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(2)N(-)) were favorable since nucleophilic ones (such as CF(3)COO(-) and CH(3)COO(-)) 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(2)N]) have been identified as the best ILtype 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'.