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

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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.

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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.

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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.

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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.

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Correspondence to Paul J Dyson.

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The authors declare no competing financial interests.

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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

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