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.

Key words

Suzuki coupling - palladium - boron - heterocycles - pyrone

References

• 1 Dickinson JM. Nat. Prod. Rep.  1993,  10:  71 
• 2 Boulanger WA. Katzenellenbogen JA. J. Med. Chem.  1986,  29:  1159 
• 3 Prasad JVNV. Para KS. Lunney EA. Ortwine DF. Dunbar JB. Ferguson D. Tummino PJ. Hupe D. Tait BD. Domagala JM. Humblet C. Bhat TN. Liu B. Guerin DMA. Baldwin ET. Erickson JW. Sawyer TK. J. Am. Chem. Soc.  1994,  116:  6989 
• 4 Joule JA. Mills K. Heterocyclic Chemistry   Blackwell Science; Oxford: 2000. 
• 5 Posner GH. Wettlaufer DG. J. Am. Chem. Soc.  1986,  108:  7373 
• 6 Markó IE. Seres P. Evans GR. Swarbrick TM. Tetrahedron Lett.  1993,  34:  7305 
• 7 Afarinkia K. Berna-Canovas J. Tetrahedron Lett.  2000,  41:  4955 
• 8 Gravett EC. Hilton PJ. Jones K. Romero F. Tetrahedron Lett.  2001,  42:  9081 
• 9 Henaff N. Whiting A. Tetrahedron  2000,  56:  5193 
• 10 Muarata M. Oyama T. Watanabe S. Masuda Y. J. Org. Chem.  2000,  65:  164 
• 13 Liu Z. Meinwald J. J. Org. Chem.  1996,  61:  6693 
• 14a Dobbs AP. Jones K. Veal KT. Tetrahedron  1998,  54:  2149 
• 14b Fiumana A. Jones K. Chem. Commun.  1999,  1761 
• 14c Fiumana A. Jones K. Tetrahedron Lett.  2000,  41:  4209 

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]