The Acid Azide Method

It is interesting to note that activation in the form of acid azides (Curtius 1902), the sole competitor of the acid chloride procedure at the time of its discovery. 

These improvements, however, did not effect an inherent shortcoming of the azide method, the well studied Curtius rearrangement of acid azides to isocyanates  

The latter react with the amine component and produce urea denvatives R-N=C=0 + H2N-R —— R-NH-CO-NH-R  

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Hydrazides —> Azides. The acid azide method of peptide synthesis, for example of the protected dipeptide (3), has the advantage that no racemization of the peptide vomptments occurs. However, conversion of N-carbobenzoxy-S-benzyl-u-cysteine hydni/.lde (I) into the azide by reaction with nitrous acid under normal conditions (ITor ls considerable amide as by-product (Rt ONHNHNO — RCONH> + fiBaNHaOl. Amide formation can be lUDoraiiad hv onaratlna at hlah aoiditv and... 

Similar difficulties should be expected in cyclization by the acid azide method, where Curtius rearrangement generates a cyclic urea-derivative instead of the desired cyclic peptide ... 

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