Pd(ii)-catalyzed aerobic dual C–N bond formation: oxygen-dependent divergence between dihydroquinazolinone and aza-Michael pathways, an experimental and computational study

Abstract

We report an aerobic three-component reaction of isatoic anhydrides, anilines, and acrylamides that simultaneously forms two distinct C–N bonds through two sequential Pd(II)-catalyzed cycles, affording 2,3-dihydroquinazolin-4(1H)-ones (DHQs) incorporating β-amino carbonyl motifs. The presence of O₂ is essential for the chemoselective formation of DHQs; in its absence, the reaction instead affords the competing aza-Michael adduct. To understand the origin of this chemoselectivity, we investigated the mechanistic details of the reaction using DFT calculations. Our results reveal that, in the pathway leading to DHQs, the first C–N bond is formed through a Pd(II)-catalyzed oxidative C–H/N–H coupling, for which O₂ is indispensable. O₂ reacts with a Pd–H intermediate formed in the cycle, generating a Pd–hydroperoxide species that promotes catalyst turnover via H₂O₂ release. The second C–N bond is then formed through an intramolecular nucleophilic addition, furnishing the cyclic DHQ scaffold.