Thionyl Chloride → 4-Bromo-1-(chloromethyl)-2-methylbenzene

Participants

Reaction Steps

To a solution of 4-bromo-2-methylbenzyl alcohol (9.0 g) in dichloromethane (50 mL) was added thionyl chloride (3.8 mL) under ice-cooling, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure to give 4-bromo-2-methylbenzyl chloride (9.8 g). Sodium hydride (55%, 0.84 g) was suspended in tetrahydrofuran (80 mL). To the suspension was added methyl 4-methyl-3-oxopentanoate (2.94 g) under ice-cooling, and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added 4-bromo-2-methylbenzyl chloride (4.08 g), and the mixture was stirred at 60° C. for 36 hours. To the reaction mixture was added a saturated aqueous ammonium chloride solution, and the resulting mixture was extracted with diethyl ether. The extract was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was dissolved in acetonitrile (24 mL). To the solution were added N-vinylphthalimide (3.29 g), palladium acetate(II) (0.42 g), tris(o-methylphenyl)phosphine (2.27 g) and N,N-diisopropylethylamine (13 mL), and the mixture was stirred at 100° C. for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane-n-hexane/ethyl acetate=3/1-3/2) to give N-{(E)-2-[4-(2-methoxycarbonyl-4-methyl-3-oxopentyl)-3-methylphenyl]-vinyl}phthalimide (6.45 g). To this material were added methanol (50 mL) and 10% palladium-carbon powder (3 g), and the mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. A part (1 g) of the residue was dissolved in ethanol (15 mL). To the solution was added hydrazine monohydrate (1.38 mL), and the mixture was stirred at 80° C. for 13 hours. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by solid phase extraction on ODS (washing solvent: distilled water, eluent: methanol) and benzenesulfonic acid resin (washing solvent: methanol, eluent: 2 mol/L ammonia-methanol solution) to give the title compound (0.3 g).

Provenance & Evidence