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Aldehydes as alkyl carbanion equivalents for additions to carbonyl compounds

Nature Chemistry volume 9, pages 374–378 (2017)Cite this article

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An Addendum to this article was published on 23 June 2017

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Abstract

Nucleophilic addition reactions of organometallic reagents to carbonyl compounds for carbon–carbon bond construction have played a pivotal role in modern chemistry. However, this reaction's reliance on petroleum-derived chemical feedstocks and a stoichiometric quantity of metal have prompted the development of many carbanion equivalents and catalytic metal alternatives. Here, we show that naturally occurring carbonyls can be used as latent alkyl carbanion equivalents for additions to carbonyl compounds, via reductive polarity reversal. Such ‘umpolung’ reactivity is facilitated by a ruthenium catalyst and diphosphine ligand under mild conditions, delivering synthetically valuable secondary and tertiary alcohols in up to 98% yield. The unique chemoselectivity exhibited by carbonyl-derived carbanion equivalents is demonstrated by their tolerance to protic reaction media and good functional group compatibility. Enantioenriched tertiary alcohols can also be accessed with the aid of chiral ligands, albeit with moderate stereocontrol. Such carbonyl-derived carbanion equivalents are anticipated to find broad utility in chemical bond formation.

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Figure 1: Synthetic strategies to access secondary and tertiary alcohols by carbonyl addition reactions.
Figure 2: A hypothesis is developed from a serendipitous discovery.
Figure 3: Preliminary results on enantioselective carbonyl addition.

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Change history

  • 16 December 2016

    In the version of this Article originally published, Z. Hearne was not acknowledged for proofreading the text. This has been corrected in all versions of the Article.

  • 30 May 2017

    In this Article we described a ruthenium-catalysed carbonyl addition method for alcohol production via simple unsubstituted hydrazone intermediates, but we inadvertently omitted the citation of two papers that had previously reported a similar carbanion reactivity1,2. In these papers, the authors illustrated a series of substituted hindered hydrazones (for example, tert-butyl-, trityl- and diphenyl-4-pyridylmethyl) for additions to carbonyl compounds; however, to yield the target alcohols under these circumstances, the lithium salts of these hydrazones had to be pre-formed, with subsequent C–C bond formation and removal of bulky substituents on azo-intermediates via radical decomposition. References 1. Baldwin, J. E. et al. Azo anions in synthesis: use of trityl- and diphenyl-4-pyridylmethylhydrazones for reductive C–C bond formation. Tetrahedron 42, 4235–4246 (1986). 2. Baldwin, J. E., Bottaro, J. C., Kolhe, J. N. & Adlington, R. M. Azo anions in synthesis. Use of trityl- and diphenyl-4-pyridylmethyl-hydrazones for reductive C–C bond formation from aldehydes and ketones. J. Chem. Soc. Chem. Commun. 22–23 (1984).

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Acknowledgements

The authors acknowledge the Canada Research Chair Foundation (to C.J.L.), the CFI, FQRNT Center for Green Chemistry and Catalysis, NSERC and McGill University for financial support. The authors thank Z. Hearne for proofreading. The authors thank P. Querard and Z. Huang for their donation of compound 6a and chiral (S,S)-DPEN ligand, respectively. X.J.D. thanks the chemistry department for a Heather Munroe-Blum fellowship.

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  1. Haining Wang and Xi-Jie Dai: These authors contributed equally to this work

Authors and Affiliations

  1. Department of Chemistry and FQRNT Centre for Green Chemistry and Catalysis, McGill University, 801 Sherbrooke Street West, Montreal, H3A 0B8, Quebec, Canada

    Haining Wang, Xi-Jie Dai & Chao-Jun Li

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Contributions

H.W. and X.-J.D. are co-first authors responsible for this work, regardless of the listed name order. H.W. discovered the reaction. X.-J.D. conceived the concept. X.-J.D. and H.W. designed and performed the experiments, and analysed the data. X.-J.D. and H.W. co-wrote the paper with feedback and guidance from C.-J.L. C.-J.L. directed the project. All authors discussed the experimental results and commented on the manuscript.

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Correspondence to Chao-Jun Li.

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The authors declare no competing financial interests.

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Wang, H., Dai, XJ. & Li, CJ. Aldehydes as alkyl carbanion equivalents for additions to carbonyl compounds. Nature Chem 9, 374–378 (2017). https://doi.org/10.1038/nchem.2677

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