Synthesis of 1,2-Diarylanthraquinones by Site-Selective Suzuki-Miyaura Reactions of the Bis(triflate) of Alizarin

Abstract

1,2-Diarylanthraquinones were prepared by Suzuki-Miyaura reactions of the bis(triflate) of 1,2-dihydroxyanthraquin­one (alizarin). The reactions proceed with excellent site selectivity. The first attack occurs at the sterically more hindered position 1, due to electronic reasons.

Key words

catalysis - palladium - Suzuki-Miyaura reaction - regio­selectivity - anthraquinones

References and Notes

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12

Synthesis of 1,2-Bis(trifluoromethylsulfonyloxy)-anthraquinone (2): To a solution of 1 (1.0 equiv) in CH₂Cl₂ (10 mL/mmol) was added pyridine (4.0 equiv) at r.t. under an argon atmosphere. After 10 min, Tf₂O (2.4 equiv) was added at -78 ˚C. The mixture was allowed to warm to r.t. and stirred for overnight. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The products of the reaction mixture were isolated by rapid column chromatog-raphy (flash silica gel, heptanes-EtOAc). Starting with 1 (1.90 g, 8.0 mmol), pyridine (2.6 mL, 32.0 mmol), CH₂Cl₂ (80 mL), Tf₂O (3.2 mL, 19.2 mmol), 2 was isolated as a yellow solid (3.25 g, 81%); mp 152-154 ˚C. ^¹H NMR (300 MHz, CDCl₃): δ = 7.80-7.85 (m, 3 H, ArH), 8.23-8.26 (m, 1 H, ArH), 8.29-8.32 (m, 1 H, ArH), 8.46 (d, J = 8.7 Hz, 1 H, ArH). ^¹³C NMR (75 MHz, CDCl₃): δ = 118.5 (q, J _CF = 320.9 Hz, CF₃), 118.6 (d, J _CF = 320.7 Hz, CF₃), 127.4 (CH), 127.8 (C), 128.0, 128.1, 128.9 (CH), 132.0, 133.7, 134.1 (C), 135.1, 135.2 (CH), 139.2, 145.0 (C), 180.2, 180.5 (CO). ^¹9F NMR (282 MHz, CDCl₃) δ = -73.4 (q, J _CF = 3.0, 6.0 Hz, CF₃), -72.58 (q, J _CF = 2.8, 5.8 Hz, CF₃). IR (KBr): 1674 (s), 1601, 1587, 1472 (w), 1427 (s), 1330, 1316, 1282, 1249 (w), 1208 (s), 1164, 1150 (m)1124 (s), 1007, 998, 901, 856 (m), 807 (s), 795, 738 (m), 721, 708 (s), 684, 676, 655, 643 (w), 618, 606 (m), 589, 575, 569 (s), 543, 529 (m) cm^-¹. GC-MS (EI, 70 eV): m/z (%) = 504 (36) [M]⁺, 435 (05), 375 (08), 348 (23), 279 (100), 251 (76), 223 (26), 154 (26), 126 (60). HRMS (EI, 70 eV): m/z [M⁺] calcd for C₁₆H₆O₈F₆S₂: 503.94028; found: 503.94011.

13

General Procedure for Suzuki-Miyaura Reactions: A 1,4-dioxane solution (4 mL per 3 mmol of 2) of 2, K₃PO₄, Pd(PPh₃)₄ and arylboronic acid 3 was stirred at 110 ˚C or 90 ˚C for 10 h. 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.

