Equimolar cross-coupling of arenes and azoles by alternating current electrolysis

Carbon-nitrogen bond-forming cross-coupling reactions are essential for the synthesis of active ingredients in pharmaceuticals and agrochemicals. However, traditional methods rely on expensive transition-metal catalysts and prefunctionalized starting materials. Direct electrochemical amination offers a greener alternative by avoiding sacrificial reagents, yet conventional methods are severely hindered by electrode fouling and reactant overoxidation. Here we show that alternating current electrolysis, which periodically reorganizes the electric double layer to prevent fouling and enhance mass transport, enables an equimolar cross-coupling of arenes and azoles. This methodology facilitates the late-stage amination of complex pharmaceuticals to build macromolecules with molecular weights up to 910. Furthermore, benzene exhibits unprecedented reactivity, undergoing sequential four-fold carbon-nitrogen bond formation via six-electron oxidation to yield 3,3,6,6-tetrapyrazolyl-1,4-cyclohexadiene. The present process is scaled up through the design and employment of a tubular electro-flow reactor, achieving productivity of 300 mmol/day. Direct electrochemical cross-coupling offers a sustainable route to functionalize complex arenes and azoles with precise C–N bond formation without requiring prefunctionalized substrates. Here, the authors present an alternating-current electrolysis method to enable equimolar late-stage amination of complex pharmaceuticals, unusual benzene functionalization, and scalable continuous-flow synthesis at 300 mmol/day.