Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Protocol
  • Published:

N-formylation and N-methylation of amines using metal-free N-heterocyclic carbene catalysts and CO2 as carbon source

Nature Protocols volume 12, pages 417–428 (2017)Cite this article

Subjects

Abstract

N-formylation and N-methylation of amines are important reactions that are used to produce a wide range of key intermediates and compounds. This protocol describes the environmentally benign N-formylation and N-methylation of primary and secondary amines using carbon dioxide (CO2) as the carbon source, hydrosilanes as reductants and N-heterocyclic carbenes (NHCs) as catalysts. Using CO2 as a reagent has the advantage of low cost and negligible toxicity. However, the catalyst is air-sensitive and must be generated fresh before use; consequently, the techniques used to prepare and manipulate the catalyst are described. The synthetic approach described in this protocol does not use any toxic reagents; using the appropriate catalyst, N-formylated or N-methylated products can be obtained with high selectivity. The overall time for catalyst preparation and for conducting several catalytic reactions in parallel is 15–48 h, depending on the nature of the substrates.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: N-formylation of phenylalanine ethyl ester.
Figure 2: N-methylation of N-methylaniline.
Figure 3: N-formylation and N-methylation of amines using NSC1 and PMHS.
Figure 4: Selected examples of N-methylation of amines using NHC1 and PH2SiH2.
Figure 5: The four chemical reactions proposed as options in Step 9 of the PROCEDURE.
Figure 6: Photograph of the four-parallel-reaction apparatus with the distillation distributor and distillation head.
Figure 7: Photographs illustrating Steps 3, 4, 5 and 7.
Figure 8: Change in color of the catalyst upon exposure to air.

Similar content being viewed by others

References

  1. Liu, Q., Wu, L., Jackstell, R. & Beller, M. Using carbon dioxide as a building block in organic synthesis. Nat. Commun. 6, 1–15 (2015).

    CAS  Google Scholar 

  2. Li, Y., Sorribes, I., Yan, T., Junge, K. & Beller, M. Selective methylation of amines with carbon dioxide and H2 . Angew. Chem. Int. Ed. Engl. 52, 12156–12160 (2013).

    Article  CAS  Google Scholar 

  3. Li, Y., Fang, X., Junge, K. & Beller, M. A general catalytic methylation of amines using carbon dioxide. Angew. Chem. Int. Ed. Engl. 125, 9747–9750 (2013).

    Article  Google Scholar 

  4. Beydoun, K., Vom Stein, T., Klankermayer, J. & Leitner, W. Ruthenium-catalyzed direct methylation of primary and secondary aromatic amines using carbon dioxide and molecular hydrogen. Angew. Chem. Int. Ed. Engl. 52, 9554–9557 (2013).

    Article  CAS  Google Scholar 

  5. Jacquet, O., Das Neves Gomes, C., Ephritikhine, M. & Cantat, T. Recycling of carbon and silicon wastes: room temperature formylation of N-H bonds using carbon dioxide and polymethylhydrosiloxane. J. Am. Chem. Soc. 134, 2934–2937 (2012).

    Article  CAS  Google Scholar 

  6. Jacquet, O., Frogneux, X., Das Neves Gomes, C. & Cantat, T. CO2 as a C1-building block for the catalytic methylation of amines. Chem. Sci. 4, 2127 (2013).

    Article  CAS  Google Scholar 

  7. Zhou, Q. & Li, Y. The real role of N-heterocyclic carbene in reductive functionalization of CO2: an alternative understanding from density functional theory study. J. Am. Chem. Soc. 137, 10182–10189 (2015).

    Article  CAS  Google Scholar 

  8. Riduan, S.N., Ying, J.Y. & Zhang, Y. Mechanistic insights into the reduction of carbon dioxide with silanes over N-heterocyclic carbene catalysts. ChemCatChem 5, 1490–1496 (2013).

    Article  CAS  Google Scholar 

  9. Das, S., Bobbink, F.D., Laurenczy, G. & Dyson, P.J. Metal-free catalyst for the chemoselective methylation of amines using carbon dioxide as a carbon source. Angew. Chem. Int. Ed. Engl. 53, 12876–12879 (2014).

    Article  CAS  Google Scholar 

  10. Das, S., Bobbink, F.D., Bulut, S., Soudani, M. & Dyson, P.J. Thiazolium carbene catalysts for the fixation of CO2 onto amines. Chem. Commun. 52, 2497–2500 (2016).

