Efficient Synthesis of Arylated Coumarins by Site-Selective Suzuki-Miyaura Cross-Coupling Reactions of the Bis(triflate) of 4-Methyl-5,7-dihydroxy­coumarin

Abstract

Arylated coumarins were prepared by site-selective ­Suzuki-Miyaura cross-coupling reactions of the bis(triflate) of 4-methyl-5,7-dihydroxycoumarin.

Key words

cyclization - domino reaction - 4-chloro-3-formylcoumarin - biaryl lactones - heterocycles

References and Notes

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21

4-Methyl-2-oxo-2 H -chromene-5,7-diyl Bis(trifluoro-methanesulfonate) (2) To a solution of 5,7-dihydroxycoumarin (1, 0.5 g, 2.60 mmol) in CH₂Cl₂ (30 mL) was added Et₃N (0.36 mL, 10.4 mmol) at r.t. under an argon atmosphere. After 10 min, Tf₂O (1.0 mL, 6.2 mmol) was added at -78 ˚C. The mixture was allowed to warm to 20 ˚C and stirred for 6 h. The reaction mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by chromatography (flash silica gel, heptanes-EtOAc = 10:1) without aqueous workup to give 2 as a colourless solid (0.9 g, 75%), mp 131-132 ˚C. ^¹H NMR (300 MHz, CDCl₃): δ = 2.56 (d, J = 1.3 Hz, CH₃), 6.32 (d, J = 1.3 Hz, 1 H), 7.19 (d, J = 2.5 Hz, 1 H), 7.28 (d, J = 2.5 Hz, 1 H). ^¹³C NMR (75.46 MHz, CDCl₃): δ = 21.9 (CH₃), 110.0, 110.6 (CH), 113.1 (C), 117.3 (q, J _F,C = 320.0 Hz, CF₃), 117.6 (q, J _F,C = 320.0 Hz, CF₃), 118.1 (CH), 144.8, 147.9, 148.5, 154.5 (C), 156.4 (CO). ^¹9F NMR (282.4, MHz): δ = -72.6, -72.2. IR (KBr): ν = 3181, 3111, 3084, 3065, 3020, 2935, 1795 (w), 1728, 1615 (s), 1566, 1547, 1530, 1476, 1454 (w), 1434, 1415 (s), 1379, 1359 (m), 1326, 1285 (w), 1244, 1235, 1218, 1202, 1132, 1124 (s), 1071 (m), 1052, 1006, 993 (s), 898, 878, 870 (m), 834, 796 (s), 771 (w), 759, 730, 707, 659 (m), 610, 589, 579 (s), 550, 538 (w) cm^-¹. GC-MS (EI, 70 eV): m/z (%) = 456 (100) [M]⁺, 323 (25), 295 (79), 231 (47), 203 (22), 162 (30), 134 (37). HRMS (EI, 70 eV): m/z calcd for C₁₂H₆F₆O₈S₂ [M]⁺: 455.94028; found: 455.941352.

22

General Procedure for Suzuki-Miyaura Reactions
A solution of K₃PO₄ (1.5 equiv per cross-coupling), Pd(PPh₃)₄ (3 mol% per cross-coupling step), and arylboronic acid 3 (1.1 equiv per cross-coupling) in the solvent indicated was stirred at the indicated temperature and for the indicated time. After cooling to 20 ˚C, distilled H₂O was added. The organic and the 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 (flash silica gel, heptanes-EtOAc).

23

5,7-Bis(4-methoxyphenyl)-4-methyl-2 H -chromen-2-one (4c) Starting with 2 (80 mg, 0.18 mmol), 3c (48 mg, 0.35 mmol), Pd(PPh₃)₄ (6 mg, 3 mol%, 0.005 mmol), K₃PO₄ (111 mg, 0.525 mmol), and a toluene-1,4-dioxane mixture (1:1, 4 mL), 4c was isolated by chromatography (flash silica gel, heptanes-EtOAc = 10:1) as a colourless solid (54 mg, 83%), mp 132-134 ˚C. ^¹H NMR (300 MHz, CDCl₃): δ = 1.71 (d, J = 1.2 Hz, 3 H, CH₃), 3.76 (s, 3 H, OCH₃), 3.79 (s, 3 H, OCH₃), 6.05 (d, J = 1.2 Hz, 1 H), 6.88 (m, 4 H), 7.14 (d, J = 8.7 Hz, 2 H), 7.22 (d, J = 2.0 Hz, 1 H), 7.42 (d, J = 2.0 Hz, 1 H), 7.50 (d, J = 8.8 Hz, 2 H). ^¹³C NMR (75.46 MHz, CDCl₃): δ = 24.0 (CH₃), 55.3, 55.4 (OCH₃), 113.4, 113.7, 114.5, 116.1 (CH), 117.0 (C), 126.2, 128.2, 130.3 (CH), 130.9, 134.3, 141.7, 142.5 153.9, 155.0, 159.4, 160.1 (C), 160.6 (CO). IR (KBr): ν = 3040, 2998, 2964, 2931, 2906, 2834, 1900, 1864, 1790 (w), 1722, 1715, 1597 (s), 1557, 1538 (m), 1514 (s), 1462, 1435 (m), 1514 (s), 1462, 1435 (m), 1393, 1378, 1351, 1309 (m), 1292, 1240 (s), 1195, 1177, 1138, 1110 (m), 1085 (w), 1032 (s), 1019 (m), 965, 942, 914, 894, 873, 849 (w), 830 (s), 793, 774, 738, 730, 718 (w), 706 (m), 672, 649, 629, 612, 603, 585, 546 (w). GC-MS (EI, 70 eV): m/z (%) = 372 (100) [M]⁺, 371 (13), 344 (17), 329 (12). HRMS (EI, 70 eV): m/z calcd for C₂₄H₂₀O₄ [M]⁺: 372.13561; found: 372.135278.

