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

Int J Mol Sci. 2008 Jan;9(1):33-44. doi: 10.3390/ijms9010033. Epub 2008 Jan 16.


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'.

Keywords: Mukaiyama's reagent; amino acid; esterification; ionic liquid; microwave.