A Simple One-Pot Procedure for the Synthesis of 1,2,4-Triazolo[1,5-a]pyrid-ines via Pseudo Five-Component Reactions Catalyzed by Molecular Iodine

Abstract

In this paper we report the synthesis of the 1,2,4-triazolo[1,5-a]pyridine ring system. The reaction between benzylidenehydrazines, dialkyl acetylenedicarboxylates, benzaldehydes, and malononitrile proceeds in EtOH at reflux in the presence of molecular iodine as catalyst in good to excellent yields.

Key words

benzylidenehydrazine - dialkyl acetylenedicarboxylate - benzaldehyde - malononitrile - 1,2,4-triazolo[1,5-a]pyridine - catalyst - iodine - multicomponent reaction

• References and Notes

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• 11 Typical Procedure for the Preparation of Dimethyl 7-(4-Chlorophenyl)-8-cyano-2-phenyl-[1,2,4]triazolo[1,5-a]pyridine-5,6-dicarboxylate (4a)A solution of benzaldehyde (0.212 g, 2 mmol) and hydrazine hydrate (0.16 g, 1 mmol) was magnetically stirred in EtOH (5 mL) for 20 min. Then a solution of DMAD (0.142 g, 1 mmol) was added, and the mixture was stirred for 3 min. At this point, the condensation product of 4-chlorobenz-aldehyde (0.140 g, 1 mmol) and malononitrile (6a, 0.066 g, 1 mmol) was added, and the reaction mixture was stirred for 3 h under reflux and progress was followed by TLC. After completion, the reaction mixture was cooled to r.t., I₂ (0.1 mmol) was added, and the mixture was stirred for a further 2 h. The progress of the reaction was again followed by TLC and, after completion, the solvent was removed under reduced pressure, and the residue was purified by column chromatography (n-hexane–EtOAc, 5:1). All products gave satisfactory spectroscopic data in accordance with the assigned structures.Representative Spectroscopic Data
  Dimethyl 7-(4-Chlorophenyl)-8-cyano-2-phenyl-[1,2,4]triazolo[1,5-a]pyridine-5,6-dicarboxylate (4a)White powder; yield: 0.26 g (59%); mp 263–265 °C. IR (KBr): 2358 (CN), 1748 (CO₂Me), 1538 and 1443 (Ar), 1251 (C–O of ester) cm^–1. ¹H NMR (500.13 MHz, CDCl₃): δ = 3.65 (3 H, s, OCH₃), 4.17 (3 H, s, OCH₃), 7.38 (2 H, d, ³ J _HH = 8.0 Hz, 2 CH of Ar), 7.52–7.54 (5 H, m, 5 CH of Ar), 8.37 (2 H, d, ³ J _HH = 8.0 Hz, 2 CH of Ar) ppm. ¹³C NMR (125.75 MHz, CDCl₃): δ = 53.4 (OCH₃), 54.3 (OCH₃), 102.4 (C⁸), 112.6 (C⁵), 118.6 (CN), 128.3 (2 CH _meta of Ph), 128.8 (2 CH of Ar), 128.9 (C⁶), 129.2 (2 CH of Ar), 129.7 (2 CH _ortho of Ph), 131.5 (CH _para of Ph), 132.8 (C _ipso of Ph), 135.3 (C–Cl), 