14

Synthesis of 1,2-Bis(4-(tert-butylphenyl)anthraquinone (4c): Starting with 2 (250 mg, 0.5 mmol), 4-tert-butyl-phenylboronic acid (3c; 213 mg, 1.2 mmol), Pd(PPh₃)₄ (34 mg, 6 mol%, 0.03 mmol), K₃PO₄ (320 mg, 1.5 mmol) and 1,4-dioxane (4 mL), 4c was isolated by rapid column chromatography (flash silica gel, heptanes-EtOAc) as yellow crystals (180 mg, 76%); mp 234-236 ˚C. ^¹H NMR (300 MHz, CDCl₃): δ = 1.15 (s, 9 H, 3 × Me), 1.20 (s, 9 H, 3 × Me), 6.75-6.83 (m, 4 H, ArH), 7.01-7.14 (m, 4 H, ArH), 7.60-7.65 (m, 2 H, ArH), 7.70 (d, J = 8.0 Hz, 1 H, ArH), 8.01-8.03 (m, 1 H, ArH), 8.17-8.20 (m, 1 H, ArH), 8.34 (d, J = 8.1 Hz, 1 H, ArH). ^¹³C NMR (62.9 MHz, CDCl₃): δ = 31.2 (3 × Me), 31.4 (3 × Me), 34.4 (C), 34.4 (C), 124.2, 124.3, 126.6, 127.0, 127.5, 129.0, 129.0 (CH), 131.3, 132.9 (C), 133.5 (CH), 133.6 (C), 134.1, 134.9 (CH), 135.0, 136.9, 137.2, 142.7, 149.1, 149.8, 149.8 (C), 183.4, 183.7 (CO). IR (KBr): 2959 (m), 2901, 2866 (w), 1675 (s), 1663, 1588 (m), 1575, 1566, 1548, 1513, 1475, 1456, 1410, 1394, 1360 (w), 1330, 1315 (m), 1298 (s), 1280, 1262, 1253, 1211, 1199 (m), 1185, 1160 (w), 1113 (m), 1072 (w), 1016 (m), 979 (w), 956 (m), 942, 904 (w), 860, 836 (m), 822 (s), 795 (m), 774, 768, 755, 745 (w), 719 (s), 690 (m), 682 (w), 662, 645 (m), 587 (s), 568, 559, 543 (m) cm^-¹. GC-MS (EI, 70 eV): m/z (%) = 472 (45) [M]⁺, 457 (93), 439 (4), 415 (100), 401 (23), 383 (11). HRMS (EI, 70 eV): m/z [M⁺] calcd for C₃₄H₃₂O₂: 472.23968; found: 472.23868.

15

Synthesis of 1-(4- tert -Butylphenyl)-2-(trifluoromethyl-sulfonyloxy)anthraquinone (5c): Starting with 2 (250 mg, 0.5 mmol), 4-tert-butylphenylboronic acid (3c; 90 mg, 0.5 mmol), Pd(PPh₃)₄ (17 mg, 3 mol%, 0.015 mmol), K₃PO₄ (160 mg, 0.75 mmol) and 1,4-dioxane (3 mL), 5c was isolated by rapid column chromatography (flash silica gel, heptanes-EtOAc) as yellow crystals (149 mg, 61%); mp 160-162 ˚C. ^¹H NMR (250 MHz, CDCl₃): δ = 1.31 (s, 9 H, 3 × Me), 7.07 (d, J = 8.4 Hz, 2 H, ArH), 7.42 (d, J = 8.5 Hz, 2 H, ArH), 7.58-7.67 (m, 3 H, ArH), 7.96-8.00 (m, 1 H, ArH), 8.11-8.14 (m, 1 H, ArH), 8.36 (d, J = 8.8 Hz, 1 H, ArH). ^¹³C NMR (75.4 MHz, CDCl₃): δ = 31.3 (3 × Me), 34.7 (C), 118.2 (q, J _CF = 318.5 Hz, CF₃), 125.2, 126.3, 126.9, 127.7, 128.3, 129.3 (CH), 130.5, 132.4, 133.4 (C), 134.1 (CH), 134.1 (C), 134.5 (CH), 134.6, 137.6, 151.2, 151.8 (C), 181.9, 182.0 (CO). ^¹9F NMR (282 MHz, CDCl₃): δ = -74.2 (3 × F, CF₃). IR (KBr): 2960, 2930, 2869, 1675, 1665, 1590, 1580, 1573, 1429 (w), 1410 (m), 1362, 1329, 1316, 1297 (w), 1267 (m), 1205 (s), 1165 (m), 1129 (s), 1079, 1040, 1017, 997 (w), 946, 879, 843 (m), 820 (s), 792, 775, 767, 757, 745 (w), 725 (m), 713 (s), 683, 671 (w), 642 (m), 603 (s), 573 (m) cm^-¹. GC-MS (EI, 70 eV): m/z (%) = 488 (18) [M]⁺, 473 (100), 431 (31), 325 (58), 299 (26), 239 (8). HRMS (EI, 70 eV): m/z [M⁺] calcd for C₂₅H₁₉O₅F₃S: 488.08998; found: 488.090070.

