 (CO–N), 155.5 (C=N), 154.6 (=C–N=), 153.2 (C–NO 2 ), 143.4 (C–Cl), 131.2 (CH), 130.8 (2CH), 130.0 (C–N), 129.4 (CH), 129.0 (2CH), 127.6 (C), 122.0 (CH), 121.4 (CH), 116.2 (C–CN), 115.9 (CN), 104.7 (C–CONH).
8-(4-chlorophenyl)-4,7-dioxo-5-(p-tolyl)-3,4,7,8-tetrahydropyrido[2,3-d]pyrimidine-6-carbonitrile (11h)
White crystalline solid, IR (KBr): υ max 3228 (NH), 2971 (C=C), 2228 (CN), 1699 (CO–NH), 1615 (CO–N), 1524 (C=N), 1254 (C–N), 1212, 830 cm −1 . MS: m/z 388, 373, 353, 345, 338, 318, 310, 297, 277, 186, 111, 91. Anal. Calcd. for C 21 H 13 ClN 4 O 2 : C, 64.87; H, 3.37; N, 14.41%. Found: C, 64.78; H, 3.26; N, 14.34%. 1 H NMR (DMSO- d 6 , 400 MHz): δ 11.10 (s, −NH pyrimidine , 1H), 8.11 (s, =CH pyrimidine , 1H), 7.69–7.71 (d, J = 8.4 Hz, 2CH), 7.59–7.61 (d, J = 8.4 Hz, 2CH), 7.25–7.28 (d, J = 7.0 Hz, 2CH), 6.88–6.90 (d, J = 7.0 Hz, 2CH), 2.45 (s, CH3, CH). 13 C NMR (DMSO- d 6 , 100 MHz): δ 172.4 (C–ArMe), 171.4 (CO–NH), 162.8 (CO–N), 154.2 (C=N), 152.6 (=C–N=), 147.6 (C–Cl), 140.3 (C–Me), 132.2 (2CH), 131.5 (2CH), 130.8 (C–N), 129.4 (2CH), 128.8 (C), 126.4 (2CH), 116.6 (C–CN), 115.6 (CN), 105.8 (C–CONH), 23.2 (CH 3 ).
RESULTS AND DISCUSSION
There are several strategies to prepare pyrido[2,3- d ]pyrimidines e.g. the 2-amino-3-cyanopyromodones react with formamide and arylidene of different aldehydes or the 2-amino-3-cyano-4,6-disubstituted pyridines reacting with thiourea, formamide and arylisocynate. 23,26 In accordance with our strategy, two 2-cyano-N-phenylacetamides ( 4, 5 ) were prepared by refluxing the aromatic amine ( 1, 2 ) with cyanoacetic acid ester ( 3 ) under solvent free conditions. 27 The 6-amino-2-oxo-1,2-dihydropyridine-3,5-dicarbonitriles ( 8, 9 ) were prepared by reacting cyanoacetamides with aldehydes and malononitrile via Hantzsch pyridine synthesis.
The compounds 8–9 are useful intermediates for synthesizing various pyridine fused heterocylic compounds. Firstly, compound 4 , 4 -methoxy benzaldehyde ( 6a ) and malononitrile ( 7 ) were refluxed in methanol using piperidine as catalyst ( 1 ). After 16 hours the complete conversion of 4 occurred and 8a was isolated in good yields ( 1 ).
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Synthesis of 6-amino-2-oxo-1,2-dihydropyridine-3,5-dicarbonitriles.
Preparation of 6-amino-2-oxo-1,2-dihydropyridine-3,5-dicarbonitriles (8–9)
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*Isolated yield in DMF
The preliminary experimentations showed that when 8a was reacted with formic acid in the presence of a catalytic amount of sulfuric acid (H 2 SO 4 ) afforded 10a in poor yield (30%) under reflux conditions for 23 hours ( 2 ). But when the same reaction was performed under microwave condition, we surprisingly found that the reaction time was reduced dramatically and the yield was improved remarkably ( 10a , 2 ).
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Synthesis of pyrido[2,3-d]pyrimidines.
Comparison of microwave and conventional methods for the synthesis of pyrido[2,3-d]pyrimidines (10,11)
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*Isolated yield in DMF. †Continuous irradiation, The melting points of compounds 10a–h, 11a–h are above 300 ℃.
