4-Chloropyridine → HCID 59135228, compound

Participants

Reaction Steps

A solution of 2-(dimethylamino)ethanol (471 mg, 531 mL, 5.28 mmol) in dry hexanes (3.3 mL) was cooled to −5° C. and n-butyllithium (1.6 M in hexanes, 6.60 mL, 10.6 mmol) was added dropwise under N2. After 30 min at 0° C., the solution was cooled to −78° C. and a solution of 4-chloropyridine (obtained by washing a solution of the corresponding HCl salt (264 mg, 1.76 mmol) in CH2Cl2 (20 mL) with saturated K2CO3 (10 mL), then back extracting with CH2Cl2 (2×20 mL), combining the organic layers, drying (Na2SO4) and concentrating in vacuo) in hexanes (3.3 mL) was added dropwise by cannula. The solution became dark red in color and after 1 h at −78° C., a solution of the electrophile (prepared by adding isopropylmagnesium chloride (2M in THF, 1.29 mL, 2.59 mmol) to a solution of benzyl {(1S)-2-[methoxy(methyl)amino]-1-methyl-2-oxoethyl}carbamate (702 mg, 2.64 mmol) in dry THF (3.5 mL) at −15° C. under N2 and stirring for 15 min) was added by cannula. The reaction was allowed to warm slowly to room temperature overnight. Water (25 mL) and saturated NH4Cl (50 mL) were added and the mixture was extracted with EtOAc (3×50 mL). The combined extracts were dried (MgSO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Si, 40×160 mm, 0-30% EtOAc in hexanes gradient) to afford benzyl [(1S)-2-(4-chloropyridin-2-yl)-1-methyl-2-oxoethyl]carbamate. Rf=0.46 (20% EtOAc in hexanes). LCMS calc.=319.1; found=319.3 (M+1)+. 1H NMR (500 MHz, CDCl3) δ 8.58 (d, J=5.0 Hz, 1H), 8.04 (s, 1H), 7.47 (dd, J=5.2, 2.0 Hz, 1H), 7.35-7.30 (m, 5H), 5.78 (s, 1H), 5.72 (m, 1H), 5.11 (m, 2H), 1.47 (d, J=7.0 Hz, 3H).

Provenance & Evidence