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General procedure: 4.2.1. General procedures I for the synthesis of starting materials 1 a-n. Compounds 1a-g, i-n were synthesized according to general procedures I. Compound 1h was commercially available. Method A:16, 17 A two-necked round-bottomed flask equipped with a reflux condenser and a magnetic stir bar was charged withthe 2-bromobenzoic acid (20 mmol) and freshly distilled methanol(25 mL). The solution was heated in a hot water bath, conc. H2SO4(8 mmol) was added slowly and the reaction mixture was refluxed for 24 h. After cooling to room temperature around half of theamount of the solvent was removed in vacuo and the residue was partitioned between water (50 mL) and diethyl ether (70 mL). The organic layer was separated and washed with saturated NaHCO3(250 mL), water (50 mL) and brine (50 mL), dried over anhydrous MgSO4 and the volatiles were removed under reduced pressure.The crude product thus obtained was purified by flash chromatographyon silica gel to afford the alkyl-2-halobenzoate.In a two-necked round-bottomed flask equipped with a reflux condenser and a magnetic stir bar the alkyl 2-halobenzoate(22.5 mmol) was dissolved in freshly distilled dry THF (30 mL) under argon. The solution was cooled to 0 °C using an ice bath and NaH (60percent in mineral oil, 15 mmol) was added portion wise. After stirring for 15 min a solution of the alkyl acetate (15 mmol) in dry THF (30 mL) was added dropwise to the reaction mixture at 0 °C.The mixture was warmed up, stirred at room temperature for 2 h and heated under reflux for 24 h. After cooling to room temperature around half of the amount of the solvent was removed in vacuo and the reaction mixture was diluted with toluene (50 mL). The resulting mixture was washed with 2N HCl (50 mL), saturated NH4Cl (50 mL), dried over anhydrous MgSO4 and the volatiles were removed under reduced pressure. The crude product was purifiedby flash column chromatography on silica gel to afford the alkyl 3-(20-halophenyl)-3-oxo-propanoate 1.
203.6 g
With sulfuric acid;Reflux;
Step 1: To a 2 L round-bottom flask, 2,5-dibromobenzoic acid (250 g, 0.90 mol) in MeOH (2 L) and concentrated H2SO4 (18.4 g, 0.19 mol) were added. The mixture was refluxed overnight before cooled to room temperature. The resulting precipitate was then filtered, washed with cold methanol and dried under vacuum. It yielded 203.6 g methyl 2,5-dibromobenzoate as a yellow solid. To a 2 L round-bottom flask was added 2,5-dibromobenzoate (198.2 g, 0.68 mol) in 1 L dry DMF. CuCN (122 g, 1.36 mol) and NaI (22.8 g, 0.15 mol) were introduced next. The mixture was stirred overnight at 130 °C under nitrogen atmosphere. After the reaction was complete, it was extracted with ethyl acetate (500 mL × 3),washed with water (500 mL) and purified over silica gel (PE/EtOAc = 5/1) to give 95.2 g methyl 2,5-dicyanobenzoate as a brown solid (yield: 75.1 percent).
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