Lithium Hexamethyldisilazide → 3-(fluoro(phenylsulfonyl)methyl)-1-(2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)benzyl)-3-hydroxyindolin-2-one

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Reaction Conditions

Reaction Steps

1-(2-Fluoro-4-(1-methyl-1H-pyrazol-4-yl)benzyl)indoline-2,3-dione (1 g, 3.0 mmol) was added to a flame-dried round bottom flask with stir bar and dissolved in THF (30 mL). Next, ((fluoromethyl)sulfonyl)benzene (780 mg, 4.5 mmol) was added, and the mixture was cooled to −78° C. Lithium hexamethyldisilazide (1M in THF, 4.5 mL, 4.5 mmol) was added dropwise to the cooled solution, and the mixture was allowed to gradually warm to room temperature overnight. The reaction was quenched by addition of excess saturated brine, and then extracted with 3×50 mL ethyl acetate. The organic layers were combined, dried over magnesium sulfate, evaporated and purified by silica gel chromatography (30-100% EtOAc in hexanes gradient) to afford 3-(fluoro(phenylsulfonyl)methyl)-1-(2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)benzyl)-3-hydroxyindolin-2-one as a yellowish foam. To a scintillation vial containing a magnetic stir bar was added 3-(fluoro(phenylsulfonyl)methyl)-1-(2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)benzyl)-3-hydroxyindolin-2-one (305 mg, 0.6 mmol), followed by DMF (6 mL), magnesium powder (150 mg, 6 mmol), and 3 mL of an acetic acid/sodium acetate (1:1) buffer solution (8 mol/L). The vial was sealed and allowed to stir at room temperature overnight. The mixture was diluted with water (100 mL), and then extracted with 5×25 mL ethyl acetate. The organic layers were combined, dried over magnesium sulfate, evaporated, and purified by reversed-phase HPLC using 0.1% TFA in water/acetonitrile as a mobile phase to afford the title compound. LCMS: RT=0.67 min, >99% @ 254 nm, >99% @ 215 nm; m/z (M+1)+=370. 1HNMR (400 MHz, CDCl3, δ (ppm)): 7.53 (s, 1H), 7.47 (s, 1H), 7.3 (dt, J=7.8, 1.1 Hz, 1H), 7.2-7.1 (m, 2H), 7.1-7.0 (m, 2H), 6.9 (d, J=7.9 Hz, 1H), 5.0 (d, J=15.8 Hz, 1H), 4.9 (d, J=15.8 Hz, 1H), 4.8 (quartet, J=3.6 Hz, 1H), 4.6 (quartet, J=9.1, 4.0 Hz, 1H), 3.9 (s, 3H), HRMS calculated for C20H18N3O2F2 (M+H)+ m/z: 370.1367, measured: 370.1366.

Provenance & Evidence