ISSN: A one-pot multi component synthesis of triazolopyrimidines

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1 Trade Science Inc. ISS: Volume 8 Issue 11 rganic CEMISTRY CAIJ, 8( [ ] A one-pot multi component synthesis of triazolopyrimidines Ranjit Pada, aresh Ram*, Ram andaniya, Dipti Dodiya, Viresh Shah Department of Chemistry, Kachchh University, Bhuj , Gujarat, (IDIA) ram.haresh2007@gmail.com Received: 4 th March, 2012 ; Accepted: 4 th April, 2012 ABSTRACT Synthesis of a series of triazolopyrimidines (4a-j) was achieved from different acetoacetamides, 4-(phenoxymethyl)benzaldehyde and 5-amino-1,2,4- triazole using multi component synthesis within minutes with high yield. The structures of the products were supported by FTIR, PMR and mass spectral data Trade Science Inc. - IDIA KEYWRDS Triazolo[1,5-a]pyrimidines; Acetoacetamides; 5-Amino-1,2,4-triazole; Multi component synthesis. ITRDUCTI and environmental friendliness (Scheme 1). The condensation of a ring of 1,2,4-triazole and another one of pyrimidine gives rise to the formation of bicyclic heterocycles known as 1,2,4- triazolopyrimi-dines. Among these isomeric families of compounds, 1,2,4-triazolo[1,5-a]pyrimidine derivatives are thermodynamically more stable and, thus, the most studied ones [1]. Revisions surveying the synthesis, reactivity, spectroscopic characterization and crystallographic studies of 1,2,4-triazolo[1,5- c]pyrimidines [2], 1,2,4-triazolo[4,3-a]pyrimidines [3] and 1,2,4-triazolo[4,3-c]pyrimidines [4] have also been published. Pharmacological activities, such as antitumor potency [5,], inhibition of KDR kinase [7], antifungal effect [8] and macrophage activation [9]. Anticancer acticity [10], Acetohydro-xyacid synthase inhibitor [11], CDK-2 inhibitors [12], Anti-inflammatory [13], fungicidal activities [14], antimycoba-cterial agents [15], A2A adenosine receptor antagonists [1], latent leishmanicidal activity [17] We have developed a new one-pot multi component synthesis of novel triazolo[1,5-a]pyridmidines (4aj) with the advantages of short reaction time, high yield + 2 C (1) DMF MW, min R (2) + R 3 C Scheme 1 (4a-j) (3a-j) C 3

2 420 EXPERIMETAL Melting points were measured in open capillaries and are uncorrected. 1 MR spectra were recorded on BRUKUR spectrophotometer (400Mz). Chemical shifts are expressed in units relative to TMS signal as internal reference. IR spectra were recorded on FT- IR SIMADZU-FT-IR 8400 spectrophotometer on KBr pallets. Mass spectra were recorded on GCMS QP2010 Gas Chromatograph SIMADZU. Thin Layer Chromatography (TLC) was performed on silica gel-g using hexane: ethylacetate solvent system. Typical exaperimental procedure for the synthesis of 1,2,4 triazolopyrimidines A mixture of the 5-amino-1,2,4-triazole (2 mmol acetoacetaminde (1 mmol) and 4- (phenoxymethyl)benzaldehyde (1 mmol) in 0.4 ml of DMF was refluxed under microwave irradiation for min. After cooling, methanol (~10 ml) was added. The reaction