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Chemoselective synthesis of ketones and ketimines by addition of organometallic reagents to secondary amides

Nature Chemistry volume 4, pages 228–234 (2012)Cite this article

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Abstract

The development of efficient and selective transformations is crucial in synthetic chemistry as it opens new possibilities in the total synthesis of complex molecules. Applying such reactions to the synthesis of ketones is of great importance, as this motif serves as a synthetic handle for the elaboration of numerous organic functionalities. In this context, we report a general and chemoselective method based on an activation/addition sequence on secondary amides allowing the controlled isolation of structurally diverse ketones and ketimines. The generation of a highly electrophilic imidoyl triflate intermediate was found to be pivotal in the observed exceptional functional group tolerance, allowing the facile addition of readily available Grignard and diorganozinc reagents to amides, and avoiding commonly observed over-addition or reduction side reactions. The methodology has been applied to the formal synthesis of analogues of the antineoplastic agent Bexarotene and to the rapid and efficient synthesis of unsymmetrical diketones in a one-pot procedure.

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Figure 1: Strategies for the conversion of carboxylic acid derivatives to ketones.
Figure 2: Applications of the chemoselective secondary amides transformation to ketones.

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Acknowledgements

This work was supported by the Natural Science and Engineering Research Council of Canada (NSERC), the Canada Research Chair Program, the Canada Foundation for Innovation, the FQRNT Centre in Green Chemistry and Catalysis (CGCC) and the Université de Montréal. W.S.B. and G.P. are grateful to NSERC, FQRNT and the Université de Montréal for postgraduate scholarships. The authors would like to thank A. Lemire and P. Lavallée (Université de Montréal), P. Lapointe (IRIC) and M. Grenon (Lundbeck) for supplying starting materials and reagents.

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  1. Department of Chemistry, Université de Montréal, PO Box 6128, Station Downtown, Montréal, H3C 3J7, Québec, Canada

    William S. Bechara, Guillaume Pelletier & André B. Charette

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  1. William S. Bechara
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  2. Guillaume Pelletier
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W.S.B. and G.P. carried out the experimental work, organized the research, analysed data and wrote the manuscript. All the authors contributed to the design of the experiments and editing of the manuscript.

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Correspondence to André B. Charette.

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Bechara, W., Pelletier, G. & Charette, A. Chemoselective synthesis of ketones and ketimines by addition of organometallic reagents to secondary amides. Nature Chem 4, 228–234 (2012). https://doi.org/10.1038/nchem.1268

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