Pd-Catalyzed Ring Assembly by Vinylation and Intramolecular Heck Coupling: A Versatile Strategy Towards Functionalized Azadibenzocyclooctynes

Authors

  • Dr. Michael Jäger ,

    1. Laboratory of Organic and Macromolecular Chemistry (IOMC), Jena Center for Soft Matter (JCSM), Friedrich-Schiller-University Jena, Humboldtstraße 10, 07743 Jena (Germany), Fax: (+49) 3641-948-202
    2. Dutch Polymer Institute (DPI), John F. Kennedylaan 2, 5612 AB Eindhoven (The Netherlands)
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  • Dr. Helmar Görls,

    1. Institute of Analytical and Inorganic Chemistry (IAAC), Humboldtstraße 2, 07743 Jena (Germany)
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  • Dr. Wolfgang Günther,

    1. Laboratory of Organic and Macromolecular Chemistry (IOMC), Jena Center for Soft Matter (JCSM), Friedrich-Schiller-University Jena, Humboldtstraße 10, 07743 Jena (Germany), Fax: (+49) 3641-948-202
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  • Prof. Dr. Ulrich S. Schubert 

    Corresponding author
    1. Laboratory of Organic and Macromolecular Chemistry (IOMC), Jena Center for Soft Matter (JCSM), Friedrich-Schiller-University Jena, Humboldtstraße 10, 07743 Jena (Germany), Fax: (+49) 3641-948-202
    2. Dutch Polymer Institute (DPI), John F. Kennedylaan 2, 5612 AB Eindhoven (The Netherlands)
    • Laboratory of Organic and Macromolecular Chemistry (IOMC), Jena Center for Soft Matter (JCSM), Friedrich-Schiller-University Jena, Humboldtstraße 10, 07743 Jena (Germany), Fax: (+49) 3641-948-202
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Abstract

A new modular approach based on Pd-catalyzed C[BOND]C bond formation is presented for the assembly of a benzannulated azocine scaffold, the key intermediate in the synthesis of functionalized azadibenzocyclooctynes (aza-DIBOs). The intramolecular ring-closing Heck coupling was investigated by variation of the C[BOND]X bond. The reaction rate is limited by the initial oxidative addition step and the regiochemistry strongly depends on the auxiliary phosphine. Under optimized conditions, the 8-endo regioisomer was obtained in 71 % yield over two steps (with no protecting group chemistry) or in one pot, inclusive of C[BOND]N bond formation. The practical generation of the octyne triple bond of a prototypical N-benzoyl aza-DIBO, without the need for chromatographic purification, is also described. The structural features, including those of the ring-strained cyclic octyne, were elucidated by NMR spectroscopy and X-ray crystallographic analysis. The high reactivity of the N-benzoyl aza-DIBO synthesized is demonstrated in a strain-promoted azide–alkyne cycloaddition reaction with an alkyl azide (k=0.38 M−1 s−1).

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