136.5 (C _ipso of Ar), 147.6 (C^8a), 150.77 (C⁷), 159.9 (C²),163.6 (C=O), 167.8 (C=O) ppm. MS (EI, 70 eV): m/z (%) = 446 (22) [M⁺], 367 (35), 298 (31), 224 (22), 190 (36), 167 (22), 149 (57), 111 (28), 97 (46), 81 (57), 69 (100), 57 (65). Anal. Calcd (%) for C₂₃H₁₅ClN₄O₄ (446.85): C, 61.82; H, 3.38; N, 12.54. Found: C, 61.79; H, 3.39; N, 12.55.Dimethyl 2,7-Bis(4-chlorophenyl)-8-cyano-[1,2,4]triazolo[1,5-a]pyridine-5,6-dicarboxylate (4f)White powder; yield: 0.24 g (51%); mp 281–283 °C. IR (KBr): 2357 (CN), 1746 (CO₂Me), 1440 (Ar), 1259 (C–O of ester) cm^–1. ¹H NMR (400.13 MHz, CDCl₃): δ = 3.66 (3 H, OCH₃), 4.17 (3 H, OCH₃), 7.38 (2 H, d, ³ J _HH = 8.0 Hz, 2 CH of Ar), 7.50 (2 H, d, ³ J _HH = 8.0 Hz, 2 CH of Ar), 7.54 (2 H, d, ³ J _HH = 8.0 Hz, 2 CH of Ar), 8.32 (2 H, d, ³ J _HH = 8.0 Hz, 2 CH of Ar) ppm. ¹³C NMR (100.61 MHz, CDCl₃): δ = 53.4 (OCH₃), 54.40 (OCH₃), 102.4 (C⁸), 112.5 (C⁵), 118.8 (CN), 127.3 (C⁶), 129.1 (2 CH of Ar), 129.2 (2 CH of Ar), 129.5 (2 CH of Ar), 129.6 (2 CH of Ar), 132.6 (C _ipso of Ar), 135.2 (C–Cl), 136.7 (C _ipso of Ar), 137.7 (C–Cl) 147.7 (C^8a), 150.7 (C⁷), 159.7 (C²), 163.5 (C=O), 166.7 (C=O) ppm. MS (EI, 70 eV): m/z (%) = 481 (31) [M⁺], 480 (100) [M⁺ – 1], 449 (22), 364 (51), 190 (22), 163 (22), 138 (72), 102 (30), 75 (53), 59 (33). Anal. Calcd (%) for C₂₃H₁₄Cl₂N₄O₄ (481.30): C, 57.40; H, 2.93; N, 11.64. Found: C, 57.42; H, 2.92; N, 11.65.Dimethyl 7-(3-Bromophenyl)-8-cyano-2-p-tolyl-[1,2,4]triazolo[1,5-a]pyridine-5,6-dicarboxylate (4h)White powder; yield: 0.25 g (55%); mp 287–289 °C. IR (KBr): 2359 (CN), 1742 (CO₂Me), 1441 (Ar), 1264 (C–O of ester) cm^–1. ¹H NMR (400.13 MHz, CDCl₃): δ = 2.45 (3 H, s, Me), 3.66 (3 H, OCH₃), 4.17 (3 H, OCH₃), 7.33 (2 H, d, ³ J _HH = 8.0 Hz, 2 CH of Ar), 7.38 (2 H, d, ³ J _HH = 8.0 Hz, 2 CH of Ar), 7.54 (2 H, d, ³ J _HH = 8.0 Hz, 2 CH of Ar), 8.27 (2 H, d, ³ J _HH = 8.0 Hz, 2 CH of Ar) ppm. ¹³C NMR (100.61 MHz, CDCl₃): δ = 29.7 (Me), 53.3 (OCH₃), 54.3 (OCH₃), 100.2 (C⁸), 112.7 (C⁵), 118.3 (CN), 126.0 (C⁶), 128.2 (2 CH of Ar), 129.2 (2 CH of Ar), 129.5 (2 CH of Ar), 129.6 (2 CH of Ar), 132.4 (C _ipso of Ar), 135.6 (C–Cl), 136.5 (C _ipso of Ar), 140.6 (C–Me), 142.0 (C^8a), 151.8 (C⁷), 155.0 (C²), 164.6 (C=O), 166.0 (C=O) ppm. MS (EI, 70 eV): m/z (%) = 460 (53) [M⁺], 422 (38), 391 (27), 364 (89), 199 (43), 163 (43), 138 (100), 111 (49), 75 (46), 59 (58) (32). Anal. Calcd (%) for C₂₄H₁₇ClN₄O₄ (460.87): C, 62.55; H, 3.72; N, 12.16. Found: C, 62.53; H, 3.73; N, 12.14.