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 beta-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 beta-addition (i.e., hetero-Michael addition) products. On the contrary, the formation of alpha-hydroxyl or alkoxyl amides through conjugate addition needs an alpha,beta-inverse addition. Nevertheless, a regio-inversed nucleophilic alpha-addition of oxygen-centered nucleophiles to alpha,beta-unsaturated carbonyl compounds still remains less explored because of the electronic mismatch. In this research, we discovered the first alpha-specific nucleophilic addition of alpha,beta-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 alpha,beta-unsaturated amides to take place alpha-nucleophilic addition other than the normal beta-addition.