Cesium carbonate → Tert-butyl 5-chloro-4-(2-(4,4-difluorocyclohexyl)ethoxy)-2-fluorobenzoate

Participants

Reaction Conditions

Reaction Steps

To a of solution ethyl 2-(4,4-difluorocyclohexyl)acetate (1.44 g, 7.00 mmol) in anhydrous tetrahydrofuran (23 mL) and anhydrous methanol (0.6 mL) was added lithium borohydride (4 M in tetrahydrofuran, 3.5 mL, 16.00 mmol) at 0° C. and the mixture was heated to reflux for 2 hours. The mixture was then cooled to 0° C. and quenched with methanol until gas evolution ceased. The solution was warmed to ambient temperature then poured into water (50 mL). The aqueous layer was separated and extracted with diethyl ether (3×20 mL). The combined organic layers were washed with brine; dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude alcohol (0.98 g), which was dissolved in anhydrous dimethylsulfoxide (6 mL), tert-butyl 5-chloro-2,4-difluorobenzoate (1.64 g, 6.60 mmol) and cesium carbonate (4.11 g, 12.6 mmol) was added. The reaction mixture was heated at 70° C. for 2 hours and then cooled to ambient temperature and diluted with water (60 mL) and extracted with ethyl acetate (4×20 mL). The combined organic layers were washed with brine; dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (0% to 10% ethyl acetate in hexanes) to afford the title compound (0.681 g, 29%): 1H NMR (300 MHz, CDCl3) δ 7.88 (d, J=7.7 Hz, 1H), 6.63 (d, J=12.1 Hz, 1H), 4.08 (t, J=6.6 Hz, 2H), 2.17-2.07 (m, 2H), 1.77-1.62 (m, 5H), 1.57 (s, 9H), 1.42-1.29 (m, 4H).

Provenance & Evidence