Regioselective C-H Functionalization of Heteroarene N-Oxides Enabled by a Traceless Nucleophile

Angew Chem Int Ed Engl. 2020 Dec 7;59(50):22675-22683. doi: 10.1002/anie.202010597. Epub 2020 Oct 12.


Although N-alkenoxyheteroarenium salts have been widely used as umpoled synthons with nucleophilic (hetero)arenes, the use of electron-poor heteroarenes has remained unexplored. To overcome the inherent electron deficiency of quinolinium salts, a traceless nucleophile-triggered strategy was designed, wherein the quinolinium segment is converted into a dearomatized intermediate, thereby allowing simultaneous C8-functionalization of quinolines at room temperature. Experimental and computational studies support the traceless operation of a nucleophile, which enables the previously inaccessible transformation of N-alkenoxyheteroarenium salts. Remarkably, the generality of this strategy has been further demonstrated by broad applications in the regioselective C-H functionalization of other electron-deficient heteroarenes such as phenanthridine, isoquinoline, and pyridine N-oxides, offering a practical tool for the late-stage functionalization of complex biorelevant molecules.

Keywords: C−H functionalization; N-alkenoxyheteroarenium salts; regioselectivity; traceless nucleophile; umpolung.

Publication types

  • Research Support, Non-U.S. Gov't