1-Piperidinecarboxaldehyde → 2-Methoxy-5-(methoxymethoxy)-4-pyridinecarboxaldehyde

Participants

Reaction Conditions

Reaction Steps

To a solution of 2-methoxy-5-(methoxymethoxy)pyridine (20 g, 0.12 mol) in THF was added diisopropylamine (0.24 g, 2.4 mmol). The solution was cooled to −40° C. followed by addition of MeLi (3M/THF, 72 mL, 0.216 mol) slowly. The resulting mixture was warmed to 0° C., stirred at 0° C. for 3 h, cooled back down to −40° C. and added N-formylpiperidine (24 mL, 0.216 mol). After stirring at −40° C. for 2 h, the mixture was quenched with a mixed solution of HCl (37%, 120 mL) and THF (250 mL). The temperature was then raised to rt and diluted with water (200 mL) and EtOAc (200 mL). The pH of the mixture was adjusted to 8-9 with solid K2CO3 and extracted with EtOAc (300 mL) twice. The organic layer was combined, dried over Na2SO4, and concentrated. The residue was purified on silica gel with 25% EtOAc/hexanes as eluent to give 2-methoxy-5-(methoxymethoxy)isonicotinaldehyde (10 g, 42%) as a pale yellow oil. 1H NMR (400 MHz; CD3OD) 7.90 (s, 1H), 6.92 (s, 1H), 5.64 (s, 1H), 5.20 (s, 2H), 3.84 (s, 3H), 3.48 (s, 3H).

Provenance & Evidence