Mechanistic Insights into Copper-Catalyzed Alkene Aminofluorination and Rational Design of a Metal-Free Strategy

The β-fluoroalkylamine motif holds great value in drug development due to the unique properties imparted by fluorine incorporation. Currently, the most promising way for accessing this motif involves alkene aminofluorination, which heavily relies on transition-metal (TM) catalysts. Inspired by a control experiment reported in a related previous study, we herein rationally design a novel metal-free strategy for alkene aminofluorinations. Quantum chemical calculations revealed that the desired aminofluorination pathway (ΔΔ<i>G</i>^‡ = 38.5 kcal/mol) is inherently less favorable than the competing alkene polymerization side reaction (ΔΔ<i>G</i>^‡ = 18.7 kcal/mol). To overcome this challenge, we utilized the Energy Decomposition Analysis with Natural Orbitals for Chemical Valence (EDA-NOCV) method to gain insight into various electrophilic amination reagents and found that N-halogeno-amines with weakened N-X bonds (X = F, Cl, Br, I) could be promising candidates for system optimization. Among these, N-I-amines proved most effective, steering the reaction toward aminofluorination. Further reaction kinetics simulations confirmed that the optimized system can achieve an 80% yield of β-fluoroalkylamines within 3 h at 343 K, which is comparable to experimentally reported transition metal-catalyzed system. Therefore, this study introduces a sustainable, metal-free approach for alkene aminofluorination via a radical chain mechanism, offering a greener alternative to the traditional TM-catalyzed process.