mixture was allowed to stand overnight and then filtered to give the solid triazolopyrimidine products (4a-j which were crystallized from ethanol and subsequently dried in air. -(3-chlorophenyl)-4,7-dihydro-5-methyl-7-(4- a]pyrimidine--carboxamide (4a) M. p. 219 ºC; white crystals; 1 MR (DMSd ) ä ppm: (ä 2.13) (s, 3, a 3.33) (s, 2, b (ä.4) (s, 1, c ) (d, 2, dd,.8-.88) (d, 1, e, ) (t, 2, ff ) (t, 1, g ) (m, 5, h-l ) (dd, 2, mn 7.1) (s, 1, o 9.78) (s, 1, p (ä 10.19) (s, 1, q ). FT IR (cm -1 ): 3259 (- stretching of secondary amine 3032 (C- stretching of aromatic ring 2920 (C- asymmetrical stretching of C 3 group 2875 (C- asymmetrical stretching of C 3 group 18 (C= stretching of amide 10 (C= stretching of triazole ring 1550 (- deformation of pyrimidine ring 1514 and 1480 (C=C stretching of aromatic ring 1440 (C- asymmetrical deformation of C 3 group 1410 (C- symmetrical deformation of C 3 group 1330 (C- stretching 1247 (C--C stretching 1028 (C- in plane deformation of aromatic ring 821 (C- out of plane rganic CEMISTRY A one-pot multi component synthesis of triazolopyrimidines CAIJ, 8(11) 2012 bending of 1,4-disubstituion 73 (C-Cl stretching Mass: m/z 472; Anal. Calcd. for C 2 22 Cl 5 2 : C,.17;, 4.70;, Found: C,.01;, 4.52;, 14.73%. -(4-fluorophenyl)-4,7-dihydro-5-methyl-7-(4- a]pyrimidine--carboxamide (4b) M. p. 179 ºC; white crystals; 1 MR (DMSd) ä ppm: (ä 1.7) (s, 3, a 4.9) (m, 2, b (ä.8) (s, 1, c.73) (s, 1, d.85-.8) (d, 1, e, ) (m, 4, f-i ) (m, 5, j-n ) (s, 1, o (ä ) (d, 2, p,q, 9.33 (s, 1, r 10.01) (s, 1, s). FT IR (cm-1): 3217 (- stretching of secondary amine 3045 (C- stretching of aromatic ring 294 (C- asymmetrical stretching of C3 group 2872 (C- asymmetrical stretching of C3 group 1 (C= stretching of amide 1595 (C= stretching of triazole ring 151 (- deformation of pyrimidine ring 1440, 1400 (C=C stretching of aromatic ring 1411 (C- asymmetrical deformation of C3 group 1344 (C- symmetrical deformation of C3 group 1280 (C- stretching 1247 (C--C stretching 1033 (C- in plane deformation of aromatic ring 819 (C- out of plane bending of 1,4- disubstituion). Mass: m/z 455; Anal. Calcd. for C222F52: C, 8.5;, 4.87;, Found: C, 8.32;, 4.7;, 15.29%. -(4-chlorophenyl)-4,7-dihydro-5-methyl-7-(4- (phenoxymethyl)phenyl)-[1,2,4]triazolo[1,5 a]pyrimidine--carboxamide (4c) M. p. 257 o C; white crystals; 1 MR (DMSd) ä ppm: (ä 2.14) (s, 3, a 4.95) (t, 2, b (ä.48) (s, 1, c ) (d, 2, d,e, (d, 1, d, ) (t, 1, f, ) (m,, g-l ) (t, 1, n (ä 7.3) (s, 2, m ) (m, 1, o-q 9.92) (s, 1, r 10.27) (s, 1, s). FT IR (cm- 1): 329 (- stretching of secondary amine 3024 (C- stretching of aromatic ring 2922 (C- asymmetrical stretching of C3 group 288 (C- asymmetrical stretching of C3 group 1 (C= stretching of amide 118 (C= stretching of triazole ring 1550 (- deformation of pyrimidine ring 1510, 1479

