Synthesis of Flavone Derivatives through Versatile Palladium-Catalyzed Cross-Coupling Reactions of Tosyloxy- and Mesyloxyflavones

Abstract

Tosyloxy- and mesyloxyflavones derived from abundant and biologically important hydroxyflavones were used to synthesize a series of functionalized flavones through versatile palladium-catalyzed cross-coupling reactions. A Pd(OAc)₂/2-[2-(dicyclohexylphosphino)phenyl]-1-methyl-1H-indole system effectively catalyzed the reactions of a broad range of tosyloxy- and mesyloxyflavones as electrophilic coupling partners with various nucleophiles to give the corresponding products in good to excellent yields. Catalyst loadings of as little as 0.1 mol% Pd were successfully used. Importantly, we demonstrated that this protocol provided a significantly improved efficiency in the synthesis of a potential chromen-4-one-based analogue of a potent inhibitor of DNA-dependent protein kinase.

Key words

palladium catalysis - phosphine ligands - cross-coupling reactions - tosylates - mesylates - flavones

• References and Notes

• 1a Hodnick WF, Roettger WJ, Kung FS, Bohmant CW, Pardini RS. In Plant Flavonoids in Biology and Medicine . Liss AR. National Academy Press; Washington: 1986
• 1b Cushman M, Zhu H, Geahlen RL, Kraker AJ. J. Med. Chem. 1994; 37: 3353
• 1c Huck CW, Huber CG, Ongania K.-H, Bonn GK. J. Chromatogr. A 2000; 870: 453
• 1d Kim Y.-W, Hackett JC, Brueggemeier RW. J. Med. Chem. 2004; 47: 4032
• 1e Haghiac M, Walle T. Nutr. Cancer 2005; 53: 220
• 1f Pushpavalli G, Kalaiarasi P, Veeramani C, Pugalendi KV. Eur. J. Pharmacol. 2010; 631: 36
• 1g Singh M, Kaur M, Silakari O. Eur. J. Med. Chem. 2014; 84: 206
• 1h Nile SH, Keum YS, Nile AS, Jalde SS, Patel RV. J. Biochem. Mol. Toxicol. 2018; 32: e22002
• 2a Schreiber SL. Science 2000; 287: 1964
• 2b Burker MD, Schreiber SL. Angew. Chem. Int. Ed. 2004; 43: 46
• 2c Shimokawa J. Tetrahedron Lett. 2014; 55: 6156
• 3 Climent MJ, Corma A, Iborra S, Primo J. J. Catal. 1995; 151: 60
• 4a Mahal HS, Venkataraman K. J. Chem. Soc. 1934; 1767
• 4b Baker W. J. Chem. Soc. 1933; 1381
• 5 Sarda SR, Pathan MY, Paike VV, Pachmase PR, Jadhav WN, Pawar RP. ARKIVOC 2006; (xvi): 43
• 6 Allan J, Robinson R. J. Chem. Soc., Trans. 1924; 125: 2192
• 7 Su WK, Zhu XY, Li ZH. Org. Prep. Proced. Int. 2009; 41: 69
• 8 Das J, Ghosh S. Tetrahedron Lett. 2011; 52: 7189
• 9a Hassan J, Sévignon M, Gozzi C, Schulz E, Lemaire M. Chem. Rev. 2002; 102: 1359
• 9b Metal-Catalyzed Cross-Coupling Reactions . de Meijere A, Diederich F. Wiley-VCH; Weinheim: 2004. 2nd ed., Vols. 1 and 2
• 9c Corbet J.-P, Mignani G. Chem. Rev. 2006; 106: 2651
• 9d Palladium-Catalyzed Coupling Reactions: Practical Aspects and Future Developments. Molnár Á. Wiley-VCH; Weinheim: 2013
• 9e Metal-Catalyzed Cross-Coupling Reactions and More . Vols. 1–3. de Meijere A, Bräse S, Oestreich M. Wiley-VCH; Weinheim: 2014
• 9f New Trends in Cross-Coupling: Theory and Applications. Calacot TJ. RSC; Cambridge: 2015
• 10 Deng B.-L, Lepoivre JA, Lemière G. Eur. J. Org. Chem. 1999; 2683
• 11 Pal M, Dakarapu R, Parasuraman K, Subramania V, Yeleswarapu KR. J. Org. Chem. 2005; 70: 7179
• 12 Fitzmaurice RJ, Etheridge ZC, Jumel E, Woolfson DN, Caddick S. Chem. Commun. 2006; 4814
• 13a Eleya N, Malik I, Reimann S, Wittler K, Hein M, Patonay T, Villinger A, Ludwig R, Langer P. Eur. J. Org. Chem. 2012; 1639
