New Developments in the Synthesis of (E)-8-Styrylflavones

Abstract

A novel route for the synthesis of new (E)-8-styrylflavones is reported. This methodology involves the regio- and stereoselective Heck cross-coupling reaction of 8-iodoflavones and styrene derivatives. The Heck precursors, 8-iodoflavones, were obtained through an efficient regioselective one-pot oxidative cyclization–iodination reaction of (E)-2′-hydroxychalcones by applying the iodine/dimethyl sulfoxide system.

Keywords

palladium - Heck reaction - styrylflavones - iodoflavones - cyclodehydrogenation

• References and Notes

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• 33 Optimized Experimental Procedure for the Synthesis of 2′-Hydroxy-4′,6′-dimethoxyacetophenone K₂CO₃ (7.23 g, 52.32 mmol) and Me₂SO₄ (2.48 mL, 26.16 mmol) were added to a solution of 2′,4′,6′-trihydroxyacetophenone (1, 2.00 g, 11.89 mmol) in acetone (50 mL). The reaction mixture was refluxed for 20 min under nitrogen atmosphere. After that, K₂CO₃ was filtered off, the acetone evaporated, and the residue recrystallized in EtOH affording the 2′-hydroxy-4′,6′-dimethoxyacetophenone in good yield (82%, 1.91 g).
• 34 Physical Data of (E)-2′-Hydroxy-3,4,4′,6′-tetramethoxychalcone (3b) Yellow needles; mp 156–157 °C. ¹H NMR (300.13 MHz, CDCl₃): δ = 3.84 and 3.92 (2 s, 2 × 3 H, 4′- and 6′-OCH₃), 3.94 (s, 3 H, 4-OCH₃), 3.95 (s, 3 H, 3-OCH₃), 5.98 (d, 1 H, J = 2.3 Hz, H-5′), 6.12 (d, 1 H, J = 2.3 Hz, H-3′), 6.90 (d, 1 H, J = 8.4 Hz, H-5), 7.13 (d, 1 H, J = 1.8 Hz, H-2), 7.22 (dd, 1 H, J = 1.8, 8.4 Hz, H-6), 7.78 (AB, 1 H, J = 15.6 Hz, H-β), 7.83 (AB, 1 H, J = 15.6 Hz, H-α), 14.41 (s, 2′-OH, 1 H) ppm. ¹³C NMR (75.47 MHz, CDCl₃): δ = 55.6, 55.8, 55.9, and 56.0 (3-, 4-, 4′-, and 6′-OCH₃), 91.3 (C-5′), 93.8 (C-3′), 106.3 (C-1′), 110.4 (C-2), 111.2 (C-5), 122.6 (C-6), 125.4 (C-α), 128.6 (C-1), 142.7 (C-β), 149.1 (C-3), 151.1 (C-4), 162.4 and 166.1 (C-4′ and C-6′), 168.4 (C-2′), 192.5 (C=O) ppm. ESI⁺-MS: m/z (%) = 345 (17) [M + H]⁺, 367 (100) [M + Na]⁺, 711 (5) [2M + Na]⁺. Anal. Calcd (%) for C₁₉H₂₀O₆: C, 66.27; H, 5.85. Found: C, 65.99; H, 5.77.
• 35 General Optimized Experimental Procedure for the Synthesis of (E)-2′-Hydroxychalcones 3a,b NaOH (aq, 60%, 37 mL) was added to a solution of 2′-hydroxy-4′,6′-dimethoxyacetophenone (1.50 g, 7.645 mmol) in MeOH (37 mL; in the case of derivative a), or in MeOH–DMSO (v/v, 37:4.5 mL; in the case of derivative b). After that, the appropriate benzaldehyde 2a,b (15.04 mmol) was added, and the reaction mixture was stirred for 3 h (derivative a) and 4 h (derivative b) at r.t. Then, the mixture was poured into ice (50 g) and H₂O (100 mL) and the pH adjusted to 4 with a solution of HCl (20%). After filtration, the precipitate was taken in CH₂Cl₂, washed repeatedly with a sat. solution of KHCO₃ (1 × 300 mL) and H₂O (3 × 300 mL), and the organic layer was dried over anhydrous Na₂SO₄. Subsequently, after solvent evaporation, the residue was recrystallized in EtOH giving the correspondent (E)-2′-hydroxychalcones 3a,b in good yields [3a (77%, 1.78 g); 3b (61%, 1.61 g)].
