Site-Selective Suzuki-Miyaura Reactions of the Bis(triflate) of 5,10-dihydroxy-11H-benzo[b]fluoren-11-one

Abstract

5,10-Diaryl-11H-benzo[b]fluoren-11-ones were prepared by Suzuki-Miyaura reactions of the bis(triflate) of 5,10-dihydroxy-11H-benzo[b]fluoren-11-one. The reactions proceed with excellent site-selectivity. The first attack occurs at position 10, due to electronic reasons.

Key words

catalysis - palladium - Suzuki-Miyaura reaction - regio­selectivity - fluorenones

References and Notes

• 1a Talapatra SK. Bose S. Malliks Asok K. Talapatra B. Tetrahedron  1985,  41:  2765 
• 1b Sargent MV. J. Chem. Soc., Perkin Trans. 1  1987,  2553 
• 1c Fan C. Wang W. Wang Y. Qin G. Zhao W. Phytochemistry  2001,  57:  1255 
• 1d Wu XY. Qin GW. Fan DJ. Xu RS. Phytochemistry  1994,  36:  477 
• 2 Campo MA. Larock RC. J. Org. Chem.  2002,  67:  5616 ; and references cited therein
• 3 Tierney MT. Grinstaff MW. J. Org. Chem.  2000,  65:  5355 
• 4 Perry PJ. Read MA. Davies RT. Gowan SM. Reszka AP. Wood AA. Kelland LR. Neidle S.
  J. Med. Chem.  1999,  42:  2679 
• 5a Gould SJ. Melville CR. Cone MC. Chen J. Carney JR. J. Org. Chem.  1997,  62:  320 
• 5b Mal D. Hazra NK. Tetrahedron Lett.  1996,  37:  2641 ; and references cited therein
• 5c Cragoe EJ, Marangos PJ, and Weimann TR. inventors; U.S. Patent, 6251898  BI. 
• 6 Wang S. Wen B. Wang N. Liu J. He L. Arch. Pharm. Res.  2009,  32:  2009 
• 7 Goel A. Chaurasia S. Dixit M. Kumar V. Parakash S. Jena B. Verma JK. Jain M. Anand RS. Manoharan S. Org. Lett.  2009,  11:  1289 ; and references cited therein
• 8 Tilly D. Samanta SS. Faigl F. Mortier J. Tetrahedron Lett.  2002,  43:  8347 
• 9a Underwood HW. Kochmann EL. J. Am. Chem. Soc.  1924,  46:  2073 
• 9b Lemal DM. Gosselink EP. McGregor SD. J. Am. Chem. Soc.  1966,  88:  582 
• 9c Bandyopadhyay TK. Bhattacharya AJ. Indian J. Chem. Sect. B  1980,  19:  439 
• 9d Kym PR. Hummert KL. Nilsson AG. Lubin M. Katzenellenbogen JA.
  J. Med. Chem.  1996,  39:  4897 
• 9e Gruber J. Li RWC. Aguiar LH. Benvenho JMC. Adriano RV. Lessmann R. Huemmelgen IA. J. Mater. Chem.  2005,  15:  517 
• 9f Olah GA. Mathew T. Farnia M. Prakash S. Synlett  1999,  1067 
• 10 Danheiser LR. Gould EA. Pradilla FR. Helgason LA. J. Org. Chem.  1994,  59:  5514 
• 11a Murahashi S.-I. Komiya N. Oda Y. Kuwabara T. Naota T. J. Org. Chem.  2000,  65:  9186 
• 11b Lippert E. Walter H. Angew. Chem.  1959,  71:  429 
• 12 Fu J.-M. Zhao B.-P. Sharp MJ. Snieckus V. J. Org. Chem.  1991,  56:  1683 
• 13 Yu Z. Velasco D. Tetrahedron Lett.  1999,  40:  3229 
• 14 Ciske FL. Jones WD. Synthesis  1998,  1195 
• 15 Schmidt JM. Tremblay GB. Page M. Mercure J. Feher M. Dunn-Dufault R. Peter MG. Redden PR.
  J. Med. Chem.  2003,  46:  1289 
• 16 Reim S. Lau M. Adeel M. Hussain I. Yawer MA. Riahi A. Ahmed Z. Fischer C. Reinke H. Langer P. Synthesis  2009,  445 
• For reviews of cross-coupling reactions of polyhalogenated heterocycles, see:
• 17a Schröter S. Stock C. Bach T. Tetrahedron  2005,  61:  2245 
• 17b Schnürch M. Flasik R. Khan AF. Spina M. Mihovilovic MD. Stanetty P. Eur. J. Org. Chem.  2006,  3283 
• For Suzuki-Miyaura reactions of bis(triflates) from our laboratory, see, for example:
• 18a Methyl 2,5-dihydroxy-benzoate: Nawaz M. Ibad MF. Abid O.-U.-R.
  Khera RA. Villinger A. Langer P. Synlett  2010,  150 
• 18b Alizarin: Mahal A. Villinger A. Langer P. Synlett  2010,  1085 
• 18c 3,4-Dihydroxybenzophenone: Nawaz M. Khera RA. Malik I. Ibad MF. Abid O.-UR. Villinger A. Langer P. Synlett  2010,  979 
• 18d Phenyl 1,4-dihydroxynaphthoate: Abid O.-U.-R. Ibad MF. Nawaz M. Ali A. Sher M. Rama NH. Villinger A. Langer P. Tetrahedron Lett.  2010,  51:  1541 
• 25 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 

