Chemoselective Suzuki–Miyaura Cross-Coupling Reactions of 6-Bromo-3-(trifluoromethylsulfonyloxy)flavone

Abstract

Arylated flavones were prepared by Suzuki–Miyaura reactions of 6-bromo-3-(trifluoro-sulfonyloxy)flavone. The reactions proceeded with very good chemoselectivity in favor of position 3.

Key words

catalysis - flavones - heterocycles - palladium - cross-coupling reactions

• References and Notes

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• 34 6-Bromo-3-hydroxyflavone (1) was prepared by the reaction of the corresponding 2′-hydroxychalcone with ethanolic alkaline hydrogenperoxide solution,²⁹ the product was obtained after recrystallization (EtOH) in 56% yield; mp 189–191 °C, lit.^35a; mp 180–181 °C, lit.^35a; mp 183–184 °C.
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• 36 Synthesis of 6-Bromo-4-oxo-2-phenyl-4H-chromen-3-yl Trifluoromethanesulfonate (2) Tf₂O (0.53 mL, 3.20 mmol) was added at 0 °C to a solution of 1 (0.5 g, 1.58 mmol) and pyridine (0.64 mL, 7.88 mmol) in CH₂Cl₂ (15 mL). The reaction mixture was stirred at r.t. under argon atmosphere for 18 h. To the reaction mixture was added toluene (10 mL), and the solution was concentrated in vacuo. The residue was purified by chromatography (EtOAc–heptanes) without aqueous workup to yield 2 as a white solid (0.674 g, 95%); mp 160–162 °C. ¹H NMR (300 MHz, CDCl₃): δ = 7.42 (d, 1 H, J = 8.9 Hz, ArH), 7.48–7.60 (m, 3 H, ArH), 7.77–7.81 (m, 3 H, ArH), 8.35 (d, 1 H, J = 2.5 Hz, ArH). ¹⁹F NMR (282.4 MHz, CDCl₃): δ = –73.7. ¹³C NMR (62.9 MHz, CDCl₃): δ = 118.20 (q, J _C,F = 320.9, CF₃), 119.7 (C), 120.2 (CH), 124.8, 128.1 (C), 128.2 (2 CH), 129.0, 132.7 (CH), 133.8 (C), 137.8 (CH), 154.2, 159.2 (C), 170.0 (CO). IR (KBr): ν = 3083, 3070, 2928 (w), 1651, 1620 (s), 1604, 1538, 1496, 1461, 1451 (m), 1425 (s), 1367 (m), 1335, 1321, 1292, 1269, 1250, 1232 (w), 1212, 1201, 1170, 1139, 1120 (s), 1078, 1060, 1033 (w), 990 (m), 975, 932, 912, 894 (w), 856, 827, 804 (s), 784 (w), 767, 764 (s), 711 (m), 693, 678, 661 (s), 646 (m), 619 (s), 571, 559, 545, 529 (m) cm^–1. GC–MS (EI, 70 eV): m/z (%) = 450 (13) [M, ⁸¹Br]⁺, 448 (13) [M, ⁷⁹Br]⁺, 319 (12), 318 (59), 317 (35), 316 (59), 315 (53), 290 (19), 289 (100), 287 (95), 261 (17), 259 (12). HRMS (EI, 70 eV): m/z calcd for C₁₆H₈BrF₃O₅S [M, ⁷⁹Br]⁺: 447.92224; found: 447.92265; m/z calcd. for C₁₆H₈BrF₃O₅S [M, ⁸¹Br]⁺: 449.92020; found: 449.92043.
• 37 General Procedure for the Synthesis of 4a–g A 1,4-dioxane solution of 2 (0.11 mmol), arylboronic acid (2.3 equiv), K₃PO₄ (3.0 equiv), and Pd(PPh₃)₄ (6 mol%) was heated at 90 °C for 12 h under argon atmosphere. After cooling to 20 °C, H₂O was added, and the reaction mixture was extracted with CH₂Cl₂ (3 × 25 mL). Organic layers were dried over Na₂SO₄, filtered, and concentrated in vacuo. The residue was purified by column chromatography (EtOAc–heptanes)