• 13b Akrawi OA, Patonay T, Kónya K, Langer P. Synlett 2013; 24: 860
• 13c Kónya K, Paitás D, Kiss-Szikszai A, Patonay T. Eur. J. Org. Chem. 2015; 828
• 13d Paitás D, Kónya K, Kiss-Szikszai A, Džubák P, Pethő Z, Varga Z, Panyi G, Patonay T. J. Org. Chem. 2017; 82: 4578
• 13e Jordán S, Paitás D, Patonay T, Langer P, Kónya K. Synthesis 2017; 49: 1983
• 14 The commercial availability of 7-bromoflavone is far less than that of 7-hydroxyflavone.
• 15 According to the 2018 Aldrich Catalog: mesyl chloride ($173.5/1 L), tosyl chloride ($85.1/1 kg), triflic anhydride ($1620/1 kg).
• 16a Yu D.-G, Li B.-J, Shi Z.-J. Acc. Chem. Res. 2010; 43: 1486
• 16b Kozhushkov SI, Potukuchi HK, Ackermann L. Catal. Sci. Technol. 2013; 3: 562
• 16c Zeng H, Qiu Z, Domínguez-Huerta A, Hearne Z, Chen Z, Li C.-J. ACS Catal. 2017; 7: 510
• 17a So CM, Lau CP, Kwong FY. Org. Lett. 2007; 9: 2795
• 17b So CM, Yeung CC, Lau CP, Kwong FY. J. Org. Chem. 2008; 73: 7803
• 17c So CM, Chow WK, Choy PY, Lau CP, Kwong FY. Chem. Eur. J. 2010; 16: 7996
• 17d So CM, Kwong FY. Chem. Soc. Rev. 2011; 40: 4963
• 17e Chung KH, So CM, Wong SM, Luk CH, Zhou Z, Lau CP, Kwong FY. Chem. Commun. 2012; 48: 1967
• 17f Fu WC, So CM, Chow WK, Yuen OY, Kwong FY. Org. Lett. 2015; 17: 4612
• 17g Yuen OY, So CM, Man HW. Kwong F. Y. Chem. Eur. J. 2016; 22: 6471
• 18 Hardcastle IR, Cockcroft X, Curtin NJ, Dessage El-Murr M, Leahy JJ. J, Stockley M, Golding BT, Rigoreau L, Richardson C, Smith GC. M, Griffin RJ. J. Med. Chem. 2005; 48: 7829
• 19 Suzuki–Miyaura Coupling of Tosyloxy- or Mesyloxyflavones; General Procedure A Schlenk tube containing a Teflon-coated magnetic stirrer bar was charged with Pd(OAc)₂ (2.24 mg, 0.010 mmol) and CM-Phos (Pd/L = 1:4). The tube was then evacuated and flushed with N₂ three times. Precomplexation was conducted by adding freshly distilled CH₂Cl₂ (1.0 mL) and Et₃N (0.1 mL) to the tube. The solution was stirred and placed in a preheated oil bath at 50 °C for 1–2 min until the solvent started boiling. The solvent was then evaporated under high vacuum. The appropriate tosyloxy- or mesyloxyflavone (0.5 mmol), arylboronic acid (1.0 mmol), and K₃PO₄·H₂O (345 mg, 1.5 mmol) or K₃PO₄ (318 mg, 1.5 mmol) were then added to the tube, which was evacuated and flushed with N₂three times. t-BuOH (1.5 mL) was added, the tube was sealed, and the mixture was stirred at r.t. for 1 min. The tube was then placed in a preheated oil bath at 110 °C for the time shown in Table 2. When the reaction was complete, the tube was allowed to cool to r.t. and EtOAc or CH₂Cl₂ (~10 mL) and H₂O (~3 mL) were added. The organic layer was subjected to GC analysis. The filtrate was concentrated under reduced pressure to give a crude product that was purified by flash column chromatography [silica gel (230–400 mesh)].6-[2-(Hydroxymethyl)phenyl]-2-phenyl-4H-chromen-4-one (3a) White solid; yield: 123 mg (75%); mp 157.6–161.5 °C; R_f  = 0.10 (EtOAc–hexane, 1:4). ¹H NMR (400 MHz, CD₂Cl₂): δ = 2.17 (br s, 1 H), 4.64 (s, 2 H), 6.85 (s, 1 H), 7.35–7.48 (m, 3 H), 7.57–7.63 (m, 4 H), 7.68 (d, J = 8.6 Hz, 1 H), 7.80–7.82 (m, 1 H), 8.00–8.03 (m, 2 H), 8.20 (d, J = 2.2 Hz, 1 H). ¹³C NMR (100 MHz, CD₂Cl₂): δ = 62.7, 107.4, 118.0, 123.6, 125.6, 126.3, 127.7, 128.1, 128.8, 129.0, 130.1, 131.6, 131.8, 135.0, 138.0, 138.5, 139.7, 155.5, 163.5, 178.1. MS (EI): m/z (%) = 326.4 (M+, 100), 298.3 (81), 196.2 (65), 168.2 (18), 139.2 (44). HRMS: m/z [M + H]⁺ calcd for C₂₂H₁₇O₃: 329.1172; found: 329.1181.