    Article  CAS  Google Scholar 

  11. Tlili, A., Frogneux, X., Blondiaux, E. & Cantat, T. Creating added value with a waste: methylation of amines with CO2 and H2 . Angew. Chem. Int. Ed. Engl. 53, 2543–2545 (2014).

    Article  CAS  Google Scholar 

  12. Tlili, A., Blondiaux, E., Frogneux, X. & Cantat, T. Reductive functionalization of CO2 with amines: an entry to formamide, formamidine and methylamine derivatives. Green Chem. 17, 157–168 (2015).

    Article  CAS  Google Scholar 

  13. González-Sebastián, L., Flores-Alamo, M. & García, J.J. Selective N-methylation of aliphatic amines with CO2 and hydrosilanes using nickel-phosphine catalysts. Organometallics 34, 763–769 (2015).

    Article  CAS  Google Scholar 

  14. Chong, C.C. & Kinjo, R. Hydrophosphination of CO2 and subsequent formate transfer in the 1,3,2-diazaphospholene-catalyzed N-formylation of amines. Angew. Chem. Int. Ed. Engl. 54, 12116–12120 (2015).

    Article  CAS  Google Scholar 

  15. Riduan, S.N., Ying, J.Y. & Zhang, Y. Solid poly-N-heterocyclic carbene catalyzed CO2 reduction with hydrosilanes. J. Catal. 343, 46–51 (2016).

    Article  CAS  Google Scholar 

  16. Hao, L. et al. Imidazolium-based ionic liquids catalyzed formylation of amines using carbon dioxide and phenylsilane at room temperature. ACS Catal. 5, 4989–4993 (2015).

    Article  CAS  Google Scholar 

  17. Frogneux, X., Blondiaux, E., Thuéry, P. & Cantat, T. Bridging amines with CO2: organocatalyzed reduction of CO2 to aminals ACS Catal. 5, 3983–3987 (2015).

  18. Zhang, S. et al. Copper-catalyzed N-formylation of amines with CO2 under ambient conditions. RSC Adv. 6, 32370–32373 (2016).

    Article  CAS  Google Scholar 

  19. Nale, D.B. & Bhanage, B.M. An efficient protocol for formylation of amines using carbon dioxide and PMHS under transition-metal-free conditions. Synlett 27, 1413–1417 (2016).

    Article  CAS  Google Scholar 

  20. Lv, H., Xing, Q., Yue, C., Lei, Z. & Li, F. Solvent-promoted catalyst-free N-formylation of amines using carbon dioxide under ambient conditions. Chem. Commun. 52, 6545–6548 (2016).

    Article  CAS  Google Scholar 

  21. Moret, S., Dyson, P.J. & Laurenczy, G. Direct synthesis of formic acid from carbon dioxide by hydrogenation in acidic media. Nat. Commun. 5, 4017 (2014).

    Article  CAS  Google Scholar 

  22. Sorribes, I., Junge, K. & Beller, M. Direct catalytic N-alkylation of amines with carboxylic acids. J. Am. Chem. Soc. 136, 14314–14319 (2014).

    Article  CAS  Google Scholar 

  23. Fu, M.C., Shang, R., Cheng, W.M. & Fu, Y. Boron-catalyzed N-alkylation of amines using carboxylic acids. Angew. Chem. Int. Ed. 54, 9042–9046 (2015).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank the Ecole polytechnique fédérale de Lausanne (EPFL) and the Commission for Technology and Innovation (CTI) Swiss Competence Centre of Energy Research (SCCER) for financial support.

Author information

Authors and Affiliations

  1. Institut des Sciences et Ingénierie Chimiques, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland

    Felix D Bobbink, Shoubhik Das & Paul J Dyson

Authors
  1. Felix D Bobbink
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shoubhik Das
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Paul J Dyson
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

F.D.B., S.D. and P.J.D. planned the original project. F.D.B. performed the catalytic reactions in the protocol. F.D.B. and P.J.D. wrote the protocol.

Corresponding author

Correspondence to Paul J Dyson.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bobbink, F., Das, S. & Dyson, P. N-formylation and N-methylation of amines using metal-free N-heterocyclic carbene catalysts and CO2 as carbon source. Nat Protoc 12, 417–428 (2017). https://doi.org/10.1038/nprot.2016.175

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nprot.2016.175

This article is cited by

Comments

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.

Search

Advanced search

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