DFT Investigation of 2-Aminothiazole-Catalyzed Five-Component Reaction of CO2 /Amines/Aldehydes: Multi-Species Synergistic Activation and Chemoselective Control in N-Methylation

Abstract

This study employs density functional theory (DFT) calculations to elucidate the mechanism of a five-component reductive amination reaction involving aldehydes, amines, CO2, BH3•NMe3, and 2-aminothiazole-derived catalysts, with a central focus on establishing the catalyst-mediated multi-species synergistic activation paradigm.The catalytic pathway proceeds via six sequentially coupled stages: (I) amine-aldehyde condensation, (II) imine formation, (III) CO2 reduction to formamide, (IV) formamide reduction, (V) catalyst regeneration, and (VI) generation of the methylated amine. Computational analysis identifies a complex network of 61 intermediates and transition states, where the catalyst functions as a "synergistic hub" coordinating substrates (amines, aldehydes, CO2), reductant (BH3•NMe3), and reaction intermediates. Boron-mediated hydride transfers, enabled by this synergistic coordination, drive the triple reduction of CO2-derived carbon. The catalyst's N-C-N moiety serves as a dual-functional scaffold: one Lewis base center coordinates with the boron Lewis acid (from BH3•NMe3), while the other forms dual C-H•••N hydrogen bonds with intermediates. This multi-species interaction stabilizes key transition states, lowering the dehydrogenation barrier by 3.8 kcal/mol compared to non-catalytic pathways and enabling chemoselective methylation. Additionally, bio-derived catalysts incorporating the N-C-N moiety recapitulate this multi-species synergistic effect, demonstrating feasible catalytic activity for CO2-mediated reductive methylation under mild conditions. This study establishes a carbon-negative framework for high-value N-methylamine synthesis and provides a rational design principle for catalysts in complex multi-component reactions.