A Scaffold Approach to 3,6,8-Trisubstituted Flavones

Abstract

An efficient synthetic approach to 3,6,8-trisubstituted flavone scaffolds has been developed based on Pd-mediated coupling reactions.

Key words

catalysis - flavone - Heck reaction - palladium - scaffold - Stille reaction

References and Notes

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9

All compounds reported herein gave spectral data consistent with the assigned structures as well as satisfactory elemental analyses.

14

General Procedure for the Heck Reaction in Position 8 - Synthesis of 6-Chloro-8-(2-methoxycarbonylethenyl)-flavone (4).
A solution of 2 (150 mg, 0.45 mmol), Pd(OAc)₂ (10 mg, 0.045 mmol), Pd(o-tolyl)₃ (30 mg, 0.9 mmol), Et₃N (0.12 mL, 0.9 mmol) and methyl acrylate (0.08 mL, 0.9 mmol) in DMF (4 mL) in a microwave tube was heated in a microwave cavity for 30 min at 160 °C. The solution was filtered through Celite^® and H₂O (10 mL) was added. The mixture was extracted with CH₂Cl₂ (4 × 10 mL). The combined organic phases were dried over anhyd Na₂SO₄ before the solvent was removed under vacuum. The residue was purified by column chromatography on silica gel using CH₂Cl₂ as eluent to afford 133 mg (87%) of 4 as a light-yellow powder; mp 181-182 °C. ¹H NMR (400 MHz, CDCl₃): δ = 3.87 (s, 3 H), 6.66 (d, J = 16.1 Hz, 1 H), 6.84 (s, 1 H), 7.56-7.59 (m, 3 H), 7.86 (d, J = 2.6 Hz, 1 H), 7.90-7.92 (m, 2 H), 8.21 (d, J = 2.6 Hz, 1 H), 8.21 (d, J = 16.1 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 52.3, 108.0, 122.7, 125.7, 126.6, 126.8, 127.1, 129.6, 131.4, 131.5, 131.8, 132.3, 135.7, 152.5, 163.9, 166.7, 176.9. Anal. Calcd for C₁₉H₁₃ClO₄: C, 66.97, H, 3.85. Found: C, 66.82, H, 3.77.

15

General Procedure for Stille Coupling in Positions 3 and 8 - Synthesis of 8-Allyl-6-chloro-flavone (3).
A solution of 2 (400 mg, 1.2 mmol), Pd(PPh₃)₄ (140 mg, 0.12 mmol) and allyltributyltin (600 mg, 1.8 mmol) in dioxane (30 mL) under N₂ was warmed to 80 °C for 14 h. The mixture was allowed to cool to r.t. and filtered through Celite^®. A sat. aq KF solution (15 mL) was added and stirred for 30 min. The solution was extracted with CH₂Cl₂ (4 × 30 mL). The combined organic phases were washed with H₂O (2 × 10 mL), dried over anhyd MgSO₄ before the solvent was removed under vacuum. The residue was purified by column chromatography on silica gel using CH₂Cl₂ as eluent to afford 282 mg (79%) of 3 as a white powder; mp 127-128 °C. ¹H NMR (400 MHz, CDCl₃): δ = 3.74 (d, J = 6.6 Hz, 2 H), 5.19-5.25 (m, 2 H), 6.01-6.12 (m, 1 H), 6.83 (s, 1 H), 7.50 (d, J = 2.6 Hz, 1 H), 7.54-7.57 (m, 3 H), 7.89-7.91 (m, 2 H), 8.07 (d, J = 2.6 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 33.9, 107.5, 118.1, 123.4, 125.1, 126.4, 129.4, 131.1, 131.8, 132.0, 134.2, 134.5, 152.8, 163.4, 177.6. Anal. Calcd for C₁₈H₁₃ClO₂: C, 72.85, H, 4.42. Found: C, 72.67, H, 4.35.

