Computational Insights into the Mechanism of [4 + 2] Cycloaddition of Aza-ortho-quinone Methides with Terminal...

Aza-ortho-quinone methides (ao-QMs) are highly reactive intermediates that have emerged as versatile four-atom synthons for constructing nitrogen heterocycles via cycloaddition reactions. Employing density functional theory (DFT) calculations and a suite of wave function analysis methods, this work systematically elucidates the reaction pathways and regioselectivity of the [4 + 2] cycloaddition between the ao-QMs and ethynyl methyl ketone (AAE). The results show that the whole reaction includes the cycloaddition and aromatization stages. The cycloaddition stage belongs to a classical synergistic mechanism. The aromatization stage is a stepwise mechanism involving initial extraction of the acidic hydrogen by 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), followed by N-S bond cleavage, which is the origin of the regioselectivity. In addition, the Fukui function, average local ionization energy (ALIE), and molecular electrostatic potential (ESP) analysis confirm that the high electrophilicity of the acidic hydrogen in the key intermediate drives the DBU attack. The activation strain model and energy decomposition analysis further reveal that the pathway leading to the 2-substituted quinoline product exhibits stronger orbital interactions and more favorable noncovalent interactions. The regioselectivity is governed by an aromatization-driven reaction mode. Collectively, this work provides an in-depth understanding of the reaction mechanism and regioselectivity of [4 + 2] cycloaddition between ao-QMs and AAE.