Copper-Catalyzed Synthesis of 1,2,4-Triazoles via Sequential Coupling and Aerobic Oxidative Dehydrogenation of Amidines

Hao Xu; Yuyang Jiang; Hua Fu

doi:10.1055/s-0032-1317692

Synlett, Table of Contents

Synlett 2013; 24(1): 125-129
DOI: 10.1055/s-0032-1317692

letter

Copper-Catalyzed Synthesis of 1,2,4-Triazoles via Sequential Coupling and Aerobic Oxidative Dehydrogenation of Amidines

Hao Xu

^aKey Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Department of Chemistry, Tsinghua University, Beijing 100084, P. R. of China, Fax: +86(10)62781695 Email: fuhua@mail.tsinghua.edu.cn

^bSchool of Chemistry and Chemical Engineering, Henan University, Kaifeng 475001, P. R. of China

,

Yuyang Jiang

^cKey Laboratory of Chemical Biology (Guangdong Province), Graduate School of Shenzhen, Tsinghua University, Shenzhen 518057, P. R.of China

,

Hua Fu*

^aKey Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Department of Chemistry, Tsinghua University, Beijing 100084, P. R. of China, Fax: +86(10)62781695 Email: fuhua@mail.tsinghua.edu.cn

^cKey Laboratory of Chemical Biology (Guangdong Province), Graduate School of Shenzhen, Tsinghua University, Shenzhen 518057, P. R.of China

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Abstract

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Abstract

A convenient, efficient, and practical copper-catalyzed one-pot method for the synthesis of 1,2,4-triazoles has been developed via reactions of amidines. The procedure underwent sequential base-promoted intermolecular coupling (nucleophilic substitution) between two amidines and intramolecular aerobic oxidative dehydrogenation, and the inexpensive, convenient, and efficient method for the synthesis of 1,2,4-triazoles will attract much attention in academic and industrial research.

Key words

copper - aerobic oxidative - dehydrogenation - amidines - 1,2,4-triazoles

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References

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16 General Procedure for the Synthesis of Compounds 2a–s A 10 mL Schlenk tube was charged with a magnetic stirrer and DMSO (1.5 mL). For entries 1–5 in Table 2, aromatic amidine (1 mmol), Cu powder (0.1 mmol, 6.4 mg), and Cs₂CO₃ (2 mmol, 489 mg) were added to the tube. The mixture was stirred at 120 °C for 24 h under nitrogen atmosphere, and then the nitrogen atmosphere was changed into oxygen atmosphere (other conditions were kept). The following aerobic oxidative intramolecular formation of N–N bond was carried out at 120 °C for 48 h. The resulting mixture was cooled to r.t. and filtered, and the solid was washed with EtOAc (3 × 3 mL). The combined filtrate was concentrated by a rotary evaporator, and the residue was purified by column chromatography on silica gel using PE–EtOAc as eluent to give the desired target product. For entries 6–19 in Table 2, aromatic amidine (1.0 mmol), aliphatic amidine (0.5 mmol), Cu powder (0.1 mmol, 6.4 mg), and Cs₂CO₃ (3.0 mmol, 978 mg) were added to the tube. The mixture was stirred at 120 °C under nitrogen atmosphere, and additional aromatic amidine (2 × 0.5 mmol) was added to the resulting solution after 8 h and 16 h, respectively. The reaction was performed for a total 24 h under nitrogen atmosphere, and then the nitrogen atmosphere was changed into oxygen atmosphere (other conditions were kept). The following aerobic oxidative intramolecular formation of N–N bond was carried out at 120 °C for 48 h. The workup procedure was similar to that of entries 1–5 in Table 2. Data for three representative examples are given here. 3-Methyl-5-phenyl-4H-1,2,4-triazole (2f) ¹⁴ Eluent: PE–EtOAc (1:1); yield 64 mg (80%); white solid; mp 163–165 °C (lit.¹⁴ mp 163–165 °C). ¹H NMR (600 MHz, DMSO-d ₆): δ = 13.75 (s, 1 H), 7.95 (d, 2 H, J = 7.56 Hz), 7.44–7.33 (m, 3 H), 2.35 (s, 3 H). ¹³C NMR (150 MHz, DMSO-d ₆): δ = 160.8, 154.3, 131.7, 129.3, 129.1, 126.2, 126.1, 12.5. ESI-MS: m/z = 160.3 [M + H]⁺; m/z = 182.2 [M + Na]⁺. 3-(4-Chlorophenyl)-5-cyclopropyl-4H-1,2,4-triazole (2o) ¹⁴ Eluent: PE–EtOAc (6:1); yield 85 mg (78%); white solid; mp 203–205 °C (lit.¹⁴ mp 202–203 °C). ¹H NMR (600 MHz, DMSO-d ₆): δ = 13.71 (s, 1 H), 7.91 (d, 2 H, J = 8.9 Hz), 7.57–7.40 (m, 2 H), 2.09–1.96 (m, 1 H), 1.06–0.80 (m, 4 H). ¹³C NMR (150 MHz, DMSO-d ₆): δ = 160.2, 160.1, 133.7, 131.0, 129.2, 127.9, 8.6, 7.5. ESI-MS: m/z = 220.2 [M + H]⁺; m/z = 242.0 [M + Na]⁺. 4-(5-Methyl-4H-1,2,4-triazol-3-yl)pyridine (2q) ¹⁷ Eluent: PE–EtOAc (4:1); yield 56 mg (70%); white solid; mp 104–106 °C (lit.¹⁷ mp 207–209 °C). ¹H NMR (600 MHz, DMSO-d ₆): δ = 13.94 (s, 1 H), 8.81–8.55 (m, 2 H), 7.91 (d, 2 H, J = 3.4 Hz), 2.44 (s, 3 H). ¹³C NMR (150 MHz, DMSO-d ₆): δ = 159.4, 154.8, 150.8, 139.1, 120.5, 12.2. ESI-MS: m/z = 161.2 [M + H]⁺; m/z = 183.1 [M + Na]⁺.
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