Mechanistic Origins of Chemoselectivity in Trifluorodiazoethane [3 + 2] Cycloadditions: Pseudoradical Versus Zwitterionic Reactivity

Abstract The competition between the three-component synthesis of spiro-oxazolidine oxindoles and the two-component formation of spiro-cyclopropane-oxindoles from trifluorodiazoethane, nitrosoarenes, and phenacylideneoxindoles was investigated within the molecular electron density theory (MEDT) at the M06–2X/6–311G(d,p) computational level. The three-component domino process is initiated by a polar asynchronous one-step [3 + 2] cycloaddition (32CA) of nitrosobenzene with trifluorodiazoethane (ΔG‡ = 18.1 kcal/mol), followed by a nearly barrierless N2 extrusion to generate a zwitterionic nitrone intermediate. The resulting nitrone subsequently undergoes a second nonpolar 32CA reaction with the phenacylideneoxindole (ΔG‡ = 18.5 kcal/mol) to afford the spiro-oxazolidine-oxindole product. The competing two-component reaction between trifluorodiazoethane and phenacylideneoxindole was found to proceed preferentially through a close-shell two-stage one-step mechanism (ΔG‡ = 15.6 kcal/mol), whereas the alternative stepwise diradical pathway is kinetically disfavored. Subsequent N2 extrusion proceeds via an open-shell singlet transition state to form a diradical intermediate. ELF analysis reveals that trifluorodiazoethane exhibits pseudomonoradical (pmr-type) character, accounting for its enhanced reactivity relative to the zwitterionic nitrone and favors spiro-cyclopropane formation. Consequently, to obtain the desired spiro-oxazolidine-oxindole, a sequential addition protocol is required to suppress the kinetically dominant two-component route. This study establishes a mechanistic framework for understanding and controlling chemoselectivity in multicomponent reactions involving trifluorodiazoethane.