A New Protocol for Catalyst-Free Regioselective Synthesis of 5,9-Dihydropyrimido[5,4-e][1,2,4]triazolo[1,5-a]pyrimidine-6,8(4H,7H)-diones

Abstract

A novel, environmentally friendly synthesis of 5,9-dihydro­pyrimido[5,4-e][1,2,4]triazolo[1,5-a]pyrimidine-6,8(4H,7H)-diones has been developed by using a one-pot condensation of 1,3-dimethylbarbituric acid, 3-amino-1H-1,2,4-triazoles, and aromatic aldehydes. The reactions were established based on green chemistry principles under catalyst- and solvent-free conditions.

Key words

nitrogen heterocycles - triazoles - green chemistry - aromatic aldehydes - multicomponent reactions

• References and Notes

• 1 Powner MW, Zheng SL, Szostak JW. J. Am. Chem. Soc. 2012; 134: 13889
• 2 Isambert N, Duque MD. M. S, Plaquevent JC, Génisson Y, Rodriguez J, Constantieux T. Chem. Soc. Rev. 2011; 40: 1347
• 3 Akritopoulou-Zanze I. Curr. Opin. Chem. Biol. 2008; 12: 324
• 4 Kolos NN, Kovalenko LU, Borovskoy VA. Chem. Heterocycl. Compd. 2011; 47: 983
• 5 Gladkov ES, Gura KA, Sirko SM, Desenko SM, Groth U, Chebanov VA. Beilstein J. Org. Chem. 2012; 8: 2100
• 6 Shaabani A, Rahmati A, Rezayan AH, Darvishi M, Badri Z, Sarvari A. QSAR Comb. Sci. 2007; 26: 973
• 7 Ryabukhin SV, Plaskon AS, Boron SY, Volochnyuk DM, Tolmachev AA. Mol. Diversity 2011; 15: 189
• 8 Boutaleb-Charki S, Marín C, Maldonado CR, Rosales MJ, Urbano J, Guitierrez-Sánchez R, Quirós M, Salas JM, Sánchez-Moreno M. Drug Metab. Lett. 2009; 3: 35
• 9 Ruisi G, Canfora L, Bruno G, Rotondo A, Mastropietro TF, Debbia EA, Girasolo MA, Megna B. J. Organomet. Chem. 2010; 695: 546
• 10 El-Gendy MM. A, Shaaban M, Shaaban KA, El-Bondkly AM, Laatsch H. J. Antibiot. 2008; 61: 149
• 11 Zidar N, Kikelj D. Acta Chim. Slov. 2011; 58: 151
• 12 Vieira AA, Gomes NM, Matheus ME, Fernandes PD, Figueroa-Villar JD. J. Braz. Chem. Soc. 2011; 22: 364
• 13 Rao NV, Vaisalini N, Mounika B, Harika VL, Kumardesu P, Nama S. Int. J. Pharm. Chem. Res. 2013; 2: 14
• 14 Rathod SB, Gambhire AB, Arbad BR, Lande MK. Bull. Korean Chem. Soc. 2010; 31: 339
• 15 Sami S, Nandi GC, Kumar R, Singh MS. Tetrahedron Lett. 2009; 50: 7096
• 16 Zhu J, Bienaymé HE. Multicomponent Reactions . Wiley-VCH; Weinheim: 2005
• 17 Dömling A, Ugi IA. Angew. Chem. Int. Ed. 2000; 39: 3168
• 18 Simon C, Constantieux T, Rodriguez J. Eur. J. Org. Chem. 2004; 4957
• 19 Belwal S. Modern Chemistry 2013; 1: 22
• 20 Martínez-Palou R. J. Mex. Chem. Soc. 2007; 51: 252
• 21 Bandyopadhyay D, Smith LC, Garcia DR, Yadav RN, Banik BK. Org. Med. Chem. Lett. 2014; 9: 27
• 22 Synthesis of 4a–l; General Procedure: A mixture of 1,3-dimethylbarbituric acid (1 mmol), 3-amino-1H-1,2,4-triazole (1 mmol), and aryl aldehyde (1 mmol) was stirred at 120 °C under solvent-free conditions for 10–30 min. Upon completion of the reaction, as indicated by TLC (hexane–EtOAc, 2:1), the obtained powder was recrystallized from EtOH to afford the pure product. Selected Characterization Data 5,7-Dimethyl-9-phenyl-5,9-dihydropyrimido[4,5-d][1,2,4]-triazolo[1,5-a]pyrimidine-6,8(4H,7H)-dione (4a): Yield: 0.285 g (92%); white solid; mp 231–232 °C. IR (KBr): 3226, 1720, 1695 cm^–1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 8.54 (s, 1 H), 8.04 (s, 1 H), 7.69 (d, J = 4 Hz, 2 H), 7.63–7.67 (m, 1 H), 7.46 (t, J = 4 Hz, 2 H), 5.60 (s, 1 H), 3.24 (s, 3 H), 3.19 (s, 3 H) ppm. ¹³C NMR (100 MHz, DMSO-d ₆): δ = 161.05, 153.43, 150.04, 145.50, 139.15, 136.95, 128.00, 127.87, 126.64, 92.38, 40.05, 28.59, 28.00. Anal. Calcd for C₁₅H₁₄N₆O₂: C, 58.06; H, 4.55; N, 27.08. Found: C, 57.85; H, 4.50; N, 27.12. 9-(4-Chlorophenyl)-5,7-dimethyl-5,9-dihydropyrimido[4,5-d]-[1,2,4]triazolo[1,5-a]pyrimidine-6,8(4H,7H)-dione (4b): Yield: 0.330 g (96%); yellow solid; mp 251–252 °C. IR (KBr): 3223, 1708, 1664 cm^–1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 8.35 (s, 1 H), 7.57 (s, 1 H), 7.36 (d, J = 8 Hz, 2 H), 7.31 (d, J = 8 Hz, 2 H), 5.27 (s, 1 H), 2.87 (s, 3 H), 2.73 (s, 3 H). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 162.86, 155.45, 153.78, 129.67, 128.85, 128.74, 128.52, 128.07, 126.99, 95.03, 59.63, 28.26, 27.41. Anal. Calcd for C₁₅H₁₃ClN₆O₂: C, 52.26; H, 3.80; N, 24.38. Found: C, 52.16; H, 3.85; N, 23.88. 9-(4-Bromophenyl)-5,7-dimethyl-5,9-dihydropyrimido[4,5-d]-[1,2,4]triazolo[1,5-a]pyrimidine-6,8(4H,7H)-dione (4c): Yield: 0.354 g (91%); yellow solid; mp 263–265 °C. IR (KBr): 3213, 1709, 1664 cm^–1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 8.88 (s, 1 H), 7.77 (s, 1 H), 7.34 (d, J = 8 Hz, 2 H), 7.17 (d, J = 8 Hz, 2 H), 4.66 (s, 1 H), 2.94 (s, 3 H), 2.62 (s, 3 H). ¹³C NMR (100 MHz, DMSO-d:): δ = 166.06, 162.06, 154.77, 153.83, 148.03, 142.71, 136.14, 129.41, 127.40, 99.02, 58.12, 24.48, 21.06. Anal. Calcd for C₁₅H₁₃BrN₆O₂: C, 46.29; H, 3.37; N, 21.59. Found: C, 46.41; H, 3.23; N, 21.65.