A Facile Synthesis of Benzofuro[2,3-c]quinolines via a Multicomponent Reaction and Staudinger–Aza-Wittig–Dehydroaromatization Sequence

Abstract

An iodine-mediated pyridinium ylide assisted multicomponent reaction for the synthesis of tetrahydrobenzofurans through a halogenation–S_N2 displacement–Michael addition–cyclization sequence was developed and its further use in the preparation of benzofuro[2,3-c]quinolines through subsequent Staudinger–aza-Wittig–dehydroaromatization reactions was also investigated.

Key words

tetrahydrobenzofurans - azides - MCR - benzofuro[2,3-c]quinolones - dehydroaromatization

• References and Notes

• 1 These authors contributed equally.
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Molecular iodine was selected for the reason that its halogenation conditions were more suitable in one pot for the formation of ylide than other common halogenation reagents such as NBS, NIS, and Br₂. For reviews over synthetic applications of molecular iodine, see:
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• 17 General Procedure for the Preparation of Tetrahydrobenzofurans 4 Iodine (0.761 g, 3 mmol) was added to a stirred solution of acetophenone 1 (3 mmol) in pyridine (3 mL) at r.t. After 30 min of stirring under reflux conditions, compound 2 (3 mmol), 3 (3 mmol), and Et₃N (1 mL, 7.5 mmol) were added sequentially, followed by MeCN (10 mL). The reaction was vigorously stirred at refluxing temperature under argon atmosphere conditions. Progress of the reaction was monitored by TLC. Once completed, the reaction mixture was cooled to r.t. and quenched with H₂O (15 mL), extracted with CH₂Cl₂ (30 mL). The combined organic extracts were washed with H₂O and brine and dried (Na₂SO₄). After evaporating the solvent under reduced pressure, the residue was purified on silica gel with PE–EtOAc as eluent to give tetrahydrobenzofurans 4. Analytical Data for Compound 4a Yield 915 mg (85%); white crystals; mp 111–112 °C. IR (KBr): 2972, 2918, 2882, 2133, 1702, 1650, 1633, 1564, 1465, 1439, 1402, 776 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.85 (d, J = 8.0 Hz, 2 H, ArH), 7.63–7.48 (m, 1 H, ArH), 7.47–7.44 (m, 2 H, ArH), 7.34–7.30 (m, 1 H, ArH), 7.17–7.13 (m, 3 H, ArH), 5.76 (d, J = 5.2 Hz, 1 H, CH), 4.82 (d, J = 5.2 Hz, 1 H, CH), 2.68 (t, J = 5.2 Hz, 2 H, CH₂), 2.38–2.34 (m, 2 H, CH₂), 2.16–2.13 (m, 2 H, CH₂) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 194.1, 192.7, 177.7, 137.5, 134.0, 133.7, 131.9, 128.9, 128.8, 128.7, 128.6, 125.2, 118.4, 115.1, 90.2, 43.3, 36.7, 23.9, 21.6 ppm. LC–MS: m/z = 359. Anal. Calcd for C₂₁H₁₇N₃O₃: C, 70.18; H, 4.77; N, 11.69. Found: C, 70.23; H, 4.65; N, 11.82.
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• 19 General Procedure for the Preparation of 7 To a stirred solution of tetrahydrobenzofuran 4 (1 mmol) in CH₂Cl₂ (5 mL) was added dropwise Ph₃P (0.26 g, 1 mmol) in CH₂Cl₂ (5 mL) at r.t. After the reaction mixture was stirred for 2 h at r.t. and then for 3–8 h under reflux conditions (monitored by TLC). Once completed, the solvent was removed under reduced pressure, and the residual was recrystallized from CH₂Cl₂–PE to give benzofuro[2,3-c]quinoline 7. Analytical Data for Compound 7a Yield 250 mg (80%); white crystals; mp 166–167 °C. IR (KBr): 2988, 2868, 1679, 1580, 1556, 1518, 1446, 1399, 1190, 771, 729, 690 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 9.50–9.47 (m, 1 H, ArH), 8.38–8.24 (m, 3 H, ArH), 7.76–7.50 (m, 5 H, ArH), 3.19 (t, J = 8.4 Hz, 2 H, CH₂), 2.76 (t, J = 8.4 Hz, 2 H, CH₂), 2.38–2.32 (m, 2 H, CH₂) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 193.3, 171.9, 146.5, 145.1, 143.7, 135.7, 129.7, 129.5, 128.9, 128.5, 128.3, 127.6, 126.4, 122.7, 118.2, 38.6, 24.2, 21.9 ppm. LC–MS: m/z = 313. Anal. Calcd for C₂₁H₁₅NO₂: C, 80.49; H, 4.83; N, 4.47. Found: C, 80.41; H, 4.97; N, 4.59.
• 20 Crystallographic data of compound 7j in this manuscript have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication number CCDC 1416029. Copies of the data can be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax: [phone] or e-mail: [e-mail]].