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New ligands for nickel catalysis from diverse pharmaceutical heterocycle libraries

Abstract

Ligands are essential for controlling the reactivity and selectivity of reactions catalysed by transition metals. Access to large phosphine ligand libraries has become an essential tool for the application of metal-catalysed reactions industrially, but these existing libraries are not well suited to new catalytic methods based on non-precious metals (for example, Ni, Cu and Fe). The development of the requisite nitrogen- and oxygen-based ligand libraries lags far behind that of the phosphines and the development of new libraries is anticipated to be time consuming. Here we show that this process can be dramatically accelerated by mining for new ligands in a typical pharmaceutical compound library that is rich in heterocycles. Using this approach, we were able to screen a structurally diverse set of compounds with minimal synthetic effort and identify several new ligand classes for nickel-catalysed cross-electrophile coupling. These new ligands gave improved yields for challenging cross-couplings of pharmaceutically relevant substrates compared with those of those of previously published ligands.

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Figure 1: State-of-the-art in cross-electrophile coupling.
Figure 2: Strategy employed for mining the Pfizer compound library for new ligands.
Figure 3: Results of screening a focused pyridyl carboxamidine ligand library (A1A15) and a collection of known bipyridine and phenanthroline ligands (C1C5) against two challenging reactions.
Figure 4: Examination of substrate scope for the Ni-catalysed cross-electrophile coupling.

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Acknowledgements

We acknowledge funding from Pfizer and from the National Institutes of Health (R01 GM097243). We thank D. Batesky (University of Rochester) for the synthesis of several amidine ligands used in this study. We thank S. Monfette (Pfizer) for helpful discussions. This work was influenced by the on-going efforts of the Non-Precious Metal Catalysis Alliance between Pfizer, Boehringer-Ingelheim and Abbvie.

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N.J.G. conducted preliminary experiments with amidine ligands. E.C.H. and D.J.P. conducted the screens at Pfizer. E.C.H., D.J.P. and A.C.W. ran the reactions, and isolated and characterized the products in Fig. 3. Data analysis and study design were the product of meetings with all the authors. All authors discussed the results and commented on the manuscript.

Corresponding authors

Correspondence to Eric C. Hansen or Daniel J. Weix.

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The authors declare no competing financial interests.

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Hansen, E., Pedro, D., Wotal, A. et al. New ligands for nickel catalysis from diverse pharmaceutical heterocycle libraries. Nature Chem 8, 1126–1130 (2016). https://doi.org/10.1038/nchem.2587

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