To expand the course of this reaction, different starting materials were synthesized. For that we subsequently used two different 2-cyano- N -phenylacetamides ( 4 and 5 ) and eight different aldehydes ( 6a–h , with electron donating and withdrawing groups), over all 16 reactions were performed and isolated yield of corresponding 8–9 is shown in 1 . Microwave magnetron power was varied for the all the reactions performed, but maximum yield was obtained at lower irradiation (100 MW). There were substantial differences regarding the nature of substrate.
To demonstrate the practicality of the developed microwave protocol, large-scale experiments (30 mmol of 8e and 9g ) were carried out in the synthesis of 10e and 11g using a 250 mL Erlenmeyer flask as the reaction vessel. High yields of 10e (77%) and 11g (79%) were afforded under microwave irradiation at 100 MW with exposure times of 30 min.
- Biological Activity
The wide range of activity profile of pyrido[2,3- d ]pyrimidines probes us to test and study the biological activities of some of the synthesized novel analogues. Many antimicrobial agents have been introduced into therapy; however, the field still needs extensive efforts for the development of new antimicrobial agents to overcome the highly resistant strains of microorganisms. The newly synthesized compounds 8a–h to 11a–h were tested in vitro for their antibacterial activity against Escherichia coli, Pseudomonas aeruginosa, Bacillus subtillus, Staphylococcus aureus , and Micrococcus luteus bacteria by the agar well diffusion method. 28 DMSO was used as a control solvent and, chloramphenicol and cefixime as standard drugs.
After 24 h incubation at 37 ℃, the zone of inhibition was measured in mm. The results are depicted in 3 . The results showed that almost all compounds were active against the microorganism tested. It is worth noting here that compounds 10b, 10e, 11b and 11e exhibited significant activity against E. coli, P. aeruginosa, B. subtillu s and M. letus . The other compounds showed moderate-to-low activity. The structure–activity relationship (SAR) shows that the presence of cyclic amide in pyrimidine ring might have increased the activity especially when R 2 is halogen at para position. The electron donating group at the para position as in case of 8h, 9h, 10h and 11h , diminishes the activity.
Antibacterial activity of synthesized compounds8a–h,9a–h,10a–hand11a–h
PPT Slide
Lager Image
*Std. 1 = Cefixime (Standard). †Std. 2 = Chloramphenicol (Standard). Zone diameter of growth inhibition (mm) after 24 h, <10 mm (−), Concentration 1 mg/mL in DMSO. Microorganisms selected are as follows: E.c, Escherichia coli; P.a, Pseudomonas aeruginosa; B.s, Bacillus subtillus; S.a, Staphylococcus aureus; M.l, Micrococcus luteus. Values are expressed as mean ± standard deviation of the three replicates.
Compounds 8a–h to 11a–h were also screened in vitro for their antifungal activity against four species using the agar plate technique. 29 The linear growth of the fungus was obtained by measuring the diameter of the fungal colony after 7 days. The amount of growth inhibition in each case was calculated as percentage inhibition. The results shown in 4 indicated that compounds 10b, 10e, 11e exhibited significant activity against Trichphyton longifusus , 11b against Candida albicans and 11e against Micrococcus luteus . It is worth noting that compounds 10b, 10e, 11b and 11e exhibited significant (maximum) antibacterial and antifungal activities, possibly because of the presence of halogen substitution at the 4-position (para) of the N -phenyl substituent, in addition to the cyclic amide group.
Antifungal activity of synthesized compounds8a–h,9a–h,10a–hand11a–h
PPT Slide
Lager Image
*Std=Miconazole (Standard) Conc. of sample 200 µg/mL in DMSO at 27 ℃, <20 mm (−), Incubation period 7 days. Microorganisms selected are as follows: T.l, Trichphyton longifusus; C.a, Candida albicans; M.c, Microsporum canis; F.s, Fusarium solani, Values are expressed as mean ± standard deviation of the three replicates.
CONCLUSION
In summary, a straightforward and effective method to synthesize novel 5-8-diaryl tetrahydro pyrido[2,3- d ]pyridines has been developed using microwave-assisted synthesis. The substrates were obtained in good yields and in short reaction times. The microwave technique provides a rapid, simple, and effective method to synthesize such compounds that may have the potential application in the field of drug discovery. Moreover the reaction is simple, one pot and also gives excellent yields at larger scales. The compounds 10b, 10e, 11b and 11e exhibited significant (maximum) antibacterial and antifungal activities, which may develop into the potential class of antimicrobial agents. The antimicrobial activity results indicated that some of the tested compounds showed the most promising antibacterial and antifungal activities. Further studies are in progress in our laboratories and will be reported upon in the future.
Acknowledgements
Publication cost of this paper was supported by the Korean Chemical Society.
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