Triethylamine-Promoted Oxidative Cyclodimerization of 2H-Azirine-2-carboxylates to Pyrimidine-4,6-dicarboxylates: Experimental and DFT Study

Abstract

An unprecedented oxidative cyclodimerization reaction of 2H-azirine-2-carboxylates to pyrimidine-4,6-dicarboxylates under heating with triethylamine in air is described. In this reaction, one azirine molecule undergoes formal cleavage across the C-C bond and another across the C=N bond. According to the experimental study and DFT calculations, the key steps of the reaction mechanism include nucleophilic addition of N,N-diethylhydroxylamine to an azirine to form an (aminooxy)aziridine, generation of an azomethine ylide, and its 1,3-dipolar cycloaddition to the second azirine molecule. The crucial condition for the synthesis of pyrimidines is generation of N,N-diethylhydroxylamine in the reaction mixture in a very low concentration, which is ensured by the slow oxidation of triethylamine with air oxygen. Addition of a radical initiator accelerated the reaction and resulted in higher yields of the pyrimidines. Under these conditions, the scope of the pyrimidine formation was elucidated, and a series of pyrimidines was synthesized.

2H‐Azirines: Recent Progress in Synthesis and Applications

“…[98] Recently, heating of 2H-azirine-2-carboxylates with triethylamine has achieved an oxidative cyclodimerization to give pyrimidine-4,6-dicarboxylates in rational yields (Scheme 61). [99] The reaction initiated by the slow generation of N,N-diethylhydroxylamine with oxygen in air, enabling nucleophilic addition with one azirine molecule and consequent cleavage of CÀ C to get azomethine ylide. According to the experimental study and DFT calculations, the formed azomethine ylide could capture another azirine molecule via 1,3-dipolar cycloaddition to afford fused adduct azirinopyrrolidines with rather low barriers (< 22.0 kcal/mol), which indirectly confirmed a thermodynamically favorable reaction path.…”

Stable 2-Azaallyl Salts as a Bridge between 2H-Azirines and Densely Functionalized 2H-Pyrroles

“…The opening of the azirine ring at the C–C bond in nucleophilic reactions is a very rare case. The recently reported reaction of methyl 3-phenyl-2 H -azirine-2-carboxylate with hydroxyl amine is the only example of such a process to date (Scheme , reaction 4) …”