Binuclear Copper-Catalyzed Enantioselective C,N-Dipolar (3 + 2) Cycloadditions: Mechanistic Insights and Selectivity Control via DFT Analysis

2-Aminoallyl cations serve as highly versatile intermediates in organic synthesis. Their cycloaddition with unsaturated compounds provides an efficient strategy for the construction of heterocycles, which are key structural motifs found in a wide range of natural products, bioactive molecules, and agrochemicals. The mechanism and enantioselectivity of the C,N-dipolar (3 + 2) cycloaddition of 2-aminoallyl cations with indoles have been investigated using density functional theory (DFT). We proposed that binuclear copper-assisted decarboxylation produces the 2-aminoallyl cation from ethynyl methylene cyclic carbamates (EMCCs), which then undergoes an enantioselective (3 + 2) cycloaddition reaction with indoles to yield the final product. Our results indicate that the concerted mechanism is more favorable than the stepwise mechanism. The concerted mechanism involves asynchronous bond formation processes. The enantioselectivity is predominantly governed by the distortion energy. The atomic dipole moment corrected Hirshfeld (ADCH) charge indicates that the regioselectivity is determined by the charge matching principle. The electron-poor carbon (C4: + 0.033) of the indole preferentially reacts with the nitrogen atom (N2: - 1.010) of the dipolar intermediate, leading to the formation of the major product. To validate the binuclear activation hypothesis, we computationally rationalized that chiral benzo[<i>c</i>]cinnoline-dioxazoline-supported binuclear copper catalysts ([L₁(Cu)₂]²⁺) exhibit enhanced catalytic efficiency for the C,N-dipolar (3 + 2) cycloaddition reaction.