Potassium carbonate (3.3 g, 24 mmol) was added to a stirred solution of 4-bromo-2-fluoro-1-nitrobenzene (2.45 g, 11 mmol) and ethyl 3-(4-fluorophenyl)-3-oxopropanoate (2.7 g, 13 mmol) in DMSO (11 mL). The yellow solution turned purple and the reaction was stirred at r.t. After 8 h, the reaction was neutralized with 25 mL of 1N HCl and extracted with EtOAc. The organic phase was washed with water (×3) and brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography on a Biotage 40+M column (gradient elution 5% to 25% EtOAc/hexanes over 10 column volumes, fraction collection at μ, =254 nm) to afford the title compound as a viscous amber oil, 4.8 g (105% yield, contains ˜10 weight % EtOAc by 1H NMR). 1H NMR (˜0.6:1 ratio of keto:enol tautomers, 500 MHz, CDCl3) δ ppm 13.47 (s, 1H) 7.94-8.05 (m, 2H) 7.86 (d, J=8.55 Hz, 1 H) 7.62-7.72 (m, 1.2 H) 7.51 (dd, J=8.55, 2.14 Hz, 1H) 7.29-7.35 (m, 2H) 7.15-7.21 (m, 1.2 H) 7.12 (d, J=2.14 Hz, 1H) 6.94 (t, J=8.55 Hz, 2H) 6.35 (s, 0.6 H) 4.20-4.34 (m, 2H) 4.04-4.11 (m, 1.2 H) 1.23-1.27 (m, 2H) 1.18 (t, J=7.17 Hz, 3 H). LC/MS was performed on a Shimadzu-VP instrument with UV detection at 220 nm and Waters Micromass. LC/MS method: solvent A=5% CH3CN/95% H2O/10 mM NH4OAc, solvent B=95% CH3CN/5% H2O/10 mM NH4OAc, start % B=0, final % B=100, gradient time=2 min, stop time=3 min, flow rate=5 ml/min, column: XBridge C18 5 μm 4.6×50 mm; 2 peaks elute with HPLC Rt=1.69 and 1.83 min (˜1:2 ratio), (ES−) m/z (M−) for both=408, 410 (1:1 ratio).
