A Novel One-Pot Method for Highly Regioselective Synthesis of Triazoloapyrimidinedicarboxylates Using Silica Sodium Carbonate

Abstract

A novel synthesis of dimethyl 4,5-dihydro-5-aryl-[1,2,4]triazolo[1,5-a]pyrimidine-6,7-dicarboxylates is reported. This methodology consists of the one-pot condensation of 3-amino-1H-1,2,4-triazole, dimethyl acetylenedicarboxylate, and aryl aldehydes using silica sodium carbonate as a solid base catalyst. The use of silica sodium carbonate as a heterogeneous reusable catalyst makes this procedure mild, convenient, and environmentally benign.

Key words

4,5-dihydro-5-aryl-[1,2,4]triazolo[1,5-a]pyrimidine-6,7-di­carboxylates - 3-amino-1H-1,2,4-triazole - dimethyl acetylenedicarboxylate - aryl aldehydes - silica sodium carbonate

• References and Notes

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• 23 Preparation of Silica Sodium Carbonate (SSC) ¹⁷ To a 250 mL round-bottom flask equipped with a reflux condenser, silica gel 60 (10 g) that had been previously dried at 120 °C for 6 h was added. Then SOCl₂ (40 mL) was added dropwise with cooling in an ice bath (caution). After the addition of the SOCl₂, the reaction mixture was removed from the ice bath and stirred for 0.5 h at r.t. and 48 h under reflux conditions. The mixture was then filtered to obtain the silica chloride. Subsequently, to a stirred 250 mL round-bottom flask containing NaHCO₃ (10 g) and n-hexane (25 mL) under reflux, 10 g of silica chloride (after drying at 120 °C for 6 h) was added. After 24 h, the reaction mixture was filtered to separate the catalyst, and the solid product was washed with distilled H₂O (10×), using 5 mL each time until filtrate neutral, in order to remove the remaining NaHCO₃. Finally, after drying the catalyst at 100 °C for 12 h, 14 g of SSC was obtained.
• 24 General Experimental Procedure for the Synthesis of Compounds 4a–j To a stirred solution of 3-amino-1H-1,2,4-triazole (1 mmol), aryl aldehyde (1 mmol), and DMAD (1 mmol) in CHCl₃ (5 ml) SSC (10 mol%, 0.2 g) was added. The resulting mixture was stirred for 60–120 min at r.t. After completion of the reaction, the solvent was evaporated. Next, boiling EtOAc (10 mL) was added, and the catalyst was separated by filtration. Further purification was achieved by recrystallization from EtOH. Dimethyl 5-Phenyl-4,5-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine-6,7-dicarboxylate (4a) White solid (0.28 g, 90%); mp 228–231 °C. ¹H NMR (400 MHz, DMSO-d ₆): δ = 8.44 (d, J =8.8 Hz, 1 H), 8.23 (s, 1 H), 7.88 (d, J = 8.0 Hz, 2H), 7.74 (t, J = 7.2 Hz, 2 H), 7.56 (t, J = 7.2 Hz, 1 H), 4.05 (d, J = 8.8 Hz, 1 H), 3.43 (s, 3 H), 2.99 (s, 3 H) ppm. ¹³C NMR (100 MHz, DMSO-d ₆): δ = 166.87, 159.34, 156.10, 152.66, 139.47, 136.88, 128.58, 127.92, 127.87, 127.43, 56.58, 55.61, 55.58 ppm. IR (KBr): ν_max = 3201, 1729, 1698 cm^–1. Anal. Calcd for C₁₅H₁₄N₄O₄: C, 58.06; H, 4.55; N, 27.08. Found: C, 58.01; H, 4.63; N, 27.01. Dimethyl 5-(4-Chlorophenyl)-4,5-dihydro-[1,2,4]triazolo-[1,5-a]pyrimidine-6,7-dicarboxylate (4c) Yellow solid (0.32 g, 92%); mp 235–237 °C. ¹H NMR (400 MHz, DMSO-d ₆): δ = 8.47 (d, J = 8.0 Hz, 1 H), 7.85 (s, 1 H), 7.43 (d, J = 8.0 Hz, 2 H), 7.19 (d, J = 8.0 Hz, 2 H), 4.69 (d, J = 8.0 Hz, 1 H), 3.04 (s, 3 H), 2.62 (s, 3 H) ppm.¹³C NMR (100 MHz, DMSO-d ₆): δ = 160.01, 159.83, 157.91, 155.05, 154.06, 145.66, 131.62, 129.41, 128.88, 120.41, 57.52, 52.20, 51.72 ppm. IR (KBr): ν_max = 3215, 1731, 1705 cm^–1. Anal. Calcd for C₁₅H₁₃ClN₄O₄: C, 51.66; H, 3.76; N, 16.07. Found: C, 51.60; H, 3.78; N, 16.10. Dimethyl 5-(m-Tolyl)-4,5-dihydro-[1,2,4]triazolo[1,5-a]-pyrimidine-6,7-dicarboxylate (4e) Pale yellow solid (0.30 g, 89%); mp 223–225 °C. ¹H NMR (400 MHz, DMSO-d ₆): δ = 8.91 (d, J = 8 Hz, 1 H), 8.59 (s, 1 H), 7.98 (s, 1 H), 7.60–7.67 (m, 1 H), 7.18 (d, J = 7.6 Hz, 2 H), 4.89 (d, J = 8.0 Hz, 1 H), 3.22 (s, 3 H), 2.91 (s, 3 H), 2.63 (s, 3 H) ppm. ¹³C NMR (100 MHz, DMSO-d ₆): δ = 160.23, 159.75, 157.92, 155.14, 153.77, 148.23, 147.97, 134.53, 130.66, 122.33, 122.03, 120.22, 56.74, 56.16, 49.19, 30.49 ppm. IR (KBr): ν_max = 3220, 1729, 1710 cm^–1. Anal. Calcd for C₁₆H₁₆N₄O₅: C, 55.81; H, 4.68; N, 16.27. Found: C, 55.82; H, 4.69; N, 16.29. Dimethyl 5-(4-Nitrophenyl)-4,5-dihydro -[1,2,4]triazolo[1,5-a]pyrimidine-6,7-dicarboxylate (4i) Yellow solid (0.34 g, 95%); mp 264–266 °C. ¹H NMR (400 MHz, DMSO-d ₆): δ = 8.86 (d, J = 8.0 Hz, 1 H), 8.34 (s, 1 H), 8.21 (d, J = 8.0 Hz, 2 H), 6.96 (d, J = 8.0 Hz, 2 H), 4.87 (d,J = 8.0 Hz, 1 H), 3.73 (s, 6 H) ppm. ¹³C NMR (100 MHz, DMSO-d ₆): δ = 160.01, 159.81, 157.94, 154.95, 153.76, 144.66, 131.62, 129.44, 128.85, 120.41, 57.50, 50.15, 50.00 ppm. IR (KBr): ν_max = 3106, 1728, 1708 cm^–1. Anal. Calcd for C₁₅H₁₃N₅O₆: C, 50.14; H, 3.65; N, 19.49. Found: C, 50.15; H, 3.67; N, 19.48.