• 38 3,6-Bis(4-methoxyphenyl)-2-phenyl-4H-chromen-4-one (4a) Starting with 2 (50 mg, 0.11 mmol), (4-methoxyphenyl)boronic acid (39 mg, 0.26 mmol), K₃PO₄ (70 mg, 0.33 mmol), and Pd(PPh₃)₄ (8 mg, 6 mol%), 4a was prepared as a white solid (48 mg, 90%); mp 181–183 °C. Reaction temperature: 90 °C for 12 h. ¹H NMR (250 MHz, CDCl₃): δ = 3.73 (s, 3 H, OCH₃), 3.79 (s, 3 H, OCH₃), 6.77 (d, 2 H, J = 8.8 Hz, ArH), 6.94 (d, 2 H, J = 8.8 Hz, ArH), 7.08 (d, 2 H, J = 8.8 Hz, ArH), 7.18–7.28 (m, 3 H, ArH), 7.34–7.38 (m, 2 H, ArH), 7.49 (d, 1 H, J = 8.7 Hz, ArH), 7.55 (d, 2 H, J = 8.8 Hz, ArH), 7.82 (dd, 1 H, J = 8.8, 2.4 Hz, ArH), 8.37 (d, 1 H, J = 2.3 Hz, ArH). ¹³C NMR (75.5 MHz, CDCl₃): δ = 55.2, 55.4, (OCH₃), 113.9, 114.4, 118.4, (CH), 122.4 (C), 123.0 (CH), 123.6 125.0 (C), 128.1, 128.3, 129.6, 129.9 (CH), 132.1 (C), 132.2, 132.4 (CH), 133.5, 137.8, 155.1, 159.0, 159.5, 161.2 (C), 177.7 (CO). IR (KBr): ν = 3060, 3035, 2954, 2929, 2834 (w), 1633, 1605 (s), 1580, 1563 (m), 1557 (s), 1538 (w), 1511 (m), 1494 (w), 1479, 1446, 1439, 1410 (s), 1291, 1282, 1268 (m), 1244, 1229, 1179 (s), 1149, 1122, 1106, 1079, 1055 (w), 1031, 1018 (m), 1005, 973 (w), 928 (m), 916, 905, 848 (w), 835 (m), 813 (s), 797, 770 (m), 732, 709 (w), 689 (m), 673, 661, 652, 639, 624, 584, 579, 563 (w), 585, 539 (m) cm^–1. GC–MS (EI, 70 eV): m/z (%) = 434 (76) [M]⁺, 433 (100) [M – H]⁺, 418 (4), 390 (6), 311 (24), 226 (4). HRMS (EI, 70 eV): m/z calcd for C₂₉H₂₂O₄ [M]⁺: 434.15126; found: 434.14966; m/z calcd for C₂₉H₂₁O₄ [M – H]⁺: 433.14344; found: 433.14334.
• 39 General Procedure for the One-Pot Synthesis of 5a–g A toluene–MeOH (9:1) solution of 2 (0.11 mmol), arylboronic acid (1.1 equiv), K₃PO₄ (1.5 equiv), and Pd(PPh₃)₄ (3 mol%) was heated at 65 °C for 24 h under argon atmosphere. After cooling to 20 °C, H₂O was added, and the reaction mixture was extracted with CH₂Cl₂ (3 × 25 mL). The organic layers were dried over Na₂SO₄, filtered, and concentrated in vacuo. The residue was purified by column chromatography (EtOAc–heptanes)
• 40 6-Bromo-3-(4-methoxyphenyl)-2-phenyl-4H-chromen-4-one (5a)
  Starting with 2 (50 mg, 0.11 mmol), 5a was prepared as a white solid (37 mg, 82%), mp 237–238 °C. Reaction temperature: 65 °C for 24 h. ¹H NMR (300 MHz, CDCl₃): δ = 3.73 (s, 3 H, OCH₃), 6.77 (d, 2 H, J = 8.9 Hz, ArH), 7.06 (d, 2 H, J = 8.9 Hz, ArH), 7.19–7.37 (m, 6 H, ArH), 7.70 (dd, 1 H, J = 8.9, 2.5 Hz, ArH), 8.33 (d, 1 H, J = 2.5 Hz, ArH). ¹³C NMR (62.9 MHz, CDCl₃): δ = 55.2 (OCH₃), 113.9 (CH), 118.3 (C), 119.9 (CH), 122.6, 124.4, 124.8 (C), 128.2, 128.9, 129.5, 130.1, 132.3 (CH), 133.1 (C), 136.5 (CH), 154.8, 159.1, 161.4 (C), 176.3 (CO). IR (KBr): ν = 3081, 3059, 3015, 2928, 2850, 2832 (w), 1635, 1604 (s), 1574, 1563 (w), 1556 (s), 1510 (w), 1466, 1455, 1444 (m), 1426, 1361 (s), 1288, 1270 (m), 1232, 1219, 1177 (s), 1146, 1121, 1107, 1061, 1048 (w), 1027, 1000 (s), 976, 960 (w), 928 (m), 906, 