19

Synthesis of 11-Oxo-11 H -benzo[ b ]fluorene-5,10-diyl Bis(trifluoromethanesulfonate) (2): To a solution of 1 (2.0 g, 7.6 mmol) in CH₂Cl₂ (80 mL) was added pyridine (2.5 mL, 30.5 mmol), at 20 ˚C under an argon atmosphere. After stirring for 10 min, Tf₂O (3.0 mL, 18 mmol) was added at -78 ˚C. The mixture was allowed to warm to 20 ˚C and stirred overnight. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by chromatography (flash silica gel, heptanes-EtOAc) without aqueous work up to give 2 as a yellow solid (3.5 g, 88%); mp 186-188 ˚C. ^¹H NMR (300 MHz, CDCl₃): δ = 7.43 (t, 1 H, J = 7.7 Hz, ArH), 7.59-7.79 (m, 4 H, ArH), 8.01 (t, 2 H, J = 8.0 Hz, ArH), 8.10 (d, 1 H, J = 8.3 Hz, ArH). ^¹9F NMR (282.4 MHz, CDCl₃): δ = -72.29, -72.3. ^¹³C NMR (75.5 MHz, CDCl₃): δ = 118.6 (q, J _F,C = 320.5 Hz, CF₃), 118.7 (q, J _F,C = 321.4 Hz, CF₃), 122.8, 124.0, 125.36 (CH), 128.2 (C), 129.4, 131.2, 131.3 (CH), 132.0, 135.7 (C), 135.9 (CH), 136.8, 140.2, 141.2 (C), 187.2 (CO). IR (KBr): 3085, 2926, 2854 (w), 1721 (m), 1635, 1600, 1591, 1581, 1516, 1466 (w), 1435, 1405 (m), 1391, 1337, 1289, 1274, 1241 (w), 1203 (s), 1173 (m), 1128 (s), 1082 (m), 1043 (w), 1011, 975 (m), 891 (s), 865, 814, 782 (m), 760, 747, 722 (s), 688 (m), 662, 651, 638 (w), 621, 595, 590 (s), 570, 528 (m) cm^-¹. GC-MS (EI, 70 eV): m/z (%) = 526 (53) [M⁺], 393 (77), 329 (99), 301 (100). HRMS (EI, 70 eV): m/z calcd for C₁₉H₈O₇S₂F₆: 525.96101; found: 525.961568

20

General Procedure for Suzuki-Miyaura Reactions: A 1,4-dioxane solution (4-5 mL/0.3 mmol of 2) of K₃PO₄ (1.5-2.0 equiv), Pd(PPh₃)₄ (3 mol% per cross-coupling) and arylboronic acid 3 (1.0-1.1 equiv per cross-coupling) was stirred at 60-90 ˚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.

