Methyl 2-chloropyridine-4-carboxylate → Methyl 2-(3,4-difluorobenzyl)isonicotinate

Participants

Reaction Conditions

Reaction Steps

Methyl 2-chloroisonicotinate (5.6 g, 32.64 mmol) and Pd(PPh3)4 (0.754 g, 0.65 mmol) were dissolved in THF (100 mL) under nitrogen. (3,4-Difluorobenzyl)zinc(II) bromide (0.5 M in THF) (100 mL, 50.00 mmol) was added and the brown solution was stirred at 60° C. overnight. The reaction was quenched by addition of methanol (50 mL). The solution was diluted with EtOAc and washed with NH4Cl (aq). The organic layer was dried over MgSO4, filtered and evaporated to yield a yellow oil. The compound was purified via Biotage, SNAP 340 g KP-SIL, eluent isocratic heptane/ethyl acetate 8:2 for 2 CV, then linear gradient heptane/ethyl acetate 8:2 to 5:5 over 6 CV to yield methyl 2-(3,4-difluorobenzyl)isonicotinate (7.7 g, 90%) as a yellow oil. 1H NMR (400 MHz, cdcl3) δ 3.93 (s, 3H), 4.16 (s, 2H), 6.94-7.01 (m, 1H), 7.02-7.12 (m, 2H), 7.66-7.71 (m, 2H), 8.70 (dd, 1H). MS m/z 264 (M+H)+

Provenance & Evidence