3 CAIJ, 8(11) 2012 and 1442 (C=C stretching of aromatic ring 1413 (C- asymmetrical deformation of C3 group 1329 (C- symmetrical deformation of C3 group 1280 (C- stretching 1247 (C--C stretching 1033 (C- in plane deformation of aromatic ring 825 (C- out of plane bending of 1,4-disubstituion. MS: m/z 471; Anal. Calcd. for C222Cl52: C,.17;, 4.70;, 14.84;,.78. Found: C, 4.38;, 4.29;, 14.75%. -(4-nitrophenyl)-4,7-dihydro-5-methyl-7-(4- a] pyrimidine--carboxamide (4d) M. p. 179 o C; white crystals; 1 MR (DMSd ) ä ppm: (ä 2.03) (s, 3, a 3.13) (s, 2, b (ä.33) (s, 1, c ) (d, 2, dd, ) (d, 1, e, ) (t, 2, ff (ä ) (t, 1, g ) (m, 5, h-l (ä ) (dd, 2, mn 7.58) (s, 1, o 9.74) (s, 1, p (ä 10.1) (s, 1, q ). FT IR (cm-1): 3309 (- stretching of secondary amine 3014 (C- stretching of aromatic ring 2952 (C- asymmetrical stretching of C3 group 2858 (C- asymmetrical stretching of C3 group 15 (C= stretching of amide 108 (C= stretching of triazole ring 1540 (- deformation of pyrimidine ring 1511, 149 and 1432 (C=C stretching of aromatic ring 1403 (C- asymmetrical deformation of C3 group itro: ( (C- symmetrical deformation of C3 group 1229 (C- stretching 1227 (C--C stretching 1031 (C- in plane deformation of aromatic ring 820 (C- out of plane bending of 1,4-disubstituion. MS: m/z 482; Anal. Calcd. for C2224: C, 4.72;, 4.0;,17.42;, Found: C, 4.1;, 4.50;, 17.24%. -(3-nitrophenyl)-4,7-dihydro-5-methyl-7-(4- a] pyrimidine--carboxamide (4e) M. p. 199 o C; white crystals; 1 MR (DMSd ) ä ppm: (ä 2.11) (s, 3, a 3.58) (s, 2, b (ä.01) (s, 1, c.4-.) (d, 2, dd,.2-.70) (d, 1, e, ) (t, 2, ff ) (t, 1, g ) (m, 5, h-l ) (dd, 2, mn 7.53) (s, 1, o 9.87) (s, 1, p (ä 10.25) (s, 1, q ). FT IR (cm-1): 3312 (- stretching of secondary amine 3001 (C- aresh Ram et al. 421 stretching of aromatic ring 2924 (C- asymmetrical stretching of C3 group 2822 (C- asymmetrical stretching of C3 group 105 (C= stretching of amide 100 (C= stretching of triazole ring 1527 (- deformation of pyrimidine ring 1509, 145 and 1435 (C=C stretching of aromatic ring 1405 (C- asymmetrical deformation of C3 group itro: ( (C- symmetrical deformation of C3 group 1257 (C- stretching 1213 (C--C stretching 1010 (C- in plane deformation of aromatic ring 835 (C- out of plane bending of 1,4-disubstituion. mp 274 ºC; MS: m/z 482; Anal. Calcd. for C2224: C, 4.72;, 4.0;, 17.42;, Found: C, 4.10;, 4.54;, 1.89%. -(4-hydroxyphenyl)-4,7-dihydro-5-methyl-7-(4- (phenoxymethyl)phenyl)-[1,2,4]triazolo-[1,5- a]pyrimidine--carboxamide (4f) M. p. 222 ºC; white crystals; 1 MR (DMSd) ä ppm: (ä 1.) (s, 3, a 4.89) (m, 2, b.81) (s, 1, c.75 (s, 1, d.85-.8) (d, 1, e, ) (m, 4, fi (ä ) (m, 5, j-n ) (s, 1, o ) (d, 2, p,q 9.13) (s, 1, r 10.01) (s, 1, s). FT IR (cm-1): 3599 (Free -) 3317 (- stretching of secondary amine 305 (C- stretching of aromatic ring 290 (C- asymmetrical stretching of C3 group 2852 (C- asymmetrical stretching of C3 group 11 (C= stretching of amide 1592 (C= stretching of triazole ring 1501 (- deformation of pyrimidine ring 1430, 1412 (C=C stretching of aromatic ring 1405 (C- asymmetrical deformation of C3 group 1342 (C- symmetrical deformation of C3 group 1275 (C- stretching 1237 (C--C stretching 1023 (C- in plane deformation of aromatic ring 811 (C- out of plane bending of 1,4-disubstituion). Maas: m/z 453; Anal. Calcd. for C22353: C, 8.8;, 5.11;, 15.44;, Found: C, 7.08;, 4.39;, 20.1%. -(2-chlorophenyl)-4,7-dihydro-5-methyl-7-(4- a]pyrimidine--carboxamide (4g) M. p. 227 o C; white crystals; 1 MR (DMSd) ä ppm: (ä 2.11) (s, 3, a 4.85) (t, 2, b rganic CEMISTRY

4 422 (ä.59) (s, 1, c.5-.9) (d, 2, d,e, (ä.8-.78) (d, 1, d, ) (t, 1, f, (ä ) (m,, g-l ) (t, 1, n 7.5) (s, 2, m(ä ) (m, 1, oq (ä 9.98) (s, 1, r10.25) (s, 1, s). FT IR (cm-1): 3259 (- stretching of secondary amine 3031 (C- stretching of aromatic ring 2912 (C- asymmetrical stretching of C3 group 2858 (C- asymmetrical stretching of C3 group 11 (C= stretching of amide 110 (C= stretching of triazole ring 1558 (- deformation of pyrimidine ring 1511, 1485 and 1441 (C=C stretching of aromatic ring 1410 (C- asymmetrical deformation of C3 group 1312 (C- symmetrical deformation of C3 group 1275 (C- stretching 1241 (C--C stretching 101 (C- in plane deformation of aromatic ring 832 (C- out of plane bending of 1,4- disubstituion. Mass: m/z 471; Anal. Calcd. for C222Cl52: C,.17;, 4.70;, 14.84;,.78. Found: C, 5.8;, 4.45;, 14.58%. -(4-methoxyphenyl)-4,7-dihydro-5-methyl-7-(4- (phenoxymethyl)phenyl)- [1,2,4]triazolo[1,5- a]pyrimidine--carboxamide (4h) M. p. 199 o C; white crystals; 1 MR (DMSd ) ä ppm: (ä 2.23) (s, 3, a 3.4) (s, 2, b (ä.25) (s, 1, c ) (d, 2, dd, ) (d, 1, e, ) (t, 2, ff ) (t, 1, g ) (m, 5, h-l ) (dd, 2, mn 7.52) (s, 1, o 9.72) (s, 1, p (ä 10.10) (s, 1, q ). FT IR (cm-1): 3354 (- stretching of secondary amine 3015 (C- stretching of aromatic ring 2959 (C- asymmetrical stretching of C3 group 2855 (C- asymmetrical stretching of C3 group 152 (C= stretching of amide 115 (C= stretching of triazole ring 1554 (- deformation of pyrimidine ring 1521, 142 and 1438 (C=C stretching of aromatic ring 141 (C- asymmetrical deformation of C3 group itro: ( (C- symmetrical deformation of C3 group 125 (C- stretching 1221 (C--C stretching 1013 (C- in plane deformation of aromatic ring 823 (C- out of plane bending of 1,4-disubstituion. mp 274 ºC; MS: m/z 47; Anal. Calcd. for C272553: C, 9.3;, 5.39;, Found: C, 8.8;, 5.09;, 14.18%. rganic CEMISTRY A one-pot multi component synthesis of triazolopyrimidines CAIJ, 8(11) (4-bromophenyl)-4,7-dihydro-5-methyl-7-(4- a]pyrimidine--carboxamide (4i) M. p. 189 ºC; white crystals; 1 MR (DMSd) ä ppm: (ä 1.0) (s, 3, a 4.54) (m, 2, b (ä.74) (s, 1, c.5) (s, 1, d.75-.7) (d, 1, e,.