Dimethylformamide → (S)-3-formyl-5-(1-methylpyrrolidin-2-yl)-4H-pyridine-1-carboxylic Acid Methyl Ester

Participants

Reaction Steps

To a solution of DMF (0.04 mL, 0.54 mmol) in 4 mL of CH2Cl2 cooled at 0° C. was slowly added POCl3 (0.025 mL, 0.27 mmol). The ice bath was removed and the mixture was stirred at RT for 30 min. It was then transferred via a double tipped needle to a solution of 3-(1-methyl-pyrrolidin-2-yl)-4H-pyridine-1-carboxylic acid methyl ester II (0.0404 g, 0.18 mmol) in 4 mL of CH2Cl2 cooled at 0° C. The reaction mixture was stirred at RT for 1 day. A solution of NaOAc (0.024 g, 0.29 mmol) in 0.5 mL of water was added and the reaction mixture was stirred at RT for 20 min. A saturated aqueous solution of NaHCO3 was slowly added until pH was basic (about 10 mL). The aqueous layer was extracted with CH2Cl2 (4 times), and the combined organic layers were dried over MgSO4. After evaporation of the solvent under reduced pressure, the crude material was purified by RPLC (15% EtOAc/hexanes) to afford 0.0241 g (54%) of (S)-3-formyl-5-(1-methylpyrrolidin-2-yl)-4H-pyridine-1-carboxylic acid methyl ester III as white crystals, mp 78–80° C. IR (thin film, neat, NaCl): 2955, 2767, 1731, 1667, 1620, 1437, 1394, 1203, 991 cm−1; 1H NMR (CDCl3, 300 MHz) δ 9.45 (s, 1 H), 7.65 (m, 1 H), 6.81 (s, 1 H), 3.91 (s, 3 H), 3.12–3.07 (m, 1 H), 2.93 (s, 2 H), 2.59 (m, 1 H), 2.20–2.12 (m, 3 H), 1.81–1.62 (m, 5 H); 13C NMR (CDCl3, 75 MHz) δ 191.13, 141.44, 122.61, 120.52, 118.42, 69.75, 56.98, 54.47, 40.61, 29.45, 22.91, 19.86. HRMS Calcd for C13H18N2O3: 251.1396 [M+H]+. Found: 251.1390 [M+H]+. [α]25D−51.7 (c=0.8, CH2Cl2).

Provenance & Evidence