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.

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

References and Notes

1a Römpp Lexikon Naturstoffe   Steglich W. Fugmann B. Lang-Fugmann S. Thieme; Stuttgart: 1997. 

1b Harborne JB. Baxter H. The Handbook of Natural Flavonoids   Vol. 1:  John Wiley and Sons; Chichester: 1999. 

1c Beecker GR. J. Nutr.  2003,  133:  3248S 

1d Havsteen BH. Pharmacol. Ther.  2002,  96:  67 

1e Middleton E. Kandaswami C. Theoharides TC. Pharmacol. Rev.  2000,  52:  672 

2a Daskiewies J. Depeint F. Viornery L. Bayet C. Geraldine C. Comte G. Gee J. Johnson I. Ndjoko K. Hostettmann K. Barron D. J. Med. Chem.  2005,  48:  2790 

2b Rao YK. Fang SH. Tzeng YM. Bioorg. Med. Chem.  2005,  13:  6850 

2c Wang SF. Jiang Q. Ye YH. Li Y. Tan RX. Bioorg. Med. Chem.  2005,  13:  4880 

2d Gao H. Kawabata J. Bioorg. Med. Chem.  2005,  13:  1661 

2e Gao GY. Li DJ. Keung WM. J. Med. Chem.  2001,  44:  3320 

3a Su B. Hackett JC. Diaz-Cruz ES. Kim YW. Brueggemeier RW. Bioorg. Med. Chem.  2005,  13:  6571 

3b Kim YW. Hackett JC. Brueggemeier RW. J. Med. Chem.  2004,  47:  4032 

3c Traxler P. Green J. Mett H. Sequin U. Furet P. J. Med. Chem.  1999,  42:  1018 

3d Cushman M. Zhu H. Geahlen RL. Kraker AJ.
J. Med. Chem.  1994,  37:  3353 

For reviews of cross-coupling reactions of polyhalogenated heterocycles, see:

4a Schröter S. Stock C. Bach T. Tetrahedron  2005,  61:  2245 

4b Schnürch M. Flasik R. Khan AF. Spina M. Mihovilovic MD. Stanetty P. Eur. J. Org. Chem.  2006,  3283 

5a Dang TT. Dang TT. Ahmad R. Reinke H. Langer P. Tetrahedron Lett.  2008,  49:  1698 

5b Dang TT. Villinger A. Langer P. Adv. Synth. Catal.  2008,  350:  2109 

5c Hussain M. Nguyen TH. Langer P. Tetrahedron Lett.  2009,  50:  3929 

5d Tengho Toguem S.-M. Hussain M. Malik I. Villinger A. Langer P. Tetrahedron Lett.  2009,  50:  4962 

5e Dang TT. Dang TT. Rasool N. Villinger A. Langer P. Adv. Synth. Catal.  2009,  351:  1595 

6a Miyaura N. Suzuki A. Chem. Rev.  1995,  95:  2457 

6b Miyaura N. Top. Curr. Chem.  2002,  219:  11 

7 Nawaz M. Ibad MF. Obaid-Ur-Rahman A. Khera RA. Villinger A. Langer P. Synlett  2010,  150 

8a Zembower D. Zhang H. J. Org. Chem.  1998,  63:  9300 

8b Zheng X. Meng W. Qing F. Tetrahedron Lett.  2004,  45:  8083 

8c Huang X. Tang E. Xu WM. Cao J. J. Comb. Chem.  2005,  7:  802 

8d Peng W.-J. Han X.-W. Yu B. Chin. J. Chem.  2006,  24:  1154 

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.

10

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.

14

CCDC-781627 contains 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].

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