A scalable, metal-, azide- and halogen-free method for the preparation of triazoles

Clark, Peter R. and Williams, Glynn D. and Hayes, Jerome F. and Tomkinson, Nicholas C. O. (2020) A scalable, metal-, azide- and halogen-free method for the preparation of triazoles. Angewandte Chemie International Edition, 59 (17). pp. 6740-6744. ISSN 1433-7851

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    Abstract

    A scalable metal-, azide-, and halogen-free method for the synthesis of substituted 1,2,3-triazoles has been developed. The reaction proceeds through a 3-component coupling of α-ketoacetals, tosyl hydrazide, and a primary amine. The reaction shows outstanding functional-group tolerance with respect to both the α-ketoacetal and amine coupling partners, providing access to 4-, 1,4-, 1,5-, and 1,4,5-substituted triazoles in excellent yield. This robust method results in densely functionalised 1,2,3-triazoles that remain challenging to prepare by azide–alkyne cycloaddition (AAC, CuAAC, RuAAC) methods and can be scaled in either batch or flow reactors. Methods for the chemoselective reaction of either aliphatic amines or anilines are also described, revealing some of the potential of this novel and highly versatile transformation.