51% |
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,4-dioxane; water; at 100℃; for 1h;Sealed tube; Inert atmosphere; Microwave irradiation; |
In a sealed microwave vial under nitrogen, a mixture of 4-cyclopropyl-9-[2-fluoro-4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]methyl}-l-oxa-4,9- diazaspiro[5.5]undecan-3-one (100 mg, 0.225 mmol), <strong>[89892-22-8]7-bromoquinazoline</strong> (47.0 mg, 0.225 mmol), 1 , 1 '-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (10 mg, 0.012 mmol) and 2M aq. potassium carbonate solution (1 mL, 2 mmol) in 1,4-dioxane (2 mL) was stirred at 100 °C for 1 h. The reaction was cooled to room temperature, diluted with ethyl acetate (10 mL), and the layers were separated. The aqueous layer was treated with 5N sodium hydroxide solution (3 mL) to ensure pH > 12, then back- extracted with ethyl acetate (20 mL). The organic layers were combined, dried over magnesium sulfate, and concentrated in vacuo to give a brown residue. The residue was purified by reverse phase HPLC (10-90percent acetonitrile + 0.1percent TFA/water + 0.1percent TFA). The desired tubes were concentrated in vacuo. Each tube was diluted with 5N sodium hydroxide solution (2 mL) and ethyl acetate (2 mL). The contents of each tube were combined and the layers were separated. The organic layer was dried over magnesium sulfate and concentrated in vacuo to afford the title compound as a white solid (52 mg, 51percent). MS(ES)+ m/e 447.2 [M+H]+; 1H NMR (400 MHz, DMSO-d6) delta ppm 9.65 (s, 1 H), 9.34 (s, 1 H), 8.34 (s, 1 H), 8.27 (d, J=8.59 Hz, 1 H), 8.17 (dd, J=8.46, 1.64 Hz, 1 H), 7.73 - 7.87 (m, 2 H), 7.51 - 7.66 (m, 1 H), 3.97 (s, 2 H), 3.61 (s, 2 H), 3.12 (s, 2 H), 2.69 - 2.83 (m, 1 H), 2.53 - 2.63 (m, 2 H), 2.23 - 2.44 (m, 2 H), 1.67 - 1.80 (m, 2 H), 1.52 - 1.67 (m, 2 H), 0.64 - 0.77 (m, 2 H), 0.53 - 0.64 (m, 2 H). |