Discovery of Oxygen α‑Nucleophilic Addition to α,β-Unsaturated Amides Catalyzed by Redox-Neutral Organic Photoreductant

The conjugate additions of oxygen-centered
nucleophiles to conjugate
acceptors are among the most powerful C–O bond formation reactions.
The conjugate addition normally takes place at the β-position
carbon to the electron-withdrawing group, resulting in the formation
of a stabilized carbanion intermediate that can be quenched by proton
or electrophiles to form the β-addition (i.e., hetero-Michael
addition) products. On the contrary, the formation of α-hydroxyl
or alkoxyl amides through conjugate addition needs an α,β-inverse
addition. Nevertheless, a regio-inversed nucleophilic α-addition
of oxygen-centered nucleophiles to α,β-unsaturated carbonyl
compounds still remains less explored because of the electronic mismatch.
In this research, we discovered the first α-specific nucleophilic
addition of α,β-unsaturated amides with oxygen and fluoride
nucleophiles. This region-inversed nucleophilic addition is enabled
by the catalysis of a novel redox-neutral nondonor–acceptor
organic photoreductant (CBZ6). As low as 0.5 mol % of
visible light photoreductant was employed. The mechanistic insights
were also explored. The oxidative potential of the excited state of CBZ6 is obtained in −1.92 V (vs SCE), presenting a
stronger reductive potential than representative metal-cored or organic
photoredox catalysts. This feature enabled the umpolung of α,β-unsaturated
amides to take place α-nucleophilic addition other than the
normal β-addition.