Cu-Catalyzed Three-Component Alkene Carboamination: Mechanistic Insights and Rational Design to Overcome Limitations

Herein,
we report mechanistic investigations into the
Cu-catalyzed
three-component carboamination of alkenes with α-halo carbonyls
and aryl amines via an oxocarbenium intermediate. Monitoring the reaction
reveals the formation of transient atom transfer radical addition
(ATRA) intermediates with both electron-neutral and deficient vinyl
arenes as well as unactivated alkenes. Based on our experimental studies
and density functional theory calculations, the oxocarbenium is generated
through atom transfer and subsequent intramolecular substitution.
Further, mechanistic factors that dictate the regioselectivity of
the nucleophilic attack onto the oxocarbenium to afford the γ-amino
ester, γ-iminolactone, or γ-lactone are discussed. A strategy
to overcome scope limitation with respect to unactivated alkenes is
developed using the mechanistic insights gained herein. Finally, we
demonstrate that under modified conditions, our Cu catalyst enables
the ATRA reaction between a variety of alkyl halides and vinyl arenes/α-olefins,
and we present a one-pot, two-step carbofunctionalization with an
array of nucleophiles through ATRA/SN2.