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Synlett 2015; 26(18): 2601-2605
DOI: 10.1055/s-0035-1560633
letter
© Georg Thieme Verlag Stuttgart · New York

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

Dávid Pajtás
a   Department of Organic Chemistry, University of Debrecen, Egyetem tér 1, 4032, Debrecen, Hungary
,
Károly Dihen
a   Department of Organic Chemistry, University of Debrecen, Egyetem tér 1, 4032, Debrecen, Hungary
,
Tamás Patonay
a   Department of Organic Chemistry, University of Debrecen, Egyetem tér 1, 4032, Debrecen, Hungary
,
Krisztina Kónya
a   Department of Organic Chemistry, University of Debrecen, Egyetem tér 1, 4032, Debrecen, Hungary
,
Alexander Villinger
b   Department of Chemistry, Organic Chemistry, University of Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany
,
Peter Langer*
b   Department of Chemistry, Organic Chemistry, University of Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany
c   Leibniz-Institute for Catalysis e.V. at the University of Rostock (LIKAT), Albert-Einstein-Str. 3a, 18059 Rostock, Germany
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Further Information

Publication History

Received: 14 July 2015

Accepted after revision: 18 September 2015

Publication Date:
18 September 2015 (online)

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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

Supporting Information

    Supporting information for this article is available online at http://dx.doi.org/10.1055/s-0035-1560633.
  • Supporting Information
 

  • 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.