24

4-Methyl-2-oxo-7-( p -tolyl)-2 H -chromen-5-yl Trifluoromethanesulfonate (4a) Starting with 2 (80 mg, 0.18 mmol), 3a (24 mg, 0.18 mmol), Pd(PPh₃)₄ (6 mg, 3 mol%, 0.005 mmol), K₃PO₄ (55 mg, 0.26 mL), and toluene (3 mL), 4a was isolated by chromatog-raphy (flash silica gel, heptanes-EtOAc = 10:1) as a colourless solid (55 mg, 80%), mp 135-136 ˚C. ^¹H NMR (300 MHz, CDCl₃): δ = 2.35 (s, 3 H, CH₃), 2.56 (d, J = 1.2 Hz, 3 H, CH₃), 6.24 (d, J = 1.2 Hz, 1 H), 7.23 (d, J = 8.0 Hz, 2 H), 7.41 (d, J = 1.8 Hz, 1 H), 7.42 (d, J = 8.0 Hz, 2 H), 7.49 (d, J = 1.8 Hz, 1 H). ^¹³C NMR (75.47 MHz, CDCl₃): δ = 21.2, 22.9 (CH₃), 112.3 (C), 115.0, 116.0, 117.7 (CH), 118.4 (q, J _F,C = 318.8 Hz, CF₃), 126.8, 130.1 (CH), 134.2, 139.8, 144.8, 145.7, 149.6, 155.3 (C), 159.0 (CO). ^¹9F NMR (282.4, MHz): δ = -72.6. IR (KBr): ν = 3071, 3053, 3033, 2923, 2852, 1914, 1803 (w), 1735, 1613 (s), 1577, 1529, 1482, 1452 (w), 1424 (m), 1398 (s), 1386, 1364, 1292 (m), 1206, 1179, 1133 (s), 1089 (m), 1039, 926, 880, 869, 813, 787, 764, 758 (s), 735, 712, 703, 690 (w), 656 (m), 640, 633, 617 (w), 601, 574 (m), 548, 539 (w) cm^-¹. GC-MS (EI, 70 eV): m/z (%) = 398 (100) [M]⁺, 265 (16), 238 (17), 237 (85), 209 (34), 165 (32). HRMS (EI, 70 eV): m/z calcd for C₁₈H₁₃F₃O₅S [M]⁺: 398.04303; found: 398.04309.

25

7-(4-Methoxyphenyl)-4-methyl-5-( p -tolyl)-2 H -chromen-2-one (6c) The reaction was carried out in a one-pot procedure with sequential addition of the boronic acids. Catalyst and base had to be added two times. Starting with 2 (80 mg, 0.175 mmol), 3c (20 mg, 0.175 mmol), Pd(PPh₃)₄ (6 mg, 3 mol%, 0.005 mmol), K₃PO₄ (55 mg, 0.26 mmol), and then followed by toluene (3 mL), 3a (23 mg, 0.18 mmol), Pd(PPh₃)₄ (6 mg, 3 mol%, 0.005 mmol), K₃PO₄ (55 mg, 0.26 mmol), and dioxane (3 mL), 6c was isolated by chromatography (flash silica gel, heptanes-EtOAc = 10:1) as a colorless solid (47 mg, 75%), mp 256-258 ˚C. ^¹H NMR (300 MHz, CDCl₃): δ = 1.73 (d, J = 1.2 Hz, 3 H, CH₃), 2.32 (s, 3 H, CH₃), 3.80 (s, 3 H, OCH₃), 6.09 (d, J = 1.2 Hz, 1 H), 6.88 (d, J = 8.7 Hz, 2 H), 7.15-7.20 (m, 4 H), 7.26 (d, J = 2.0 Hz, 1 H), 7.45-7.49 (m, 3 H). ^¹³C NMR (75.47 MHz, CDCl₃): δ = 21.1, 24.1 (CH₃), 55.3 (OCH₃), 113.4, 114.1, 116.3 (CH₃), 117.3 (C), 126.5, 126.9, 129.7, 130.3 (CH), 134.3, 135.6, 138.6, 141.7, 142.8, 153.9, 154.9, 159.4 (C), 160.5 (CO). IR (KBr): ν = 3029, 2927, 2852, 2836 (w), 1725 (s), 1642 (w), 1599 (s), 1574, 1536 (w), 1510 (s), 1464, 1439, 1391, 1379, 1354, 1286 (m), 1243 (s), 1191, 1176, 1137 (s), 1108, 1084 (w), 1032 (s), 1017 (w), 963 (s), 893, 875, 853, 834 (w), 816 (s), 795, 778, 726, 714, 672, 648 (w), 613, 582, 555 (w) cm^-¹. GC-MS (EI, 70 eV): m/z (%) = 356 (100) [M]⁺, 355 (11), 328 (26). HRMS (EI, 70 eV): m/z calcd for C₂₄H₂₀O₃ [M]⁺: 356.14070; found: 356.140927.