The general procedure for the synthesis of 4-(2-hydroxyethyl)pyridine from 4-(chloromethyl)pyridine and formaldehyde is as follows: in a two-necked Schlenk flask equipped with a magnetic stirring bar and a septum, the flask is first heated for 10 min under high vacuum using a hot air gun (ca. 400 °C). After the flask was cooled to room temperature, it was rinsed three times with argon gas. Subsequently, zinc powder (654 mg, 2.0 equivalents, 10.0 mmol) and THF (20 mL) were added to the flask. 1,2-dibromoethane (5 mol%) was added and the reaction mixture was heated to boiling. After cooling to room temperature, chlorotrimethylsilane (1 mol%) was added and the mixture was again heated to boiling. After cooling to room temperature again, a solution of 4-(chloromethyl)pyridine (633 mg, 5.0 mmol, 1 eq.) in THF (10 mL) was added and the mixture was heated at 70 °C for 2 hours and then cooled to room temperature. Paraformaldehyde (450 mg, 3.0 eq, 15.0 mmol) was slowly added at room temperature and the flask was heated at 70 °C for another 6 hours. After completion of the reaction, the solution was cooled to room temperature and saturated NH4Cl solution was added. The phases were separated and the aqueous layer was extracted with ethyl acetate (100 mL). The organic layers were combined and washed sequentially with water (20 mL) and brine (10 mL), then dried over Na2SO4. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography using cyclohexane or cyclohexane/ethyl acetate as eluent to afford 4-(2-hydroxyethyl)pyridine (510 mg, 83%) as a colorless liquid.
