Synthesis
The general procedure for the synthesis of N-benzyl-L-prolinol from (R)-1-benzylpyrrolidine-2-carboxylic acid methyl ester was as follows: under nitrogen atmosphere, 25.75 g (0.68 mol) of lithium aluminum hydride (LiAlH4) was slowly added through a powder funnel into a cooled anhydrous (S)-1-benzylpyrrolidine-2-carboxylic acid methyl ester (49.6 g, 0.23 mol) tetrahydrofuran (THF, 400 mL) solution. The reaction mixture was stirred at 0 °C for 1 h and then gradually warmed up to room temperature followed by refluxing for 3 h. The reaction was carried out by stirring at 0 °C for 1 h. The reaction mixture was then refluxed for 3 h. Upon completion of the reaction, the mixture was cooled to 0 °C again to quench the reaction. The quenching process was carried out by carefully adding the cold reaction mixture to 1.5 L of ice in a 4 L conical flask fitted with a cooling bath. After the ice melted, the resulting suspension was filtered through a diatomaceous earth pad to remove the alkaline material and the solid residue was washed with 300 mL of hot ethyl acetate. The resulting biphasic filtrate was separated, the THF in the aqueous layer was removed by rotary evaporator and the residual liquid was re-extracted with an equal amount of cold ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate (Na2SO4) and concentrated, and the crude product was distilled under reduced pressure (110 °C, 1.5 mmHg) to afford 41.8 g (0.22 mol) of the target product, N-benzyl-L-prolinol ((S)-5), as a colorless liquid of 97% purity.
References
[1] Heterocycles, 2012, vol. 86, # 2, p. 1275 - 1300
[2] Letters in Organic Chemistry, 2018, vol. 15, # 5, p. 352 - 358
[3] Journal of Organic Chemistry, 2016, vol. 81, # 18, p. 8625 - 8632
[4] Tetrahedron, 2011, vol. 67, # 7, p. 1485 - 1500
[5] European Journal of Organic Chemistry, 2002, # 19, p. 3304 - 3314
