Hydrochloric Acid → Methyl 2-(3-fluoro-4-(trifluoromethyl)benzyl)isonicotinate

Participants

Reaction Conditions

Reaction Steps

To a solution of methyl 2-chloroisonicotinate (5.15 g, 30 mmol) and Pd(PPh3)4 (0.693 g, 0.60 mmol) in tetrahydrofuran (40 mL) under nitrogen in a dried flask was added freshly prepared (3-fluoro-4-(trifluoromethyl)benzyl)zinc(II) bromide (12.55 g, 38.91 mmol) in tetrahydrofuran (50 mL). The resulting bright yellow mixture was heated to 60° C. for 2 h 20 min, then cooled to room temperature. The reaction was quenched by the addition of 10% NH4Cl. It was diluted with ethyl acetate. After phase separation, the organic layer was washed with brine, dried over MgSO4 and evaporated. The residue was suspended in 150 mL MTBE and sonicated, then the yellow insolubles were filtered off and washed with MTBE. The volume of the filtrate was increased to ca. 200 mL, then hydrogen chloride (7.50 mL, 30.00 mmol) (4M in dioxane) was added dropwise. A colorless precipitate formed. The resulting suspension was stirred for ca. 1 h, then sonicated for 2 min. The formed solid was collected and washed with MTBE and dried. The solid was dissolved in DCM and washed with 10% K2CO3. After phase separation, the aqueous layer was extracted with DCM. The combined organic layers were dried over MgSO4 and evaporated. Methyl 2-(3-fluoro-4-(trifluoromethyl)benzyl)isonicotinate (8.26 g, 88%) was isolated as a pale orange oil. 1H NMR (400 MHz, cdcl3) δ 3.94 (s, 3H), 4.24 (s, 2H), 7.06-7.18 (m, 2H), 7.52 (t, 1H), 7.69-7.75 (m, 2H), 8.68-8.75 (m, 1H). MS m/z 314 (M+H)+

Provenance & Evidence