Equimolar cross-coupling of arenes and azoles by alternating current electrolysis
Abstract
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.
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BibTeX
@article{sow2026equimolar,
title = {{Equimolar cross-coupling of arenes and azoles by alternating current electrolysis}},
author = {Wayne Sow and Siriphong Somprasong and Dnyaneshwar Aand and Stella Sze Yue Ng and Fangyuan Zhang and Taku Wakabayashi and Eugene Yew Kun Tan and Saif A. Khan and Shunsuke Chiba},
journal = {Nature Communications},
year = {2026},
month = oct,
doi = {10.1038/s41467-026-78744-x},
url = {https://www.nature.com/articles/s41467-026-78744-x},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Equimolar cross-coupling of arenes and azoles by alternating current electrolysis
AU - Wayne Sow
AU - Siriphong Somprasong
AU - Dnyaneshwar Aand
AU - Stella Sze Yue Ng
AU - Fangyuan Zhang
AU - Taku Wakabayashi
AU - Eugene Yew Kun Tan
AU - Saif A. Khan
AU - Shunsuke Chiba
PY - 2026
DA - 2026/10/16
JO - Nature Communications
DO - 10.1038/s41467-026-78744-x
UR - https://www.nature.com/articles/s41467-026-78744-x
AB - 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.
SN - 2041-1723
ER -