Site-Selective Suzuki–Miyaura Reaction of 6,8-Dibromoflavone

Abstract

8-Aryl- and 6,8-diarylflavones were prepared by Suzuki–­Miyaura reactions of 6,8-dibromoflavone. In spite of the greater steric hindrance, the first attack proceeded with good site selectivity at position 8.

Key words

palladium - catalysis - flavones - Suzuki–Miyaura reaction - regioselectivity

• References and Notes

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• 15 Procedure for Synthesising 6,8-Diarylflavone Derivatives 6a–g To a mixture of 6,8-dibromoflavone (4, 95 mg, 0.25 mmol), K₃PO₄ (160 mg, 0.75 mmol), and boronic acid 5 (0.75 mmol) in dry dioxane (4 mL), Pd(PPh₃)₄ (17 mg, 0.015 mmol) was added in a dried pressure tube under argon. The reaction mixture was stirred and heated in an aluminum heating block till full conversion. The solvent was removed under reduced pressure, and the solid mixture was dissolved in CH₂Cl₂. The solution was submitted to adsorptive filtration on silica gel using CH₂Cl₂ as eluent to remove the inorganic compounds. The CH₂Cl₂ was evaporated; the residue was washed two times with acetone then filtered to give the pure cross-coupled product 6.
• 16a Procedure for Synthesising 8-Aryl-6-bromoflavone Derivatives 7a–d To a mixture of 6,8-dibromoflavone (4, 95 mg, 0.25 mmol), K₃PO₄ (106 mg, 0.5 mmol), and boronic acid 5 (0.30 mmol) in dry dioxane (4 mL), Pd(PPh₃)₄ (17 mg, 0.015 mmol) was added in a dried pressure tube under argon. The reaction mixture was stirred and heated at 80 °C for 48 h in an aluminum heating block. The solvent was removed in vacuum, and the solid mixture was dissolved in CH₂Cl₂. The solution was submitted to adsorptive filtration on silica gel using CH₂Cl₂ as eluent to remove the inorganic compounds. The eluted solution was concentrated then the mixture was purified by column chromatography (eluent: heptane–EtOAc mixture; the ratio is given at the compound) to give the monosubstituted product.
• 16b ¹H NMR Spectroscopic Data of Flavone ¹H NMR (400 MHz, CDCl₃): δ = 8.24 (d, J = 8.9 Hz, 1 H, 5-H), 7.97–7.89 (m, 2 H, 2′,6′-H), 7.70 (t, J = 8.4 Hz, 1 H, 7-H), 7.58 (d, J = 8.3 Hz, 1 H, 8-H), 7.56–7.50 (m, 3 H, 3′,4′, 5′-H), 7.43 (t, J = 7.5 Hz, 1 H, 6-H), 6.83 (s, 1 H, 3-H).
• 17 CCDC-1052200 contains all crystallographic details of this publication and is available free of charge at www.ccdc.cam.ac.uk/conts/retrieving.html.
• 18 Procedure for Synthesizing Differently Substituted 6,8-Diarylflavone Derivatives 9a–d To a mixture of 8-aryl-6-bromoflavones 7c,d (0.10 mmol), K₃PO₄ (54 mg, 0.25 mmol), and boronic acid 5a,e (0.20 mmol) in dry dioxane (4 mL), Pd(PPh₃)₄ (5.8 mg, 0.005 mmol) was added in a dried pressure tube under argon. The reaction mixture was stirred and heated at 100 °C for 2 h in an aluminum heating block. The solvent from the crude reaction mixture was removed in vacuum, and the solid residue was dissolved in CH₂Cl₂. The solution was submitted to adsorptive filtration on silica gel using CH₂Cl₂ as eluent to remove the inorganic compounds. The eluted solution was concentrated, then the mixture was purified by column chromatography (eluent: heptane–EtOAc mixture; the ratio is given at the compound) to give the nonsymmetric diarylated product.
