A New Efficient Method for the Total Synthesis of Linear Furocoumarins

Abstract

A new efficient method for the synthesis of linear furocoumarins by a Nef reaction and intramolecular cyclocondensation in one pot results in the construction of a benzofuran ring. This method provides a new strategy to furnish the benzofuran framework easily, and also allows the convenient synthesis of furocoumarin derivatives with different substituents on the coumarin ring by a subsequent Pechmann reaction. This strategy has also been applied to the preparation of four additional benzofuran derivatives.

Nef reaction - Pechmann reaction - furocoumarins - total synthesis - intramolecular cyclocondensation

References and Notes

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24

Benzofuran 4: Compound 2 (2 mmol) was added to an aq soln of 2 M NaOH (15 mL) and stirred at r.t. for 30 min under an N₂ atmosphere. After cooling to 0 °C, the resultant solution was added dropwise to a well-stirred aq solution of 3 M H₂SO₄ (25 mL) at 0 °C. The reaction was stirred at r.t. for about 4 h until the reaction was complete. The solution was extracted with EtOAc and the organic phase was dried over anhyd Na₂SO₄. After removal of the solvent, the residue was purified by flash chromatography on silica gel to afford the desired compound 4. [28] Mp 54-55 °C. IR (KBr): 3423, 3122, 1602, 1446, 1132, 837 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 7.52 (d, J = 2.2 Hz, 1 H), 7.42 (d, J = 8.5 Hz, 1 H), 7.00 (m, 1 H), 6.79 (dd, J = 8.5 Hz, J = 2.2 Hz, 1 H), 6.69 (dd, J = 2.2 Hz, J = 0.9 Hz, 1 H), 5.16 (br s, 1 H). EI-MS: m/z (%) = 134 (M⁺, 100), 105(30), 78 (35), 51 (15). Anal. Calcd for C₈H₆O₂: C, 71.64; H, 4.51. Found: C, 71.57; H, 4.52.

25

5b-f; General Procedure: To a mixture of 4 and an appropriate β-ketoester (ratio 1:1.2), an excess of MsOH (0.5 mL per mmol of 4) was slowly added, and stirred at 0 °C for 30 min. Stirring was continued at r.t. until the reaction was complete (monitored by TLC). The resulting mixture was poured into ice-water, stirred for 1 h at r.t., extracted with EtOAc, the organic phase was dried over anhyd Na₂SO₄, and then concentrated in vacuo. The residue was purified by flash chromatography over silica gel (PE-acetone) to afford the title compounds 5b-f.
5b Yield: 72%; mp 186-187 °C (acetone) (lit. [29] 185-186 °C). IR (KBr): 3161, 1724, 1631, 1385, 746 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 7.82 (s, 1 H), 7.69 (d, J = 2.4 Hz, 1 H), 7.48 (d, J = 0.4 Hz, 1 H), 6.86 (dd, J = 2.4 Hz, J = 0.4 Hz, 1 H), 6.27 (s, 1 H), 2.51 (s, 3 H). EI-MS: m/z (%) = 200 (M⁺, 100), 172 (70), 171 (75), 144 (10), 115 (25).
5c Yield: 70%; mp 170-171 °C. IR (KBr): 3122, 2972, 1716, 1629, 1583, 1130 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 7.86 (s, 1 H), 7.69 (d, J = 2.4 Hz, 1 H), 7.49 (d, J = 0.8 Hz, 1 H), 6.84 (dd, J = 2.4 Hz, J = 0.8 Hz, 1 H), 6.28 (t, J = 1.2 Hz, 1 H), 2.89 (dq, J = 7.2 Hz, J = 1.2 Hz, 2 H), 1.38 (t, J = 7.2 Hz, 3 H). EI-MS: m/z (%) = 214 (M⁺, 75), 185 (30), 171 (100), 115 (15). Anal. Calcd for C₁₃H₁₀O₃: C, 72.89; H, 4.71. Found: C, 72.97; H, 4.65.
5d Yield: 65%; mp 127-128 °C (lit. [30] 128-129 °C). IR (KBr): 3112, 2955, 1708, 1630, 1576, 1161, 1112 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 7.84 (s, 1 H), 7.68 (d, J = 2.4 Hz, 1 H), 7.47 (s, 1 H), 6.84 (d, J = 2.4 Hz, 1 H), 6.25 (s, 1 H), 2.81 (t, J = 7.6 Hz, 2 H), 1.79 (m, 2 H), 1.08 (t, J = 7.6 Hz, 3 H). EI-MS: m/z (%) = 228 (M⁺, 100), 200(35), 185 (70), 171 (70), 115 (20).
5e Yield: 67%; mp 142-143 °C. IR (KBr): 3101, 1731, 1628, 1581, 1450, 1283, 1151 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 7.97 (q, J = 1.9 Hz, 1 H), 7.75 (d, J = 2.2 Hz, 1 H), 7.56 (d, J = 0.5 Hz, 1 H), 6.90 (dd, J = 2.2 Hz, J = 0.8 Hz, 1 H), 6.79 (s, 1 H). EI-MS: m/z (%) = 254 (M⁺, 90), 226 (100), 198 (20), 169 (20). Anal. Calcd for C₁₂H₅F₃O₃: C, 56.71; H, 1.98. Found: C, 56.67; H, 2.10.
5f Yield: 58%; mp 177-178 °C. IR (KBr): 3128, 3124, 1722, 1626, 1568, 1375, 1149 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 7.68 (s, 1 H), 7.67 (br s, 1 H), 7.57-7.47 (m, 6 H), 6.76 (dd, J = 2.2 Hz, J = 1.0 Hz, 1 H), 6.34 (s, 1 H). EI-MS: m/z (%) = 262 (M⁺, 90), 234 (100), 205 (35), 176 (30), 76 (20). Anal. Calcd for C₁₇H₁₀O₃: C, 77.85; H, 3.84. Found: C, 77.94; H, 3.92.

