Modular click chemistry libraries for functional screens using a diazotizing reagent

Abstract

Click chemistry is a concept in which modular synthesis is used to rapidly find new molecules with desirable properties1. Copper(i)-catalysed azide–alkyne cycloaddition (CuAAC) triazole annulation and sulfur(vi) fluoride exchange (SuFEx) catalysis are widely regarded as click reactions2,3,4, providing rapid access to their products in yields approaching 100% while being largely orthogonal to other reactions. However, in the case of CuAAC reactions, the availability of azide reagents is limited owing to their potential toxicity and the risk of explosion involved in their preparation. Here we report another reaction to add to the click reaction family: the formation of azides from primary amines, one of the most abundant functional groups5. The reaction uses just one equivalent of a simple diazotizing species, fluorosulfuryl azide6,7,8,9,10,11 (FSO2N3), and enables the preparation of over 1,200 azides on 96-well plates in a safe and practical manner. This reliable transformation is a powerful tool for the CuAAC triazole annulation, the most widely used click reaction at present. This method greatly expands the number of accessible azides and 1,2,3-triazoles and, given the ubiquity of the CuAAC reaction, it should find application in organic synthesis, medicinal chemistry, chemical biology and materials science.

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Fig. 1: Preparation of fluorosulfuryl azide (FSO2N3) and its reactivity towards primary amino groups in the diazotransfer reaction.
Fig. 2: Isolated azide products, prepared from the corresponding primary amines.
Fig. 3: Preparation of the 1,224-azide library and the 1,224-triazole library from the amine library in microplates.

Data availability

The UPLC chromatograms (UV absorption) of the reaction mixtures for the preparations of the azide compounds in Fig. 2 are available in Supplementary Information 2. The structures of the 1,224 compounds in the azide library, and the UPLC chromatograms of the 1,224 CuAAC reaction mixtures, are also shown in Supplementary Information 2. Information on the source of each amine substrate used is available upon reasonable request from the corresponding authors.

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Acknowledgements

We acknowledge the National Natural Science Foundation of China (NSFC 21672240, NSFC 21421002), the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB20020300), the Key Research Program of Frontier Sciences (CAS, grant no. QYZDB-SSW-SLH028) and Shanghai Sciences and Technology Committee (18JC1415500, 18401933502) for financial support. We thank J. Yang for help with the thermal and mechanical stability tests; K. Ding for support; and P. Gao, T. Wang, Y. Liang, X. Zhan and J. Chen for assistance with the management of the amine compounds.

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Authors

Contributions

G.M. developed the procedure for the preparation of fluorosulfuryl azide. T.G., G.M., Y.S. and T.M. prepared the 1,224-amine library. G.M. and T.G. developed the procedure for the diazotransfer reaction. T.G., T.M., J.Z., Y.S. and G.M. synthesized the isolated azide compounds. T.G. prepared the 1,224-azide library. T.M. carried out the CuAAC reaction with the 1,224-azide library. G.M. and T.G. analysed the UPLC–MS chromatograms of the CuAAC reactions. J.D. and K.B.S. supervised the project and conceived the style of the manuscript.

Corresponding authors

Correspondence to Karl Barry Sharpless or Jiajia Dong.

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Competing interests

Shanghai Institute of Organic Chemistry, CAS has filed patent applications for this technology (Chinese patent application numbers PCT/CN2018/116922, CN201810609851.4 and CN201810609157.2).

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Peer review information Nature thanks Joseph Topczewski and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Supplementary information

Supplementary Information 1

This file contains the detailed procedures for the preparation of the compounds mentioned in the paper. Characterization data for the isolated compounds and the chemical structures for the 1,224-azide compound library are also provided.

Supplementary Information 2

This file contains the illustrated UPLC chromatograms for the reaction mixtures of all the copper(i)-catalyzed azide-alkyne cycloaddition (CuAAC) reactions carried out with the azide compound library.

Supplementary Information 3

This file provides the original study report for the acute oral toxicity of 1-(fluorosulfuryl)-2,3-dimethyl-1H-imidazol-3-ium trifluoromethanesulfonate (compound 1 in this paper) in SD rats.

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Meng, G., Guo, T., Ma, T. et al. Modular click chemistry libraries for functional screens using a diazotizing reagent. Nature 574, 86–89 (2019). https://doi.org/10.1038/s41586-019-1589-1

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