Solid Phase Synthesis of Quinoxalines [1]

Abstract

A versatile method for the solid phase synthesis of quinoxalines has been developed. Polymer-linked 2-nitrophenyl carbamate is treated with α-bromoketones followed by reduction of the nitro group, which underwent spontaneous intramolecular cyclization to afford polymer bound quinoxalines. Finally acidolytic cleavage gave the desired compounds via aerial oxidation in high yields and good purities.

combinatorial chemistry - solid-phase synthesis - heterocyclic - cyclization - quinoxaline

References

1

CDRI Communication No.6391.

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22

General Experimental Procedure for 5 and 9: To the 100 mg of Wang resin (1.13 mmol/g) in 1mL dry toluene was added o-nitrophenyl isocyanate (5 equiv, 1.13 mmol) and 78.7 µL of Et₃N (10 equiv, 0.565 mmol). The reaction mixture was stirred at 100 °C for 16 h. Finally the resin was filtered and washed with with DMF (3 × 2 mL), MeOH (3 × 2 mL), CH₂Cl₂ (3 × 2 mL), and Et₂O (3 × 2mL) and dried in vacuo to get resin bound o-nitrophenyl carbamate 1. To the resin 1 in 1 mL of dry DMF was added 12.4 mg of NaH (5 equiv, 0.565 mmol) and reaction was allowed to stir at 35 °C for 90 min. Substituted phenacyl bromide/chloropropiophenone was added (10 equiv, 1.13 mmol) to the above reaction mixture and the reaction was allowed to stir at 80 °C for 16 h. Finally the solvent was drained and the resin was washed sequentially with DMF (3 × 2 mL), MeOH (3 × 2 mL), CH₂Cl₂ (3 × 2 mL), and Et₂O (3 × 2mL) and dried in vacuo to get 2 or 7. To this was added either 1.5 mL of 2 M of SnCl₂·2H₂O in DMF or a mixture of 393.0 µL of Et₃N (25 equiv, 2.84 mmol,), PhSH (20 equiv, 2.26 mmol, 232.0 µl) and SnCl₂ (5 equiv, 0.564 mmol, 106.8 mg) in dry THF. For reduction under acidic condition the reaction mixture was stirred at 60 °C for 6 h whereas under basic condition it was shaken at r.t. for 2 h. Finally the resin was washed sequentially with DMF (3 × 2 mL), MeOH (3 × 2 mL), CH₂Cl₂ (3 × 2 mL), and Et₂O (3 × 2mL) and dried in vacuo to get the resin bound desired products 3 or 8. The intermediate and final compounds were cleaved from the resin by 50% TFA in CH₂Cl₂ by shaking for 2 h. The filtrate was collected and evaporated to dryness. The residue was freeze dried after dissolving in t-BuOH/H₂O (4:1) to get the desired compounds.

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26

2-(2-Nitro-phenylamino)-1-phenyl-ethanone Trifluoroacetate (cleaved product from resin 2, R¹ = H, R² = C₆H₅): ESI-MS: 257.3 [M + H⁺]. ¹H NMR (300 MHz, CDCl₃): δ = 4.7 (s, 2 H, CH₂), 6.71-6.84 (m, 2 H, Ar-H), 7.36-7.66 (m, 4 H, Ar-H) 8.05 (d, J = 6.9 Hz, 2 H, Ar-H), 8.24 (d, J = 8.4 Hz, 1 H, Ar-H), 8.91 (br s, 1 H, NH). Anal. Calcd for C₁₄H₁₂N₂O₃·CF₃COOH: C, 51.90; H, 3.54; N, 7.57. Found: C, 51.78; H, 3.76; N, 7.38%.
3-(2-Nitro-phenylamino)-1-phenyl-propan-1-one Trifluoroacetate (cleaved product from resin 7, R¹ = H): ESI-MS: 271.52 [M + H]⁺. ¹H NMR (300 MHz, CDCl₃): δ = 3.41 (t, J = 13.5 Hz, 2 H, CH₂), 3.80 (br s, NH), 3.83 (t, J = 12.8 Hz, 2 H, CH₂), 6.65-6.79 (m, 1 H, Ar-H), 6.96 (d, J = 8.7 Hz, 1 H, Ar-H), 7.45-7.63 (m, 4 H, Ar-H), 7.99 (d, J = 8.1 Hz, 2 H, Ar-H), 8.19 (d, J = 8.7 Hz, 1 H, Ar-H). Anal. Calcd for C₁₅H₁₄N₂O₃·CF₃COOH: C, 53.13; H, 3.93; N, 7.29%. Found: C, 53.42; H, 3.61; N, 7.33%.
2-Phenyl-quinaxoline 5a: ¹H NMR (300 MHz, DMSO-d ₆): δ = 7.51-7.61 (m, 3 H, Ar-H), 7.83-7.91 (m, 2 H, Ar-H), 8.11-8.16 (m, 2 H, Ar-H), 8.34 (dd, J = 8.1, 1.3 Hz, 2 H, Ar-H), 9.50 (s, 1 H) Anal. Calcd for C₁₄H₁₀N₂: C, 81.53; H, 4.89; N, 13.58%. Found: C, 81.35; H, 5.01; N, 13.63%.
4-Phenyl-2,3-dihydro-1 H -benzo[ b ][1,4]diazepine 9: ESI-MS: 223.32 [M + H]⁺. ¹H NMR (300 MHz, CDCl₃): δ = 2.12 (t, J = 13.5 Hz, 2 H, CH₂), 3.25 (t, J = 12.8 Hz, 2 H, CH₂), 5.72 (br s, NH), 6.84-6.92 (m, 2 H, Ar-H), 7.04-7.24 (m, 5 H, Ar-H), 7.90 (d, J = 8.1 Hz, 2 H, Ar-H). Anal. Calcd for C₁₅H₁₄N₂: C, 81.05; H, 6.35; N, 12.60%. Found: C, 81.25; H, 6.02; N, 12.52%.