Revisiting the Ullmann-ether reaction: a concise and amenable synthesis of novel dibenzoxepino[4,5-d]pyrazoles by intramolecular etheration of 4,5-(o,o'-halohydroxy)arylpyrazoles

J Org Chem. 2002 Oct 18;67(21):7215-25. doi: 10.1021/jo025767j.

Abstract

A concise synthesis of a series of novel dibenzoxepino[4,5-d]pyrazoles was accomplished by implementation of an intramolecular Ullmann-ether reaction on o,o'-halohydroxy-4,5-diarylpyrazoles mediated by CuBr.DMS. An alternative useful approach based on the palladium-catalyzed biaryl-ether linkage formation (Buchwald-Hartwig reaction) was also successfully applied, offering limitations with regard to the steric demand of the substituents. The synthesis of the key o,o'-halohydroxy-4,5-diarylpyrazole intermediates proceeds through the construction of the heterocyclic ring by a tandem amine-exchange/heterocyclization sequence of 3-N,N-(dimethylamino)-1,2-diarylpropenones with phenylhydrazine followed by basic hydrolysis for deprotection. The enamino ketone precursors were conveniently prepared from the corresponding O-sulfonyloxy and O-benzoyloxy ortho-substituted 1,2-diarylethanones, starting from inexpensive salicylaldehyde or phenylacetic derivatives. Preliminary binding affinity experiments against peripheral and central nervous system receptors have been done with negative results.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Dibenzoxazepines / chemistry*
  • Ethers
  • Indicators and Reagents
  • Models, Molecular
  • Molecular Conformation
  • Pyrazoles / chemical synthesis*
  • Pyrazoles / chemistry*
  • Structure-Activity Relationship

Substances

  • Dibenzoxazepines
  • Ethers
  • Indicators and Reagents
  • Pyrazoles