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Non-innocent electrophiles unlock exogenous base-free coupling reactions

Nature Catalysis volume 5, pages 324–331 (2022)Cite this article

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Abstract

Numerous important transition metal-catalysed reactions rely on stoichiometric quantities of an exogenous base to enable catalytic turnover. Despite playing a fundamental role, the base poses major challenges, such as restricting the accessible chemical space or causing heterogeneous reaction mixtures. Here we introduce a unifying strategy that eliminates the need for an exogenous base through the use of non-innocent electrophiles (NIE), which are equipped with a masked base that is released in a controlled fashion during the reaction. The universal applicability of this concept was demonstrated by turning multiple, traditionally base-dependent, catalytic reactions into exogenous base-free homogeneous processes. Furthermore, the advantageous features of NIEs were demonstrated in multiple applications, such as in a micromole-scale fluorescence-based assay. This led to the discovery of a Ni-catalysed deoxygenation reaction of aryl carbamates using isopropanol as a benign reductant. In a broader context, this work provides a conceptual blueprint for the strategic utilization of NIEs in catalysis.

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Fig. 1: Context of this work.
Fig. 2: Reactivity assessment and optimized conditions.
Fig. 3: Scope of the exogenous base-free BHA, MHR and SMC.
Fig. 4: Extension of reactivity and scale-down experiments.
Fig. 5: Fluorescence-based reactivity assay.
Fig. 6: Micromole-scale fluorescence-based assay for reaction discovery using NIEs.

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Data availability

The data that support the findings of this study are available within the article and its Supplementary Information. All data are available from the authors upon reasonable request. Crystallographic data for compounds 22 and 30 were deposited on the Cambridge Structural Database and are freely available via the Cambridge Crystallographic Data Centre under CCDC numbers 2070177 and 2070176.

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Acknowledgements

ETH Zurich is acknowledged for financial support. G.T. acknowledges the Studienstiftung des deutschen Volkes (German Academic Scholarship Foundation) for a predoctoral scholarship. We thank the NMR, MS (MoBiAS) and X-ray (SMoCC) technology platforms at ETH Zurich for technical assistance. H. Schmitt (ETH Zurich) is acknowledged for reproducing results. We thank J. W. Bode (ETH Zurich) for access to the fluorescence microplate reader and A. Schuhmacher (ETH Zurich) for instruction and technical assistance. The authors thank the Morandi group for discussion and proofreading of the manuscript.

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  1. Laboratory of Organic Chemistry, Department of Chemistry and Applied Biosciences, ETH, Zurich, Switzerland

    Georgios Toupalas & Bill Morandi

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  1. Georgios Toupalas
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Contributions

G.T. conceived the project. G.T. designed and performed the experimental studies. B.M. supervised the research. Both authors contributed to the writing and editing of the final manuscript.

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Correspondence to Bill Morandi.

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Nature Catalysis thanks Michael Shevlin and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary information

Supplementary Information

Supplementary Methods, Figs. 1–16, Tables 1–31 and refs.

Supplementary Data 1

Crystallographic data of compound 30.

Supplementary Data 2

Crystallographic data of compound 22.

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Toupalas, G., Morandi, B. Non-innocent electrophiles unlock exogenous base-free coupling reactions. Nat Catal 5, 324–331 (2022). https://doi.org/10.1038/s41929-022-00770-x

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