Investigation of 1,3,4-Oxadiazol-2(3H)-ones as Heterocyclic, Amidoisocyanate Precursors

Abstract

Isocyanate chemistry is well-known and has been studied and exploited for years. N-Isocyanate derivatives, however, are scarce and far less understood. These are divided in three subclasses: the aminoisocyanates, the iminoisocyanates, and the rarest of them all, the amido-isocyanates. The latter are underdeveloped and understudied. Herein, studies that resulted in evidence for the existence of N_β-amido–isocyanates, and validated their use in a masked isocyanate strategy, will be described. Suitable precursors, N_β-acyl phenylcarbazide derivatives (activated aza-dipeptides), were synthesized in the context of aza-tripeptide synthesis. The 1,3,4-oxadiazol-2(3H)-one intermediate was formed quickly in the course of the reaction, and an equilibrium between the free N_β-amido-isocyanate and the 1,3,4-oxadiazol-2(3H)-ones was established. Longer reaction times, in presence of amino amide nucleophiles, led to the formation of hydantoins or aza-tripeptides with full consumption of both the starting material and the oxadiazolone intermediate, yielded 14 hydantoins and 4 aza-tripeptides in 51-79% isolated yields. Experiments were performed to support the formation of an amido-isocyanate intermediate and discriminate between pathways possibly involving the formation of a tetrahedral oxyanionic intermediate versus the trapping of an N-isocyanate by a nucleophile. A control reaction in which the N_α in the starting material was methylated completely suppressed the formation of the isocyanate intermediate and shut down the reaction, lending supporting the isocyanate formation pathway. The hydrogen at this position is crucial for the formation of the isocyanate, which can be deprotonated and form a neutral isocyanate species. To further support the mechanistic hypothesis, established C-isocyanate chemistry, in which isocyanates react with carboxylates to form amides, was applied to a series of oxadiazolones. This transformation cannot occur in the absence of an isocyanate. This reaction yielded 8 different N_β-acyl hydrazides with moderate to good yields, again supporting the formation of the rare amido-isocyanates. Overall, this work supports the formation of amido-isocyanates in equilibrium with their corresponding 1,3,4-oxadiazol-2(3H)-ones and validated that the latter are masked amido-isocyanates, species that have been rarely studied in the literature.