Indole Synthesis by Conjugate Addition of Anilines to Activated Acetylenes and an Unusual Ligand-Free Copper(II)-Mediated Intramolecular Cross-Coupling

Authors

  • Detian Gao,

    1. Department of Chemistry, University of Calgary, Calgary, AB, T2N 1N4 (Canada), Fax: (+1) 403-289-9488
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  • Prof. Dr. Thomas G. Back

    Corresponding author
    1. Department of Chemistry, University of Calgary, Calgary, AB, T2N 1N4 (Canada), Fax: (+1) 403-289-9488
    • Department of Chemistry, University of Calgary, Calgary, AB, T2N 1N4 (Canada), Fax: (+1) 403-289-9488
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Abstract

A versatile new synthesis of indoles was achieved by the conjugate addition of N-formyl-2-haloanilines to acetylenic sulfones, ketones, and esters followed by a copper-catalyzed intramolecular C-arylation. The conjugate addition step was conducted under exceptionally mild conditions at room temperature in basic, aqueous DMF. Surprisingly, the C-arylation was performed most effectively by employing copper(II) acetate as the catalyst in the absence of external ligands, without the need for protection from air or water. An unusual feature of this process, for the case of acetylenic ketones, is the ability of the initial conjugate-addition product to serve as a ligand for the catalyst, which enables it to participate in the catalysis of its further transformation to the final indole product. Mechanistic studies, including EPR experiments, indicated that copper(II) is reduced to the active copper(I) species by the formate ion that is produced by the base-catalyzed hydrolysis of DMF. This process also served to recycle any copper(II) that was produced by the adventitious oxidation of copper(I), thereby preventing deactivation of the catalyst. Several examples of reactions involving acetylenic sulfones attached to a modified Merrifield resin demonstrated the feasibility of solid-phase synthesis of indoles by using this protocol, and tricyclic products were obtained in one pot by employing acetylenic sulfones that contain chloroalkyl substituents.

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