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Issue 2, 2013
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Combining Zn ion catalysis with homogeneous gold catalysis: an efficient annulation approach to N-protected indoles

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Abstract

The Fischer indole synthesis is perhaps the most powerful method for indole preparation, but it often suffers from low regioselectivities with unsymmetrical aliphatic ketone substrates and strongly acidic conditions and is not suitable for α,β-unsaturated ketones. In this edge article, we disclose an efficient synthesis of N-protected indoles from N-arylhydroxamic acids/N-aryl-N-hydroxycarbamates and a variety of alkynes via cooperative gold and zinc catalysis. The zinc catalysis is similar to the related zinc ion catalysis in metalloenzymes such as human carbonic anhydrase II and substantially enhances the O-nucleophilicity of N-acylated hydroxylamine by forming the corresponding Zn chelates. The Zn chelates can attack gold-activated alkynes to form O-alkenyl-N-arylhydroxamates, which can undergo facile 3,3-sigmatropic rearrangements and subsequent cyclodehydrations to yield N-protected indole products. This new chemistry offers several important improvements over the Fischer indole synthesis: (a) the reaction conditions are mildly acidic and can tolerate sensitive groups such as Boc; (b) broader substrate scopes including substrates with pendant carbonyl groups (reactive in the Fischer chemistry) and alkyl chlorides; (c) better regioselectivities for the formation of 2-substituted indoles under much milder conditions; (d) 2-alkenylindoles can be prepared readily in good to excellent yields, for which Fischer chemistry could not be used; (e) with internal alkynes both steric and electronic controls are available for achieving good regioselectivities, while Fischer chemistry is in general problematic.

Graphical abstract: Combining Zn ion catalysis with homogeneous gold catalysis: an efficient annulation approach to N-protected indoles

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Publication details

The article was received on 23 Aug 2012, accepted on 07 Nov 2012 and first published on 05 Dec 2012


Article type: Edge Article
DOI: 10.1039/C2SC21333H
Citation: Chem. Sci., 2013,4, 739-746
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    Combining Zn ion catalysis with homogeneous gold catalysis: an efficient annulation approach to N-protected indoles

    Y. Wang, L. Liu and L. Zhang, Chem. Sci., 2013, 4, 739
    DOI: 10.1039/C2SC21333H

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