Synthesis of Flavonoid/Chromonoid–β-d-Ribofuranose Derivatives by Palladium-Catalyzed Cross-Coupling Reactions

Dedicated to the memory of Professor Tamás Patonay.

Abstract

Structurally novel carbohydrate–flavone and –chromone derivatives with an unsaturated carbon bridge were synthesized by a phosphine-free palladium-catalyzed cross-coupling reaction.

Key words

cross-coupling - catalysis - palladium - Mizoroki–Heck reaction - isomerism

• References

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• 16 Flavone–Ribose Derivatives: General Procedures Conditions A (Jeffery’s Conditions): A stirred mixture of bromoflavone 1a or 1b (75 mg, 0.249 mmol), allyl derivative 2a or 2b (0.249 mmol, 1.0 equiv), K₂CO₃ (52 mg, 0.375 mmol, 1.5 equiv), KCl (19 mg, 0.250 mmol, 1.0 equiv), TBAB (162 mg, 0.500 mmol, 2.0 equiv), and Pd(OAc)₂ (4 mg, 0.015 mmol, 6 mol%) in anhyd DMF (5 mL) was heated at 110 °C for 2 h under N₂. The mixture was cooled, silica gel was added, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography. Condition B (Classic Mizoroki–Heck Conditions): A stirred mixture of bromoflavone 1a or 1b (75 mg, 0.249 mmol), allyl derivative 2a (0.249 mmol, 1.0 equiv), Et₃N (39 μL, 0.274 mmol, 1.1 equiv), Ph₃P (7 mg, 0.025 mmol, 10 mol%), and Pd(OAc)₂ (4 mg, 0.015 mmol, 6 mol%) in anhyd DMF (5 mL) was heated at 110 °C for 2 h under N₂. The mixture was cooled, silica gel was added, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography. 7-[(1E)-3-{(2S,3S,4R,5R)-3,4-Bis(benzyloxy)-5-[(benzyloxy)-methyl]tetrahydrofuran-2-yl}prop-1-en-1-yl]-2-phenyl-4H-chromen-4-one (3a) White crystals; mp 126–127 °C; yield (conditions A): 147 mg (89%); yield (conditions B): 104 mg (63%). IR (KBr): 2922, 2903, 2856, 1639, 1624, 1450, 1372, 1101, 697 cm^–1. ¹H NMR (360 MHz, CDCl₃): δ = 2.45–2.63 (m, 2 H), 3.52 (m, 2 H), 3.66 (t, J = 6.1 Hz, 1 H), 3.93 (t, J = 4.6 Hz, 1 H), 4.21 (m, 2 H), 4.42–4.64 (m, 6 H), 6.44 (s, 2 H), 6.80 (s, 1 H), 7.29 (m, 15 H), 7.39 (s, 1 H), 7.52 (m, 4 H), 7.90 (m, 2 H), 8.10 (d, J = 8.2 Hz, 1 H). ¹³C NMR (90 MHz, CDCl₃): δ = 36.7, 70.3, 71.7, 72.0, 73.3, 79.8, 80.0, 81.6, 107.6, 114.9, 122.5, 123.1, 125.6, 126.2, 127.4, 127.6, 127.7, 128.0, 128.1, 128.3, 128.9, 130.5, 130.7, 131.4, 131.8, 137.7, 138.0, 143.2, 156.5, 163.2, 178.1. Anal. Calcd for C₄₄H₄₀O₆: C, 79.50; H, 6.06. Found: C, 79.54; H, 6.10. 