Synthesis of 7,8-Diarylflavones by Site-Selective Suzuki-Miyaura Reactions

Abstract

7,8-Diarylflavones were prepared by Suzuki-Miyaura reactions of the bis(triflate) of 7,8-dihydroxyflavone. The first attack proceeded with very good site selectivity at position 7, due to steric and electronic reasons.

Key words

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

References and Notes

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• 15 For a simple guide for the prediction of the site-selectivity of palladium(0)-catalyzed cross-coupling reactions based on the ^¹H NMR chemical shift values, see: Handy ST. Zhang Y. Chem. Commun.  2006,  299 

9

Synthesis of 4-Oxo-2-phenyl-4 H -chromene-7,8-diyl-bis(trifluoromethanesulfonate (2) To a CH₂Cl₂ solution (10 mL) of 1 (254 mg, 1.0 mmol) was added pyridine (0.32 mL, 4.0 mmol) at -78 ˚C under argon atmosphere. After stirring for 10 min, Tf₂O (0.40 mL, 2.4 mmol) was added at -78 ˚C. The mixture was allowed to warm to 0 ˚C and stirred for 4 h. The reaction mixture was filtered, and the filtrate was concentrated in vacuo. Product 2 was isolated by rapid column chromatography (flash silica gel, heptanes-EtOAc) as a white solid (393 mg, 76%), mp 142-143 ˚C. ^¹H NMR (300 MHz, CDCl₃): δ = 6.82 (s, 1 H), 7.43-7.52 (m, 4 H, ArH), 7.88-7.91 (m, 2 H, ArH), 8.25 (d, J = 9.4 Hz, 1 H). ^¹³C NMR (75.5 MHz, CDCl₃): δ = 108.3 (CH), 118.6 (q, J _F,C = 321.6 Hz, CF₃), 118.7 (q, J _F,C = 320.4 Hz, CF₃), 118.9 (CH), 124.7 (C), 126.6, 126.7, 129.3 (CH), 129.9, 130.2 (C), 132.6 (CH), 143.9, 149.5, 164.5, 175.3 (C). ^¹9F NMR (282 MHz, CDCl₃): δ = -72.66, -72.85. IR (KBr): ν = 3080 (w), 1660 (s), 1613 (m), 1427 (s), 1359 (m), 1210, 1126 (s), 1053, 996, 955, 836, 794, 756 (m), 733 (w), 684 (m) cm^-¹. GC-MS (EI, 70 eV): m/z (%) = 518 (95) [M⁺], 385 (7), 357 (15), 321 (29), 293 (100), 219 (66), 191 (79). HRMS (EI, 70 eV): m/z calcd for C₁₇H₈F₆O₈S₂ [M⁺]: 517.95700; found: 517.95651.

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General Procedure for Suzuki-Miyaura Cross-Coupling Reactions
A 1,4-dioxane solution (3-4 mL) of 2 (1.0 equiv), arylboronic acid 3 (1.0-1.3 equiv per desired cross-coupling reaction), K₃PO₄ (1.5-2.0 equiv per desired cross-coupling reaction), and Pd(PPh₃)₄ (5 mol%) was heated at 70-100 ˚C for 4 h. After cooling to 20 ˚C, a sat. aq solution of NH₄Cl was added, the organic and aqueous layers were separated, and the latter was extracted with CH₂Cl₂. The combined organic layers were dried (Na₂SO₄), filtered, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography.

11

2-Phenyl-7,8-di( p -tolyl)-4 H -chromen-4-one (4f) Starting with 2 (259 mg, 0.5 mmol), K₃PO₄ (424 mg, 2.0 mmol), Pd(PPh₃)₄ (5 mol%), 4-methylphenylboronic acid (3f, 177 mg, 1.3 mmol), and 1,4-dioxane (5 mL), 4f was isolated as a crystalline light yellow solid (148 mg, 74%), mp 248-249 ˚C. ^¹H NMR (300 MHz, CDCl₃): δ = 2.19 (s, 3 H, CH₃), 2.29 (s, 3 H, CH₃), 6.75 (s, 1 H), 6.90-7.04 (m, 8 H, ArH), 7.24-7.33 (m, 3 H, ArH), 7.39 (d, 1 H, J = 8.2 Hz, ArH), 7.48-7.51 (m, 2 H, ArH), 8.16 (d, 1 H, J = 8.2 Hz, ArH). ^¹³C NMR (75MHz, CDCl₃): δ = 21.2, 21.4 (CH₃), 106.7 (CH), 122.8 (C), 124.4, 126.2, 127.4, 128.6, 128.7, 128.9, 129.7 (CH), 130.2 (C), 131.0, 131.4 (CH), 131.6, 131.7, 137.0, 137.1, 146.7, 153.9, 163.2, 178.6 (C). IR (KBr): ν = 2917 (w), 1631 (m), 1592 (w), 1446, 1371 (m), 1238 (w), 1145, 1016 (m), 917 (w), 816, 773, 690 (s), 665 (m) cm^-¹. GC-MS (EI, 70 eV): m/z (%) = 402 (100) [M⁺], 387 (34), 359 (3), 331 (4), 299 (4), 285 (7), 243 (9), 229 (12). HRMS (EI): m/z calcd for C₂₉H₂₂O₂ [M⁺]: 402.16143; found: 402.161442.

