Hexachloroethane → 4-Chloro-2-(trifluoromethyl)nicotinic acid

Participants

Reaction Conditions

Reaction Steps

To a stirred solution of 2,2,6,6-tetramethylpiperidine (21.0 mL, 124 mmol) in dry THF (200 mL) in a −78° C. bath is added n-Butyl lithium (66.2 mL of a 2.5M solution in hexanes, 166 mmol). The solution is stirred at −78° C. for 30 minutes, followed by the addition of a solution of 2-(trifluoromethyl)nicotinic acid (7.90 g, 41.4 mmol) in THF (35 mL) via canula. The solution is stirred at −78° C. for 20 minutes, followed by warming to −50° C. for 1 hour (to provide the corresponding lithiated pyridine). In a separate flask, hexachloroethane (29.4 g, 124 mmol) is dissolved in THF (200 mL) and cooled to −15° C. and stirred rapidly. The solution containing the lithiated pyridine is added to the hexachloroethane solution via canula. After complete addition, the mixture is allowed to ward to room temperature. Water (ca 200 mL) is added, followed by removal of the tetrathydrofuran in vacuo. The remaining aqueous residue is extracted with ether-pentane (1:1, 100 mL). The organic layer was discarded. The aqueous layer is acidified with hydrochloric acid (ca. 50 mL of a 1.0 M solution). The aqueous layer is extracted with ethyl acetate. The organic layer is dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford 8.75 g (94%) of the title compound as a tan solid: 1H NMR (400 MHz, CD3OD), 8.63 (d, 1H), 7.79 (d, 1H). LC/MS (M+1)=226.1; [see: Schlosser et al., Eur. J. Org. Chem. 2003, 1559].

Provenance & Evidence