Toluene → 1-(t-Butoxycarbonyl)-4-(3,3-difluoro-3-(2-pyridyl)prop-1-en-1-yl)piperidine

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Reaction Steps

A suspension of ((1-(t-butoxycarbonyl)piperidin-4-yl)methyl)triphenylphosphonium iodide (5.29 g, 9.00 mmol, from EXAMPLE 155, Step C) in THF (70 mL) was stirred at RT for 40 min. A toluene solution of potassium bis(trimethylsilyl)amide (18 mL, 0.5 M, 9.0 mmol) was added, giving an orange suspension. After 40 min., crude 2,2difluoro-2-(2-pyridyl)-1-methoxyethanol (940 mg, 4.97 mmol) was added in THF (20 mL). After an additional 50 min., the mixture was quenched by the addition of saturated aq. NH4Cl (10 mL). The mixture was partitioned between EtOAc (100 mL) and H2O (100 ml), and the aqueous layer was extracted with EtOAc (3×100 mL). The organic layers were washed in succession with saturated aq. NaCl (100 mL), dried (Na2SO4), decanted, and evaporated. Purification by flash column chromatography on silica gel, eluting with 90:10 v/v to 80:20 v/v hexanes/EtOAc, gave 1.18 mg of the title compound (approximately 95:5 cis/trans mixture) as an oil which soldified upon standing. For the title compound: 1H NMR (500 MHz, CDCl3) S 8.68 (d, J=5, 1H), 7.84 (td, J=8, 2, 1H), 7.70 (d, J=8, 1H), 7.39 (dd, J=8, 5, 1H), 5.93 (td, J=14, 11, 1H), 5.70 (ddt, J=11, 10, 2, 1H), 4.17-3.99 (bs, 2H), 2.80-2.62 (m, 3H), 1.58 (d, J=12,22H), 1.46 (s, 9H), 1.26 (qd, J=12, 4, 2H); ESI-MS 339 (M+H); HPLC A: 4.28 min.

Provenance & Evidence