6-[(1E)-3-{(2S,3S,4R,5R)-3,4-Bis(benzyloxy)-5-[(benzyloxy)-methyl]tetrahydrofuran-2-yl}prop-1-en-1-yl]-2-phenyl-4H-chromen-4-one (4a) White crystals; mp 89–90 °C; yield (conditions A): 152 mg (92%). IR (KBr): 3029, 2875, 1639, 1614, 1451, 1360, 1097, 731, 697 cm^–1. ¹H NMR (360 MHz, CDCl₃): δ = 2.52–2.59 (m, 2 H), 3.52 (m, 2 H), 3.66 (t, J = 5.8 Hz, 1 H), 3.91 (t, J = 4.6 Hz, 1 H), 4.15–4.22 (m, 2 H), 4.43–4.62 (m, 6 H), 6.25–6.34 (m, 1 H), 6.37–6.48 (m, 1 H), 6.79 (s, 1 H), 7.28 (m, 14 H), 7.43 (t, J = 6.6 Hz, 1 H), 7.50 (m, 4 H), 7.59 (d, J = 6.6 Hz, 1 H), 7.90 (m, 2 H), 8.08 (s, 1 H). ¹³C NMR (90 MHz, CDCl₃): δ = 36.7, 70.2, 71.7, 71.9, 73.3, 77.1, 79.8, 80.1, 81.3, 107.3, 118.1, 122.6, 123.7, 126.1, 127.4, 127.6, 127.6, 127.7, 127.9, 128.2, 128.7, 128.9, 130.5, 131.0, 131.4, 131.6, 134.7, 137.6, 137.7, 138.7, 155.2, 163.1, 178.2. Anal. Calcd for C₄₄H₄₀O₆: C, 79.50; H, 6.06. Found: C, 79.55; H, 6.08. 6-[(1E)-3-{(2S,4S,5R)-4-(Benzyloxy)-5-[(benzyloxy)methyl]-tetrahydrofuran-2-yl}prop-1-en-1-yl]-2-phenyl-4H-chromen-4-one (4b) White crystals; mp 82–83 °C; yield (conditions A): 104 mg (75%). IR (KBr): 3059, 3030, 2902, 2876, 1650, 1615, 1453, 1360, 1097, 741, 698 cm^–1. ¹H NMR (360 MHz, CDCl₃): δ = 1.67–1.80 (m, 2 H), 2.43–2.61 (m, 2 H), 3.46–3.59 (m, 2 H), 4.00–4.04 (m, 1 H), 4.15–4.17 (m, 1 H), 4.23–4.29 (m, 1 H), 4.50 (s, 2 H), 4.56 (s, 2 H), 6.29–6.36 (m, 1 H), 6.49–6.53 (m, 1 H), 6.79 (s, 1 H), 7.31 (m, 8 H), 7.45 (m, 4 H), 7.67 (d, J = 8.7 Hz, 1 H), 7.89 (m, 2 H), 8.12 (d, J = 7.2 Hz, 1 H). ¹³C NMR (90 MHz, CDCl₃): δ = 37.6, 38.6, 70.9, 73.3, 73.3, 78.1, 81.0, 83.5, 107.3, 118.1, 122.5, 123.7, 126.1, 127.5, 128.1, 128.2, 128.7, 128.9, 130.4, 131.2, 131.5, 131.6, 134.8, 138.0, 138.1, 155.2, 163.1, 178.3. Anal. Calcd for C₃₇H₃₄O₅: C, 79.55; H, 6.13; H, 6.06. Found: C, 79.57; H, 6.09. 