• 36 General Optimized Experimental Procedure for the Synthesis of 8-Iodoflavones 4a,b I₂ (0.100 g; 0.3181 mmol) was added to a solution of the appropriate (E)-2′-hydroxychalcone 3a,b (0.3181 mmol) in DMSO (1.0 mL), and the reaction mixture was refluxed for 45 min under N₂ atmosphere. After that, the reaction mixture was poured into ice (25 g), H₂O (50 mL), and Na₂S₂O₃·5H₂O (1 g). The obtained solid was filtered, taken in CH₂Cl₂ (100 mL), and washed with Na₂S₂O₃ (aq, 20%) (100 mL) and H₂O (3 × 100 mL). The organic layer was dried over anhydrous Na₂SO₄ concentrated and purified by flash column chromatography with a mixture of EtOAc–CH₂Cl₂(4:1) leading to 8-iodoflavones 4a,b in good yields [4a (77%, 107.3 mg); 4b (75%, 111.7 mg)].
• 37 Physical Data of α-Hydroxy-7-iodo-4,4′,6-trimethoxyaurone (5) White powder. ¹H NMR (300.13 MHz, CDCl₃): δ = 3.83 (s, 3 H, 4′-OCH ₃), 4.03 and 4.06 (2 s, 2 × 3 H, 5-OCH₃ and 7-OCH₃), 6.18 (s, 1 H, H-5), 6.84 (d, 2 H, J = 8.9 Hz, H-3′,5′), 7.77 (d, 2 H, J = 8.9 Hz, H-2′,6′) ppm. ¹³C NMR (75.47 MHz, CDCl₃): δ = 55.6 (4′-OCH₃), 56.6 and 57.3 (4- and 6-OCH₃), 58.2 (C-7), 90.0 (C-5), 101.3 (C-2), 103.6 (C-3a), 114.4 (C-3′,5′), 124.3 (C-1′), 132.2 (C-2′,6′), 161.0 (C-4 or C-6), 165.0 (C-4′), 168.2 (C-4 or C-6), 172.2 (C-7a), 188.5 (C-α), 190.5 (C-3) ppm. ESI⁺-MS: m/z (%) = 493 (100) [M + K]⁺.
• 38 Physical Data of 3,8-Di-iodo-4′,5,7-trimethoxyflavone (6) White powder. ¹H NMR (300.13 MHz, CDCl₃): δ = 3.90 (s, 3 H, 4′-OCH₃), 4.03 (s, 6 H, 5,7-OCH₃), 6.45 (s, 1 H, H-6), 7.03 (d, 2 H, J = 8.8 Hz, H-3′,5′), 8.02 (d, 2 H, J = 8.8 Hz, H-2′,6′) ppm. ¹³C NMR (75.47 MHz, CDCl₃): δ = 55.5 (4′-OCH₃), 56.6 and 56.8 (5- and 7-OCH₃), 63.9 (C-8), 89.2 (C-3), 92.0 (C-6), 106.2 (C-4a), 113.4 (C-3′,5′), 126.2 (C-1′), 132.0 (C-2′,6′), 157.6 (C-8a), 161.7 (C-2, C-5, C-7, or C-4′), 161.8 (C-2, C-5, C-7, or C-4′), 161.9 (C-2, C-5, C-7, or C-4′), 162.9 (C-5 or C-7), 172.7 (C-4) ppm. ESI⁺-MS: m/z (%) = 565 (94) [M + H]⁺, 587 (100) [M + Na]⁺.