896, 841 (w), 824, 815 (s), 794 (w), 777 (s), 728 (w), 701, 696, 676, 666, 653, 648 (m), 640, 619, 610, 551 (w), 540, 530 (m) cm^–1. GC–MS (EI, 70 eV): m/z (%) = 408 (67) [M, ⁸¹Br]⁺, 407 (100) [M – H, ⁸¹Br]⁺, 406 (69) [M, ⁷⁹Br]⁺, 405 (84) [M – H, ⁷⁹Br]⁺, 364 (5), 362 (5), 327 (7), 283 (6), 255 (6), 226 (5), 208 (22). HRMS (ESI-TOF/MS): m/z calcd. for C₂₂H₁₆BrO₃ [M + H, ⁷⁹Br]⁺: 407.02773; found: 407.0270; m/z calcd for C₂₂H₁₆BrO₃ [M + H, ⁸¹Br]⁺: 409.02597; found: 409.02509.
• 41 General Procedure for the One-Pot Synthesis of 6a–d A toluene–MeOH (9:1) solution of 2 (0.17 mmol), Ar¹B(OH)₂ (1.0 equiv), K₃PO₄ (1.5 equiv), and Pd(PPh₃)₄ (3 mol%) was heated at 65 °C for 36 h under argon atmosphere. After cooling to 20 °C, Ar²B(OH)₂ (1.3 equiv), Pd(PPh₃)₄ (6 mol%), and MeOH (0.2 mL) were added, and the reaction mixture was heated at 105 °C for further 12 h. The reaction mixture was cooled again to 20 °C, H₂O was added, and the reaction mixture was extracted with CH₂Cl₂ (3 × 25 mL).The combined organic layers were dried over Na₂SO₄, filtered, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (EtOAc–heptanes)
• 42 3-(4-Ethoxyphenyl)-2-phenyl-6-(m-tolyl)-4H-chromen-4-one (6c)
  Starting with 2 (75 mg, 0.17 mmol), (4-ethoxyphenyl)boronic acid as Ar¹B(OH)₂ (29 mg, 0.17 mmol), K₃PO₄ (53 mg, 0.26 mmol), Pd(PPh₃)₄ (6 mg, 3 mol%), and (3-methylphenyl)boronic acid as Ar²B(OH)₂ (30 mg, 0.22 mmol), 6c was prepared as a light yellow highly viscous oil (66 mg, 91%). Reaction temperature: 65 °C for 36 h, then 105 °C for 12 h. ¹H NMR (300 MHz, CDCl₃): δ = 1.33 (t, 3 H, J = 7.0 Hz, CH₃), 2.36 (s, 3 H, CH₃), 3.95 (q, 2 H, J = 7.0 Hz, OCH₂), 6.75 (d, 2 H, J = 8.8 Hz, ArH), 7.07 (d, 2 H, J = 8.8 Hz, ArH), 7.11–7.31 (m, 5 H, ArH), 7.34–7.43 (m, 4 H, ArH), 7.50 (d, 1 H, J = 8.7 Hz, ArH), 7.84 (dd, 1 H, J = 8.7, 2.3 Hz, ArH), 8.41 (d, 1 H, J = 2.3 Hz, ArH). ¹³C NMR (75.5 MHz, CDCl₃): δ = 14.9, 21.6 (CH₃), 63.4 (OCH₂), 114.4, 118.4 (CH), 122.5, 123.6 (C), 124.1, 124.3 (CH), 124.8 (C), 128.0, 128.1, 128.5, 128.9, 129.6, 129.9, 132.4, 132.6 (CH), 133.5, 138.3, 138.7, 139.5, 155.4, 158.5, 161.2 (C), 177.7 (CO). IR (KBr): ν = 3055, 3034, 2975, 2922, 2871 (w), 1636, 1606 (s), 1558 (m), 1510 (s), 1494 (w), 1474 (s), 1444 (m), 1405, 1393 (w), 1361 (s), 1285, 1270 (w), 1224, 1174 (s), 1143, 1114, 1094, 1076 (w), 1041, 1029 (m), 1012, 1000, 933, 919, 845 (w), 825, 782, 769, 729, 718, 692 (s), 665 (w), 643, 631 (m), 597, 564, 531 (w) cm^–1. GC–MS (EI, 70 eV): m/z (%) = 432 (79) [M]⁺, 431 (100) [M – H]⁺, 403 (18), 375 (5), 222 (10). HRMS (EI, 70 eV): m/z calcd for C₃₀H₂₄O₃ [M]⁺: 432.17200; found: 432.17124.
• 43 Joo YH, Kim JK. Kang S.-H, Noh M.-S, Ha J.-Y, Choi JK, Lim KM, Lee CH, Chung S. Bioorg. Med. Chem. 2003; 13: 413

For reviews of site-selective palladium(0)-catalyzed cross-coupling reactions, see:
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