A New Route to 5-Aryl and 5-Heteroaryl-2-pyrones via Suzuki Coupling of a 2-Pyrone-5-boronate ester

Abstract

The synthesis of the 2-pyrone-5-boronate ester 5 is described along with its palladium-catalysed coupling reactions with a range of aryl and heteroaryl halides and triflates.

Suzuki coupling - palladium - boron - heterocycles - pyrone

References

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11

Preparation of(5): A mixture of 5-bromo-2-pyrone (13 g, 74 mmol), pinacolborane (16.2 mL, 14.7 g, 111 mmol), triethylamine (31 mL, 22.1 g, 222 mmol) and PdCl₂(PPh₃)₂ (1.56 g, 2.2 mmol) in dry tolune (100 mL) was heated to reflux under a N₂ atmosphere for 6 hours. After this time, TLC analysis showed no remaining 5-bromo-2-pyrone. The dark solution was filtered through a short plug of silica and this was further eluted with dichloromethane (250 mL). The solvent was removed under reduced pressure to give a dark crystalline solid. Flash column chromatography using dichloromethane as eluent gave the 2-pyrone-5-boronate 5 (13.6 g, 61.4 mmol, 83%) as a pale yellow crystalline solid, mp 91-93 °C. This material was used in all coupling reactions. An analytically pure sample with the same mp could be obtained as white crystals by sublimation at 0.7 mm Hg pressure. δ_H (CDCl₃, 300 MHz) 1.29 (6 H, s), 6.27 (1 H, dd, J = 9.6 and 1.2 Hz), 7.50 (1 H, dd, J = 9.6 and 2.1 Hz) and 7.84 (1 H, dd, J = 2.1 and 1.2 Hz); δ_C (CDCl₃, 75 MHz) 24.8, 84.5, 96.9, 115.6, 146.3 and 160.1; HRMS calcd for C₁₁H₁₅ ¹¹BO₄: 222.1063; found: 222.1059. Anal. Calcd for C₁₁H₁₅BO₄: C, 59.50; H, 6.81. Found: C, 59.66; H, 6.83.

12

Typical procedure for Suzuki coupling: Phenyl triflate (50 mg, 0.22 mmol), 2-pyrone-5-boronate 5 (55 mg, 0.25 mmol), and PdCl₂(dppf) (20 mg, 0.022 mmol) were dissolved in dry DMF (4 mL) under a N₂ atmosphere. Finely crushed K₃PO₄ (180 mg, 0.82 mmol) was added to the DMF solution and this slurry was heated to 60 °C for 6 hours. The DMF was removed under reduced pressure to give a dark solid that was initially purified by dissolving in dichloromethane and filtering through a plug of silica, followed by washing with dichloromethane (30 mL). The solvent was removed under reduced pressure to give a solid that was further purified by flash column chromatography (10% ethyl acetate in dichloromethane) to yield 5-phenyl-2-pyrone (30.2 mg, 0.172 mmol, 80%). δ_H (CDCl₃, 300 MHz) 6.38 (1 H, dd, J = 9, 1 Hz, H-3), 7.35 (5 H, m, aromatic-H), 7.56 (1 H, dd, J = 9, 3 Hz), 7.62 (1 H, dd, J = 3, 1 Hz); δ_C (CDCl₃, 75 MHz) 116.5, 120.6, 126.0, 128.4, 129.3, 133.5, 144.0, 148.3, 161.2; m/z 172 (M⁺, 90%), 144(38), 115(100), 89(12), 63(10). These data match those reported. [7]

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