[Synthesis]
General procedure for the synthesis of tert-butyl 2-bromo-5-fluorobenzoate from 2-bromo-5-fluorobenzoic acid and tert-butanol: To a solution of dichloromethane (15 mL) containing 2-bromo-5-fluorobenzoic acid (3.22 g, 14.7 mmol), tert-butanol (4.20 mL, 44.1 mmol), and 4-dimethylaminopyridine (1.44 g, 11.8 mmol) at 0 °C was added slowly. ) solution of N,N'-dicyclohexylcarbodiimide (3.34 g, 16.2 mmol) was slowly added. The reaction mixture was stirred at room temperature for 15 h. The reaction was quenched with water (30 mL) and extracted with ethyl acetate (50 mL × 3). The organic layers were combined and washed sequentially with saturated aqueous ammonium chloride solution (50 mL) and saturated aqueous sodium bicarbonate solution (50 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by neutral silica gel column chromatography (hexane/ethyl acetate = 25:1) to afford tert-butyl 2-bromo-5-fluorobenzoate in 86% yield (3.49 g, 12.7 mmol). The product was a colorless oil; IR (ATR) ν 2980, 1714, 1467, 1300, 1249, 1158, 1028, 817, 609 cm^-1; ^1H NMR (400 MHz, CDCl_3) δ 1.61 (9H, s), 6.98-7.05 (1H, m), 7.41 (1H, dd, J_H-F = 8.8 Hz, J_H-H = 3.1 Hz), 7.57 (1H, dd, J_H-H = 8.8 Hz, J_H-F = 5.1 Hz); ^13C NMR (100 MHz, CDCl_3) δ 28.1, 83.2, 115.3, 118.0 (d, J_C-F = 24.5 Hz), 119.2 (d, J_C-F = 22.1 Hz), 135.45, 135.52, 161.4 (d, J_C-F = 248.5 Hz), 164.4; ^19F NMR (376 MHz, CDCl_3) δ -51.6 (1F, td, J_F-H = 8.8, 5.1 Hz); MS (ESI-TOF) m/z 297 [M + Na]^+, 299 [M + 2 + Na]^+; HRMS calculated value C_11H_12BrFNaO_2 [M + Na]^+, 296.9902; measured value, 296.9900. |