5-Bromo-2-methylbenzoic acid (1.0 g, 4.7 mmol) was placed in a 200 mL round-bottomed flask under nitrogen protection and methanol was added via syringe. A hexane solution of 2 M diazomethyltrimethylsilane (3.5 mL, 23.0 mmol) was slowly added dropwise over 10 min and the reaction mixture was stirred for 1 h at room temperature. Subsequently, glacial acetic acid (16 mL) was added and stirring was continued for 45 minutes. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (100 mL) and washed sequentially with 1 M aqueous sodium hydroxide solution (30 mL), saturated aqueous sodium bicarbonate solution (30 mL) and brine (30 mL). The organic layer was dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give methyl 5-bromo-2-methylbenzoate 1.01 g (99% yield).
Methyl 5-bromo-2-methylbenzoate (1.04 g, 4.5 mmol) was placed in a 50 mL round-bottom flask under nitrogen protection and carbon tetrachloride (15 mL) was added. Subsequently, N-bromosuccinimide (1.49 g, 8.3 mmol) and 2,2'-azobisisobutyronitrile (40 mg, 0.2 mmol) were added, a condenser was mounted, and the reaction was refluxed for 4 hours. After completion of the reaction, it was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the crude product was pre-adsorbed through silica gel. The residue was purified by silica gel column chromatography using a gradient elution with a hexane solution of dichloromethane (0 to 50%) to afford methyl 5-bromo-2-bromomethylbenzoate 977 mg (70% yield).
Methyl 5-bromo-2-bromomethylbenzoate (0.984 g, 3.20 mmol) and the method described in Part I were used to replace the synthetic step of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydroisoindol-1-one, which was prepared to give 509 mg of methyl 2-methyl-5-bromobenzoate (75% yield).
