Copper-Catalyzed Hydrodifluoroalkylation of N-benzylacrylamides via Intramolecular 1,4-Hydrogen Atom Transfer: Reaction Development and Mechanistic Insights

A one-pot protocol for Cu(I)-catalyzed hydro-difluoroalkylation of benzyl-protected acrylamides to construct difluoropentanedioate compounds in moderate to excellent yields has been achieved by using the benzyl group as a traceless redox-active hydrogen donor. The mechanistic studies confirmed that the reaction proceeds by adding a difluoroalkyl radical to acrylamide, followed by unexpected intramolecular 1,4-hydrogen atom transfer (HAT) and SET oxidation reaction. DFT calculations demonstrate that the destabilizing steric repulsion is the key factor controlling the chemoselectivity, which switches from 1,4-HAT to 5-exo spirocyclization. This work provides an important basis for the 1,4-HAT reaction in theoretical and practical synthesis applications.

Automated summary

A Cu(I)-catalyzed one-pot protocol utilizing benzyl group as a traceless redox-active hydrogen donor has been successfully developed for the hydro-difluoroalkylation of benzyl-protected acrylamides, leading to difluoropentanedioate compounds in moderate to excellent yields. Mechanistic investigations revealed that the reaction proceeds through the addition of a difluoroalkyl radical to acrylamide, followed by unexpected intramolecular 1,4-hydrogen atom transfer (HAT) and SET oxidation reaction. DFT calculations indicated that the chemoselectivity is controlled by destabilizing steric repulsion, resulting in the switch from 1,4-HAT to 5-exo spirocyclization. This work provides a crucial foundation for the application of 1,4-HAT reaction in theoretical and practical synthesis.