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'.
Highlights
Amino acid esters are versatile intermediates for many synthetic reactions including peptide synthesis [1,2]
If its anion (I-) can be substituted by other anions, the melting point of this salt may be considerably lowered
As illustrated in Scheme 3, the Mukaiyama’s reaction is generally considered as a two-step strategy [16,17]: (1) a nucleophilic aromatic substitution of halogen atom (Cl) in Mukaiyama’s reagent by the carboxylate in L-3 under a basic condition, resulting in pyridinium salt 4; this is a fast step due to a facial displacement. (2) nucleophilic attack of methanol to give the key intermediate 5, which is further converted into N-acetyl phenylalanine methyl ester (6) and N-methyl-2-pyridone (7)
Summary
Amino acid esters are versatile intermediates for many synthetic reactions including peptide synthesis [1,2]. If its anion (I-) can be substituted by other anions (such as anions in 1b-1f of Scheme 1, which appear in common RTILs), the melting point of this salt may be considerably lowered Another advantage of such a modification is that the halogen exchange (Scheme 2) within the Mukaiyama’s reagent 1a results in a non-reactive form (N-methyl-2iodopyridinium chloride, 2); this non-reactive form is unable to activate the carboxylic acids [29]. We carried out the esterification of N-acetyl-L-phenylalanine (L-3) as a model reaction in achieving the following objectives: (1) substituting conventional heating with microwave irradiation; (2) making the process ‘greener’ (such as using excess alcohol as solvent instead of dichloromethane, and using 1-methylimidazole as the base instead of toxic triethylamine or tributylamine); (3) modifying the original Mukaiyama’s reagent into ILs
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