Potassium Phosphate, Tribasic → Tert-butyl 5-cyclopropyl-4-(2-(4,4-difluorocyclohexyl)ethoxy)-2-fluorobenzoate

Participants

Reaction Conditions

Reaction Steps

To a solution of tert-butyl 5-chloro-4-(2-(4,4-difluorocyclohexyl)ethoxy)-2-fluorobenzoate (0.681 g, 1.70 mmol) in toluene-water (v/v 20:1, 10.5 mL) was added cyclopropylboronic acid (0.227 g, 2.60 mmol), tricyclohexylphosphine tetrafluoroborate (0.064 g, 0.17 mmol) and potassium phosphate tribasic (1.658 g, 7.80 mmol). The mixture was sparged with nitrogen gas for 10 minutes and sonicated for an additional 5 minutes. Palladium (II) acetate (0.019 g, 0.082 mmol) was added and the reaction mixture heated at 100° C. under nitrogen for 16 hours. The mixture was then cooled to ambient temperature then charged with additional cyclopropylboronic acid (0.227 g, 2.60 mmol), tricyclohexylphosphine tetrafluoroborate (0.070 g, 0.19 mmol) and palladium(II) acetate (0.021 g, 0.094 mmol). The mixture was heated to 100° C. and stirred for an additional 24 hours. The solution was then cooled to ambient temperature and filtered through diatomaceous earth with ethyl acetate. The solution was concentrated in vacuo and purified by column chromatography (0% to 20% ethyl acetate in hexanes) to afford the title compound (0.173 g, 25%): 1H NMR (300 MHz, CDCl3) δ 7.38 (d, J=8.4 Hz, 1H), 6.51 (d, J=12.7 Hz, 1H), 4.04 (t, J=6.2 Hz, 2H), 2.15-2.07 (m, 2H), 2.02-1.95 (m, 1H), 1.88-1.61 (m, 7H), 1.57 (s, 9H), 1.43-1.31 (m, 2H), 0.92-0.86 (m, 2H), 0.66-0.61 (m, 2H).

Provenance & Evidence