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Activation of diverse carbon–heteroatom and carbon–carbon bonds via palladium(ii)-catalysed β-X elimination

Abstract

Chemists’ ability to synthesize structurally complex, high-value organic molecules from simple starting materials is limited by methods to selectively activate and functionalize strong alkyl C(sp3) covalent bonds. Recent activity has focused on the activation of abundant C–O, C–N and C–C bonds via a mechanistic paradigm of oxidative addition of a low-valent, electron-rich transition metal. This approach typically employs nickel(0), rhodium(i), ruthenium(0) and iron catalysts under conditions finely tuned for specific, electronically activated substrates, sometimes assisted by chelating functional groups or ring strain. By adopting a redox-neutral strategy involving palladium(ii)-catalysed C–H activation followed by β-heteroatom/carbon elimination, we describe here a catalytic method to activate alkyl C(sp3)–oxygen, nitrogen, carbon, fluorine and sulfur bonds with high regioselectivity. Directed hydrofunctionalization of the resultant palladium(ii)-bound alkene leads to formal functional group metathesis. The method is applied to amino acid upgrading with complete regioselectivity and moderate to high retention of enantiomeric excess. Low-strain heterocycles undergo strong-bond activation and substitution, giving ring-opened products.

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Fig. 1: Summary of previous and current work.
Fig. 2: The presented β-elimination approach to strong-bond activation has exceptional regioselectivity that would be difficult to achieve through an oxidative addition approach.
Fig. 3: Mechanistic experiments support the proposed β-elimination mechanism over a Lewis-acid-catalysed substitution mechanism.

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Acknowledgements

This work was financially supported by TSRI, Bristol-Myers Squibb (Unrestricted Grant), Pfizer, Inc., and the National Institutes of Health (1R35GM125052). We also gratefully acknowledge the following graduate fellowship programs: Frank J. Dixon Fellowship (V.T.T.), Donald E. and Delia B. Baxter Foundation (J.A.G.), and the National Science Foundation (NSF/DGE-1346837) (J.A.G.). We thank Dr. Jason S. Chen for determination of enantiomeric excess, along with Dr. Dee-Hua Huang and Dr. Laura Pasternack for assistance with NMR spectroscopy. We also thank Prof. Arnold L. Rheingold, Dr. Milan Gembicky, and Dr. Curtis E. Moore (UCSD) for X-ray crystallographic analysis. Prof. Jin-Quan Yu is thanked for helpful discussions.

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Contributions

V.T.T., J.A.G., K.S.Y., and K.M.E. conceived this work. V.T.T. and J.A.G. performed the experiments and analyzed the data. V.T.T. and K.M.E. wrote the manuscript with input from J.A.G. and K.S.Y.

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Correspondence to Keary M. Engle.

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Supplementary information

Supplementary information

General information, optimization data, mechanistic studies, substrate synthesis, general procedures, additional references and characterization data

Crystallographic data

CIF for compound 1m’; CCDC reference: 1840316

Crystallographic data

CIF for compound S1; CCDC reference: 1840315

NMR data

Original NMR data in FID format

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Tran, V.T., Gurak, J.A., Yang, K.S. et al. Activation of diverse carbon–heteroatom and carbon–carbon bonds via palladium(ii)-catalysed β-X elimination. Nature Chem 10, 1126–1133 (2018). https://doi.org/10.1038/s41557-018-0110-z

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  • DOI: https://doi.org/10.1038/s41557-018-0110-z

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