Microwave-assisted esterification of N-acetyl-L-phenylalanine using modified Mukaiyama's reagents: A new approach involving ionic liquids

Abstract

Inspired by the concept of ionic liquids (ILs), this study modified the original Mukaiyama's reagent, 2-chloro-1-methylpyridinium iodide (m.p. 200-dec), from ionic solid into liquids by changing its anion. The esterification of N-acetyl-L-phenylalanine was investigated as a model reaction. The microwave irradiation was more effective in esterifying N-acetyl-L-phenylalanine than the conventional reflux method. The original Mukaiyama's reagent was modified into ILs through manipulating its anion. However, only non-nucleophilic anions (such as EtSO 4- and Tf 2N -) were favorable since nucleophilic ones (such as CF 3COO - and CH 3COO -) could exchange with chlorine resulting in non-reactive coupling reagents. Two modified Mukaiyama's compounds (i.e. hydrophilic [2-ClMePy][EtSO 4] and hydrophobic [2-ClMePy][Tf 2N]) have been identified as the best IL-type coupling reagents. The esterification reaction was greatly enhanced by using 1-methylimidazole as the base instead of conventional toxic tertiary amines, and by using excess amount of alcohols as solvents instead of dichloromethane. Overall, the method reported is effective and 'greener'. © 2008 by MDPI.