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Atom-efficient regioselective 1,2-dearomatization of functionalized pyridines by an earth-abundant organolanthanide catalyst

Nature Chemistry volume 6, pages 1100–1107 (2014)Cite this article

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Abstract

Developing earth-abundant, non-platinum metal catalysts for high-value chemical transformations is a critical challenge to contemporary chemical synthesis. Dearomatization of pyridine derivatives is an important transformation to access a wide range of valuable nitrogenous natural products, pharmaceuticals and materials. Here, we report an efficient 1,2-regioselective organolanthanide-catalysed pyridine dearomatization process using pinacolborane, which is compatible with a broad range of pyridines and functional groups and employs equimolar reagent stoichiometry. Regarding the mechanism, derivation of the rate law from NMR spectroscopic and kinetic measurements suggests first order in catalyst concentration, fractional order in pyridine concentration and inverse first order in pinacolborane concentration, with C=N insertion into the La–H bond as turnover-determining. An energetic span analysis affords a more detailed understanding of experimental activity trends and the unusual kinetic behaviour, and proposes the catalyst ‘resting’ state and potential deactivation pathways.

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Figure 1: Importance of saturated six-membered nitrogenous heterocycles and recent progress toward their synthesis.
Figure 2: Plausible elementary reaction sequence for catalytic pyridine dearomatization.
Figure 3: DFT-derived energetics of the catalytic pyridine dearomatization reaction coordinate.
Figure 4: Catalytic pyridine dearomatization mechanistic summary.
Figure 5: DFT-computed versus experimental organolanthanide-catalysed TOFs for functionalized pyridines.

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Acknowledgements

The authors acknowledge financial support from the National Science Foundation (NSF, grant no. CHE-1213235). A.S.D. is supported by the Camille and Henry Dreyfus Postdoctoral Program in Environmental Chemistry. V.L.W. thanks the NSF for a Graduate Research Fellowship. NMR instrumentation purchases at IMSERC at Northwestern University were supported by the NSF (CHE-1048773). Computational resources supporting this work were provided by the Northwestern University Quest High Performance Computing cluster (M.D.) and CINECA Award HP10CPZK0T 2013 (A.M.). The authors thank S. Kozuch (University of North Texas) for providing the AUTOF program and valuable suggestions and R.J. Thomson (Northwestern University) for helpful discussions.

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  1. Alexander S. Dudnik and Victoria L. Weidner: These authors contributed equally to this work

Authors and Affiliations

  1. Department of Chemistry, Northwestern University, Evanston, 60208-3113, Illinois, USA

    Alexander S. Dudnik, Victoria L. Weidner, Massimiliano Delferro & Tobin J. Marks

  2. Dipartimento di Scienze Chimiche, Università di Catania and INSTM, UdR Catania, 95125, Catania, Italy

    Alessandro Motta

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Contributions

A.S.D., M.D. and T.J.M. conceived and designed the experiments. V.L.W., A.S.D. and M.D. performed the experiments and analysed the data. A.M. performed DFT calculations. A.S.D., A.M., M.D. and T.J.M. co-wrote the manuscript. All authors contributed to revising the manuscript.

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Correspondence to Massimiliano Delferro or Tobin J. Marks.

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Dudnik, A., Weidner, V., Motta, A. et al. Atom-efficient regioselective 1,2-dearomatization of functionalized pyridines by an earth-abundant organolanthanide catalyst. Nature Chem 6, 1100–1107 (2014). https://doi.org/10.1038/nchem.2087

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