• 39 Physical Data of 8-Iodo-3′,4′,5,7-tetramethoxyflavone (4b) Pale yellow powder; mp 273–275 °C. ¹H NMR (300.13 MHz, CDCl₃): δ = 3.97 (s, 3 H, 4′-OCH₃), 4.00 (s, 3 H, 3′-OCH₃), 4.04 (s, 6 H, 5- and 7-OCH₃), 6.44 (s, 1 H, H-6), 6.67 (s, 1 H, H-3), 6.99 (d, 1 H, J = 9.0 Hz, H-5′), 7.63–7.67 (m, 2 H, H-2′,6′) ppm. ¹³C NMR (75.47 MHz, CDCl₃): δ = 56.08 and 56.14 (3′- and 4′-OCH₃), 56.6 and 56.8 (5- and 7-OCH₃), 64.9 (C-8), 91.8 (C-6), 107.0 (C-3), 109.2 (C-2′), 109.9 (C-4a), 111.2 (C-5′), 119.9 (C-6′), 123.6 (C-1′), 149.2 (C-3′), 151.8 (C-4′), 157.5 (C-8a), 160.9 (C-2), 162.0 and 162.6 (C-5 and C-7), 177.5 (C-4) ppm. ESI⁺-MS: m/z (%) = 469 (100) [M + H]⁺, 491 (11) [M + Na]⁺, 959 (40) [2M + Na]⁺. Anal. Calcd (%) for C₁₉H₁₇IO₆: C, 48.74; H, 3.66. Found: C, 48.90; H, 3.64.
• 40 Physical Data of (E)-8-[2-(4-Methoxyphenyl)vinyl]-4′,5,7-trimethoxyflavone (8a) Pale yellow powder; mp 224–225 °C. ¹H NMR (300.13 MHz, CDCl₃): δ = 3.86 (s, 3 H, 4′′-OCH₃), 3.88 (s, 3 H, 4′-OCH₃), 4.03 (s, 3 H, 5-OCH₃), 4.04 (s, 3 H, 7-OCH₃), 6.46 (s, 1 H, H-6), 6.62 (s, 1 H, H-3), 6.93 (d, 2 H, J = 8.7 Hz, H-3′′,5′′), 6.98 (d, 2 H, J = 8.8 Hz, H-3′,5′), 7.30 (d, 1 H, J = 16.6 Hz, H-α), 7.45 (d, 1 H, J = 16.6 Hz, H-β), 7.48 (d, 2 H, J = 8.7 Hz, H-2′′,6′′), 7.86 (d, 2 H, J = 8.8 Hz, H-2′,6′) ppm. ¹³C NMR (75.47 MHz, CDCl₃): δ = 55.4 and 55.5 (4′- and 4′′-OCH₃), 56.0 and 56.4 (5- and 7-OCH₃), 91.6 (C-6), 107.4 (C-3), 108.0 (C-8), 109.1 (C-4a), 114.2 (C-3′′,5′′), 114.5 (C-3′,5′), 115.7 (C-α), 124.2 (C-1′), 127.4 (C-2′′,6′′), 127.9 (C-2′,6′), 131.3 (C-1′′), 132.4 (C-β), 156.2 (C-8a), 159.2 (C-4′′), 159.7 (C-5), 161.0 (C-2), 161.2 (C-7), 162.0 (C-4′), 178.2 (C-4) ppm. ESI⁺-MS: m/z (%) = 445 (100) [M + H]⁺, 467 (11) [M + Na]⁺, 911 (60) [2M + Na]⁺. EI⁺-HRMS: m/z calcd for [C₂₇H₂₄O₆]: 444.1573; found: 444.1572.
