Chemistry of amino acid thionoester derivatives. An unexpected change in the reaction course between heterocyclic‐2‐carboxylic acid hydrazides and N‐substituted thionoglycinates. Preferential formation of 4‐amino‐1,2,4‐triazole adducts over 1,3,4‐oxadiazole products
Authors: Sikorski James A. , Mischke Deborah A. , Schulte Brett J. 
Published: April 2009

The reaction between benzoic acid hydrazides and ethyl N‐carbobenzyloxythionoglycinate produces the expected 2‐aminomethyl‐1,3,4‐oxadiazoles in good yield. Heterocyclic carboxylic acid hydrazides give similar products when the hydrazide moiety is located at either the three or four position (relative to the heteroatom) in the ring. However, when heterocyclic‐2‐carboxylic acid hydrazides are utilized, oxadiazole formation is dramatically reduced. Instead, the intermediate imidates are usually isolated as the major products of the reaction from one equivalent of these hydrazides. These imidate products are accompanied by significant amounts of 4‐amino‐1,2,4‐triazole derivatives which arise from incorporation of two equivalents of the hydrazide. The structure of these unexpected 4‐aminotriazole products was confirmed by nmr and mass spectral data as well as an X‐ray analysis. In the presence of a stoichiometric amount of these hydrazides, the 4‐aminotriazoles become the major products of the reaction. This phenomenon was found to be general for 2‐thienyl, 2‐furoic, picolinic, and pyrazinoic acid hydrazides. The intermediate imidates for each of these systems were isolated, characterized and found to have a remarkable thermal stability. Conversion of these imidates to the corresponding 1,3,4‐oxadiazoles could only be accomplished in hot acetic anhydride. A mechanistic rationale is presented which suggests that some stabilization of the intermediate imidate must occur in these examples which allows an intermolecular process to compete so effectively with an intramolecular cyclization. Since the cyclization to oxadiazole is presumed to be acid catalyzed, this stabilization is proposed to occur specifically by the formation of a hydrogen bond between the ring heteroatom and the proton‐ated imino nitrogen present in the imidate prior to cyclization. The formation of such a hydrogen bond removes the carboxylate oxygen from its opportune position for cyclization, while the protonated imino nitrogen can still activate the imidate for subsequent reaction with a second equivalent of hydrazide. In all cases where this heteroatom is capable of hydrogen bond formation, 4‐aminotriazoles predominate. The relative amount of 4‐aminotriazole product is directly correlatable with the donor capability of the ring hetero‐atom. This proposed model was tested by examining a system where steric congestion would be expected to prevent hydrogen bond formation. Indeed, when N‐methyl‐2‐pyrrole carboxylic acid hydrazide was utilized in the reaction, the corresponding 1,3,4‐oxadiazole was formed as expected in high yield. Conversely, an acyclic aliphatic hydrazide specifically bearing a beta heteroatom (N‐carbobenzyloxyglycine hydrazide) produced the expected 4‐aminotriazole adduct in high yield. This therefore appears to be a general phenomenon which provides a useful synthetic entry to several new unsymmetrically substituted 4‐amino‐1,2,4‐triazole derivatives.