Chemoselective synthesis of ketones and ketimines by addition of organometallic reagents to secondar

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. To achieve chemoselective additions of organometallics to carbonyls, it is important to consider the combination of acylating agent and organometallic as a reactive pair rather than either one in isolation. Here, a chemoselective, controlled and general methodology for the conversion of secondary amides to ketones and ketimines is described.

Cite this article

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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