A New Preparative Route to Substituted Dibenzofurans by Benzannulation Reaction. An Application to the Synthesis of Cannabifuran

Abstract

A new regioselective pathway to substituted dibenzo­furan derivatives is described here. According to this procedure substituted 1-acetoxy-3-alkoxycarbonyl dibenzofurans are obtained by treatment of 6-(2-methoxyaryl)-3-alkoxycarbonylhex-3-en-5-ynoic acids with acetic anhydride in the presence of sodium acetate. The latter acids are prepared from the easily available substituted o-iodo-anisoles by Sonogashira coupling with propargylic alcohol and Wittig reaction as the key steps. The described benzannulation reaction proceeds in regioselective fashion and a range of sub­stituents are tolerated. Its synthetic utility is demonstrated by a new synthesis of cannabifuran, a naturally occurring dibenzofuran.

Key words

annulations - enynes - benzofurans - phenols - natural products

References

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  The coupling reaction was performed in THF solution using 2 equiv of propargyl alcohol, Et₃N as base and an equimolar amount of copper and palladium catalysts (0.01 equiv). When the coupling reaction was performed with diiodoanisole 5e, only 1 equiv of propargyl alcohol was used in the preparation.

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13

Acids 9a-f (50 mmol) were dissolved in acetic anhydride (48 mL, 0.5 mol). To this solution, anhyd sodium acetate (8.2 g, 0.1 mol) and hydroquinone (275 mg, 2.5 mmol) were added in one portion. The obtained heterogeneous mixture was heated at reflux for 1 h under a nitrogen atmosphere. After cooling to r.t., the acetic anhydride was removed in vacuo and the residue was treated with ethyl acetate (250 mL) and water (100 mL). The organic phase was separated, dried (Na₂SO₄) and concentrated under reduced pressure. The residue was purified by chromatography and crystallization to give phenol derivatives 4a-f.

17

All new compounds were fully characterized. Selected analytical data:
12: Anal. Calcd for C₁₄H₁₈O₂: C, 77.03; H, 8.31. Found: C, 77.15; H, 8.35. Bp 150 °C/0.5 mmHg. ¹H NMR (250 MHz, CDCl₃): δ = 1.22 (6 H, d, J = 6.9 Hz), 2.23 (3 H, s), 2.50-2.85 (1 H, bs), 3.38 (1 H, m), 3.86 (3 H, s), 4.58 (2 H, s), 6.93 (1 H, d, J = 8.0 Hz), 7.10 (1 H, d, J = 8.0 Hz). EI-MS: m/z = 219 (M⁺ + 1), 218 (M⁺), 203, 187, 172, 159, 141, 128, 115, 105, 91, 77. FT-IR (film): ν = 813, 1029, 1077, 1237, 1273, 1405, 1459, 1481, 1571, 2225, 2929, 3407 cm^-1.
13: Anal. Calcd for C₂₀H₂₄O₅: C, 69.75; H, 7.02. Found: C, 69.60; H, 7.10. Mp 59-60 °C (hexane). ¹H NMR (250 MHz, CDCl₃): δ = 1.22 (6 H, d, J = 6.9 Hz), 1.31 (3 H, t, J = 7.1 Hz), 2.24 (3 H, s), 3.34 (1 H, m), 3.77 (2 H, s), 3.83 (3 H, s), 4.26 (2 H, q, J = 7.1 Hz), 6.95 (1 H, d, J = 8.0 Hz), 7.15 (1 H, d, J = 8.0 Hz), 7.15 (1 H, s). EI-MS: m/z = 345 (M⁺ + 1), 344 (M⁺), 316, 300, 285, 270, 255, 239, 225, 209, 195, 173, 165, 152, 128, 115, 97. FT-IR (nujol): ν = 762, 1031, 1093, 1212, 1265, 1376, 1459, 1619, 1699, 1719, 2193 cm^-1.
14: Anal. Calcd for C₂₁H₂₂O₅: C, 71.17; H, 6.26. Found: C, 71.10; H, 6.25. Mp 113-114 °C (isopropyl ether). ¹H NMR (250 MHz, CDCl₃): δ = 1.36 (6 H, d, J = 6.9 Hz), 1.42 (3 H, t, J = 7.2 Hz), 2.45 (3 H, s), 2.54 (3 H, s), 3.99 (1 H, m), 4.42 (2 H, q, J = 7.2 Hz), 7.19 (1 H, d, J = 7.7 Hz), 7.30 (1 H, d, J = 7.7 Hz), 7.75 (1 H, d, J = 1.2 Hz), 8.16 (1 H, d, J = 1.2 Hz). EI-MS: m/z = 355 (M⁺ + 1), 354 (M⁺), 312, 297, 283, 267, 255, 239, 224, 205, 195, 178, 165, 152, 139, 128, 115, 102, 89. FT-IR(nujol): ν = 770, 1065, 1195, 1229, 1310, 1368, 1411, 1463, 1510, 1571, 1712, 1771 cm^-1.
Cannabifuran 15: Anal. Calcd for C₂₁H₂₆O₂: C, 81.25; H, 8.44. Found: C, 81.00; H, 8.45. Mp 79-80 °C (hexane). ¹H NMR (250 MHz, CDCl₃): δ = 0.89 (3 H, t, J = 6.6 Hz), 1.34 (6 H, d, J = 6.8 Hz), 1.20-1.46 (4 H, m), 1.55-1.81 (2 H, m), 2.53 (3 H, s), 2.66 (2 H, t, J = 7.5 Hz), 4.41 (1 H, m), 5.55
(1 H, bs), 6.46 (1 H, s), 7.01 (1 H, s), 7.17 (2 H, m). EI-MS: m/z = 311 (M⁺ + 1), 310 (M⁺), 295, 281, 267, 254, 238, 225, 211, 191, 178, 165, 152, 139, 119, 105, 89. FT-IR (nujol):
ν = 760, 815, 1048, 1061, 1219, 1252, 1426, 1514, 1588, 1618, 1635, 3500 cm^-1.