26

Psoralen 5a: A mixture of ZnCl₂ (210 mg, 1.5 mmol), ethyl propiolate (0.5 mL, 5 mmol), and compound 4 (134 mg, 1.0 mmol) was heated at 90 °C for 3 h under a N₂ atmosphere. After cooling to r.t., 5% HCl (25 mL) was added to the resultant mixture, which was then extracted with EtOAc
(3 × 25 mL). The combined organic layer was washed with H₂O (3 × 10 mL), brine (20 mL), and dried over anhyd Na₂SO₄. The solvent was removed on a rotary evaporator to yield the crude product which was purified by flash chromatography to give the desired compound 5a. Yield: 56%; mp 162-163 °C (lit. [13a] 161-162 °C). IR (KBr): 3157, 1720, 1633, 1286, 1136, 750 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 7.81 (d, J = 9.6 Hz, 1 H), 7.70 (d, J = 1.2 Hz, 1 H), 7.69 (s, 1 H), 7.49 (s, 1 H), 6.84 (d, J = 1.2 Hz, 1 H), 6.39 (d, J = 9.6 Hz, 1 H). EI-MS: m/z (%) = 186 (M⁺, 100), 158 (90), 130 (30), 102 (40).

27

9a: [31a] ¹H NMR (400 MHz, CDCl₃): δ = 7.62 (d, J = 1.6 Hz, 1 H), 7.57 (d, J = 10.0 Hz, 1 H), 7.51 (d, J = 8.4 Hz, 1 H), 7.30-7.27 (m, 2 H), 6.77 (d, J = 1.6 Hz, 1 H). EI-MS: m/z (%) = 118 (M⁺, 100), 78 (45).
9b: [31b] ¹H NMR (400 MHz, CDCl₃): δ = 7.52 (d, J = 2.4 Hz, 1 H), 7.43 (d, J = 9.1 Hz, 1 H), 7.00 (s, 1 H), 6.81 (d, J = 9.1 Hz, 1 H), 6.69 (d, J = 2.4 Hz, 1 H), 3.78 (s, 3 H). EI-MS: m/z (%) = 148 (M⁺, 100), 134 (25), 78 (15).
9c: [31c] ¹H NMR (400 MHz, CDCl₃): δ = 7.74 (s, 1 H), 7.63 (d, J = 2.3 Hz, 1 H), 7.39 (m, 2 H), 6.73 (d, J = 2.3 Hz, 1 H). EI-MS: m/z (%) = 197 (M⁺, 95), 196 (100), 78 (25).
9d: [31d] ¹H NMR (400 MHz, CDCl₃): δ = 8.16 (d, J = 10.3 Hz, 1 H), 7.95 (d, J = 8.6 Hz, 1 H), 7.86 (d, J = 2.4 Hz, 1 H), 7.42-7.37 (m, 1 H), 6.95 (d, J = 2.4 Hz, 1 H). EI-MS: m/z (%) = 163 (M⁺, 100), 105 (25), 78 (35).

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