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Diastereoselective addition of Grignard reagents to α-epoxy N-sulfonyl hydrazones

Nature Chemistry volume 7, pages 1024–1027 (2015)Cite this article

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Abstract

The α-alkylation of ketones and their derivatives by the addition of their corresponding enolates to alkyl halides is a fundamental synthetic transformation, but its utility is limited because the key bond-forming step proceeds in a bimolecular nucleophilic substitution fashion. Here we describe how an umpolung strategy that involves the addition of Grignard reagents to α-epoxy N-sulfonyl hydrazones—directed by the alkoxide of the 1-azo-3-alkoxy propenes formed in situ via base-induced ring opening of the epoxide—leads to the syn-selective production of α-alkyl-β-hydroxy N-sulfonyl hydrazones with α-quaternary centres. This transformation is remarkable in its ability to incorporate an unprecedented range of carbon-based substituents, which include primary, secondary and tertiary alkyl, as well as alkenyl, aryl, allenyl and alkynyl groups. Subsequent hydrolysis of the β-hydroxy N-sulfonyl hydrazone products produces the corresponding β-hydroxy ketones. In addition to hydrolysis, the hydrazone products are poised to undergo numerous different known synthetic transformations via well-established chemistry, which would provide access to a wide array of useful structures.

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Figure 1: Routes to α-alkyl ketones and derivatives, and the Eschenmoser–Tanabe fragmentation.
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Acknowledgements

We are grateful to J. M. Hatcher for conducting the preliminary experiments related to this work. We also thank J. Korp (University of Houston) for the X-ray structure determination and the National Sciences Foundation (NSF 1012287) and Welch Foundation (E-0806) for support.

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Authors and Affiliations

  1. Department of Chemistry, University of Houston, Houston, USA, 77204, Texas

    Maulen M. Uteuliyev, Thien T. Nguyen & Don M. Coltart

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  1. Maulen M. Uteuliyev
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  2. Thien T. Nguyen
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  3. Don M. Coltart
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Contributions

All authors conceived and designed the experiments and analysed the data. M.M.U. and T.T.N. performed the experiments. D.M.C. wrote the paper.

Corresponding author

Correspondence to Don M. Coltart.

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The authors declare no competing financial interests.

Supplementary information

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Supplementary information (PDF 17344 kb)

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Crystallographic data for compound 14 (CIF 16 kb)

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Structure factors file for compound 14 (CIF 148 kb)

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Crystallographic data for compound 17 (CIF 17 kb)

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Structure factors file for compound 17 (CIF 155 kb)

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Crystallographic data for compound 22 (CIF 21 kb)

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Structure factors file for compound 22 (CIF 143 kb)

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Uteuliyev, M., Nguyen, T. & Coltart, D. Diastereoselective addition of Grignard reagents to α-epoxy N-sulfonyl hydrazones. Nature Chem 7, 1024–1027 (2015). https://doi.org/10.1038/nchem.2364

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