On the Role of 1-Hydroxybenzotriazole as an Epimerization Suppressant in Carbodiimide-Mediated Reactions

25 ON THE ROLE OF 1 -HYDROXYBENZOTRIAZOLE AS AN EPIMERIZATION SUPPRESSANT IN CARBODIIMIDE-MEDIATED REACTIONS 

FIGURE 2.26 On the role of 1-hydroxybenzotriazole as an epimerization suppressant in carbodiimide-mediated reactions. 

The existence of a protonated oxazolone has been demonstrated indirectly by a simple experiment. When p-nitrophenol was added to an excess of 2-alkoxy-5(4//)-oxazolone in dichloromethane, a yellow color appeared. The color persisted until all the p-nitrophenol had been consumed by the oxazolone. The anion of p-nitro-phenol is yellow. The explanation for the color of the mixture is the presence of the p-nitrophenoxide anion that was generated by abstraction of the proton by the oxazolone. In summary, protonation of the O-acylisourea suppresses the side reaction of oxazolone formation as well as the side reaction of A-acylurea formation and accelerates its consumption by enhancing its reactivity and generating an additional good nucleophile that consumes it. Protonation of the oxazolone suppresses epimerization by preventing its enolization and also increases the rate at which it is consumed.4 68 78 79 

DH Rich, J Singh. The carbodiimide method, in E Gross, J Meienhofer, eds. The Peptides Analysis, Synthesis, Biology, Academic, New York, 1979, Vol 1, pp 241-261. 

P Wipf, H Heimgartner. Coupling of peptides with C-terminal a,a-disubstituted a-amino acids via oxazol-5(47f)-one. Helv Chim Acta 69, 1153, 1986. 

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