Rapid and Convenient Synthesis of Original 5-Substituted Quinolino[3,4-b]quinoxalin-6(5H)-ones under Eco-Friendly Conditions

Abstract

We report herein the synthesis of 5-(substituted)quinolino[3,4-b]quinoxalin-6(5H)-one derivatives from ethyl 3-(2-bromophenyl)quinoxaline-2-carboxylate under one-pot Buchwald–Hartwig coupling–lactamization reaction.

Key words

quinoxaline - aromatic anilines - Buchwald–Hartwig reaction - lactamization reaction

• References and Notes

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• 17 Ethyl 3-(2-Bromophenyl)quinoxaline-2-carboxylate (3) To a mixture of ethyl 3-chloroquinoxaline-2-carboxylate (1 g, 4.22 mmol) and 2-bromophenylboronic acid (0.93 g, 4.64 mmol) in MeCN (30 mL), was added Pd(PPh₃)₄ (0.097 g, 0.084 mmol) and 2 M aq Na₂CO₃ solution (10 mL). The resulting mixture was stirred at 100 °C for 5 h. After cooling the mixture was diluted with CH₂Cl₂ and washed three times with H₂O and dried over MgSO₄. After filtration and evaporation of the solvent, the crude product was purified by silica gel chromatography with CH₂Cl₂ as eluent to furnish the product 3 as a yellow solid; yield 1.1 g (73%); mp 100 °C. ¹H NMR (250 MHz, CDCl₃): δ = 1.19 (t, J = 7.1 Hz, 3 H, CH₃), 4.33 (q, J = 7.1 Hz, 2 H, CH₂), 7.33–7.40 (m, 1 H, H_Ar), 7.45–7.85 (m, 2 H, H_Ar), 7.67 (d, J = 8.0 Hz, 1 H, H_Ar), 7.89–7.93 (m, 2 H, H_Ar), 8.19–8.23 (m, 1 H, H_Ar), 8.31–8.35 (m, 1 H, H_Ar). ¹³C NMR (62.5 MHz, CDCl₃): δ = 13.7, 62.3, 122.1, 127.6, 129.3, 130.0, 130.3, 130.5, 131.0, 132.1, 132.3, 139.8, 140.4, 142.0, 144.4, 153.2, 164.7. Anal. Calcd for C₁₇H₁₃BrN₂O₂: C, 57.16; H, 3.67; N, 7.84. Found: C, 57.61; H, 3.61; N, 7.86.
• 18 General Procedure for One-Pot Buchwald–Hartwig–Lactamization Reactions for the Synthesis of Compounds 5a–l A mixture of ethyl 3-(2-bromophenyl)quinoxaline-2-carboxylate (3, 50 mg, 0.14 mmol), aniline 4a (0.21 mmol, 1.5 equiv) in toluene (3 mL), Cs₂CO₃ (100 mg, 0.3 mmol), Pd(OAc)₂ (6.2 mg, 0.028 mmol), and BINAP (14 mg, 0.021 mmol) was added to a 4 mL vial and the vial sealed. The resulting mixture was stirred at 110 °C for 5 h. After cooling the mixture was diluted with CH₂Cl₂, washed with H₂O (3 × 40 mL) and dried over MgSO₄. After filtration and evaporation, the crude product was purified by silica gel chromatography (CH₂Cl₂–Et₂O, 97:3). 5-Phenylquinolino[3,4-b]quinoxalin-6(5H)-one (5a) Yield 97%; yellow solid; mp 240 °C. ¹H NMR (250 MHz, CDCl₃): δ = 6.73 (d, J = 7.9 Hz, 1 H, H_Ar), 7.38–7.46 (m, 4 H, H_Ar), 7.59–7.70 (m, 3 H, H_Ar), 7.87–8.01 (m, 2 H, H_Ar), 8,33 (d, J = 8.4 Hz, 1 H, H_Ar), 8.48 (d, J = 8.5 Hz, 1 H, H_Ar), 9.05–9.08 (m, 1 H, H_Ar). ¹³C NMR (62.5MHz, CDCl₃): δ = 116.9, 119.6, 123.5, 125.8, 129.0, 129.2, 130.4, 130.4, 130.7, 131.0, 131.9, 132.9, 137.6, 140.5, 143.1, 144.5, 145.7, 160.3. Anal. Calcd for C₂₁H₁₃N₃O: C, 78.00; H, 4.05; N, 13.00. Found: C, 78.12; H, 4.00; N, 12.91.