[Synthesis]
The above THF solution was transferred to a jacketed 3L three-necked round-bottomed flask equipped with a mechanical stirrer, temperature controller and nitrogen inlet. After dilution with THF (800 mL), the moisture content of the solution was detected using KF (0.053%). A THF solution of i-PrMgCl (Aldrich 2M, 286 mL, 0.572 mol) was added slowly dropwise over 1 h at 0-10 °C. The reaction was carried out by stirring the reaction solution with KF (0.053%). The reaction solution was stirred at 10 °C for 30 min (GC monitoring showed completion of the magnesium-bromine exchange reaction). Subsequently, ethyl trifluoroacetate (74 mL, 0.620 mol) was added to the Grignard solution over a period of 45 min in the range of -20 to -10 °C, slowly warmed to 0 °C, and stirring was continued at this temperature for 30 min. The reaction mixture was poured into 2N HCl (300 mL) at 0 °C and stirred at room temperature for 30 min. The organic layer was diluted with MTBE (500 mL) and washed sequentially with brine (250 mL) and water (250 mL). The organic layer solution was analyzed by GC (67% solution yield for compound 5, approximately 20% of regional isomer 6 relative to 5). The solution was concentrated to about 2x volume under reduced pressure. To remove water, THF (500 mL) was added and concentrated again to about 2x volume. This THF addition and concentration process was repeated, resulting in a solution of approximately 2x volume. Heptane (500 mL) was added and concentrated to approximately 2x volume for solvent exchange to facilitate recrystallization. Heptane (500 mL) was added again and concentrated to about 3.5 times volume. The heptane solution was transferred to a 1 L jacketed three-necked round-bottomed flask equipped with a mechanical stirrer, temperature controller and nitrogen inlet. The solution was heated to 60 °C to form a homogeneous solution, followed by slow (1-2 h) cooling to room temperature with stirring, further cooling to 0 °C and stirring at that temperature for 30 min. The crystals were collected, washed with ice-cold heptane (200 mL) and dried under vacuum at 50 °C to give a light yellow solid (Compound 5, 85.7 g, 99% GC purity, 62% yield of fluoride 1). Melting point: 83 °C (DSC onset).1H NMR (400 MHz, CDCl3) δ 7.85 (1H, d, J = 2.5 Hz), 7.48 (1H, d, J = 1.7 Hz), 7.38 (1H, d, J = 8.3 Hz), 7.31 (1H, dd, J = 8.1, 1.8 Hz), 6.33 (1H, d, J = 2.5 Hz), 2.30 (3H, s); 13C NMR (100 MHz, CDCl3) δ 184.2 (q, JC-F = 36.6 Hz), 151.7, 138.7, 138.5, 130.7, 126.4, 125.7, 124.5, 116.8, 116.1 (q, JC-F = 289.8 Hz), 109.7, 13.0; 19F NMR (376 MHz, CDCl3) δ = -76.8 (s). |