Mechanism and Reactivity Drivers of the Intramolecular Dearomative Didehydro-Diels–Alder Reaction

Ring-fused heteroarenes are essential building blocks found in a wide range of compounds, including pharmaceuticals, natural products, and organic materials. While the intramolecular dearomative didehydro-Diels–Alder (IMDDDA) reaction of heteroarenes is a powerful method for the synthesis of ring-fused heteroarenes, the reaction outcome is highly sensitive to the precursor heteroarenes, tether, and alkyne. Using a combination of experimental reaction kinetics, DFT calculations, and data science tools, we transformed this complex challenge into a clear understanding of precursor reactivity. Our analysis revealed a comprehensive reactivity picture by examining key steric and electronic factors of the precursor, including aromaticity, diene conformation, and HOMO–LUMO gap energies. We developed a two-variable multivariate linear regression model using forward stepwise selection, which highlights the critical role of vibrational frequencies and heteroarene type in predicting these complex reactivity trends.