12

7-(4-Ethylphenyl)-4-oxo-2-phenyl-4 H -chromen-8-yl Trifluoromethanesulfonate (5a) Starting with 2 (156 mg, 0.30 mmol), K₃PO₄ (96 mg, 0.45 mmol), Pd(PPh₃)₄ (5 mol%), (4-ethylphenyl)boronic acid (3a, 45 mg, 0.30 mmol), and 1,4-dioxane (3mL), 5a was isolated as a white solid (102 mg, 72%), mp 167-168 ˚C. ^¹H NMR (500 MHz, CDCl₃): δ = 1.22 (t, 3 H, J = 7.7 Hz, CH₃), 2.66 (q, 2 H, J = 7.5 Hz, CH₂), 6.83 (s, 1 H), 7.27 (d, 2 H, J = 8.0 Hz, ArH), 7.38 (d, 2 H, J = 8.3 Hz, ArH), 7.44 (d, 1 H, J = 8.3 Hz, ArH), 7.46-7.50 (m, 3 H, ArH), 7.95-7.97 (m, 2 H, ArH), 8.18 (d, 1 H, J = 8.3 Hz, ArH). ^¹³C NMR (125.76 MHz, CDCl₃): δ = 15.5 (CH₃), 28.7 (CH₂), 108.2 (CH), 118.0 (q, J _F,C = 320 Hz, CF₃), 124.2 (C), 125.1, 126.7, 127.4, 128.3, 129.1, 129.2 (CH), 130.8, 131.6 (C), 132.1 (CH), 135.1, 140.7, 145.9, 149.0, 163.8, 176.7 (C). ^¹9F NMR (282 MHz, CDCl₃): δ = -74.3. IR (KBr): ν = 2916, 2850 (w), 1622, 1568, 1447 (m), 1386 (s), 1271 (m), 1164 (s), 1041 (m), 906 (w), 811, 767, 681 (s), 634 (w) cm^-¹. GC-MS (EI, 70 eV): m/z (%) = 474 (40) [M⁺], 410 (28), 395 (18), 366 (3), 341 (100), 326 (8), 313 (20), 281 (4). HRMS (EI): m/z calcd for C₂₄H₁₇F₃O₅S [M⁺]: 474.07471; found: 474.07492.

13

8-(4-Ethylphenyl)-2-phenyl-7-( p -tolyl)-4 H -chromen-4-one (6a) Following the general procedure starting with 5c (101 mg, 0.22 mmol), K₃PO₄ (93 mg, 0.44 mmol), Pd(PPh₃)₄ (5 mol%), 4-(ethylphenyl)boronic acid (3a, 44 mg, 0.29 mmol), and 1,4-dioxane (3 mL), 6a was isolated as a yellow solid (60 mg, 66%), mp 198-199 ˚C. ^¹H NMR (500 MHz, CDCl₃): δ = 1.20 (t, 3 H, J = 7.9 Hz, CH₃), 2.23 (s, 3 H, CH₃), 2.62 (q, 2 H, J = 7.5 Hz), 6.79 (s, 1 H), 6.95-7.01 (m, 4 H, ArH), 7.07-7.12 (m, 4 H, ArH), 7.26-7.38 (m, 3 H, ArH), 7.43 (dd, 1 H, J = 3.4, 8.3 Hz, ArH), 7.50-7.54 (m, 2 H, ArH), 8.18 (d, 1 H, J = 8.3 Hz, ArH). ^¹³C NMR (125.75 MHz, CDCl₃): δ = 15.8, 21.1 (CH₃), 28.7 (CH₂), 122.8 (C), 124.3, 126.2, 127.4, 128.6, 128.7, 128.8, 128.9, 129.6, 131.0, 131.3 (CH), 131.6, 131.7, 132.0, 137.0, 143.5, 146.5, 146.7, 153.9, 136.1, 178.7 (C). IR (KBr): ν = 2962, 2923, 1644 (s), 1597 (w), 1371 (m), 1202, 1096, 1016 (w), 815, 771 (m), 688 (w) cm^-¹. GC-MS (EI, 70 eV): m/z (%) = 416 (100) [M⁺], 402 (16), 387 (49), 313 (6), 285 (14), 271 (5), 253 (6), 239 (9). HRMS (EI): m/z calcd for C₃₀H₂₄O₂ [M⁺]: 416.17783; found: 416.17762.

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