• 20 Palladium-Catalyzed Amination of Tosyloxy- and Mesyloxyflavones: General Procedure The Pd(OAc)₂–CM-Phos complex was prepared in a Schlenk tube as described above. The appropriate tosyloxy- or mesyloxyflavone (0.5 mmol), K₂CO₃ (172.5 mg, 1.25 mmol), and, if solid, the appropriate amine (0.75 mmol) and phenylboronic acid (2.44 mg, 0.02 mmol) were added to the tube, which was evacuated and flushed with N₂ three times again. t-BuOH (1.5 mL) and, if liquid, the appropriate amine (0.75 mmol) were added finally. The tube was sealed and the mixture was stirred at r.t. for 1 min. The tube was then placed in a preheated oil bath (110 °C) for the time indicated in Table 3. When the reaction was complete, the tube was allowed to cool to r.t. and EtOAc or CH₂Cl₂ (~10 mL) and H₂O (~3 mL) were added. The organic layer was subjected to GC analysis. The filtrate was concentrated under reduced pressure to give a crude product that was purified by flash column chromatography [silica gel (230–400 mesh)]. 2-Phenyl-6-(phenylamino)-4H-chromen-4-one (5a) Orange solid; yield: 146 mg (93%); This is a known compound. Melting point was not measured; R_f  = 0.80 (EtOAc–CH₂Cl₂, 1:4). ¹H NMR (400 MHz, CDCl₃): δ = 6.80 (s, 1 H), 6.99 (t, J = 7.3 Hz, 1 H), 7.13 (d, J = 7.6 Hz, 2 H), 7.28–7.32 (m, 2 H), 7.41–7.53 (m, 5 H), 7.81 (s, 1 H), 7.90–7.92 (m, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 106.8, 110.7, 118.5, 119.1, 122.0, 124.1, 124.8, 126.2, 129.0, 129.5, 131.4, 132.0, 141.2, 142.3, 151.0, 163.1, 178.2. MS (EI): m/z (%) = 312.4 (M⁺, 100), 207.2 (6), 154.2 (25), 128.2 (4), 78.2 (5).
• 21 7-Hept-1-yn-1-yl-2-phenyl-4H-chromen-4-one (6) The Pd(OAc)₂–CM-Phos complex was prepared in a Schlenk tube as described above. 7-Tosyloxyflavone (196.0 mg, 0.5 mmol) and K₃PO₄ (318.0 mg, 1.50 mmol) were added to the tube, which was evacuated and flushed with N₂ three times. Hept-1-yne (131.2 μL, 1.0 mmol) and t-BuOH (1.0 mL) were added, the tube was sealed, and the mixture was stirred at r.t. for 1 min then placed in a preheated oil bath (100 °C) for 18 h. When the reaction was complete, the tube was allowed to reach r.t., and EtOAc or CH₂Cl₂ (~10 mL) and H₂O (~3 mL) were added. The organic layer was subjected to GC analysis. The filtrate was concentrated under reduced pressure, and the crude product was purified by flash column chromatography [silica gel (230–400 mesh), EtOAc–hexane (1:4)] to give a light-orange solid; yield: 95 mg (60%); mp 105.4–106.4 °C; (R_f = 0.5). ¹H NMR (500 MHz, CDCl₃): δ = 0.94 (t, J =7.3 Hz, 3 H), 1.35–1.41 (m, 2 H), 1.42–1.48 (m, 2 H), 1.61–1.67 (m, 2 H), 2.45 (t, J = 7.2 Hz, 2 H), 6.79 (s, 1 H), 7.39 (d, J = 8.2 Hz, 1 H), 7.49–7.53 (m, 3 H), 7.57 (s, 1 H), 7.89 (d, J = 7.0 Hz, 2 H), 8.11 (d, J = 8.2 Hz, 1 H).¹³C NMR (1205 MHz, CDCl₃): δ = 13.9, 19.5, 22.2, 28.1, 31.1, 79.4, 95.1, 107.7, 120.7, 122.8, 125.4, 126.2, 128.5, 129.0, 129.9, 131.6, 155.9, 163.4, 177.9. MS (EI): m/z (%) = 316.1 (M⁺, 64), 301.1 (14), 287.1 (100), 273.1 (56), 261.1 (74), 231.1 (35). HRMS: m/z [M + H]⁺ calcd for C₂₂H₂₁O₂: 317.1536; found: 317.1539.