1-bromo-2,5-dichloro-4-methoxybenzene

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Methyl iodide (1.861 mL, 29.76 mmol) was added to a stirred suspension of 4-bromo-2,5-dichlorophenol (4.8 g, 19.84 mmol) and potassium carbonate (8.23 g, 59.53 mmol) in DMF (20 mL) at ambient temperature under air. The resulting suspension was stirred at 50° C. for 90 minutes. The reaction mixture was allowed to cool and diluted with EtOAc (200 mL), and washed sequentially with saturated brine (2×150 mL) and water (100 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 20% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford 1-bromo-2,5-dichloro-4-methoxybenzene (3.82 g, 75%) as a brown solid. to cool washed sequentially with saturated brine (2×150 mL) and water (100 mL) The organic layer was dried over MgSO4 filtered evaporated to afford crude product The crude product was purified by flash silica chromatography, elution gradient 0 to 20% EtOAc in isohexane Pure fractions were evaporated to dryness

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 1-bromo-2,5-dichloro-4-methoxybenzene (Intermediate 4-6; 3.82 g, 14.93 mmol), cesium carbonate (14.59 g, 44.78 mmol) and dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.427 g, 0.90 mmol) in toluene (220 mL) was thoughroughly degassed. The mixture was treated with diacetoxypalladium (0.101 g, 0.45 mmol) and diethyl malonate (2.505 mL, 16.42 mmol) and the resulting solution stirred under a nitrogen atmosphere at 100° C. for 18 hours. The reaction mixture was allowed to cool to ambient temperature, evaporated to dryness and partitioned between EtOAc (150 mL) and water (100 mL). The mixture was filtered and the aqueous layer was separated and re extracted with EtOAc (150 mL). The organic extracts were combined, dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 20% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford diethyl 2-(2,5-dichloro-4-methoxyphenyl)malonate (1.880 g, 37.6%) as a yellow oil. to cool to ambient temperature evaporated to dryness partitioned between EtOAc (150 mL) and water (100 mL) The mixture was filtered the aqueous layer was separated re extracted with EtOAc (150 mL) dried over MgSO4 filtered evaporated to afford crude product The crude product was purified by flash silica chromatography, elution gradient 0 to 20% EtOAc in isohexane Pure fractions were evaporated to dryness