Copper-Catalyzed Cascade Cycloamination Of α-Csp~3-H Bond Of N-Aryl Ketoimines With Azides

Transition-metal-catalyzed C-H bond cycloamination reactions provide an atom- and step-economical strategy to construct various C-N bonds. It has always been a challenging research field in organic synthetic chemistry to use the above strategy to rapidly construct complex N-heterocycles. The quinoxaline skeleton is a privileged core structure in many natural products and medical molecules, and its derivatives are commonly encountered in agricultural chemistry, biochemistry and materials chemistry. Traditional synthesis methods of quinoxalines suffer from many problems such as poor atom economy, high cost of raw material and multi-steps. Therefore, it has important scientific and applied value in enriching the research contents of N-heterocyclic chemical research to develop a simple and green way to synthesise quinoxaline ketoneses.In this context, we report the copper-catalyzed C-H bond cascade cycloamination to form quinoxaline derivatives. Through the reasonable design of substrates and screening nitrogen source, we explored a copper-catalyzed alpha-Csp³-H bond cycloamination of N-aryl ketimines. After in-depth optimization, Cu O was superior to be the best copper catalyst for the contruction of 2-phenylquinoxaline under Ph I（OAc）2/Piv OH system with NaN₃ through alpha-Csp³-H bond activation. This method tolerates a wide range of readily available N-aryl ketoimines with diverse functional groups and afforded moderate to excellent yields. For instance, ketoimines with diverse functional groups such as –OH and –Br at C-aryl rings afforded moderate yields of 55 % and 60 %, respectively. In addition, strong electron-withdrawing group such as-NO2 and –COOMe at C-aryl rings also obtainted high conversions. The electron-donating N- phenyl ring afforded quinoxaline in good to excellent yields while the electron-withdrawing group at N- phenyl rings provided moderate yields of products due to that the electronic properties of N- phenyl ring have a great influence on the reactivity. Control experiments indicate that no desired quinoxaline was observed if the reation was conducted in the absence of Cu O or in the presence of 2 equiv of TEMPO. This means that Cu O catalyst is crucial for this transformation, and a SET process and radical intermediates was possibly involved in this reaction. Based on these control experimental results, a plausible mechanism is proposed for copper-catalyzed cycloamination of alpha-Csp³-H bond of N-aryl ketimines.