C([Li])CCC.[C:6]([O:12][CH2:13][CH3:14])(=[O:11])[CH2:7][C:8]([OH:10])=O.N1C=CC=CC=1C1C=CC=CN=1.[F:27][C:28]1[C:36]([O:37][CH3:38])=[C:35]([F:39])[CH:34]=[CH:33][C:29]=1C(Cl)=O>O1CCCC1.C(OCC)(=O)C>[OH:10]/[C:8](/[C:34]1[CH:33]=[CH:29][C:28]([F:27])=[C:36]([O:37][CH3:38])[C:35]=1[F:39])=[CH:7]\[C:6]([O:12][CH2:13][CH3:14])=[O:11]Compound I is prepared using the general method of Wierenga and Skulnick (Wierenga, W.; Skulnick, H. I. J. Org. Chem. 1979, 44, 310-311). n-Butyllithium (1.6 M in hexanes) is added to a cooled (−78° C.) solution of tetrahydrofuran (50 mL) containing ethyl hydrogen malonate (2.6 mL, 22 mmol) and 2,2′-bipyridyl (˜1 mg as indicator). The temperature of the reaction mixture is allowed to rise to ca. −5° C. during the addition of n-butyllithium. Sufficient n-butyllithium (30 mL, 48 mmol) is added until a pink color persists at −5° C. for 5-10 min. A solution of 2,4-difluoro-3-methoxybenzoyl chloride (H) (11.1 mmol, vide supra) in tetrahydrofuran (10 mL) is added in one portion to the reaction mixture that has been recooled to −78° C. The resulting mixture is allowed to warm to room temperature, diluted with ethyl acetate (100 mL), and quenched with a 1 M aqueous solution of hydrochloric acid. The organic layer is washed with a 5% aqueous solution of sodium bicarbonate (2×80 mL), followed by brine (2×80 mL), dried over sodium sulfate, and evaporated under reduced pressure to give the crude product. This material is purified by flash column chromatography (eluting with 20% v/v ethyl acetate in hexanes) to give pure I as a white solid. 1H NMR (300 MHz, CDCl3): (keto, predominant tautomer, ˜80%) a 1.20 (t, JH-H=7.0 Hz, 3H, CO2CH2CH3), 3.88 (d, JH-F=4.0 Hz, 2H, CH2CO2CH2CH3), 3.98 (apparent t, JH-F=1.0 Hz, 3H, OCH3), 4.15 (q, JH-H=7.0 Hz, 2H, CO2CH2CH3), 6.92 (ddd, JH-F=11.0 Hz, JH-H=9.0 Hz, JH-F=2.0 Hz, 1H, aromatic H-5), 7.57 (ddd, JH-H=9.0 Hz, JH-F=7.5 Hz, JH-F=6.0 Hz, 1H, aromatic H-6). LCMS m/z calcd for C12H12F2O4 258 ([M+]). found 259 ([M+H]+).
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