Nitrogen → 4-Iodo-2-methoxynicotinaldehyde

Participants

Reaction Conditions

Reaction Steps

To a solution of diisopropylamine (345 mL, 249 g, 2.46 mol) in anhydrous THF (5 L) at −8 to −10° C. under a blanket of N2 was added n-BuLi (880 mL, 158 g, 2.46 mol) dropwise via cannula. The mixture was stirred at −10° C. for 30 min, cooled to −78° C. and treated with a solution of 2-fluoro-3-iodopyridine (500 g, 2.24 mol) in dry THF (2 L) dropwise. After the addition, the reaction mixture was warmed to −60° C. and this temperature was maintained for 2 h. The mixture was then cooled to −78° C., treated with ethyl formate (183 g, 2.47 mol) dropwise, followed by sodium methoxide (149 g, 2.75 mol) in MeOH (1.5 L) and warmed to ambient temperature. The reaction mixture was quenched with ice water and extracted with EtOAc. The layers were separated and the organic phase was washed with water and brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography on silica gel to afford 4-iodo-2-methoxynicotinaldehyde (380 g, 64%) as a solid. Alternatively, 4-iodo-2-methoxynicotinaldehyde can be prepared according to the procedure described in U.S. Pat. No. 5,491,237 (WO 95/29917).

Provenance & Evidence