Regioselective Suzuki–Miyaura Reactions of the Bis(triflate) of 4′,7-Dihydroxyisoflavone

In memory of our dear friend and colleague Professor Tamás Patonay

Abstract

Arylated isoflavones are prepared by Suzuki–Miyaura cross-coupling reactions of the bis(triflate) of 4′,7-dihydroxyisoflavone. The reactions proceed with very good regioselectivity in favor of the electronically more deficient position.

Key words

catalysis - palladium - Suzuki–Miyaura reaction - isoflavones

• References and Notes

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• 17 4-Oxo-3-[4-(trifluoromethylsulfonyloxy)phenyl]-4H-chromen-7-yl Trifluoromethanesulfonate (2) To a solution of 1 (0.5 g, 1.96 mmol) in CH₂Cl₂ (20 mL) was added py (0.6 mL, 7.86 mmol) and the resulting mixture was stirred at r.t. To the solution was added Tf₂O (0.8 mL, 4.72 mmol) and the mixture was stirred at r.t. for 10 min. Subsequently, the mixture was stirred at 40 °C for 30 min. After cooling, the mixture was concentrated in vacuo and the product was isolated by rapid flash column chromatography (silica gel, heptane–EtOAc, 8:2). Yield: 0.90 g (90%); white solid; mp 182–184 °C. IR (KBr): 3093, 2918, 2849 (w), 1648 (s), 1614 (m), 1578, 1551, 1536, 1530 (w) cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 7.61–7.70 (m, 3 H, ArH), 7.80 (d, J = 2.3 Hz, 1 H, ArH), 7.90 (d, J = 2.2 Hz, 1 H, ArH), 7.92–8.00 (m, 2 H, ArH), 8.75 (s, 1 H, CH=). ¹³C NMR (75.4 MHz, CDCl₃): δ = 112.5 (CH), 116.0 (q, J _C–F = 320 Hz, CF₃), 119.2 (CH), 120.0 (q, J _C–F = 320 Hz, CF₃), 121.3 (CH), 122.0, 123.8 (C), 128.5, 131.2 (CH), 132.1, 148.8, 151.8, 155.9 (C), 156.0 (CH), 174.0 (CO). ¹⁹F NMR (282.4 MHz, CDCl₃): δ = –72.53 (3 F, CF₃), –72.74 (3 F, CF₃). GC–MS (EI, 70 eV): m/z (%) = 519 (23) [M + H]⁺, 518 (100) [M]⁺, 454 (12). HRMS (EI, 70 eV): m/z [M]⁺ calcd for C₁₇H₈F₆O₈S₂: 517.95593; found: 517.95651.
• 18 CCDC 1419931 and 1419932 contain the crystallographic details for the products 2 and 5g described in this publication. Details are 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, Cambridge, CB2 1EZ, UK; fax: [phone], or [e-mail].
• 19 Compounds 4a–d; General Procedure The reactions were carried out in a pressure tube. A solution of 2 (70 mg, 0.135 mmol), K₂CO₃ (2 mL, 2 M), Pd(PPh₃)₄ (6 mol%) and arylboronic acid 3 (2.2 equiv) in DMF (4 mL) was stirred at 130 °C for 10 h under an Ar atm. To the mixture were added H₂O (20 mL) and CH₂Cl₂ (25 mL). The organic and aq layers were separated and the latter was extracted with CH₂Cl₂ (2 × 20 mL). The combined organic layers were dried (Na₂SO₄), filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica gel, heptane–EtOAc, 9:1).
• 20 3-(4′-Methoxybiphenyl-4-yl)-7-(4-methoxyphenyl)-4H-chromen-4-one (4a) The product was obtained from the reaction of 2 (70 mg, 0.135 mmol), 3a (45 mg, 0.297 mmol), Pd(PPh₃)₄ (10 mg, 0.008658 mmol, 6 mol%) and K₂CO₃ (2 mL, 2 M) in DMF (4 mL). Yield: 48 mg (82%); white solid; mp 188–190 °C. IR (KBr): 3073, 3053, 3013, 2959, 2918, 2849 (w), 1901, 1732 (w), 1641, 1620, 1606, 1578, 1555, 1518 (m) cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 3.81 (s, 6 H, 2 × OCH₃), 6.97 (d, J = 8.5 Hz, 4 H, ArH), 7.18 (s, 2 H, ArH), 7.54–7.56 (m, 7 H, ArH), 7.97 (s, 2 H, ArH), 8.25 (d, J = 8.7 Hz, 1 H, CH=). ¹³C NMR (75.4 MHz, CDCl₃): δ = 29.7, 54.4 (2 × OCH₃), 114.5, 115.1, 122.8, 122.9 (CH), 123.2, 125.5 (C), 126.8, 128.1, 128.4, 128.5 (CH), 128.6, 128.7, 128.8, 129.1, 135.2, 135.8, 136.6, 153.0 (C), 156.6 (CH), 160.5 (CO). GC–MS (EI, 70 eV): m/z (%) = 434 (100) [M]⁺, 344 (24), 343 (35), 315 (13). HRMS (EI, 70 eV): m/z [M]⁺ calcd for C₂₉H₂₂O₄: 434.15181; found: 434.15156.
