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

On Ying Yuen; Wai Hang Pang; Xiangmeng Chen; Zicong Chen; Fuk Yee Kwong; Chau Ming So

doi:10.1055/s-0037-1611742

Synlett, Table of Contents

Synlett 2019; 30(06): 731-737
DOI: 10.1055/s-0037-1611742

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

On Ying Yuen

^aDepartment of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong SAR, P. R. of China

,

Wai Hang Pang

^aDepartment of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong SAR, P. R. of China

,

Xiangmeng Chen

^aDepartment of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong SAR, P. R. of China

,

Zicong Chen

^aDepartment of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong SAR, P. R. of China

,

Fuk Yee Kwong

^aDepartment of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong SAR, P. R. of China

,

Chau Ming So *

^aDepartment of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong SAR, P. R. of China

^bThe Hong Kong Polytechnic University, Shenzhen Research Institute, No. 18 Yuexing 1st Rd, South Area, Hi-tech Park, Nanshan, Shenzhen 518057, P. R. of China Email: bccmso@polyu.edu.hk

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Abstract

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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

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References

References and Notes

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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.

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