Dimethylformamide → 2-Chloro-6-(1-methyl-piperidin-4-yloxy)-pyridine

Participants

Reaction Conditions

Reaction Steps

Add sodium hydride (60% dispersion in mineral oil, 5.4 g, 135.1 mmol) to DMF (100 mL) and cool to 0° C. Add 4-hydroxy-1-methylpiperidine (15.6 g, 135.1 mmol) in DMF (100 mL). Warm the reaction to room temperature over 1 hr., add, in portions, 2,6-dichloropyridine (20.0 g, 135.1 mmol) as a solid. Stir the reaction and heat at 120° C. for 12 hr. Cool the reaction to room temperature and partition between diethyl ether and water. Extract 3 times with diethyl ether, combine organics and wash with saturated aqueous NaCl, dry over MgSO4, and concentrate. Chromatograph (silica gel, eluting with ethylacetate, then 5% 2 M NH3-methanol/ethylacetate), to provide the title compound as a pale yellow liquid (25.5 g, 83% yield). Mass spectrum (ion spray): m/z=227.1 (M+1); 1H NMR: δ (CDCl3, ppm) 7.46 (t, J=7.2 Hz, 15.6 Hz, 1H), 6.82 (d, J=6.3 Hz, 1H), 6.59 (d, J=8.0 Hz, 1H), 5.03 (m, 1H), 2.66 (bs, 2H), 2.28 (bs, 5H), 2.00 (m, 2H), 1.80 (m, 2H); Anal calcd for C11H15ClN2O.0.8H2O: Theory: C, 54.80; H, 6.94; N, 11.62. Found: C, 54.51; H, 6.20; N, 11.60.

Provenance & Evidence