Potassium Phosphate, Tribasic → Methyl 5-cyclopropyl-4-((4,4-difluorocyclohexyl)oxy)-2-fluorobenzoate

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Reaction Steps

To an argon-degassed solution of methyl 5-chloro-4-((4,4-difluoro-cyclohexyl)oxy)-2-fluorobenzoate (0.394 g, 1.22 mmol) in toluene (15 mL) and water (3 mL) was added cyclopropylboronic acid (0.639 g, 7.44 mmol), tribasic potassium phosphate (0.826 g, 3.89 mmol), tricyclohexylphosphine tetrafluoroborate (0.30 g, 0.97 mmol), and palladium acetate trimer (0.108 g, 0.481 mmol Pd). The mixture was heated to reflux under an argon atmosphere for 21 hours, cooled to ambient temperature. The mixture was filtered through a pad of diatomaceous earth that was rinsed with ethyl acetate (100 mL). The filtrate was washed with a 2:1 mixture of saturated aqueous ammonium chloride and water (150 mL), brine (150 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to dryness. The residue was purified by column chromatography with a gradient of ethyl acetate in hexanes (0-10%) to afford the title compound as a light yellow syrup (0.30 g, 76%): 1H NMR (300 MHz, CDCl3) δ 7.46 (d, J=8.4 Hz, 1H), 6.55 (d, J=12.6 Hz, 1H), 4.57 (br s, 1H), 3.86 (s, 3H), 2.44-1.88 (m, 9H), 0.93-0.86 (m, 2H), 0.64-0.59 (m, 2H); 19F NMR (282 MHz, CDCl3) 8-92.3 (d, J=238 Hz, 1F), −102.3 (d, J=237 Hz, 1F), −109.4 (s, 1F); MS (ES+) m/z 329.1 (M+1).

Provenance & Evidence