A Facile and Expeditious One-Pot Synthesis of α-Keto-1,3,4-oxadiazoles

Abstract

An efficient and high-yielding protocol for the preparation of α-keto-1,3,4-oxadiazoles has been developed. Formation of α-keto-1,3,4-oxadiazoles involves the 2-iodoxybenzoic acid/tetraethylammonium bromide mediated oxidative cyclization of hydrazide-hydrazones generated in situ from the reaction of aryl glyoxal and hydrazides. This one-pot protocol is reasonably general for the preparation of α-keto-1,3,4-oxadiazoles under mild conditions in short reaction times.

Key words

nitrogen heterocycles - hypervalent iodine reagents - oxidation - cyclization

• References and Notes

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• 21 One-Pot Synthesis of 4a–m; General Procedure: A mixture of arylglyoxal (1 mmol) and arylhydrazide (1 mmol) was stirred in acetonitrile at r.t. for 3 h. After consumption of the starting materials, IBX (1 mmol) was added to the reaction mixture followed by addition of TEAB (1.2 mmol) and stirring was continued at r.t. for another 3 h. Upon completion of the reaction, solvent was removed in vacuo and the crude material thus obtained was diluted with H₂O and extracted with EtOAc (3 × 25 mL). The combined organic layers were washed with saturated NaHCO₃ (20 mL), brine (20 mL), and dried over anhydrous Na₂SO₄. After filtration, the solvent was evaporated under reduced pressure and the residue was recrystallized from ethanol to afford analytically pure α-keto-1,3,4-oxadiazoles 4a–m in excellent yields. Phenyl(5-phenyl-1,3,4-oxadiazol-2-yl)methanone (4a): Yield: 90%; white solid; mp 143–144 °C (Lit.¹⁹ 143–145 °C). IR (KBr): 1666, 1535, 1411, 1380, 1280, 1180 cm^–1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 8.45 (dd, J = 8.3, 1.1 Hz, 2 H), 8.15 (dd, J = 8.2, 1.3 Hz, 2 H), 7.74 (t, J = 7.4 Hz, 1 H), 7.64–7.56 (m, 5 H). ¹³C NMR (101 MHz, DMSO-d ₆): δ = 182.13, 170.13, 165.71, 139.76, 139.31, 137.90, 135.60, 134.48, 133.78, 132.43, 127.70. MS (ESI): m/z [M + H]⁺ calcd for C₁₅H₁₀N₂O₂: 251.08; found: 251.1. Phenyl(5-p-tolyl-1,3,4-oxadiazol-2-yl)methanone (4b): Yield: 91%; white solid; mp 142–143 °C (Lit.¹⁹ 139–141 °C). IR (KBr): 1659, 1489, 1450, 1381, 1265, 1173 cm^–1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 8.47 (dd, J = 8.4, 1.2 Hz, 2 H), 8.06–8.04 (m, 2 H), 7.79–7.75 (m, 1 H), 7.65–7.61 (m, 2 H), 7.45 (d, J = 8 Hz, 2 H), 2.46 (s, 3 H). ¹³C NMR (101 MHz, DMSO-d ₆): δ = 176.85, 165.49, 160.26, 143.13, 134.36, 133.64, 130.27, 129.66, 128.39, 127.13, 119.47, 21.17. MS (ESI): m/z [M + H]⁺ calcd for C₁₆H₁₂N₂O₂: 265.1; found: 265.2. [5-(4-Methoxyphenyl)-1,3,4-oxadiazol-2-yl]phenyl-methanone (4c): Yield: 91%; white crystalline solid; mp 169.6–170 °C. IR (KBr): 1612, 1574, 1551, 1489, 1380, 1285 cm^–1. ¹H NMR (500 MHz, DMSO-d ₆): δ = 8.41 (d, J = 7.7 Hz, 2 H), 8.10 (d, J = 8.5 Hz, 2 H), 7.81 (t, J = 7.2 Hz, 1 H), 7.68 (t, J = 7.5 Hz, 2 H), 7.23 (d, J = 8.5 Hz, 2 H), 3.89 (s, 3 H). MS (ESI): m/z [M + H]⁺ calcd for C₁₆H₁₂N₂O₃: 281.09; found: 281.2.
• 22 One-Pot Synthesis of 7a–e; General Procedure: A mixture of arylglyoxal (1 mmol) and 2-hydrazinopyridine (1 mmol) was stirred in acetonitrile at r.t. for 5 min. Subsequently, IBX (1 mmol) was added to the reaction mixture, followed by the addition of TEAB (1.2 mmol) in portions. The resulting mixture was stirred at r.t. for 15 min. Upon completion of the reaction, solvent was removed in vacuo, the contents were diluted with H₂O, and the mixture was extracted with EtOAc (3 × 25 mL). The combined organic layers were washed with saturated NaHCO₃ (20 mL), brine (20 mL), and dried over anhydrous Na₂SO₄. After filtration, the solvent was removed under reduced pressure and the residue thus obtained was recrystallized from ethanol to afford α-keto-1,2,4-triazolo[4,3-a]pyridines 7a–e in excellent yields. (1,2,4-Triazolo[4,3-a]pyridine-3-yl)phenylmethanone (7a): Yield: 90%; light-yellow solid; mp 167 °C. IR (KBr): 1658, 1573, 1496, 1450, 1411, 1380 cm^–1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 9.51 (dd, J = 7.0, 1.0 Hz, 1 H), 8.51 (dd, J = 5.2, 3.3 Hz, 2 H), 8.05 (dd, J = 8.1, 1.0 Hz, 1 H), 7.73–7.67 (m, 2 H), 7.62–7.57 (m, 2 H), 7.32 (t, J = 7.4 Hz, 1 H). MS (ESI): m/z [M + H]⁺ calcd for C₁₃H₁₀N₃O: 224.08; found: 224.2.