Novel Synthesis of 3-Aryl-4-hydroxybenzofurans via Four-Component Reaction from Substituted Nitrostyrenes, Aromatic Aldehydes, Cyclohexan-1,3-diones, and Ammonium Acetate

Abstract

An one-pot-reaction methodology was developed to synthesize a variety of polysubstituted 3-aryl-2-arylmethylene amino-4-hydroxybenzofurans from substituted β-nitrostyrenes, aromatic aldehydes, ammonium acetate, and cyclohexane-1,3-diones for the generation of a wide range of structurally interesting and pharmacologically significant compounds. The reaction pathway involves Michael addition of substituted nitrostyrenes and cyclohexane-1,3-diones, then nucleophilic addition of 2-(2-nitro-1-phenylethyl)cyclohexane-1,3-dione and Schiff base generated from aromatic aldehyde and ammonium acetate and intramolecular cyclization, followed by dehydroaromatization to afford the corresponding 3-aryl-2-arylmethyleneamino-4-hydroxybenzofurans.

Key words

multicomponent reaction - 4-hydroxybenzofuran - substituted β-nitrostyrene - dehydroaromatization - cyclohexane-1,3-dione

• References and Notes

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• 50 General Procedure for the Preparation of Polysubstituted 4-Hydroxybenzofurans The appropriate β-nitrostyrene (1 mmol), appropriate aromatic aldehyde (2 mmol), NH₄OAc (115 mg, 1.5 mmol), and piperidine (43 mg, 0.5 mmol) were dissolved in DMF (15 mL) at r.t., then to the resultant mixture cyclohexane-1,3-dione or 5-(4-chlorophenyl)cyclohexane-1,3-dione (1 mmol) was added dropwise under stirring and refluxing for 30 min. The reaction mixture was stirred under reflux for ca. 7 h, and the completion of reaction was confirmed by TLC (EtOAc–hexanes, 1:10). After the completion of reaction, the reaction mixture was cooled to r.t. Removal of solvent by vacuum distillation, the residues were diluted with CH₂Cl₂ (20 mL). Subsequently, the resultant solution was washed with H₂O (10 mL) and brine (10 mL), dried over anhyd Na₂SO₄. The crude product was purified by flash chromatography (silica gel; EtOAc–hexanes, 1:20) to give product 4. 2-(4-Chlorobenzylideneamino)-3-(4-methoxy-phenyl)benzofuran-4-ol (4a) Mp 179–181 °C (MeOH–CH₂Cl₂). ¹ H NMR (600 MHz, CDCl₃): δ = 9.21 (s, 1 H), 8.07 (d, J = 7.8 Hz, 1 H), 7.57 (d, J = 8.4 Hz, 2 H), 7.34 (d, J = 7.8 Hz, 1 H), 7.28 (t, J = 7.8 Hz, 1 H), 7.22 (t, J = 7.2 Hz, 1 H), 7.18 (t, J = 8.4 Hz, 1 H), 7.01–7.04 (m, 3 H), 6.63 (d, J = 7.8 Hz, 1 H), 5.26 (s, 1 H), 3.83 (s, 3 H) ppm. ¹³C NMR (150 MHz, CDCl₃): δ = 158.58, 151.99, 151.34, 150.29, 149.65, 135.24, 132.61, 130.94, 130.33, 129.00, 127.42, 126.00, 125.96, 123.06, 115.68, 114.22, 113.43, 108.23, 102.87, 54.38 ppm. IR (KBr): 3381, 2962, 1603, 1511, 1404, 1385, 1309, 1247, 1159, 1037, 813. 779 cm^–1. MS (EI): m/z (%) = 376.32 (100) [M – 1]⁺. Anal. Calcd for C₂₂H₁₆ClNO₃ (%): C, 69.94; H, 4.27; N, 3.71. Found: C, 70.20; H, 4.39; N, 3.72. 2-(2-Methoxybenzylideneamino)-6-(4-chlorophenyl)-3-(4-methoxyphenyl)benzofuran-4-ol (4b) Mp 223–224 °C (MeOH–CH₂Cl₂). ¹ H NMR (600 MHz, CDCl₃): δ = 9.33 (s, 1 H), 8.07 (d, J = 7.8 Hz, 1 H), 7.66 (d, J = 7.2 Hz, 2 H), 7.56 (d, J = 7.2 Hz, 2 H), 7.39–7.42 (m, 3 H), 7.28 (s, 1 H), 7.08 (d, J = 7.8 Hz, 2 H), 6.99 (t, J = 7.2 Hz, 1 H), 6.44 (t, J = 8.4 Hz, 1 H), 6.93 (s, 1 H), 5.38 (s, 1 H), 3.95 (s, 3 H), 3.90 (s, 3 H) ppm. ¹³C NMR (150 MHz, CDCl₃): δ = 159.90, 159.61, 153.41, 152.76, 152.43, 150.54, 139.52, 138.71, 133.52, 132.88, 131.27, 129.00, 128.39, 127.60, 125.24, 124.31, 120.92, 116.39, 114.62, 113.17, 111.22, 108.37, 102.30, 55.70, 55.43 ppm. IR (KBr): 3504, 2923, 2834, 1597, 1510, 1358, 1247, 1173, 1062, 813, 747 cm^–1. MS (EI): m/z (%) = 484.64 (100) [M + 1]⁺. Anal. Calcd for C₂₉ H₂₂ClNO₄ (%): C, 71.97; H, 4.58; N, 2.89. Found: C, 72.02; H, 4.81; N, 2.78.
• 51 Crystallographic data for 4l have been deposited with the Cambridge Crystallographic Data Centre with the deposition number CCDC 928646. These data can be obtained free of charge on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax [phone], e-mail: [e-mail]].
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