-7.00) (m, 4, f-i ) (m, 5, j-n ) (s, 1, o (ä ) (d, 2, p,q, 9.11) (s, 1, r 10.00) (s, 1, s). FT IR (cm-1): 3544 (Free -) 3300 (- stretching of secondary amine 3012 (C- stretching of aromatic ring 2952 (C- asymmetrical stretching of C3 group 2854 (C- asymmetrical stretching of C3 group 100 (C= stretching of amide 1554 (C= stretching of triazole ring 1500 (- deformation of pyrimidine ring 1423, 1402 (C=C stretching of aromatic ring 1400 (C- asymmetrical deformation of C3 group 1305 (C- symmetrical deformation of C3 group 1255 (C- stretching 1277 (C--C stretching 1015 (C- in plane deformation of aromatic ring 80 (C- out of plane bending of 1,4-disubstituion). Maas: m/z 51; Anal. Calcd. for C222Br52: C, 0.47;, 4.29;, 13.5; Found: C, 0.01;, 3.89;, 12.4%. -(3-bromophenyl)-4,7-dihydro-5-methyl-7-(4- (phenoxymethyl)phenyl)- [1,2,4]triazolo[1,5- a]pyrimidine--carboxamide (4j) M. p. 18 o C; white crystals; 1 MR (DMSd) ä ppm: (ä 2.01) (s, 3, a 4.05) (t, 2, b (ä.48) (s, 1, c ) (d, 2, d,e,.58-.8) (d, 1, d, ) (t, 1, f, ) (m,, g-l ) (t, 1, n (ä 7.51) (s, 2, m ) (m, 1, o-q 9.89) (s, 1, r 10.20) (s, 1, s). FT IR (cm- 1): 3333 (- stretching of secondary amine 315 (C- stretching of aromatic ring 295 (C- asymmetrical stretching of C3 group 2854 (C- asymmetrical stretching of C3 group 12 (C= stretching of amide 12 (C= stretching of triazole ring 1551 (- deformation of pyrimidine ring 1502, 1421 and 1401 (C=C stretching of aromatic ring 135 (C- asymmetrical deformation of C3 group 1302 (C- symmetrical deformation of C3 group 125 (C- stretching 1223 (C--C stretching 1010 (C- in plane deformation of aromatic ring 823 (C- out of

5 CAIJ, 8(11) 2012 plane bending of 1,4-disubstituion. Maas: m/z 51; Anal. Calcd. for C222Br52: C, 0.47;, 4.29;, 13.5; Found: C, 0.01;, 3.89;, 12.4%. REFERECES [1] G.Fischer; Adv.eterocycl.Chem., 57, 81 (1993). [2] M.A.E.Shaban, A.E.A.Morgan; Adv.eterocycl. Chem., 77, 345 (2002). [3] M.A.E.Shaban, A.E.A.Morgan; Adv.eterocycl. Chem., 73, 131 (2002). [4] M.A.E.Shaban, A.E.A.Morgan; Adv.eterocycl. Chem., 75, 243 (2002). [5].Zhang, A.K.Semiramis,.Thai et al.; J.Med. Chem., 50, 319 (2007). [] L.avlicek, K.Fuksova, V.Krystof, et al.; Bioorg. Med.Chem., 13, 5399 (2009). [7] M.E.Fraley, W.F.offman, R.S.Rubino; Bioorg. Med.Chem.Lett., 12, 277 (2002). [8] Q.Chen, X.L.Zhu, Z.M.Liu, et al.; Eur.J.Med. Chem., 43, 595 (2008). [9] S.Uryu, S.Tokuhiro, T.Murasugi, et al.; Brain Research, 4, 298 (2002). aresh Ram et al. 423 [10] C.F.Beyer,.Zhang, R.ernandez, D.Vitale, J.Lucas, T.guyen, C.Discafani, S.Ayral- Kaloustian, J.Gibbons; J.Cancer Res., 8, 2292 (2008). [11] Q.Chen, X.Zhu, L.Jiang, Z.Liu, G.Yang; European Journal of Medicinal Chemistry, 43, 595 (2008). [12].Li, J.Tatlock, A.Linton, J.Gonzalez, T.Jewell, L.Patel, S.Ludlum, M.Drowns, S.V.Rahavendran,.Skor, R.unter, S.T.Shi, K.J.erlihy,.Parge, M.ickey, X.Yu, F.Chau, J.onomiya, C.Lewis; J.Med.Chem., 52, 1255 (2009). [13] C.Chen, L.Lv, F.Ji, Q.Chen,.Xu, C.iu, Z.Xi, G.Yang; Bioorg.Med.Chem., 17, 3011 (2009). [14] Q.Chen, Z.M.Liu, C..Chen, L.L.Jiang, G.F.Yang; Chem.Biodivers., ( (2009). [15] Arch Pharm, Weinheim, 342( (2009). [1].Peng, G.Kumaravel, G.Yao, L.Sha, J.Wang,.Van Vlijmen, T.Bohnert, C.uang, C.B.Vu, C.L.Ensinger,.Chang, T.M.Engber, E.T.Whalley, R.C.Petter; J.Med.Chem., 47, 218 (2004). [17] V.Ram, P.Srivastava, S.K.Singh, M.Kandpal, B.L.Tekwani; Bioorg.Med.Chem.Lett., 7, 1087 (1997). rganic CEMISTRY