Computation Study on Copper-Catalyzed Aerobic Intramolecular Aminooxygenative CC Bond Cleavage to Imides: Different Roles of Mononuclear and Dinuclear Copper Complexes

Cu-catalyzed aerobic reactions are a powerful protocol for the synthesis of value-added chemicals based on the ideal oxidant O2. Despite the long research history, the mechanistic studies clarifying the details of the whole catalytic cycle, where Cu-O2 complexes and their derivatives directly participate in the conversion of substrates, are limited, leaving the mechanisms of emerging aerobic reactions far from understanding. Herein, a computational study on the mechanism of Cu-catalyzed aerobic aminooxygenation of alkene-tethered amides to imides is reported. It is found that the Cu­(I) precursor is not the active species but can generate two types of Cu­(II) complexes LCu­(OAc)­OH and LCu­(OAc)­OOR to start the aminooxygenation through the successive formation of dinuclear Cu­(III) oxo complex, dinuclear Cu­(II) hydroxide complex, and hetero-dinuclear Cu­(II)-Cu­(I) complex, followed by alkylperoxo radical capture with Cu­(I) species. LCu­(OAc)­OH catalyzes the aminooxygenation via a mononuclear mechanism, while LCu­(OAc)­OOR is an active intermediate therein. In the initial catalytic stage, LCu­(OAc)­OH transforms alkene-tethered amides to α-amidated aldehydes through N–H activation, amide isomerization, cyclization, alkyl radical release, alkyl radical capture by O2, alkylperoxo radical capture by in situ-generated Cu­(I) species to LCu­(OAc)­OOR, acetate-assisted proton-coupled electron transfer (PCET), and concerted PCET/O–O bond cleavage. In the second catalytic stage for the generation of imides from α-amidated aldehydes, the previously proposed aldehyde Cα–H pathway is possible, but it is more likely to generate CO2 and H2 as the byproducts. Instead, a more feasible pathway involving C­(O)–H activation to acyl radical, decarbonylation, and radical capture to LCu­(OAc)­OOR′ was discovered. The C­(O)–H activation pathway generates CO and H2O as the byproducts and is consistent with the experimental observations. The concerted PCET/O–O bond cleavage steps generating α-amidated aldehydes and imides have close energy barriers and both can be the rate-determining steps. The presented outcome revised and expanded the knowledge of Cu-catalyzed aerobic conversion of CC bonds and amide N–H bonds, highlighting the different roles of mononuclear and dinuclear copper complexes in the aerobic reactions and the in situ generation of Cu­(II) catalysts, respectively.