A Short and Efficient Synthesis of Licochalcone E

Abstract

Licochalcone E was synthesized concisely via an abnormal Claisen rearrangement and Claisen-Schmidt condensation as the key reactions in a three-step sequence. The overall yield is 20% starting from prenyl bromide and 4-hydroxy-2-methoxybenzaldehyde.

licochalcone E - abnormal Claisen rearrangement - Claisen-Schmidt condensation - total synthesis

References and Notes

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21

Procedures for the Preparation of Licochalcone E and Selected Spectral Data: At r.t., K₂CO₃ (2.8 g, 20.3 mmol) which had been grinded carefully was added to the stirred solution of 4-hydroxy-2-methoxybenzaldehyde (2.0 g, 13.2 mmol) in anhyd acetone. Then after 10 min, prenyl bromide (1.80 mL, 15.3 mmol) was added to the reaction mixture by pipette. The reaction was stirred for 24 h, until it was complete (checked by TLC). K₂CO₃ was removed by filtration, and the solvent was evaporated under vacuum. The crude residue was recrystallized from PE to generate the white-colored solid compound 9 (2.4 g, yield 86%).
R _f 0.41 (PE-acetone = 10:2). MS: m/z = 243.2 [M + Na]⁺. ^¹H NMR (300 MHz, CDCl₃): δ = 1.76 (s, 3 H), 1.81 (s, 3 H), 3.89 (s, 3 H), 4.57-4.59 (d, J = 6.9 Hz, 2 H), 5.46-5.51 (t, J = 6.9 Hz, 1 H), 6.46-6.47 (d, J = 2.1 Hz, 1 H), 6.54-6.57 (dd, J = 2.1, 8.7 Hz, 1 H), 7.79-7.82 (d, J = 8.7 Hz, 1 H), 10.29 (s, 1 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 18.20, 25.79, 55.52, 65.11, 98.56, 106.20, 118.62, 118.86, 130.66, 139.25, 163.50, 165.45, 188.28. IR (KBr): 2970, 2940, 1680, 1620, 1580, 1500, 1450, 1420, 1390, 1310, 1290, 1270, 1200, 1120, 1030, 928, 818, 787, 642, 602 cm^-¹. Anal. Calcd for C₁₃H₁₆O₃: C, 70.89; H, 7.32. Found: C, 70.82; H, 7.29.
A solution of compound 9 (1.0 g, 4.54 mmol) in freshly distilled N,N-dimethylaniline (5 mL) under nitrogen atmosphere protection was stirred for 26 h at about 185 ˚C in sealed tube. Then after cooling to r.t., the reaction mixture was neutralized by dilute 10% HCl solution until its pH changed to 5-7. The solution was extracted with Et₂O. The Et₂O layer was washed with sat. NaHCO₃ and NaCl solution separately, and then dried with anhyd MgSO₄. The residue obtained after evaporation of the solvent was separated via silica gel column chromatography using mixtures of PE and acetone (30:1) as eluent to give the key intermediate 5 as a white solid (0.32 g, 32%), accompanied by decomposed starting material 4-hydroxy-2-methoxybenzaldehyde (1; 40 mg, yield: 4%).
R _f : 0.18 (PE-acetone = 10:2). MS: m/z = 221.3 [M + H]⁺. ^¹H NMR (300 MHz, CDCl₃): δ = 1.41-1.44 (d, J = 7.2 Hz, 3 H), 1.63 (s, 3 H), 3.46-3.53 (q, J = 7.2 Hz, 1 H), 3.86 (s, 3 H), 5.07 (s, 1 H), 5.16 (s, 1 H), 6.40 (s, 1 H), 6.43 (s, 1 H), 7.66 (s, 1 H), 10.29 (s, 1 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 18.27, 20.66, 41.50, 55.65, 99.58, 111.96, 118.36, 122.31, 129.32, 149.64, 162.32, 162.76, 188.76. UV: λ_max (EtOH; log ε) = 278 (0.32), 235 (0.46), 206 (0.43) nm. IR (KBr): 3180, 1660, 1590, 1510, 1450, 1380, 1285, 1253, 1120, 1020, 891, 841, 694, 594 cm^-¹. Anal. Calcd for C₁₃H₁₆O₃: C, 70.89; H, 7.32. Found: C, 70.90; H, 7.33.
4-Hydroxyacetophenone (0.27 g, 2 mmol) and intermediate 5 (0.40 g, 1.82 mmol) were dissolved in anhyd EtOH (2 mL), cooled by ice-water bath, then anhyd 1.5-2.0 M HCl-EtOH (5 mL) was added slowly to the stirred solution. The mixture was continuously stirred for 2 h at 0-5 ˚C until the reaction was finished completely (checked by TLC). HCl and EtOH solvent were removed under vacuum; the mixture was then extracted with EtOAc, washed with H₂O, sat. NaHCO₃, then H₂O separately. The extracted layer was dried over MgSO₄, filtered, and the solvent was removed under vacuum. Then the title compound licochalcone E (7) was obtained as an orange solid (0.45 g, yield 72%) over silica gel column using mixtures of PE and acetone (10:1) as eluent.:
Licochalcone E also may be purified according to the following method: theg orange solid was precipitated completely after cooled H₂O was added slowly to the reaction mixture. The precipitated solid was then filtered, and recrystallized from cold EtOH-H₂O to provide the target compound.
R _f : 0.10 (PE-acetone = 10:4). MS: m/z = 337.3 [M + H]⁺. ^¹H NMR (300 MHz, CDCl₃): δ = 1.45-1.47 (d, J = 7.2 Hz, 3 H), 1.69 (s, 3 H), 3.47-3.54 (q, J = 7.2 Hz, 1 H), 3.88 (s, 3 H), 5.09 (s, 1 H), 5.16 (s, 1 H), 5.67 (s, 1 H), 6.06 (s, 1 H), 6.43 (s, 1 H), 6.92-6.95 (d, J = 9.0 Hz, 2 H), 7.37 (s, 1 H), 7.53-7.59 (d, J = 15.9 Hz, 1 H), 7.99-8.02 (d, J = 9.0 Hz, 2 H), 7.99-8.04 (d, J = 15.9 Hz, 1 H). ^¹³C NMR (75 MHz, CD₃OD): δ = 19.79, 22.54, 38.97, 56.09, 99.59, 110.16, 116.31, 116.48, 119.29, 125.74, 129.91, 131.44, 132.07, 141.98, 150.39, 160.38, 160.51, 163.52, 191.79. UV: λ_max (EtOH; log ε) = 379 (1.33), 309 (0.94), 262 (0.84) nm. IR (KBr): 3400, 2970, 1640, 1600, 1560, 1500, 1450, 1410, 1340, 1290, 1210, 1170, 1120, 1040, 984, 895, 837, 756, 638, 611, 575 cm^-¹. Anal. Calcd for C₂₁H₂₂O₄: C, 74.54; H, 6.55. Found: C, 74.52; H, 6.56.