• 41 General Optimized Experimental Procedure for the Synthesis of (E)-8-Styrylflavones 8a–c The appropriate styrene 7a,b (0.45 mmol) was added to a mixture of the appropriate 8-iodoflavone 4a,b (0.09 mmol), KCl (0.09 mmol), TBAB (0.14 mmol), K₂CO₃ (0.14 mmol), and PdCl₂ (5.4 µmol) in NMP (1.5 mL). Each reaction mixture was heated to 100 °C for 24 h under N₂ atmosphere. After this time, the mixture was poured into H₂O (100 mL) and the pH was adjusted to 5 by adding dropwise a solution of HCl (50%). Afterwards, the obtained residue was extracted with CH₂Cl₂ (100 mL), washed with H₂O (4 × 200 mL) and the organic layer dried over anhydrous Na₂SO₄. To remove any traces of NMP, the residue was dissolved in toluene and evaporated to dryness. Purification by TLC [two mixtures were used as eluent: first CH₂Cl₂–MeOH (9:1) and then CH₂Cl₂–acetone (4:1)] with subsequent recrystallization in EtOH lead to (E)-8-styrylflavones 8a–c in good yields [8a (87%, 34.8 mg); 8b (90%, 38.4 mg); 8c (93%, 42.2 mg)].
• 42 Physical Data of 8-[1-(4-Methoxyphenyl)vinyl]-4′,5,7-trimethoxyflavone (9a) Pale yellow powder; mp 151–152 °C. ¹H NMR (300.13 MHz, CDCl₃): δ = 3.78, 3.82, 3.88, and 4.05 (4 s, 4 × 3 H, 4′-, 4′′′-, 5-, and 7-OCH₃), 5.25 (d, 1 H, J = 0.7 Hz, H-2′′_a), 6.02 (d, 1 H, J = 0.7 Hz, H-2′′_b), 6.50 (s, 1 H, H-6), 6.55 (s, 1 H, H-3), 6.83 (d, 2 H, J = 8.8 Hz, H-3′,5′ or H-3′′′,5′′′), 6.84 (d, 2 H, J = 8.9 Hz, H-3′,5′or H-3′′′,5′′′), 7.32 (d, 2 H, J = 8.8 Hz, H-2′′′,6′′′), 7.46 (d, 2 H, J = 8.9 Hz, H-2′,6′) ppm. ESI⁺-MS: m/z (%) = 445 (100) [M + H]⁺, 467 (32) [M + Na]⁺, 911 (19) [2M + Na]⁺. ESI⁺-HRMS: m/z calcd for [C₂₇H₂₄O₆ + H⁺] 445.1646; found: 445.1639.
• 43 Physical Data of 4′,5,7-Trimethoxyflavone (10) White powder; mp 154–156 °C. ¹H NMR (300.13 MHz, CDCl₃): δ = 3.88 (s, 3 H, 4′-OCH₃), 3.91 (s, 3 H, 7-OCH₃), 3.96 (s, 3 H, 5-OCH₃), 6.37 (d, 1 H, J = 2.2 Hz, H-6), 6.56 (d, 1 H, J = 2.2 Hz, H-8), 6.60 (s, 1 H, H-3), 7.00 (d, 2 H, J = 8.8 Hz, H-3′,5′), 7.83 (d, 2 H, J = 8.8 Hz, H-2′,6′) ppm. ¹³C NMR (75.47 MHz, CDCl₃): δ = 55.5 (4′-OCH₃), 55.8 (7-OCH₃), 56.5 (5-OCH₃), 92.8 (C-8), 96.1 (C-6), 107.7 (C-3), 109.2 (C-4a), 114.4 (C-3′,5′), 123.9 (C-1′), 127.6 (C-2′,6′), 159.9 (C-8a), 160.1 (C-2), 160.9 (C-5), 162.0 (C-4′), 163.9 (C-7), 177.7 (C-4) ppm. ESI⁺-MS: m/z (%) = 313 (43) [M + H]⁺, 335 (27) [M + Na]⁺, 647 (100) [2M + Na]⁺.