21

Synthesis of 5,10-Bis(4-methoxyphenyl)-11 H -benzo[ b ]-fluoren-11-one (4a): Starting with 2 (150 mg, 0.28 mmol), 4-methoxyphenylboronic acid (3a; 96 mg, 0.63 mmol), Pd(PPh₃)₄ (19 mg, 6 mol%), K₃PO₄ (178 mg, 0.84 mmol) and 1,4-dioxane (5 mL), 4a was isolated as a yellow solid (100 mg, 80%); mp 243-245 ˚C. ^¹H NMR (300 MHz, CDCl₃): δ = 3.85 (s, 3 H, OMe), 3.90 (s, 3 H, OMe), 6.31-6.36 (m, 1 H, ArH), 7.02 (d, 2 H, J = 8.4 Hz, ArH), 7.07-7.12 (m, 4 H, ArH), 7.25-7.31 (m, 5 H, ArH), 7.35 (td, 1 H, J = 1.4, 8.1 Hz, ArH), 7.43-7.46 (m, 1 H, ArH), 7.50-7.58 (m, 1 H, ArH), 7.63-7.66 (m, 1 H, ArH). ^¹³C NMR (75.5 MHz, CDCl₃): δ = 55.3, 55.4 (OMe), 113.6, 114.8, 123.8, 123.9, 126.5, 127.1 (CH), 127.8, 128.4 (C), 128.5, 129.0 (CH), 129.8 (C), 130.9, 131.0 (CH), 133.9, 134.0 (C), 134.3 (CH), 135.8, 136.8, 137.2, 140.5, 144.5, 159.4, 159.6 (C), 192.6 (CO). IR (KBr): 3064, 2997, 2952, 2929, 2849, 2831 (w), 1704 (s), 1606, 1589 (m), 1579 (w), 1510 (s), 1462, 1441, 1410, 1361, 1335, 1311 (w), 1286 (m), 1243 (s), 1215, 1191 (m), 1173 (s), 1107, 1086, 1048 (w), 1034, 1026 (m), 1005 (w), 963 (m), 932, 899 (w), 870, 830, 805, 791 (m), 759, 727 (s), 693, 681, 655, 633 (w), 623, 596 (m), 573 (w), 559, 531 (m) cm^-¹. GC-MS (EI, 70 eV): m/z (%) = 442 (100) [M⁺], 441 (28), 411 (6), 326 (5). HRMS (EI, 70 eV): m/z calcd for C₃₁H₂₂O₃: 442.15635; found: 442.155487.

22

Synthesis of 10-(3,4-Dimethoxyphenyl)-11-oxo-11 H -benzo[ b ]fluoren-5-yl Trifluoromethanesulfonate (5g): Starting with 2 (150 mg, 0.28 mmol), 3,4-dimethoxy-phenylboronic acid (3g; 56 mg, 0.3 mmol), Pd(PPh₃)₄ (10 mg, 3 mol%), K₃PO₄ (119 mg, 0.56 mmol) and 1,4-dioxane (5 mL), 5g was isolated as a yellow solid (129 mg, 88%); mp 221-222 ˚C. ^¹H NMR (300 MHz, CDCl₃): δ = 3.79 (s, 3 H, OMe), 3.92 (s, 3 H, OMe), 6.79-6.85 (m, 2 H, ArH), 6.97 (d, 1 H, J = 8.2 Hz, ArH), 7.33 (td, 1 H, J = 0.8, 7.4 Hz, ArH), 7.39-7.44 (m, 1 H, ArH), 7.53-7.68 (m, 4 H, ArH), 8.02 (d, 2 H, J = 7.8 Hz, ArH). ^¹9F NMR (282.4 MHz, CDCl₃): δ =
-72.47. ^¹³C NMR (75.5 MHz, CDCl₃): δ = 55.9, 56.0 (OMe), 110.9, 112.9 (CH), 118.7 (q, J _F,C = 321.6 Hz, CF₃), 122.1, 124.5, 125.0 (CH), 126.6 (C), 128.0 (CH), 129.4 (C), 129.5, 129.9 (CH), 130.3 (C), 130.4 (CH), 130.9 (C), 135.1 (CH), 135.7, 136.5, 137.7, 140.3, 141.5, 148.8, 149.2 (C), 190.3 (CO). IR (KBr): 3076, 3012, 2966, 2939, 2919, 2838, 2249 (w), 1718 (s), 1623, 1600, 1579 (w), 1517, 1511 (m), 1468, 1448 (w), 1404 (s), 1374, 1345, 1334, 1319, 1297, 1255 (w), 1215 (s), 1172 (m), 1134 (s), 1090, 1054 (w), 1020 (m), 998 (s), 963 (m), 913 (w), 892 (m), 866 (w), 817, 804 (s), 788, 777 (w), 758 (s), 745 (w), 722 (s), 687 (m), 665 (w), 653, 647 (m), 629, 611 (s), 589, 559 (w) cm^-¹. GC-MS (EI, 70 eV): m/z (%) = 514 (28) [M⁺], 381 (100), 353 (4). HRMS (EI, 70 eV): m/z calcd for C₂₆H₁₇O₆F₃S: 514.06925; found: 514.070130.