17

General Procedure for the Stille Coupling in Position 6 - Synthesis of 6,8-Diallyl-flavone (5).
A solution of 3 (51 mg, 0.17 mmol), allyltributyltin (85 mg, 0.26 mmol), Pd₂(dba)₃ (10 mg, 0.01 mmol) and P(t-Bu)₃ (8 mg, 0.04 mmol) in dioxane (15 mL) under N₂ was warmed to 80 °C for 14 h. The mixture was allowed to cool to r.t. and filtered through Celite^®. A sat. aq KF solution (10 mL) was added and stirred for 30 min. The solution was extracted with CH₂Cl₂ (4 × 20 mL). The combined organic phases were washed with H₂O (2 × 10 mL), dried over anhyd MgSO₄ before the solvent was removed under vacuum. The residue was purified by column chromatography on silica gel using a manual gradient of CH₂Cl₂-Et₂O (100:0 to 95:5) as eluent to afford 12 mg (22%) of 5 as light crystals; mp 86-87 °C. ¹H NMR (400 MHz, CDCl₃): δ = 3.48 (d, J = 6.4 Hz, 2 H), 3.75 (d, J = 6.8 Hz, 2 H), 5.10-5.19 (m, 4 H), 5.94-6.14 (m, 2 H), 6.84 (s, 1 H), 7.39 (d, J = 2.2 Hz, 1 H), 7.52-7.55 (m, 3 H), 7.91-7.94 (m, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 34.3, 39.9, 107.6, 116.8, 117.2, 123.3, 124.1, 126.5, 129.3, 129.7, 131.8, 132.3, 135.0, 135.6, 136.8, 137.2, 137.3, 163.2, 179.0. Anal. Calcd for (C₂₁H₁₈O₂)₂·H₂O: C, 81.00, H, 6.15. Found: C, 80.78, H, 5.86.

18

According to NMR spectroscopy the major side products showed a Pd-mediated rearrangement of the double bond in the allyl group with or without a concomitant Stille coupling in position 6.

19

General Procedure for the Heck Reaction in Position 6 - Synthesis of 6,8-Bis(2-methoxycarbonylethenyl)-flavone (6).
Et₃N (0.04 mL, 0.26 mmol) was added to a suspension of 4 (46 mg, 0.13 mmol), Pd₂(dba)₃ (10 mg, 0.01 mmol), methyl acrylate (0.03 mL, 0.33 mmol) and [P(t-Bu)₃H]BF₄ (12 mg, 0.04 mmol) in dioxane (4 mL) under N₂ in a microwave tube. The mixture was heated in a microwave cavity for 30 min at 160 °C. The solution was filtered through Celite^® and H₂O (10 mL) was added. The mixture was extracted with CH₂Cl₂ (4 × 10 mL). The combined organic phases were dried over anhyd MgSO₄ before the solvent was removed under vacuum. The residue was purified by column chromatography on silica gel using a manual gradient of CH₂Cl₂-Et₂O (100:0 to 95:5) as eluent to afford 40 mg (79%) of 6 as a white powder; mp 214-215 °C. ¹H NMR (400 MHz, CDCl₃): δ = 3.83 (s, 3 H), 3.87 (s, 3 H), 6.56 (d, J = 15.9 Hz, 1 H), 6.71 (d, J = 16.4 Hz, 1 H), 6.85 (s, 1 H), 7.56-7.58 (m, 3 H), 7.73 (d, J = 15.9 Hz, 1 H), 7.90-7.93 (m, 2 H), 8.01 (d, J = 2.2 Hz, 1 H), 8.24 (d, J = 16.4 Hz, 1 H), 8.39 (d, J = 2.2 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃):
δ = 52.0, 52.2, 108.1, 120.2, 122.2, 124.8, 125.6, 126.5, 127.0, 129.5, 131.0, 131.3, 131.6, 132.2, 136.3, 142.3, 154.6, 163.7, 166.8, 166.9, 177.4. Anal. Calcd for C₂₃H₁₈O₆: C, 70.76, H, 4.65. Found: C, 70.59, H, 4.74.

27

8-Bromo-6-chloro-3-[3-( N -phthalimido)propoxy]-flavone (13).
A solution of 8 (6.2 g, 17.7 mmol), N-(3-bromo-propyl)phthalimide (9.5 g, 35.4 mmol) and K₂CO₃ (4.5 g, 35.4 mmol) in DMF (50 mL) was stirred at 50 °C for 15 h. The mixture was allowed to cool and H₂O was added. The solution was acidified with HCl (1 M). The precipitate was filtered off and the solid was recrystallized from EtOH to afford 8.5 g (87%) of 13 as white crystals; mp 185-186 °C. ¹H NMR (400 MHz, CDCl₃): δ = 2.10-2.17 (m, 2 H), 3.83 (t, J = 7.0 Hz, 2 H), 4.18 (t, J = 6.2 Hz, 2 H), 7.52-7.58 (m, 3 H), 7.70-7.72 (m, 2 H), 7.83-7.85 (m, 2 H), 7.88 (d, J = 1.3 Hz, 1 H), 8.14 (d, J = 1.3 Hz, 1 H), 8.23-8.25 (m, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 29.5, 53.5, 70.5, 112.9, 123.4, 124.8, 125.8, 128.9, 129.1, 130.5, 130.9, 131.5, 132.3, 134.1, 136.6, 140.7, 150.5, 156.2, 168.4, 173.5. Anal. Calcd for C₂₆H₁₇BrClNO₅: C, 57.96, H, 3.18, N, 2.60. Found: C, 57.79, H, 3.07, N, 2.48.