• 19 6,8-Bis(4-methylphenyl)flavone (6a) Starting with 4 (95 mg, 0.25 mmol), K₃PO₄ (160 mg, 0.75 mmol), Pd(PPh₃)₄ (17 mg, 0.015 mmol, 6 mol%), (4-methylphenyl)boronic acid (5a, 102 mg, 0.75 mmol), and 1,4-dioxane (4 mL), 6a was isolated as a light yellow solid (94 mg 93%), mp 247.0–248.5 °C. ¹H NMR (300 MHz, 298 K, CDCl₃): δ = 8.44 (d, J = 2.7 Hz, 1 H, 5-H), 7.96 (d, J = 2.4 Hz, 1 H, 7-H), 7.82–7.79 (m, 2 H, 2′,6′-H), 7.64–7.59 (m, 4 H, 2′′,6′′-H, 2′′′,6′′′-H), 7.49.7.46 (m, 3 H, 3′,5′-H, 4′-H), 7.37 (d, J = 9.6 Hz, 2 H, 3′′′,5′′′-H), 7.27 (d, J = 9.6 Hz, 2 H, 3′′,5′′-H), 6.96 (s, 1 H, 3-H), 2.50 (s, 3 H, 4′′′-CH₃), 2.42 (s, 3 H, 4′′-CH₃). ¹³C NMR (75 MHz, 298 K, CDCl₃): δ = 178.7 (C-4), 163.2 (C-2), 152.4 (C-8a), 138.1 (C-4′′,4′′′), 137.8 (C-6), 136.4 (C-8), 133.4 (C-7), 133.2 (C-1′′), 132.3 (C-1′′′), 131.6 (C-1′), 131.5 (C-4′), 129.7 (C-3′′,5′′), 129.5 (C-3′′′,5′′′), 129.1 (C-2′′′,6′′′), 129.0 (C-3′,5′), 127.0 (C-2′′,6′′), 126.3 (C-2′,6′), 124.5 (C-4a), 122.1 (C-5), 126.9 (C-3), 21.3 (4′′′-CH₃), 21.1 (4′′-CH₃). IR (ATR): ν = 1636, 1597, 1459, 1447, 1363, 1173, 812, 775, 687, 633, 502 cm^–1. GC-MS (EI, 70eV): m/z (%) = 402 (100) [M^+•], 300, 229, 102. HRMS: m/z calcd for C₂₉H₂₂O₂: 402.16143; found: 402.16156. 6-Bromo-8-(3,4-dimethoxyphenyl)flavone (7c) Starting with 4 (95 mg, 0.25 mmol), K₃PO₄ (106 mg, 0.5 mmol), Pd(PPh₃)₄ (17 mg, 0.015 mmol, 6 mol%), (3,4-dimethylphenyl)boronic acid (5c, 55 mg, 0.30 mmol), and 1,4-dioxane (4 mL), 7c was isolated as a white solid (62 mg 57%), mp 186.5–188 °C (eluent: heptane–EtOAc, 2:1). ¹H NMR (300 MHz, 298 K, CDCl₃): δ = 8.31 (d, 1 H, J = 2.4 Hz, 5-H), 7.80 (d, 1 H, J = 2.4 Hz, 7-H), 7.77–7.75 (m, 2 H, 2′,6′-H), 7.51–7.45 (m, 3 H, 3′,5′-H, 4′-H), 7.18–7.15 (m, 2 H, 2′′,6′′-H), 7.04 (d, J = 8.1 Hz, 1 H, 5′′-H), 6.88 (s, 1 H, 3-H), 3.99 (s, 3 H, 4′′-OCH₃), 3.88 (s, 3 H, 3′′-OCH₃). ¹³C NMR (75 MHz, 298 K, CDCl₃): δ = 177.1 (C-4), 163.3 (C-2), 151.9 (C-8a), 149.4 (C-3′′), 148.7 (C-4′′), 137.0 (C-7), 133.8 (C-1′′), 131.8 (C-4′), 131.2 (C-1′), 129.0 (C-3′,5′), 127.3 (C-8), 126.9 (C-5), 126.2 (C-2′,6′), 125.6 (C-4a), 122.2 (C-6′′), 118.6 (C-6), 112.6 (C-2′′), 111.1 (C-5′′), 106.9 (C-3), 55.9 (3′′-OCH₃, 4′′-OCH₃). IR: (ATR): ν = 3061, 2999, 2933, 2838, 1637, 1567, 1512, 1452, 1358, 1251, 1224, 1137, 1022, 882, 780, 694, 670, 637, 589 cm^–1. GC-MS (EI, 70eV): m/z (%) = 436 [M^+•], 438 [M^+• + 2], 293, 291, 184, 102. HRMS: m/z calcd for C₂₃H₁₇O₄ ⁷⁹Br: 436.03047; found: 436.03046; m/z calcd for C₂₃H₁₇O₄ ⁸¹Br: 438.02843; found: 438.02866. 6-(4-Chlorophenyl)-8-(3,4-dimethoxyphenyl)flavone (9b) Starting with 7c (44 mg, 0.10 mmol), K₃PO₄ (42 mg, 0.2 mmol), Pd(PPh₃)₄ (5.8 mg, 0.005 mmol, 5 mol%), (4-chlorophenyl)boronic acid (5e, 31 mg, 0.20 mmol), and 1,4-dioxane (4 mL), 9b was isolated as a light yellow solid (38 mg, 81%), mp 228–229 °C (eluent: heptane–EtOAc, 2:1). ¹H NMR (300 MHz, 298 K, CDCl₃): δ = 8.40 (d, J = 3.0 Hz, 1 H, 5-H), 7.90 (d, J = 3.0 Hz, 1 H, 7-H) 7.82–7.90 (m, 2 H, 2′,6′-H), 7.64 (d, J = 8.1 Hz, 2 H, 2′′,6′′-H,) 7.52–7.43 (m, 5 H, 3′,5′-H, 4′-H, 3′′,5′′-H), 7.25–7.21 (m, 2 H, 2′′′,6′′′-H), 7.07 (d, J = 8.1 Hz, 1 H, 5′′′-H), 6.93 (s, 1 H, 3-H), 4.00 (s, 3 H, 4′′′-OCH₃), 3.90 (s, 3 H, 3′′-OCH₃). ¹³C NMR (75 MHz, 298 K, CDCl₃): δ = 178.4 (C-4), 163.2 (C-2), 152.6 (C-8a), 149.3 (C-3′′′), 148.8 (C-4′′′), 137.7 (C-1′′), 136.9 (C-6), 134.1 (C-4′′), 133.1 (C-7), 132.4 (C-1′′′), 131.8 (C-4′), 131.5 (C-1′), 129.2 (C-3′,5′), 129.1 (C-3′′,5′′), 128.6 (C-8), 128.4 (C-2′′,6′′), 126.3 (C-2′,6′), 124.7 (C-4a), 122.3 (C-5), 122.2 (C-6′′′), 112.9 (C-2′′′), 111.2 (C.5′′′), 106.9 (C-3), 56.0 (3′′′-OCH₃, 4′′′-OCH₃). IR (ATR): ν = 2957, 2834, 1640, 1514, 1461, 1243, 1225, 1141, 1029, 821, 688 cm^–1. GC-MS (EI, 70eV): m/z (%) = 468 [M^+•], 470 [M^+• + 2], 425, 323, 189, 102. HRMS: m/z calcd for C₂₉H₂₁O₄ ³⁵Cl: 468.11229; found: 468.11195.