23

Synthesis of 5-(3,5-Dimethylphenyl)-10-(4-methoxyphenyl)-11 H -benzo[ b ]fluoren-11-one (6a): Starting with 2 (150 mg, 0.28 mmol), 4-methoxy-phenylboronic acid (3a; 43 mg, 0.28 mmol), Pd(PPh₃)₄ (10 mg, 3 mol%), K₃PO₄ (119 mg, 0.56 mmol), 1,4-dioxane (5 mL), and 3,5-dimethylphenylboronic acid (3d; 46 mg, 0.31 mmol), 6a was isolated as a yellow solid (90 mg, 72%); mp 220-222 ˚C. ^¹H NMR (300 MHz, CDCl₃): δ = 2.36 (s, 6 H, 2 × Me), 3.85 (s, 3 H, OMe), 6.27-6.33 (m, 1 H, ArH), 6.98 (br s, 2 H, ArH), 7.02 (d, 2 H, J = 8.8 Hz, ArH), 7.08-7.14 (m, 3 H, ArH), 7.26 (d, 2 H, J = 8.8 Hz, ArH), 7.27-7.30 (m, 1 H, ArH), 7.34 (td, 1 H, J = 1.3, 8.2 Hz, ArH), 7.43-7.46 (m, 1 H, ArH), 7.50-7.53 (m, 1 H, ArH), 7.63-7.66 (m, 1 H, ArH). ^¹³C NMR (75.5 MHz, CDCl₃): δ = 21.5 (2 × Me), 55.3 (OMe), 113.6, 123.8, 123.9, 126.5, 127.3, 127.4 (CH), 127.8, 128.4 (C), 128.5, 128.9, 129.8, 131.0 (CH), 134.0 (C), 134.4 (CH), 134.5, 135.2, 136.7, 136.8, 137.6, 139.9, 140.4, 144.5, 159.4 (C), 192.6 (CO). IR (KBr): 3068, 3000, 2955, 2923, 2852 (w), 1703, 1695, 1598, 1505 (s), 1466, 1435, 1423, 1363, 1336, 1311, 1302, 1287, 1259 (w), 1244 (s), 1202 (m), 1172 (s), 1130, 1105, 1087, 1049 (w), 1029, 998 (m), 969, 950, 939, 926, 906 (w), 873 (m), 848, 834 (w), 826, 790, 778 (m), 761 (s), 742 (w), 724 (s), 710, 703, 680, 661, 631 (w), 613, 595 (m), 579 (w), 562, 538 (m) cm^-¹. GC-MS (EI, 70 eV): m/z (%) = 440 (100) [M⁺], 409 (6), 396 (4). HRMS (ESI⁺): m/z [M + H]⁺ calcd for C₃₂H₂₄O₂: 440.17708; found: 440.176873.

24

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