Ammonium Chloride → 1-(6-Cyclopropyl-pyridin-3-yl)-4,4-difluoro-cyclohexanecarbonitrile

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Reaction Conditions

Reaction Steps

A suspension of cyclopropylboronic acid (0.94 g, 11 mmol), 1-(6-bromo-pyridin-3-yl)-4,4-difluoro-cyclohexanecarbonitrile (1.10 g, 3.67 mmol) and potassium phosphate tribasic (2.30 g, 10.8 mmol) in a mixture of toluene (16 mL) and water (4 mL) at room temperature was purged with nitrogen gas for 1 hour. Then palladium acetate (31 mg, 0.14 mmol) and tricyclohexylphosphine (51 mg, 0.18 mmol) were added and the mixture was heated at 110° C. for 18 hours. After cooling to room temperature a saturated aqueous solution of ammonium chloride was added, followed by water. The organic layer was separated and the aqueous layer was extracted again three times with AcOEt. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was then purified by silica gel chromatography to afford 1-(6-cyclopropyl-pyridin-3-yl)-4,4-difluoro-cyclohexanecarbonitrile (400 mg, 27%). LC-MS (m/z) 263.0 (MH+). 11-1 NMR (400 MHz, CDCl3) δ ppm 8.59 (d, J=2.5 Hz, 1 H), 7.64 (dd, J=8.3, 2.5 Hz, 1 H), 7.19 (d, J=8.3 Hz, 1 H), 2.00-2.39 (m, 9 H), 0.99-1.06 (m, 4 H).

Provenance & Evidence