3-[(1E)-3-{(2S,3S,4R,5R)-3,4-Bis(benzyloxy)-5-[(benzyloxy)-methyl]tetrahydrofuran-2-yl}prop-1-en-1-yl]-2-phenyl-4H-chromen-4-one (6a) Colorless oil; yield (conditions A): 55 mg (40%). IR (KBr): 3059, 3027, 2919, 2896, 2880, 1648, 1631, 1612, 1467, 1396, 1104, 762, 696 cm^–1. ¹H NMR (360 MHz, CDCl₃): δ = 2.33–2.43 (m, 2 H), 3.52 (m, 2 H), 3.69 (t, J = 5.4 Hz, 1 H), 3.87 (t, J = 5.2 Hz, 1 H), 4.15 (m, 2 H), 4.48–4.57 (m, 6 H), 6.10 (d, J = 15.8 Hz, 1 H), 6.91 (m, 1 H), 7.24 (m, 15 H), 7.44 (m, 6 H), 7.64 (m, 2 H), 8.26 (d, J = 7.6 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 28.7, 70.5, 72.2, 73.4, 77.8, 77.9, 81.4, 81.5, 81.9, 118.0, 119.6, 123.0, 124.9, 125.8, 127.6, 127.7, 127.9, 128.1, 128.3, 128.4, 128.6, 129.9, 130.4, 131.4, 133.2, 133.6, 138.1, 138.3, 156.2, 162.4, 177.9. Anal. Calcd for C₄₄H₄₀O₆: C, 79.50; H, 6.06. Found: C, 79.55; H, 6.09. 3-[(1E)-3-{(2S,4S,5R)-4-(Benzyloxy)-5-[(benzyloxy)-methyl]tetrahydrofuran-2-yl}prop-1-en-1-yl]-2-phenyl-4H-chromen-4-one (6b) Colorless oil; yield (conditions A): 29 mg (21%). IR (KBr): 2954, 2923, 2853, 1637, 1465, 1315, 1097, 758, 696 cm^–1. ¹H NMR (360 MHz, CDCl₃): δ = 1.61–1.68 (m, 1 H), 2.06 (dd, J = 13.1, 4.9 Hz, 1 H), 2.31–2.52 (m, 2 H), 3.41–3.55 (m, 2 H), 3.99–4.01 (m, 1 H), 4.08–4.10 (m, 1 H), 4.16–4.19 (m, 1 H), 4.49 (s, 2 H), 4.54 (s, 2 H), 6.16 (d, J = 15.8 Hz, 1 H), 6.79–6.84 (m, 1 H), 7.29 (m, 8 H), 7.38 (m, 5 H), 7.47 (m, 2 H), 7.56 (m, 3 H), 8.26 (d, J = 8.1 Hz, 1 H). ¹³C NMR (90 MHz, CDCl₃): δ = 37.5, 39.9, 70.9, 71.0, 73.3, 78.2, 81.2, 83.4, 117.7, 117.9, 123.1, 123.5, 124.9, 126.2, 126.3, 127.6, 128.3, 129.0, 129.7, 130.4, 133.2, 133.3, 138.2, 155.5, 162.0, 177.5. Anal. Calcd for C₃₇H₃₄O₅: C, 79.55; H, 6.13; H, 6.06. Found: C, 79.58; H, 6.15. Chromone–Ribose Derivatives; General Procedure A stirred mixture of bromochromone 8a or 8b (56 mg, 0.249 mmol), allyl derivative 2a or 2b (0.249 mmol, 1.0 equiv), K₂CO₃ (52 mg, 0.375 mmol, 1.5 equiv), KCl (19 mg, 0.250 mmol, 1.0 equiv), TBAB (162 mg, 0.500 mmol, 2.0 equiv), and Pd(OAc)₂ (4 mg, 0.015 mmol, 6 mol%) in dry DMF (5 mL) was heated at 110 °C for 2 h under N₂. The mixture was cooled, silica gel was added, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography. 