Iron(III)/TEMPO-Catalyzed Synthesis of 2,5-Disubstituted 1,3,4-Oxadiazoles by Oxidative Cyclization under Mild Conditions

◊ These authors contributed equally to this work.

Abstract

A simple and efficient cationic Fe(III)/TEMPO-catalyzed oxidative cyclization of aroyl hydrazones has been developed for the synthesis of 2,5-disubstituted 1,3,4-oxadiazole derivatives. The reaction offers a broad scope, good functional-group tolerance, and high yields under mild conditions in the presence of O₂.

Key words

oxadiazoles - iron catalysis - cyclization - oxidation - aroyl hydrazones

• References and Notes

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• 12 2-tert-Butyl-5-phenyl-1,3,4-oxadiazole (2a); Typical Procedure A mixture N′-(2,2-dimethylpropylidene)benzohydrazide (1a; 0.1021 g, 0.5 mmol), Fe(NO₃)₃·9H₂O (0.0202 g, 0.05 mmol), MgSO₄ (0.1204 g, 1.0 mmol), TEMPO (0.0078 g, 0.05 mmol), and DCE (5.0 mL) was added to a 100 mL sealed tube and vigorously stirred under O₂ at 35 °C for 6 h. H₂O (20.0 mL) was then added to the tube and the product was extracted with CH₂Cl₂ (3 × 15 mL). The organic phases were combined, dried (Na₂SO₄), and concentrated under a vacuum. The residue was purified by column chromatography to give a light yellow liquid; yield: 0.0931 g (92%). ¹H NMR (500 MHz, DMSO-d ₆): δ = 7.99 (dd, J = 8.0, 1.6 Hz, 2 H), 7.63–7.54 (m, 3 H), 1.42 (s, 9 H). ¹³C NMR (125 MHz, DMSO-d ₆): δ = 172.67, 163.77, 131.71, 129.29, 126.37, 123.58, 32.02, 27.77. HRMS: m/z [M + 1]⁺ calcd for C₁₂H₁₅N₂O: 203.1179; found: 203.1178.
• 13 2,5-Diphenyl-1,3,4-oxadiazole (4a): Typical Procedure A mixture of N′-(benzylidene)benzohydrazide (0.1120 g, 0.5 mmol), Fe(NO₃)₃·9H₂O (0.0202 g, 0.05 mmol), MgSO₄ (0.1204 g, 1.0 mmol), TEMPO (0.0078 g, 0.05 mmol), and CH₂Cl₂ (5.0 mL) was added to a 100 mL sealed tube and vigorously stirred under O₂ at 35 °C for 6 h. H₂O (20.0 mL) was then added to the tube and the product was extracted with CH₂Cl₂ (3 × 15 mL). The organic phases were combined, dried (Na₂SO₄), and concentrated under a vacuum. The residue was purified by column chromatography to give a light yellow solid; yield: 0.0911 g (82%). ¹H NMR (500 MHz, DMSO-d ₆): δ = 8.15–8.08 (m, 4 H), 7.66–7.60 (m, 6 H). ¹³C NMR (125 MHz, DMSO-d ₆): δ = 163.99, 131.99, 129.37, 126.65, 123.33. HRMS: m/z [M + 1]⁺ calcd for C₁₄H₁₁N₂O: 223.0871; found: 223.0867.