Monoethyl malonate → Ethyl 3-(5-bromo-2-fluorophenyl)-3-oxopropanoate

Participants

Reaction Conditions

Reaction Steps

3-Ethoxy-3-oxopropanoic acid (B) (2.16 mL, 18.3 mmol, 2.00 eq) was dissolved in THF (91 mL) in an oven dried round-bottom flask and 2,2′-bipyridyl (8.00 mg, 0.0512 mmol, 0.0056 eq) was added as an indicator. The reaction was cooled to −30° C. and n-butyllithium (1.6 M in hexanes) (29.0 mL, 45.6 mmol, 4.00 eq) was added dropwise over 20 minutes. Upon final addition the reaction turned red at which point it was allowed to warm to −5° C. The reaction was allowed to stir at −5° C. for 15 minutes, during which time the red color began to dissipate. Enough n-butyllithium was added to cause the red color to persist. The reaction was then cooled to −78° C. and 5-bromo-2-fluoro-benzoyl chloride (A) (2.17 g, 9.14 mmol, 1.00 eq) was added dropwise as a solution in THF (6.9 mL). The reaction was allowed to stir at −78° C. for 30 minutes and then allowed to warm to −30° C. and stirred for an additional 30 minutes. The reaction was poured onto ice-cold 1N HCl (92 mL) and the mixture was extracted with ethyl acetate (lx) and DCM (2×). The combined organics were dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica gel using 0-10% hexanes/ethyl acetate afforded 1.78 g (67%) of the title compound as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.97 (dd, J=6.5, 2.6 Hz, 1H), 7.91-7.86 (m, 1H), 7.40-7.34 (m, 1H), 4.13-4.07 (m, 4H), 1.15 (t, J=7.1 Hz, 3H); ES-MS [M+1]+: 289.0.

Provenance & Evidence