Alkyne–Azide Cycloadditions with Copper Powder in a High-Pressure Continuous-Flow Reactor: High-Temperature Conditions versus the Role of Additives

Authors

  • Sándor B. Ötvös,

    1. Institute of Pharmaceutical Chemistry, University of Szeged, H-6720 Szeged, Eötvös u. 6 (Hungary), Fax: (+36) 62-545-705
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  • Dr. István M. Mándity,

    1. Institute of Pharmaceutical Chemistry, University of Szeged, H-6720 Szeged, Eötvös u. 6 (Hungary), Fax: (+36) 62-545-705
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  • Dr. Lóránd Kiss,

    1. Institute of Pharmaceutical Chemistry, University of Szeged, H-6720 Szeged, Eötvös u. 6 (Hungary), Fax: (+36) 62-545-705
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  • Prof. Dr. Ferenc Fülöp

    Corresponding author
    1. Institute of Pharmaceutical Chemistry, University of Szeged, H-6720 Szeged, Eötvös u. 6 (Hungary), Fax: (+36) 62-545-705
    • Institute of Pharmaceutical Chemistry, University of Szeged, H-6720 Szeged, Eötvös u. 6 (Hungary), Fax: (+36) 62-545-705

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Abstract

A safe and efficient flow-chemistry-based procedure is presented for 1,3-dipolar cycloaddition reactions between organic azides and acetylenes. This simple and inexpensive technique eliminates the need for costly special apparatus and utilizes Cu powder as a plausible CuI source. To maximize the reaction rates, high-pressure/high-temperature conditions are utilized; alternatively, the harsh reaction conditions can be moderated at room temperature by the joint application of basic and acidic additives. A comparison of the performance of these two approaches in a series of model reactions has resulted in the formation of useful 1,4-disubstituted 1,2,3-triazoles in excellent yields. The risks that are associated with the handling of azides are lowered, thanks to the benefits of flow processing, and gram-scale production has been safely implemented. The synthetic capability of this continuous-flow technique is demonstrated by the efficient syntheses of some highly functionalized derivatives of the antifungal cispentacin.

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