AZA-ANNULATION REACTION FOR THE SYNTHESIS OF BIO-RELEVANT ALIPHATIC HETEROCYCLES

Abstract

Aza-heterocyclic compounds, particularly those with γ-lactams moiety, serve an important role in pharmaceuticals, agrochemicals, and materials science owing to their diverse biological application. Studies have shown that about 60% of drugs sold on the market contain azaheterocycles. Due to these important applications of aza-heterocyclic compounds, several strategies such as annulation, cyclization, cycloaddition, cycloisomerization, and fragmentation have been applied to synthesize different scaffolds of the heterocyclic compounds. However, aza-annulation is one of the simplest yet most efficient strategies for constructing aza-heterocycles since it enables rapid molecular complexity buildup, high diastereoselectivity, and minimal reaction steps. This research employed an aza-annulation reaction to construct aza-heterocyclic compound building blocks and investigated their diversification. The synthetic approach encompasses the condensation of ethyl acetoacetate with primary amines to generate enamines, followed by the aza-annulation with maleic anhydride to afford γ-lactams. Interestingly, the esterification of the carboxylic acid functionality in the aza-annulation product, followed by alkylation, resulted in a single product as a result of selective alkylation at the α-position to the γlactam for all the electrophiles (35-75%) except for iodobutane, which provided both alkylation of the enolate oxygen of the γ-lactam and the C-alkylation. The decarboxylation reaction of the aza-annulation products proceeded smoothly at 180-220 °C to afford two regioisomers (92%) in the ratio of 1:1, which upon alkylation with different electrophiles produced a single product (23-58%). In total, fourteen diversified scaffolds of the aza-heterocyclic compound have been constructed demonstrating a promising approach to accessing bio-relevant aza-heterocyclic scaffolds for future applications in pharmaceutical science.