Theoretical Studies on the Competing Reaction Mechanisms of Phosphine-Catalyzed Annulation of Benzofuran-Derived Azadienes with Allyl Carbonates: [2 + 4] versus [4 + 2]

Spiro[benzofuran-cyclohexane] skeletons are intriguing structural motifs in organic chemistry, and synthetic chemists employ a variety of strategies that typically involve the formation of the spirocyclic center through cyclization or ring-closing reactions. However, predicting the possible mechanisms and origin of stereoselectivity in these reactions remains a challenge. In this study, we conducted a theoretical investigation into the competing mechanisms involving phosphine-catalyzed [2 + 4] and [4 + 2] annulation processes of benzofuran-derived azadienes (BDAs) with allyl carbonates and ynals. Our calculations revealed that the [2 + 4] annulation is more energetically favorable compared to the [4 + 2] annulation. For the mechanism of [2 + 4] annulation, phosphine initially undergoes nucleophilic attack on the allyl carbonate, resulting in the formation of a phosphorus ylide accompanied by the elimination of BocO^-. Subsequently, the <i>t</i>-BuO^- species acquires a proton from the phosphorus ylide, followed by an intermolecular Michael addition with BDAs. This is then followed by intramolecular cyclization to form a cyclohexatone structure. Finally, the cyclohexatone undergoes <i>t</i>-BuOH assisted enolization, resulting in the formation of the spiro[benzofuran-cyclohexane] derivative, accompanied by the release of the PEt₂Ph catalyst molecule. To elucidate the origin of diastereoselectivity, we also performed noncovalent interaction (NCI), atoms in molecules (AIM) analyses, and energy decomposition analysis (EDA). These investigations offer valuable insight into the general principles and detailed mechanisms underlying the synthesis of spiro[benzofuran-cyclohexane] skeletons with unique diastereoselectivity.