Direct Catalytic Benzylation of Hydroxycoumarin - Efficient Synthesis of Warfarin Derivatives and Analogues

Abstract

Effective metal-catalyzed benzylations of 4-hydroxycoumarin have been developed. Employing a low amount of a cheap, nontoxic, and air-stable catalyst the 3-alkylated hydroxycoumarins were isolated in high yields after short reaction times. Applying this new methodology two widely used anticoagulants phenprocoumon and coumatetralyl were synthesized applying mild reaction conditions.

Key words

green chemistry - homogeneous catalysis - benzylation - bismuth - hydroalkylation

References and Notes

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14

A General Procedure for the Bismuth(III)-Catalyzed Benzylation of 4-Hydroxycoumarin
In a typical experiment 4-hydroxycoumarin (1 mmol) and Bi(OTf)_{3 (}H₂O)₄ (0.005 mmol, 0.5 mol%) were suspended in DCE (5 mL) and heated to 90 ˚C. Subsequently, 1-phenyl-ethanol dissolved in DCE (1 mL) was added (2.5 mmol) dropwise over 4 h. The resulting clear solution was allowed to cool down to r.t., the solvent evaporated under vacuum, and the crude mixture purified by column chromatography (hexane-EtOAc, 3:1) to afford 248 mg (89%) of 2a.
Selected Data
Compound 2a: white amorphous solid. ^¹H NMR (250 MHz, CDCl₃): δ = 7.76-7.66 (m, 1 H), 7.62-7.47 (m, 5 H), 7.44-7.22 (m, 3 H), 6.02 (s, 1 H), 4.85-4.72 (q, J = 7.3 Hz, 1 H), 1.72 (d, J = 7.3 Hz, 3 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 163.4, 159.6, 152.5, 141.5, 131.8, 129.9, 128.0, 127.3, 123.8, 122.9, 116.4, 116.1, 110.1, 34.6, 16.5. IR (neat): ν = 3231 (b), 1669, 1610, 11216, 753 cm^-¹. MS (EI): m/z (%) = 266.1 (100)[M]⁺ , 251.1 (48) [M - CH₃]⁺ , 189.1 (7) [M - C₆H₅]⁺ . Anal. Calcd for C₁₇H₁₄O₃: C, 76.68; H, 5.30. Found: C, 76.84; H, 5.51.
Compound 2b: white amorphous solid. ^¹H NMR (250 MHz, CDCl₃): δ = 7.77-7.70 (m, 1 H), 7.63-7.53 (m, 3 H), 7.44-7.26 (m, 4 H), 6.00 (s, 1 H), 4.72 (q, J = 7.3 Hz, 1 H), 1.71 (d, J = 7.3 Hz, 3 H). ^¹³C NMR (63 MHz, CDCl₃): δ = 163.3, 159.6, 152.6, 140.7, 132.7, 132.1, 129.1, 124.0, 122.8, 116.5, 115.9, 109.7, 34.1, 16.6. IR (neat): ν = 3436 (br), 1716, 1660, 1605, 1203, 754 cm^-¹. MS (EI): m/z (%) = 344.0(100) [M]⁺ , 345.0(22) [M]⁺ , 346.0(97) [M]⁺ , 347.0(18) [M]⁺ . Anal. Calcd for C₁₇H₁₃BrO₃: C, 59.15; H, 3.80. Found: C, 58.91; H, 3.90.