Chiral N-triflylphosphoramide-catalyzed asymmetric hydroamination of unactivated alkenes: a hetero-ene reaction mechanism

A highly enantioselective intramolecular hydroamination reaction catalyzed by chiral N-triflylphosphoramide (NTPA) that features an exceptionally broad substrate scope of isolated unactivated alkenes was recently reported by some of us. Herein we report a detailed density functional theory (DFT) study that unveil an uncommon hetero-ene reaction mechanism for this transformation. The reaction changes from a stepwise mechanism involving discrete tertiary carbocation formation to a concerted mechanism to avoid the generation of energetically unfavorable secondary carbocation species for distinctly substituted alkene substrates. The reactivity of this reaction is primarily affected by the substituents on the internal carbon of the alkene, with the carbocation-stabilizing ones promoting the reaction. In addition, the reaction is also influenced by the substituents on the terminal alkene carbons: those diminishing the innate alkene polarization of the starting alkenes retard the reaction by disfavoring the formation of related transition states featuring highly polarized alkene residues. The steric effect of all these alkene substituents was found to be largely unimportant due to the unique arrangement of the hetero-ene reaction complex that keeps the reacting alkene away from the sterically congested core region of the catalyst pocket. The lower acidity of chiral phosphoric acids than that of chiral NTPAs renders the protonated precomplex along the hetero-ene reaction pathway greatly thermodynamically disfavored. This indirectly results in a greater relative distortion in the corresponding transition state, which in turn causes reaction retardation. Our results demonstrate the use of intramolecular pericyclic reactions as an alternative strategy for alkene activation by chiral Bronsted acid catalysis and provide insights into the further development of asymmetric hydrofunctionalization of unactivated alkenes.