CC(=O)OCc1cccc2c(=O)cc(-c3ccc(Br)cc3)oc12.C[C@@H]1CNCCN1>CC(=O)O.CC(=O)O.Cc1ccccc1.O=C([O-])[O-].[Cs+].[Cs+].[Pd].c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1>C[C@@H]1CN(c2ccc(-c3cc(=O)c4cccc(CO)c4o3)cc2)CCN1diacetoxypalladium (6.02 mg, 0.03 mmol) was added to a degassed mixture of (2-(4-bromophenyl)-4-oxo-4H-chromen-8-yl)methyl acetate (200 mg, 0.54 mmol), 2,2'-bis(diphenylphosphino)-1,1'-binaphthalene (25.03 mg, 0.04 mmol) and cesium carbonate (244 mg, 0.75 mmol) in toluene (5 mL). The resulting suspension was stirred at 110 °C for 3 hours under nitrogen (see note 1). More diacetoxypalladium (6.02 mg, 0.03 mmol) was added and the reaction mixture was heated to 110°C for 1 hour and again could see no product. TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (4.91 mg, 5.36 µmol) and 2,2'-bis(diphenylphosphino)-1,1'-binaphthalene (25.03 mg, 0.04 mmol) were added and the reaction mixture was heated to 110°C for 1 hour and again could see no product. sodium 2-methylpropan-2-olate (61.8 mg, 0.64 mmol) was added and the reaction mixture was heated to 110°C for 1 hour where a small amount of product could be detected by LCMS and significant dehalogenation. The reaction mixture was allowed to cool to room temperature The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3/MeOH and fractions were evaporated to dryness to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 5% 7N NH3/MeOH in DCM. Fractions were evaporated to dryness to afford product that was not pure. The sample was dissolved in DMF (4ml) and the crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5µ silica, 30 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford (R)-8-(hydroxymethyl)-2-(4-(3-methylpiperazin-1-yl)phenyl)-4H-chromen-4-one (25.00 mg, 13.31 %) as a yellow solid.
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