The preparation and reactions of mixed anhydrides of N-alkoxycarbonylamino acids

Abstract

Pure mixed anhydrides R1OCO-Xxx-O-COOR2 (Xxx=NHCHRCO) have been obtained by reaction of N-alkoxycarbonyl-amino acids R1OCO-Xxx-OH with alkyl chloroformate R2OCOCl (R2 = methyl, ethyl, isobutyl, menthyl) in the presence of N-methylmorpholine or N-methylpiperidine (NMP) in dichloromethane at −5 °C, followed by washing the mixtures with aqueous solutions and removal of the solvent. R1OCO-Xxx-O-COOR2 (R2 = ethyl, tert-butyl) have been obtained by reaction of R1OCO-Xxx-O−•+HNMP with the corresponding dialkyl dicarbonates followed by the same work-up. Mixed anhydride generation is much slower when triethylamine is used as base. The initial reaction in the decomposition of mixed anhydrides is cyclization to the 2-alkoxy-5(4H)-oxazolone (R1O-oxazolone) followed by release of alcohol R2OH. Symmetrical anhydride (R1OCO-Xxx)2O and ester R1OCO-Xxx-OR2 are also formed. The ease of cyclization depends on R2, and is in the order methylsulfonylethyl (Ms) [Formula: see text] methyl/ethyl/isobutyl [Formula: see text] menthyl. R1OCO-Xxx-O-COOMs preparations contained a substantial amount of R1O-oxazolone. Attempts to use this reaction as a preparative procedure for obtaining R1O-oxazolones failed because they are too sensitive to hydrolysis and react too quickly with the product, forming the symmetrical anhydride. The effect of various parameters on the amount of urethane generated by aminolysis at the carbonate moiety of R1OCO-Xxx-O-COOR2 was examined without the uncertainty that any urethane arose from aminolysis of unconsumed chloroformate.