Mechanistic basis of the Cu(OAc)2 catalyzed azide-ynamine (3+2)cycloaddition reaction

Bunschoten, Roderick P. and Peschke, Frederik and Taladriz-Sender, Andrea and Alexander, Emma and Andrews, Matthew J. and Kennedy, Alan R. and Fazakerley, Neal J. and Lloyd Jones, Guy C. and Watson, Allan J. B. and Burley, Glenn A. (2024) Mechanistic basis of the Cu(OAc)2 catalyzed azide-ynamine (3+2)cycloaddition reaction. Journal of the American Chemical Society, 146 (19). pp. 13558-13570. ISSN 0002-7863 (https://doi.org/10.1021/jacs.4c03348)

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Abstract

The Cu-catalyzed azide-alkyne cycloaddition (CuAAC) reaction is used as a ligation tool throughout chemical and biological sciences. Despite the pervasiveness of CuAAC, there is a need to develop more efficient methods to form 1,4-triazole ligated products with low loadings of Cu. In this paper, we disclose a mechanistic model for the ynamine-azide (3 + 2) cycloadditions catalyzed by copper(II) acetate. Using multinuclear nuclear magnetic resonance spectroscopy, electron paramagnetic resonance spectroscopy, and high-performance liquid chromatography analyses, a dual catalytic cycle is identified. First, the formation of a diyne species via Glaser-Hay coupling of a terminal ynamine forms a Cu(I) species competent to catalyze an ynamine-azide (3 + 2) cycloaddition. Second, the benzimidazole unit of the ynamine structure has multiple roles: assisting C-H activation, Cu coordination, and the formation of a postreaction resting state Cu complex after completion of the (3 + 2) cycloaddition. Finally, reactivation of the Cu resting state complex is shown by the addition of isotopically labeled ynamine and azide substrates to form a labeled 1,4-triazole product. This work provides a mechanistic basis for the use of mixed valency binuclear catalytic Cu species in conjunction with Cu-coordinating alkynes to afford superior reactivity in CuAAC reactions. Additionally, these data show how the CuAAC reaction kinetics can be modulated by changes to the alkyne substrate, which then has a predictable effect on the reaction mechanism.