Role of 2-Hydroxyimines in Chiral Phosphoric Acid-Catalyzed Mannich-Type Reactions: Enhancing Reactivity and Selectivity via Dimerization

Chiral phosphoric acids (CPAs) have emerged as versatile catalysts for asymmetric catalysis, capable of transforming a wide selection of substrates with high stereoselectivities. However, the mechanistic role of higher aggregates in CPA-catalyzed reactions remains poorly understood, although increasing evidence suggests that dimeric and trimeric CPA species can promote challenging transformations. This work provides comprehensive experimental evidence demonstrating that special [CPA/imine]2 species critically enhance the reactivity and selectivity in CPA-catalyzed Mannich-type reactions with imines bearing an N-2-hydroxyphenyl moiety. Using low-temperature NMR spectroscopy, diffusion-ordered spectroscopy (DOSY), and molecular dynamics (MD) simulations, we revealed that imines with a N-2-hydroxyphenyl moiety promote the formation of dimeric [CPA/imine]2 aggregates, while monomeric CPA/imine complexes dominate, with imines lacking this moiety. [CPA/imine]2 formation is favored under low-temperature and high-concentration conditions. Dimers with sufficient structural flexibility provide enhanced reactivity, acidity, and selectivity. In contrast, at higher temperatures, where no [CPA/imine]2 aggregates are formed, the Mannich-type reaction proceeds inefficiently. A nonlinear effect analysis provided evidence of asymmetric amplification in the present Mannich-type reaction, proving the participation of aggregated species in the reaction pathway. Together, these results highlight the importance of controlling catalyst aggregation as a strategy to optimize the reactivity and selectivity in asymmetric organocatalysis.