7-[(1E)-3-{(2S,3S,4R,5R)-3,4-Bis(benzyloxy)-5-[(benzyl­oxy)methyl]tetrahydrofuran-2-yl}prop-1-en-1-yl]-4H-chromen-4-one (9a) Colorless oil; yield: 115 mg (79%). IR (KBr): 3063, 3029, 2901, 2865, 1654, 1621, 1430, 1127, 1027, 736, 698 cm^–1. ¹H NMR (360 MHz, CDCl₃): δ = 2.43–2.57 (m, 2 H), 3.50 (m, 2 H), 3.61–3.66 (m, 1 H), 3.90 (m, 1 H), 4.19 (m, 2 H), 4.44–4.62 (m, 6 H), 6.24 (d, J = 5.9 Hz, 1 H), 6.38 (m, 2 H), 7.27 (m, 17 H), 7.72 (d, J = 5.9 Hz, 1 H), 8.05 (d, J = 8.2 Hz, 1 H). ¹³C NMR (90 MHz, CDCl₃): δ = 36.5, 70.1, 71.5, 71.7, 73.2, 76.8, 79.7, 79.9, 81.4, 112.7, 114.8, 122.8, 123.2, 125.5, 127.3, 127.4, 127.5, 127.6, 127.8, 127.9, 128.1, 130.4, 137.5, 137.6, 137.8, 137.9, 143.0, 155.0, 156.6, 177.0. Anal. Calcd for C₃₈H₃₆O₆: C, 77.53; H, 6.16. Found: C, 77.58; H, 6.19. 3-[(1E)-3-{(2S,3S,4R,5R)-3,4-Bis(benzyloxy)-5-[(benzyl­oxy)methyl]tetrahydrofuran-2-yl}prop-1-en-1-yl]-4H-chromen-4-one (12a) Colorless oil; yield: 73 mg (50%). IR (KBr): 3063, 3029, 2901, 2865, 1654, 1621, 1430, 1127, 1027, 736, 698 cm^–1. ¹H NMR (360 MHz, CDCl₃): δ = 2.16–2.56 (m, 2 H), 3.53 (m, 2 H), 3.68 (t, J = 5.6 Hz, 1 H), 3.89 (t, J = 4.9 Hz, 1 H), 4.16 (m, 2 H), 4.48–4.61 (m, 6 H), 6.32 (d, J = 15.8 Hz, 1 H), 6.47 (m, 1 H), 7.28 (m, 15 H), 7.40 (m, 2 H), 7.64 (t, J = 7.2 Hz, 1 H), 7.76 (s, 1 H), 8.24 (d, J = 7.9 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 37.4, 70.3, 71.7, 72.0, 73.3, 77.1, 79.3, 80.5, 81.2, 117.9, 121.9, 122.4, 124.0, 124.9, 126.1, 127.5, 127.6, 127.8, 128.0, 128.3, 128.4, 128.9, 133.3, 137.8, 138.1, 151.9, 155.8, 176.4. Anal. Calcd for C₃₈H₃₆O₆: C, 77.53; H, 6.16. Found: C, 77.58; H, 6.18. 3-[(2E)-3-{(2S,3S,4R,5R)-3,4-Bis(benzyloxy)-5-[(benzyloxy)methyl]tetrahydrofuran-2-yl}prop-2-en-1-yl]-4H-chromen-4-one (13a) Colorless oil; yield: 26 mg (18%). IR (KBr): 2924, 2856, 1718, 1646, 1609, 1464, 1126, 1100, 751, 698 cm^–1. ¹H NMR (360 MHz, CDCl₃): δ = 3.22 (m, 2 H), 3.51–3.52 (m, 2 H), 3.66 (t, J = 6.1 Hz, 1 H), 3.91 (t, J = 4.9 Hz, 1 H), 4.00–4.21 (m, 2 H), 4.44–4.61 (m, 6 H), 5.56 (dd, J = 15.3, 7.3 Hz, 1 H), 5.94 (dt, J = 15.3, 6.8 Hz, 1 H), 7.28 (m, 15 H), 7.35 (m, 2 H), 7.65 (m, 2 H), 8.22 (d, J = 7.2 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 29.8, 70.4, 72.0, 72.2, 73.5, 77.5, 81.4, 81.5, 81.6, 118.1, 123.0, 123.8, 125.0, 126.0, 127.7, 127.8, 127.8, 128.0, 128.1, 128.3, 128.4, 130.2, 131.5, 133.5, 138.0, 138.9, 152.8, 156.5, 177.5. Anal. Calcd for C₃₈H₃₆O₆: C, 77.53; H, 6.16. Found: C, 77.55; H, 6.19.