Al(OTf)₃-Catalyzed Preparation of 4-Hydroxy-3-propargylic ­Coumarins and Subsequent Regioselective Cyclization towards Furo- or Pyrano[3,2-c]coumarins

Abstract

An efficient and economical approach to functionalized furo[3,2-c]coumarin and pyrano[3,2-c]coumarin derivatives has been developed from 4-hydroxy-3-(prop-2-ynyl)coumarin derivatives through organocatalysis or metallo-organocatalysis. Selective ‘5-exo-dig’ or ‘6-endo-dig’ cyclization of the 4-hydroxy-3-(prop-2-ynyl)coumarin substrates could be achieved under organocatalytic {1,8-diazabicyclo[5.4.0]undec-7-ene} or metallo-organocatalytic (N-methylmorpholine/CuBr) conditions, respectively, to yield potentially bioactive heterocycles in excellent yields.

Key words

furo[3,2-c]coumarin, pyrano[3,2-c]coumarin - Al(OTf)₃ - DBU - NMM - propargylic alcohol

• References and Notes

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• 43 Typical Procedures
  4-Hydroxy-3-(prop-2-ynyl)coumarins 3a–n Substituted 4-hydroxycoumarin derivatives (1 mmol) were dissolved in MeCN (3 mL), and the solution was stirred at r.t. for 5 min before the substituted propargyl alcohol (1.2 mmol) was added and stirring continued for an additional 5 min. After subsequent addition of Al(OTf)₃ (0.1 mmol) the mixture was heated to reflux for 5 h. Upon completion of the reaction (TLC) the solvent was removed in vacuo, H₂O was added (25 mL), and the crude product was extracted into CH₂Cl₂ (3 × 25 mL). The organic phases were combined, washed with brine (4 × 25 mL), and dried over anhydrous Na₂SO₄. After filtration and removal of the solvent, the pure products 3 were obtained by column chromatography (hexane–EtOAc, 4:1). Furo[3,2-c]coumarins 4a–n To a stirring solution of compound 3 (1 mmol) in CH₂Cl₂ (2 mL) was added DBU (0.1 mmol), and the mixture was stirred for 4 h. Upon completion of the reaction (TLC) H₂O (25 mL) was added, and the product was extracted into CH₂Cl₂ (3 × 25 mL). The combined organic phases were washed with brine (4 × 25 mL), and dried over anhydrous Na₂SO₄. After filtration, the solvent was removed by distillation and the crude product purified by column chromatography (hexane–EtOAc, 6:1). Pyrano-[3,2-c]coumarins 5a–n To a stirred solution of 4-hydroxy-3-(prop-2-ynyl)coumarin 3 (1 mmol) in CH₂Cl₂ (2 mL) at r.t. were added NMM (1 mmol) and CuBr (0.1 mmol), and stirring was continued for 4 h. Upon completion of the reaction (TLC) the mixture was filtered to remove excess solid CuBr, H₂O (25 mL) was added, and the product was extracted into CH₂Cl₂ (3 × 25 mL). The combined organic phases were washed with brine (4 × 25 mL), and dried over anhydrous Na₂SO₄. Filtration of the extract and removal of the solvent by distillation followed by column chromatography (hexane–EtOAc, 5:1) gave the desired product 5. Representative Analytical Data
  4-Hydroxy-3-(prop-2-ynyl)-coumarin (3m) ¹H NMR (300 MHz, CDCl₃): δ = 2.25 (s, 3 H), 2.31 (s, 3 H), 5.67 (s, 1 H), 7.10 (m, 3 H), 7.24–7.29 (m, 4 H), 7.41–7.44 (m, 4 H), 7.56 (br d, 1 H, J = 2.3 Hz), 8.25 (s, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = 20.9, 21.1, 33.0, 86.8, 87.6, 105.0, 115.6, 116.3, 121.5, 123.1, 127.0, 128.5, 129.1, 129.7, 131.8, 133.4, 133.8, 135.6, 137.5, 150.8, 161.1, 162.8. ESI-HRMS: m/z calcd for C₂₆H₂₀O₃ [M + Na]⁺: 403.1310; found: 403.1320. Furo[3,2-c]coumarin (4m) ¹H NMR (300 MHz, CDCl₃): δ = 2.32 (s, 3 H), 2.35 (s, 3 H), 4.08 (s, 2 H), 7.15–7.25 (m, 9 H), 7.34 (d, 2 H, J = 9.0 Hz), 7.55 (m, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 20.9, 21.4, 32.5, 109.5, 112.5, 116.9, 120.6, 121.8, 126.8, 127.6, 128.4, 128.8, 129.1, 129.7, 131.5, 134.1, 137.4, 137.9, 150.7, 152.7, 157.0, 158.0. ESI-HRMS: m/z calcd for C₂₆H₂₀O₃ [M + Na]⁺: 403.1310; found: 403.1324. Pyrano[3,2-c]coumarin (5m) Mp 172–174 °C. ¹H NMR (300 MHz, CDCl₃): δ = 2.25 (s, 3 H), 2.43 (s, 3 H), 5.19 (s, 1 H), 5.62 (s, 1 H), 7.09 (d, 2 H, J = 6.0 Hz), 7.13–7.22 (m, 3 H), 7.22 (d, 1 H, J = 6.0 Hz), 7.28–7.38 (m, 3 H), 7.52–7.58 (m, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 21.0, 21.2, 49.8, 106.5, 107.6, 111.3, 117.0, 122.3, 127.1, 127.8, 128.5, 128.6, 129.7, 134.0, 134.1, 134.2, 136.8, 137.5, 153.5, 158.0, 158.8, 164.2. ESI-HRMS: m/z calcd for C₂₆H₂₀O₃ [M + Na]⁺: 403.1310; found: 403.1319.