Bis(2-chloroethyl) ether → 4-(3-(trifluoromethyl)phenyl)tetrahydro-2H-pyran-4-carbonitrile

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A solution of 2-(3-(trifluoromethyl)phenyl)acetonitrile (2 g, 10.8 mmol) in DMF (10 mL) was added dropwise to a suspension of sodium hydride (1.05 g, 26.3 mmol, 60% in oil dispersion) in DMF (10 mL), cooled to 0° C. in an ice water bath. After addition, the mixture was warmed to room temperature and stirred for 30 min. The suspension was cooled to 0° C. and a solution of 1-chloro-2-(2-chloroethoxy)ethane (2 g, 13.98 mmol) in DMF (20 mL) was added dropwise over a period of 30 min. The dark suspension was warmed to room temperature and stirred for additional 1.5 h. The mixture was quenched by addition of aq. 10% LiCl solution (50 mL) and diluted with EtOAc (100 mL). The organic extract was separated and the aqueous layer was extracted with EtOAc (30 mL, 2×). EtOAc extracts were combined, washed with 10% aq. LiCl solution (30 mL, 3×), and brine (25 mL, 2×), dried (MgSO4), filtered, and concentrated to obtain a dark brown oil (HPLC and LC/MS). The crude oil was chromatographed on a silica gel column. Elution with 10% EtOAc in heptane, followed by 20% EtOAc in heptane afforded 4-(3-(trifluoromethyl)phenyl)tetrahydro-2H-pyran-4-carbonitrile as a light yellow solid (2.31 g, 84% yield). HPLC: tR=2.75 min, YMC Combi S5 ODS 4.6×50 mm, 4 min gradient, Detection Wave length 220 nm, Starting solvent: 10% aq. MeOH—0.2% H3PO4; Final solvent: 90% aq. MeOH—0.2% H3PO4. LC/MS: m/e 256.06 (M+H)+, 229.02 (M+H−HCN)+.

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