Substituted pyridopyrimidinones. Part IV. 2-Chloro-4H-pyrido[1,2-a]pyrimidin-4-one as a synthone of some new heterotricycles

J. Serb. Chem. Soc. 75 (1) 11–17 (2010) JSCS–3936 UDC 547.821+547.853:547.7/.8 Original scientific paper Substituted pyridopyrimidinones. Part IV. 2-Chloro-4H-pyrido[1,2-a]pyrimidin-4-one as a synthone of some new heterotricycles MOHAMED ABASS*, MOSTAFA M. ISMAIL, WAFAA R. ABDEL-MONEM and AISHA S. MAYAS Department of Chemistry, Faculty of Education, Ain Shams University, Roxy, Cairo 11757, Egypt (Received 27 November 2008, revised 9 June 2009) Abstract: 2-Chloro-4H-pyrido[1,2-a]pyrimidin-4-one (1) was utilized as a synthone precursor to prepare novel heterotricyclic systems. 2-Azido and 2-hydrazino derivatives (2 and 3) were obtained by nucleophilic replacement evolving compound 1. The hydrazine derivative 3 was transformed into the azido derivative 2 by nitrosation. Treatment of compound 3 with [bis(methylthio)methylene]malononitrile afforded 2-pyrazolylpyridopyrimidine 4. When compound 1 was reacted with 5-amino-3-(methylthio)-1H-pyrazole-4-carbonitrile, the same compound 4 was obtained with no evidence for the production of (pyrazolylamino)pyridopyrimidine 5 or pyrazolodipyridopyrimidine 6. Poly-functionalized dipyridopyrimidine 8 was obtained by reaction of compound 1 with 2-[(methylthio)-(phenylamino)methylene]propanedinitrile. Cyanoguanidine was reacted with compound 1 to afford N-pyridopyrimidinylguanidine 9, which was subjected to cyclization reaction, in presence of piperidinium acetate, to give pyridopyrimidopyrimidine 10. Keywords: pyridopyrimidine; dipyridopyrimidine; pyridopyrimidopyrimidine. INTRODUCTION Recently, a convenient new synthesis of 2-chloro-4H-pyrido[1,2-a]pyrimidin-4-one (1) was described.1 It is well-known that this type of α-haloheterocyclic compounds are susceptible to synthetically important nucleophilic substitutions.2–5 Many hetero-fused pyrimidines exhibit attractive cancer chemotherapy properties as antitumor agents.6 Risperidone, SSR6907, and ramastine are derivatives of pyrido[1,2-a]pyrimidin-4-one, which show antipsychotic activity.7–9 Dominguez et al.10 reported that some hetero-fused tricyclic systems exhibited significant antimalarial activity. It was cited that the biological reac* Corresponding author. E-mail: doi: 10.2298/JSC1001011A 11 Available online at www.shd.org.rs/JSCS/ ___________________________________________________________________________________________________________________________ 2009 Copyright (CC) SCS 12 ABASS et al. tivity of this category of compounds is essentially due to presence of the pyrido[1,2-a]pyrimidinone moiety in their molecular structure.11 In this study, it was planned to utilize the readily available chloro derivative to obtain novel polycyclic compounds, which could be expected to possess antimalarial activity. RESULTS AND DISCUSSION Analytical and spectral characterization of the prepared compounds 2-Azido-4H-pyrido[1,2-a]pyrimidin-4-one (2). Anal. Calcd. for C8H5N5O (FW 187.16): C, 51.34; H, 2.69; N, 37.42 %; Found: C, 50.96; H, 2.54; N, 37.40 %. IR (KBr, cm–1): 3073, 3042, 2129 (N3), 1718 (C=O), 1634 (C=N), 1565, 1517, 1455, 1412, 1110, 930, 839, 782, 760. 1H-NMR (200 MHz, DMSO-d6, δ / ppm): 5.85 (1H, s, C3–H), 7.55 (1H, dd, J = 7.5, 3.6 Hz, C7–H), 7.63 (1H, d, J = 7.4 Hz, C9–H), 8.08 (1H, dd, J = 7.4, 3.4 Hz, C8–H), 8.99 (1H, d, J = 7.5 Hz, C6–H). MS (m/z (I / %)): M+ 187 (34). 