Parallel Synthesis of a Library of Benzoxazoles and Benzothiazoles Using Ligand-Accelerated Copper-Catalyzed Cyclizations of ortho-Halobenzanilides

Ghotas Evindar and Robert A. Batey*
Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, Ontario, Canada M5S 3H6
J. Org. Chem., 2006, 71 (5), pp 1802–1808
DOI: 10.1021/jo051927q
Publication Date (Web): January 31, 2006
Copyright © 2006 American Chemical Society
*

 To whom correspondence should be addressed. Phone/Fax:  416-978-5059.

, rbatey@chem.utoronto.ca

Abstract

Abstract Image

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.

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History

  • Published In Issue March 03, 2006
  • Received September 14, 2005

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