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Straightforward access to N-trifluoromethyl amides, carbamates, thiocarbamates and ureas

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Abstract

Amides and related carbonyl derivatives are of central importance across the physical and life sciences1,2. As a key biological building block, the stability and conformation of amides affect the structures of peptides and proteins as well as their biological function. In addition, amide-bond formation is one of the most frequently used chemical transformations3,4. Given their ubiquity, a technology that is capable of modifying the fundamental properties of amides without compromising on stability may have considerable potential in pharmaceutical, agrochemical and materials science. In order to influence the physical properties of organic molecules—such as solubility, lipophilicity, conformation, pKa and (metabolic) stability—fluorination approaches have been widely adopted5,6,7. Similarly, site-specific modification with isosteres and peptidomimetics8, or in particular by N-methylation9, has been used to improve the stability, physical properties, bioactivities and cellular permeabilities of compounds. However, the N-trifluoromethyl carbonyl motif—which combines both N-methylation and fluorination approaches—has not yet been explored, owing to a lack of efficient methodology to synthesize it. Here we report a straightforward method to access N-trifluoromethyl analogues of amides and related carbonyl compounds. The strategy relies on the operationally simple preparation of bench-stable carbamoyl fluoride building blocks, which can be readily diversified to the corresponding N–CF3 amides, carbamates, thiocarbamates and ureas. This method tolerates rich functionality and stereochemistry, and we present numerous examples of highly functionalized compounds—including analogues of widely used drugs, antibiotics, hormones and polymer units.

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Fig. 1: Selected examples of amides and related compounds, and this work.
Fig. 2: Synthesis of N-trifluoromethyl carbamoyl building blocks.
Fig. 3: Synthesis of N-trifluoromethylated amides from trifluoromethyl carbamic fluorides and derivatization.
Fig. 4: Syntheses of additional N–CF3 derivatives.

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Data availability

The authors declare that the data supporting the findings of this study are available within the paper and its supplementary information files.

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Acknowledgements

We acknowledge RWTH Aachen University for financial support, and K. Deckers and T. Sperger for assistance and discussions.

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Authors and Affiliations

  1. Institute of Organic Chemistry, RWTH Aachen University, Aachen, Germany

    Thomas Scattolin, Samir Bouayad-Gervais & Franziska Schoenebeck

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  1. Thomas Scattolin
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  2. Samir Bouayad-Gervais
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  3. Franziska Schoenebeck
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Contributions

T.S. and S.B.-G. performed the experiments. S.B.-G. undertook the calculations. All authors analysed the data and contributed to the preparation of the manuscript. F.S. wrote the manuscript.

Corresponding author

Correspondence to Franziska Schoenebeck.

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Competing interests

A patent application has been submitted by RWTH Aachen University for this methodology, with T.S. and F.S. as inventors (2018112315090400DE).

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Peer review information Nature thanks Scott Bagley, Jonathan Clayden and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Supplementary information

Supplementary Information

This PDF file includes Materials and Methods, Experimental Procedures, Characterization Data, Stability Data, Racemization analyses, NMR study, Mechanistic Studies, Computational Details, NMR Spectra and Supplementary Figures S1 to S59.

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Scattolin, T., Bouayad-Gervais, S. & Schoenebeck, F. Straightforward access to N-trifluoromethyl amides, carbamates, thiocarbamates and ureas. Nature 573, 102–107 (2019). https://doi.org/10.1038/s41586-019-1518-3

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