16

General Procedure for the Synthesis of 6a-f: The reaction was carried out in a pressure tube. To a dioxane suspension (3 mL) of 2 (250 mg, 0.5 mmol), Ar^¹B(OH)₂ (0.5 mmol) and Pd(PPh₃)₄ (3 mol%) was added K₃PO₄ (160 mg, 0.75 mmol), and the resultant solution was degassed by bubbling argon through the solution for 10 min. The mixture was heated at 90 ˚C under an argon atmosphere for 10 h. The mixture was cooled to 20 ˚C. Ar^²B(OH)₂ (0.55 mmol), Pd(PPh₃)₄ (3 mol%), K₃PO₄ (160 mg, 0.75 mmol) and dioxane (2 mL) were added. The reaction mixtures were heated under an argon atmosphere for 10 h at 110 ˚C. They were diluted with H₂O and extracted with CH₂Cl₂ (3 × 25 mL). The combined organic layers were dried (Na₂SO₄), filtered and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (silica gel, EtOAc-heptanes).

17

Synthesis of 1-[4 (Trifluoromethyl)phenyl]-2-(4- tert -butylphenyl)anthraquinone (6a): Starting with 2 (252 mg, 0.5 mmol), 4-(trifluoromethyl)phenylboronic acid (3a; 95 mg, 0.5 mmol), Pd(PPh₃)₄ (17 mg, 3 mol%, 0.015 mmol), K₃PO₄ (160 mg, 0.75 mmol), 1,4-dioxane (3 mL), and 4-tert-butylphenylboronic acid (3c; 98 mg, 0.55 mmol), 6a was isolated by rapid column chromatography (flash silica gel, heptanes-EtOAc) as yellow crystals (157 mg, 65%); mp 225-227 ˚C. ^¹H NMR (300 MHz, CDCl₃): δ = 1.15 (s, 9 H, 3 × Me), 6.76-6.80 (m, 2 H, ArH), 7.03-7.10 (m, 4 H, ArH), 7.38 (d, J = 8.1 Hz, 2 H, ArH), 7.61-7.66 (m, 2 H, ArH), 7.70 (d, J = 8.0 Hz, 1 H, ArH), 7.94-7.98 (m, 1 H, ArH), 8.16-8.20 (m, 1 H, ArH), 8.36 (d, J = 8.0 Hz, 1 H, ArH). ^¹³C NMR (75.4 MHz, CDCl₃): δ = 31.2 (3 × Me), 34.4 (C), 124.3 (q,
J = 272.3 Hz, CF₃), 124.4 (dq, J = 7.6, 2.2 Hz), 124.7, 126,7, 127.4, 127.6 (CH), 128.5 (q, J = 32.8 Hz, C), 129.0, 129.7 (CH), 131.3, 132.8, 133.6 (C), 133.8, 134.3 (CH), 134.6 (C), 135.4 (CH), 136.3, 140.8, 144.0 (d, J = 1.7 Hz,), 149.1, 150.5 (C), 183.0, 183.6 (CO). ^¹9F NMR (282 MHz, CDCl₃): δ =
-62.33 (3 × F, CF₃). IR (KBr): 2962, 2905, 2869 (w), 1672 (m), 1613, 1588, 1552, 1513, 1462, 1409, 1399, 1363 (w), 1321 (s), 1300, 1278, 1263 (m), 1213, 1186 (w), 1158 (s), 1118 (m), 1105 (s), 1087, 1075, 1059, 1016 (m), 976 (w), 954 (m), 899, 864 (w), 837, 824 (m), 796, 784, 767, 758, 744 (w), 718 (s), 688, 671, 662, 640, 605 (w), 584 (m), 566, 564, 532 (w) cm^-¹. GC-MS (EI, 70 eV): m/z (%) = 484 (43) [M]⁺, 469 (100), 449 (10), 427 (08), 383 (02), 357 (03). HRMS (EI, 70 eV): m/z [M⁺] calcd for C₃₁H₂₃O₂F₃: 484.16447; found: 484.164850.

18

CCDC 766105, CCDC 766106 and CCDC 766107 contain all crystallographic details of this publication and is available free of charge at www.ccdc.cam.ac.uk/conts/retrieving.html or can be ordered from the following address: Cambridge Crystallographic Data Centre, 12 Union Road, GB-Cambridge CB21EZ; Fax: [phone]; or [e-mail].