Alkanoylation of quinazoline by nucleophilic aromatic substitution: Combined experimental and computational study

Abstract A combined experimental and computational study on the key intermediatesof NHC-catalyzed acylationreaction, Breslow intermediates(BIs), has been conducted in order to achieve a direct nucleophilic alkanoylation of N -heterocycles. Various BI precursors are alternatively prepared and used in the reaction with 4-chloroquinazoline. The present study reveals that the intermediateshaving benzimidazole moiety serve as acylatingagents for the introduction of straight-chain alkanoyl groups. Natural bond orbitalanalysis indicates that the reactivity of intermediatespartly correlates to the occupancy of the π C-C bonds of the hydroxyl enaminemoieties. The putative rate-determining stepof the acylationreaction has been theoretically investigated. Several new 4-alkanoylquinazolines are synthesized using the BI precursors.