Synthesis of Imidazoles and Pyrimidines Using Palladium-Catalyzed Decar­boxylative Intramolecular Condensation of 1,2,4-Oxadiazol-5(4H)-ones

Abstract

We found that 1,2,4-oxadiazol-5(4H)-ones acted as iminonitrene equivalents in the presence of a palladium catalyst and a stoichiometric amount of phosphine and that aza-Wittig-type condensation with the internal carbonyl moiety occurred to afford the corresponding imidazoles and pyrimidines.

Key words

imidazoles - palladium - decarboxylation - aza-Wittig reaction

• References and Notes


For selected examples on the material or medicinal application of imidazoles, see:
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• 8 General Procedure for the Catalytic ReactionsA solution of Pd(PPh₃)₄ (6.9 mg, 6.0 μmol) and oxadiazolone 3 (0.20 mmol) in 1,4-dioxane (1.5 mL) was stirred at 80 °C for 24 h. The reaction mixture was filtered through a pad of Florisil^®, and the filtrate was concentrated under vacuum. The residue was subjected to column chromatography on Florisil^® (hexane–EtOAc = 4:1) to afford imidazole 4.Imidazole 4aWhite solid (43.8 mg, 0.20 mmol, 99% yield; mp 160.1–160.5 °C). ¹H NMR (400 MHz, CDCl₃): δ = 7.22–7.45 (m, 7 H), 7.75 (d, J = 7.4 Hz, 2 H), 7.87 (d, J = 7.3 Hz, 2 H). ¹³C NMR (100 MHz, acetone-d ₆): δ = 114.3, 125.4, 125.9, 127.2, 129.0, 129.3, 129.5, 131.8, 135.6, 142.6, 147.4. HRMS–FAB: m/z calcd for C₁₅H₁₃N₂ [M + H]⁺: 221.1079; found: 221.1069.Imidazole 4cWhite solid (46.0 mg, 0.19 mmol, 97% yield; mp 65.0–66.1 °C). ¹H NMR (400 MHz, CDCl₃): δ = 7.08 (dd, J _HH = 8.8 Hz, J _HF = 8.8 Hz, 2 H), 7.27 (t, J = 7.3 Hz, 1 H), 7.37 (s, 1 H), 7.39 (t, J = 7.3 Hz, 2 H), 7.74 (d, J = 7.3 Hz, 2 H), 7.82 (dd, J _HH = 8.3 Hz, J _HF = 4.9 Hz, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 115.7 (d, J _CF = 21.7 Hz), 117.7, 125.0, 126.4 (d, J _CF = 3.1 Hz), 127.2, 127.3, 127.5 (d, J _CF = 8.0 Hz), 128.8, 132.4, 146.7, 163.0 (d, J _CF = 248 Hz). HRMS–FAB: m/z calcd for C₁₅H₁₂FN₂ [M + H]⁺: 239.0985; found: 239.0990.Imidazole 4iWhite solid (30.1 mg, 0.13 mmol, 67% yield; mp 168.5–171.0 °C). ¹H NMR (400 MHz, CDCl₃): δ = 7.08 (dd, J = 5.1, 3.9 Hz, 1 H), 7.27 (t, J = 7.3 Hz, 1 H), 7.34 (d, J = 5.1 Hz, 1 H), 7.35 (s, 1 H), 7.39 (d, J = 8.1 Hz, 2 H), 7.41 (d, J = 3.7 Hz, 1 H), 7.72 (br s, 2 H). ¹³C NMR (100 MHz, acetone-d₆ ): δ = 116.4, 124.1, 125.2, 126.3, 127.0, 128.2, 129.0, 134.4, 135.2, 140.5, 143.1. HRMS–FAB: m/z calcd for C₁₃H₁₁N₂S [M + H]⁺: 227.0643; found: 227.0639.Imidazole 4jPale yellow solid (35.0 mg, 0.14 mmol, 70% yield; mp 124.3–126.2 °C). ¹H NMR (400 MHz, CDCl₃): δ = 3.84 (s, 3 H), 6.93 (d, J = 8.8 Hz, 2 H), 7.27 (d, J = 8.5 Hz, 2 H), 7.35 (t, J = 7.6 Hz, 1 H), 7.42 (t, J = 7.8 Hz, 2 H), 7.67 (d, J = 8.5 Hz, 2 H), 7.87 (d, J = 7.1 Hz, 2 H). ¹³C NMR (100 MHz, acetone-d₆ ): δ = 55.3, 114.6, 125.7, 125.8, 126.6, 128.7, 129.3, 129.9, 131.1, 131.8, 146.9, 159.4. HRMS–FAB: m/z calcd for C₁₆H₁₅N₂O [M + H]⁺: 251.1184; found: 251.1181.Imidazole 4oWhite solid (29.7 mg, 0.19 mmol, 94% yield; mp 180.5–181.6 °C). ¹H NMR (400 MHz, CDCl₃): δ = 2.29 (s, 3 H), 6.82 (s, 1 H), 7.31 (t, J = 6.4 Hz, 1 H), 7.37 (t, J = 6.8 Hz, 2 H), 7.81 (d, J = 7.8 Hz, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 12.0, 119.4, 125.0, 128.2, 128.8, 130.4, 132.1, 146.0. HRMS–FAB: m/z calcd for C₁₀H₁₁N₂ [M + H]⁺: 159.0922; found: 159.0923.

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• 15 Only 15% of imidazole 4a was obtained in the reaction of the stoichiometric amount of Pd₂(dba)₃ with oxadiazolone 3a (Scheme 8). This result indicates that the reaction pathway bypassing the iminophosphorane intermediate (path b) also exists but is only a minor pathway.