Parallel synthesis of a library of benzoxazoles and benzothiazoles using ligand-accelerated copper-catalyzed cyclizations of ortho-halobenzanilides

J Org Chem. 2006 Mar 3;71(5):1802-8. doi: 10.1021/jo051927q.

Abstract

A general method for the formation of benzoxazoles via a copper-catalyzed cyclization of ortho-haloanilides is reported. This approach complements the more commonly used strategies for benzoxazole formation which require 2-aminophenols as substrates. The reaction involves an intramolecular C-O cross-coupling of the ortho-haloanilides and is believed to proceed via an oxidative insertion/reductive elimination pathway through a Cu(I)/Cu(III) manifold. The reaction is also applicable to the formation of benzothiazoles. A variety of ligands including 1,10-phenanthroline and N,N'-dimethylethylenediamine were shown to provide ligand acceleration/stabilization in the reaction. Optimal conditions for cyclization used a catalyst combination of CuI and 1,10-phenanthroline (10 mol %). The method was amenable to a parallel-synthesis approach, as demonstrated by the synthesis of a library of benzoxazoles and benzothiazoles substituted at various positions in the ring. Most examples utilized the cyclization of ortho-bromoanilides, but ortho-iodoanilides and ortho-chloroanilides also undergo a reaction under these conditions. The rate of reaction of the ortho-haloanilides follows the order I > Br > Cl, consistent with oxidative addition being the rate-determining step.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anilides / chemistry*
  • Benzothiazoles / chemical synthesis*
  • Benzoxazoles / chemical synthesis*
  • Catalysis
  • Combinatorial Chemistry Techniques*
  • Copper / chemistry*
  • Cyclization
  • Ethylenediamines / chemistry
  • Ligands
  • Palladium / chemistry
  • Phenanthrolines / chemistry
  • Temperature

Substances

  • Anilides
  • Benzothiazoles
  • Benzoxazoles
  • Ethylenediamines
  • Ligands
  • Phenanthrolines
  • dimethylethylenediamine
  • Palladium
  • Copper
  • 1,10-phenanthroline