• 21 Compounds 5a–l; General Procedure The reactions were carried out in a pressure tube. A solution of 2 (70 mg, 0.135 mmol ), K₂CO₃ (2 mL, 2 M,), Pd(PPh₃)₄ (3 mol%) and arylboronic acid 3 (1.2 equiv) in DMF (4 mL) was stirred at 85 °C for 6 h under an Ar atm. To the mixture were added H₂O (20 mL) and CH₂Cl₂ (25 mL). The organic and aq layers were separated and the latter was extracted with CH₂Cl₂ (2 × 20 mL). The combined organic layers were dried (Na₂SO₄), filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica gel, heptane–EtOAc, 9:1).
• 22 4-[7-(4-Methoxyphenyl)-4-oxo-4H-chromen-3-yl]phenyl Trifluoromethanesulfonate (5a)The product was obtained from the reaction of 2 (70 mg, 0.135 mmol), 3a (25 mg, 0.162 mmol), Pd(PPh₃)₄ (5 mg, 0.004327 mmol, 3 mol%) and K₂CO₃ (2 mL, 2 M) in DMF (4 mL). Yield: 51 mg (80%); white solid; mp 173–175 °C. IR (KBr): 3085, 3036, 2955, 2916, 2848, 2670, 2559 (w), 1633, 1621, 1604 (m), 1585, 1552, 1518 (w) cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 3.80 (s, 3 H, OCH₃), 6.94 (d, J = 1.5 Hz, 2 H, ArH), 7.26 (d, J = 1.5 Hz, 2 H, ArH), 7.53–7.63 (m, 6 H, ArH), 7.97 (s, 1 H, ArH), 8.25 (d, J = 6.7 Hz, 1 H, CH=). ¹³C NMR (75.4 MHz, CDCl₃): δ = 54.4 (OCH₃), 113.2, 114.1 (CH), 115.2 (q, J _C–F = 320 Hz, CF₃), 120.3 (C), 121.5 (CH), 122.8 (C), 123.2, 125.7, 127.5 (CH), 129.7 (C), 130.1 (CH), 131.4, 145.7, 148.3, 152.3, 155.6 (C), 159.3 (CH), 174.5 (CO). ¹⁹F NMR (282.4 MHz CDCl₃): δ = –72.75 (3 F, CF₃). GC–MS (EI, 70 eV): m/z (%) = 476 (100) [M]⁺, 344 (24), 343 (35), 315 (13). HRMS (EI, 70 eV): m/z [M]⁺ calcd for C₂₃H₁₅O₆F₃S: 476.05359; found: 476.05270.
• 23 7-(3,5-Dimethylphenyl)-3-(4′-methoxybiphenyl-4-yl)-4H-chromen-4-one (6b) The product was obtained from the reaction of 2 (70 mg, 0.135 mmol ), 3g (25 mg, 0.162 mmol), Pd(PPh₃)₄ (5 mg, 0.004327 mmol, 3 mol%) and K₂CO₃ (2 mL, 2 M) in DMF (4 mL) at 85 °C for 6 h, followed by a subsequent reaction with 3a (25 mg, 0.162 mmol), Pd(PPh₃)₄ (5 mg, 0.004327 mmol, 3 mol%) and K₂CO₃ (2 mL, 2 M) in DMF (4 mL) at 130 °C for 10 h. Yield: 47 mg (81%); white solid; mp 152–154 °C. IR (KBr) = 3059, 3053, 3012, 2958, 2916, 2849 (w), 1902, 1730 (w), 1641, 1620, 1606, 1578, 1554, 1518 (m) cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 2.53 (s, 6 H, 2 × CH₃), 3.82 (s, 3 H, OCH₃), 6.97 (d, J = 8.5 Hz, 4 H, ArH), 7.11 (s, 2 H, ArH), 7.50–7.52 (m, 6 H, ArH), 7.93 (s, 2 H, ArH), 8.20 (d, J = 8.3 Hz, 1 H, CH=). ¹³C NMR (75.4 MHz, CDCl₃): δ = 22.4 (2 × CH₃), 50.8 (OCH₃), 113.5, 114.1, 121.7, 122.6 (CH), 123.4, 124.4 (C), 125.8, 126.1, 126.5, 126.6, 127.2, 127.8 (CH), 128.5, 128.6, 128.8, 129.2, 135.3, 135.7, 136.6, 152.1 (C), 155.8 (CH), 163.8 (CO). GC–MS (EI, 70 eV): m/z (%) = 432 (100) [M]⁺, 341 (22), 323 (30), 315 (23), 133 (10). HRMS (EI, 70 eV): m/z [M]⁺ calcd for C₃₀H₂₄O₃: 432.17200; found: 432.17244.