4-Bromoanisole → 2-(4-Methoxyphenyl)benzonitrile

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Reaction Steps

To a solution of 4-bromoanisole (18.7 g, 0.1 mol) in anhydrous tetrahydrofuran (200 mL) at -78° C. was added a solution of n-BuLi (2.5M solution, 40 mL) in hexane. After stirring for 30 minutes, a solution of zinc chloride (1M solution, 100 mL) in ether was added. After the mixture was stirred for one hour at -78° C., Pd(Ph3P)4 (0.85 g, 0.73 mmol) and 2-bromobenzonitrile (18.2 g, 0.1 mol) were added. The reaction mixture was stirred at room temperature overnight, and then was concentrated in vacuo. The residue was partitioned between ethyl acetate (400 mL) and 1N hydrochloric acid (100 mL). The organic solution was washed with brine and dried over magnesium sulfate. Concentration in vacuo gave a crude intermediate 4'-methoxy[1,1'-biphenyl]-2-carbonitrile, which was directly used for the next step (the compound can be triturated with ether to obtain a pure solid product). To a solution of the crude intermediate in methylene chloride (150 mL) at -78° C. was added boron tribromide (1M solution, 200 mL) in methylene chloride. After the addition, the resulting solution was stirred at room temperature overnight. The reaction was quenched by adding very slowly methanol (100 mL) at -78° C. The mixture was then poured into ice water. Ethyl acetate (300 mL) was added to the aqueous mixture, the organic layer was washed with water and dried over magnesium sulfate. Concentration in vacuo gave a solid, which was triturated with ether to obtain the title compound (11.5 g, 59% overall). If needed, the product can also be purified by silica gel column eluting with toluene/ethyl acetate (4:1); m.p. 177-178° C.

Provenance & Evidence