2-Hydrazino-4H-pyrido[1,2-a]pyrimidin-4-one (3). Anal. Calcd. for C8H8N4O (FW 176.18): C, 54.54; H, 4.58; N, 31.80 %; Found: C, 54.42; H, 4.42; N, 31.77 %. IR (KBr, cm–1): 3428, 3340, 3328, 3270 (NHNH2), 3072, 1690 (C=O), 1636 (C=N), 1610, 1570, 1518, 1445, 1352, 1080, 776. 1H-NMR (200 MHz, DMSO-d6, δ / ppm): 4.30 (2H, b, NH2), 5.62 (1H, s, C3–H), 7.31 (dd, 1H, J = 7.4, 3.6 Hz, C7–H), 7.56 (1H, d, J = 7.2 Hz, C9–H), 7.95 (1H, dd, J = 7.2, 3.5 Hz, C8–H), 8.12 (1H, b, NH), 8.93 (1H, d, J = 7.4 Hz, C6–H). MS (m/z (I / %)): M+ 176 (80). 5-Amino-3-(methylthio)-1-(4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl)-1H-pyrazole-4-carbonitrile (4). Anal. Calcd. for C13H10N6OS (FW 298.33): C, 52.34; H, 3.38; N, 28.17; S, 10.75 %; Found: C, 52.33; H, 3.38; N, 28.10; S, 10.50 %. IR (KBr, cm–1): 3360, 3265 (NH), 3115, 3071, 3043, 2924, 2210 (CN), 1676 (C=O), 1614 (C=N), 1549, 1501, 1457, 819, 762. 1H-NMR (200 MHz, DMSO-d6, δ / ppm): 2.56 (3H, s, SCH3), 6.59 (1H, s, C3–H), 7.43 (1H, m, C7–H), 8.08 (2H, m, C9–H + C8–H), 8.38 (2H, s, NH2), 8.99 (1H, d, J = 7.4 Hz, C6–H). 13C-NMR (70 MHz, DMSO-d6, δ / ppm): 38.5, 93.7, 100.1, 116.4, 118.0, 121.3, 124.2, 130.6, 133.8, 148.7, 149.7, 154.4, 158.9. 4-Imino-2-(methylthio)-5-oxo-1-phenyl-1,5-dihydro-4H-dipyrido-[1,2-a:2',3'-d]-pyrimidine-3-carbonitrile (8). Anal. Calcd. for C19H13N5OS (FW 359.41): C, 63.50; H, 3.65; N, 19.49; S, 8.92 %; Found: C, 6.40; H, 3.30; N, 19.20; S, 8.60 %. IR (KBr, cm–1): 3292 (NH), 3065, 3039, 3001, 2928, 2202 (CN), 1671 (C=O), 1621 (C=N), 1596, 1524, 1492, 1261, 759; 1H-NMR (200 MHz, DMSO-d6, δ / ppm): 2.08 (3H, s, SCH3), 7.05–8.29 (8H, m, 5Harom.+ C7–H + C9–H + C8–H), 8.85 (1H, d, J = 7.5 Hz, C6–H), 10.19 (1H, s, NH). 13C-NMR (70 MHz, DMSO-d6, δ / ppm): 35.5, 89.3, 96.4, 115.3, 117.7, 122.4, 112.9, 125.2, 129.7, 136.2, 139.0, 140.5, 142.1, 151.2, 156.0, 160.3, 165.9. N-Cyano-N’-(4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl)guanidine (9). Anal. Calcd. for C10H8N6O (FW 228.21): C, 52.63; H, 3.53; N, 36.83 %; Found: C, Available online at www.shd.org.rs/JSCS/ ___________________________________________________________________________________________________________________________ 2009 Copyright (CC) SCS SUBSTITUTED PYRIDOPYRIMIDINONES 13 52.31; H, 3.40; N, 36.72 %; IR (KBr, cm–1): 3429, 3383 (NH), 3334, 3249, 3194 (NH), 3151, 2920, 2207 (CN), 1669 (C=O), 1639 (C=N), 1571, 1506, 1434, 1357, 777, 721, 669. 1H-NMR (200 MHz, DMSO-d6, δ / ppm): 5.40 (1H, s, NH, disappeared with D2O), 6.0 (1H, s, NH, disappeared with D2O), 6.55 (1H, s, C3– –H), 7.40 (1H, dd, J = 7.5, 3.6 Hz, C7–H), 7.49 (1H, d, J = 7.5 Hz, C9–H), 7.82 (1H, dd, J = 7.5, 3.6 Hz, C8–H), 7.95–8.08 (1H, bs, NH, disappeared with D2O), 8.80 (1H, d, J = 7.5 Hz, C6–H). 13C-NMR (70 MHz, DMSO-d6, δ / ppm): 94.3, 115.5, 119.2, 122.6, 124.9, 138.0, 151.2, 157.3, 164.8, 165.8; MS (m/z (I / %)): M+ 228 (28). 2,4-Diamino-5H-pyrido[1,2-a]pyrimido[4,5-d]pyrimidin-5-one (10). Anal. Calcd. for C10H8N6O (FW 228.21): C, 52.63; H, 3.53; N, 36.83 %; Found: C, 52.50; H, 3.20; N, 36.50 %. IR (KBr, cm–1): 3435, 3328 (NH2), 3221, 3172 (NH), 3075, 2936, 1668 (C=O), 1620 (C=N), 1585, 1535, 1440, 1330, 778, 725. 1H-NMR (200 MHz, DMSO-d6, δ / ppm): 6.59 (2H, s, NH disappeared with 2 D2O), 6.68 (2H, s, NH2 disappeared with D2O), 7.44 (1H, dd, J = 7.6, 3.7 Hz, C7–H), 7.52 (1H, d, J = 7.5 Hz, C9–H), 7.89 (1H, dd, J = 7.5, 3.6 Hz, C8–H), 8.94 (1H, d, J = 7.6 Hz, C6–H). 13C-NMR (70 MHz, DMSO-d6, δ / ppm): 98.5, 114.9, 125.4, 128.0, 136.2, 146.2, 154.6, 158.9, 165.5, 169.8; MS (m/z (I / %)): M+ 228 (100). Chemistry Reaction of the chloro-compound 1 with sodium azide was performed in DMF, leading to 2-azidopyridopyrimidinone (2).12,13 (...truncated)