Three-component coupling approach for the synthesis of diverse heterocycles utilizing reactive nitrilium trapping

Org Lett. 2014 Mar 21;16(6):1668-71. doi: 10.1021/ol500328t. Epub 2014 Feb 28.


The formation of an unexpected heterocyclic scaffold, a benzoxazole, in a three-component reaction between a ketone, isocyanide, and 2-aminophenol was encountered. This reaction involved a benzo[b][1,4]oxazine intermediate resulting from intramolecular attack of the aminophenol hydroxyl group on the nitrilium ion. Unlike previous literature examples, the trapped nitrilium benzo[b][1,4]oxazine could readily be subjected to ring opening with bis-nucleophiles. The reaction scope includes simple linear as well as complex cyclic ketones and substituted 2-aminophenols. A representative benzoxazole product could be further diversified to yield drug-like compounds.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aminophenols / chemistry*
  • Benzoxazoles / chemical synthesis*
  • Benzoxazoles / chemistry
  • Ketones / chemistry*
  • Molecular Structure
  • Nitriles / chemical synthesis*
  • Nitriles / chemistry
  • Oxazines / chemistry*
  • Stereoisomerism


  • Aminophenols
  • Benzoxazoles
  • Ketones
  • Nitriles
  • Oxazines
  • 2-aminophenol