One-Pot Selective Synthesis of Multisubstituted Quinoxalin-2(1H)-ones by a Ugi 4CR/Catalytic Aza-Wittig Sequence

Abstract

A facile, one-pot synthesis of multisubstituted quinoxalin-2(1H)-ones via a Ugi 4CR/catalytic aza-Wittig sequence has been developed. In the presence of a catalytic amount of 3-methyl-1-phenyl-2-phospholene 1-oxide, the reaction of 2-aminobenzoyl azides, aldehydes, ketoacids, and isocyanides selectively produces quinoxalin-2(1H)-ones as the sole products in high yields.

Key words

quinoxalin-2(1H)-ones - 2-aminobenzoyl azide - Ugi reaction - catalytic aza-Wittig reaction

• References and Notes

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• 24 General procedure for the preparation of Ugi intermediates 5: A mixture of 2-aminobenzoyl azide 1 (1 mmol), aldehyde 2 (1 mmol), ketoacid 3 (1 mmol), and isocyanide 4 (1 mmol) was stirred in methanol (5 mL) at room temperature for 8–12 h, after the reaction was complete, the precipitate was filtered to give 5
• 25 Compound 5h: Yield: 90%; white solid; mp 115–117 °C; ¹H NMR (CDCl₃, 600 MHz): δ = 7.99–6.69 (m, 12 H, Ar-H), 6.53–6.13 (m, 1 H, NH), 6.04–5.97 (m, 1 H, CH), 2.26–2.05 (m, 3 H, CH₃), 1.38–1.36 (m, 9 H, 3CH₃); ¹³C NMR (CDCl₃, 100 MHz): δ = 189.3, 170.7, 168.6, 166.1, 139.2, 134.5, 134.2, 134.1, 133.6, 133.2, 132.3, 131.3, 130.9, 129.8, 129.6, 128.6, 128.4, 128.0, 65.1, 51.5, 28.2, 20.7; IR (KBr): 2142, 1707, 1690, 1675, 1638 cm^–1. Anal. Calcd for C₂₈H₂₆ClN₅O₄: C, 63.22; H, 4.93; N, 13.16; Found: C, 63.00; H, 4.98; N, 13.26
• 26 General procedure for the preparation of quinoxalin-2(1H)-ones 7: A mixture of 2-aminobenzoyl azide 1 (1 mmol), aldehyde 2 (1 mmol), ketoacid 3 (1 mmol), and isocyanide 4 (1 mmol) was stirred in methanol (5 mL) at room temperature for 8–12 h, then the solvent was removed under reduced pressure at room temperature. Toluene (5 mL) and 3-methyl-1-phenyl-2-phospholene 1-oxide (0.01 g, 0.05 mmol) were added to the reaction vessel and the reaction mixture was heated to 110 °C for 2–3 h to form quinoxalin-2(1H)-ones 7. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel (ether/petroleum ether, 1:4, v/v) to give 7. Compound 7a: Yield: 75%; white solid; mp 220–223 °C. ¹H NMR (CDCl₃, 600 MHz): δ = 8.20–8.19 (m, 2 H, Ar-H), 7.90 (s, 1 H, Ar-H), 7.49–7.41 (m, 4 H, Ar-H), 7.31–7.21 (m, 5 H, Ar-H), 6.75 (s, 1 H, NH), 6.09 (s, 1 H, CH), 2.22 (s, 3 H, CH₃), 1.30 (s, 9 H, 3CH₃); ¹³C NMR (CDCl₃, 150 MHz): δ = 166.0, 154.9, 136.9, 135.4, 134.4, 132.4, 132.3, 131.4, 131.3, 130.6, 129.5, 129.4, 129.1, 128.1, 127.7, 126.9, 117.2, 61.6, 52.0, 28.3, 19.5; MS (EI, 70 eV): m/z (%) = 459 (5) [M⁺], 386 (12), 360 (75), 331 (28), 104 (100). Anal. Calcd for C₂₇H₂₆ClN₃O₂: C, 70.50; H, 5.70; N, 9.14; Found: C, 70.58; H, 5.64; N, 9.20