Mechanistic and Thermodynamic Studies on Copper-Catalyzed Directing Group-Assisted C-4/C-8 Amination of Aryl Amines with Cyclic Amines.

In the mechanistic study, we studied the pyridine amide (PA)-directed 1-naphthylamine C-4/C-8 amination reaction in a Cu-catalyzed system with pyrazole as an oxidant and morpholine in an alkaline environment. We studied the three possible single-electron transfer (SET) pathways for the C-4 amination and found that the free radical-cation intermediate generated by the intermolecular SET step was more favorable. For the C-8 amination, the C8-H activation process occurs before the reaction with the cyclic amine, and the Cu complex formed by the base ion ligand makes the reaction easier. Then, the solvation and substituent effects of the rate-determining steps were discussed. Through theoretical research, the mechanism of the directing group-assisted copper-catalyzed remote amination of naphthylamines was better understood, and suitable substrates and solvents were screened. In the study of thermodynamics, the remote amination reaction involves two mechanisms in which the SET mechanism plays a vital role. Therefore, this study reveals a variety of quantitative structure-activity relationships between and structural parameters such as SOMO energy. In addition, the concerted metalation-deprotonation (CMD) mechanism is particularly important. The activation energy of the rate-determining step and the effects of different cyclic amines on the activation energy were further studied.