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


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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

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.

Data availability

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


  1. 1.

    Greenberg, A. et al. (eds) The Amide Linkage: Structural Significance in Chemistry, Biochemistry, and Materials Science (Wiley, 2000).

  2. 2.

    Pattabiraman, V. R. & Bode, J. W. Rethinking amide bond synthesis. Nature 480, 471–479 (2011).

    ADS  CAS  Article  Google Scholar 

  3. 3.

    Schneider, N., Lowe, D. M., Sayle, R. A., Tarselli, M. A. & Landrum, G. A. Big data from pharmaceutical patents: a computational analysis of medicinal chemists’ bread and butter. J. Med. Chem. 59, 4385–4402 (2016).

    CAS  Article  Google Scholar 

  4. 4.

    Brown, D. G. & Boström, J. Analysis of past and present synthetic methodologies on medicinal chemistry: where have all the new reactions gone? J. Med. Chem. 59, 4443–4458 (2016).

    CAS  Article  Google Scholar 

  5. 5.

    Müller, K., Faeh, C. & Diederich, F. Fluorine in pharmaceuticals: looking beyond intuition. Science 317, 1881–1886 (2007).

    ADS  Article  Google Scholar 

  6. 6.

    Purser, S., Moore, P. R., Swallow, S. & Gouverneur, V. Fluorine in medicinal chemistry. Chem. Soc. Rev. 37, 320–330 (2008).

    CAS  Article  Google Scholar 

  7. 7.

    Isanbor, C. & O’Hagan, D. Fluorine in medicinal chemistry: A review of anti-cancer agents. J. Fluor. Chem. 127, 303–319 (2006).

    CAS  Article  Google Scholar 

  8. 8.

    Vagner, J., Qu, H. & Hruby, V. J. Peptidomimetics, a synthetic tool of drug discovery. Curr. Opin. Chem. Biol. 12, 292–296 (2008).

    CAS  Article  Google Scholar 

  9. 9.

    Chatterjee, J., Gilon, C., Hoffman, A. & Kessler, H. N-methylation of peptides: a new perspective in medicinal chemistry. Acc. Chem. Res. 41, 1331–1342 (2008).

    CAS  Article  Google Scholar 

  10. 10.

    Pharmaceutical Products and Market. Statista

  11. 11.

    Metcalf, L. R. in Ullmann’s Encyclopedia of Industrial Chemistry (Wiley-VCH, 2000).

  12. 12.

    Holland, J. R. et al. A controlled trial of urethane treatment in multiple myeloma. Blood 27, 328–342 (1966).

    CAS  PubMed  Google Scholar 

  13. 13.

    Sijbesma, R. P. et al. Reversible polymers formed from self-complementary monomers using quadruple hydrogen bonding. Science 278, 1601–1604 (1997).

    ADS  CAS  Article  Google Scholar 

  14. 14.

    Valeur, E. & Bradley, M. Amide bond formation: beyond the myth of coupling reagents. Chem. Soc. Rev. 38, 606–631 (2009).

    CAS  Article  Google Scholar 

  15. 15.

    van der Werf, A., Hribersek, M. & Selander, N. N-trifluoromethylation of nitrosoarenes with sodium triflinate. Org. Lett. 19, 2374–2377 (2017).

    Article  Google Scholar 

  16. 16.

    Klöter, G. & Seppelt, K. Trifluoromethanol (CF3OH) and trifluoromethylamine (CF3NH2). J. Am. Chem. Soc. 101, 347–349 (1979).

    Article  Google Scholar 

  17. 17.

    Scattolin, T., Deckers, K. & Schoenebeck, F. Efficient synthesis of trifluoromethyl amines through a formal umpolung strategy from the bench-stable precursor (Me4N)SCF3. Angew. Chem. Int. Ed. 56, 221–224 (2017).

    CAS  Article  Google Scholar 

  18. 18.

    Hagooly, Y., Gatenyo, J., Hagooly, A. & Rozen, S. Toward the synthesis of the rare N-(trifluoromethyl)amides and the N-(difluoromethylene)-N-(trifluoromethyl)amines [RN(CF3)CF2R′] using BrF3. J. Org. Chem. 74, 8578–8582 (2009).

    CAS  Article  Google Scholar 

  19. 19.

    Handa, M. & Inoue, M. O-acyl-N-aryl-N-(trifluoromethyl)hydroxylamine derivative and method for producing the same. Japanese patent JP2012062284A (2010).

  20. 20.

    Ruppert, I. Organylisocyaniddifluoride R–N=CF2 durch direktfluorierung von isocyaniden. Tetrahedron Lett. 21, 4893–4896 (1980).

    CAS  Article  Google Scholar 

  21. 21.

    Sheppard, W. A. N-Fluoroalkylamines. I. Difluoroazomethines. J. Am. Chem. Soc. 87, 4338–4341 (1965).

    CAS  Article  Google Scholar 

  22. 22.

    Pajtás, D. et al. Optimization of the synthesis of flavone–amino acid and flavone–dipeptide hybrids via Buchwald–Hartwig reaction. J. Org. Chem. 82, 4578–4587 (2017).

    Article  Google Scholar 

  23. 23.

    Schindler, C. S., Forster, P. M. & Carreira, E. M. Facile formation of N-acyl-oxazolidinone derivatives using acid fluorides. Org. Lett. 12, 4102–4105 (2010).

    CAS  Article  Google Scholar 

  24. 24.

    Clark, R. D. et al. Synthesis and evaluation of ureido- and vinylureidopenicillins as inhibitors of intraruminal lactic acid production. J. Med. Chem. 24, 1250–1253 (1981).

    CAS  Article  Google Scholar 

Download references


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

Author information




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.

Ethics declarations

Competing interests

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

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Scattolin, T., Bouayad-Gervais, S. & Schoenebeck, F. Straightforward access to N-trifluoromethyl amides, carbamates, thiocarbamates and ureas. Nature 573, 102–107 (2019).

Download citation

Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing