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New ligands for nickel catalysis from diverse pharmaceutical heterocycle libraries


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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  1. Roughley, S. D. & Jordan, A. M. The medicinal chemist's toolbox: an analysis of reactions used in the pursuit of drug candidates. J. Med. Chem. 54, 3451–3479 (2011).

    Article  CAS  Google Scholar 

  2. Magano, J. & Dunetz, J. R. Large-scale applications of transition metal-catalyzed couplings for the synthesis of pharmaceuticals. Chem. Rev. 111, 2177–2250 (2011).

    Article  CAS  Google Scholar 

  3. Busacca, C. A., Fandrick, D. R., Song, J. J. & Senanayake, C. H. The growing impact of catalysis in the pharmaceutical industry. Adv. Synth. Catal. 353, 1825–1864 (2011).

    Article  CAS  Google Scholar 

  4. Dreher, S. D., Dormer, P. G., Sandrock, D. L. & Molander, G. Efficient cross-coupling of secondary alkyltrifluoroborates with aryl chlorides—reaction discovery using parallel microscale experimentation. J. Am. Chem. Soc. 130, 9257–9259 (2008).

    Article  CAS  Google Scholar 

  5. Robbins, D. W. & Hartwig, J. F. A simple, multidimensional approach to high-throughput discovery of catalytic reactions. Science 333, 1423–1427 (2011).

    Article  CAS  Google Scholar 

  6. Santanilla, A. B. et al. Nanomole-scale high-throughput chemistry for the synthesis of complex molecules. Science 347, 49–53 (2015).

    Article  Google Scholar 

  7. Friedfeld, M. R. et al. Cobalt precursors for high-throughput discovery of base metal asymmetric alkene hydrogenation catalysts. Science 342, 1076–1080 (2013).

    Article  CAS  Google Scholar 

  8. Knappke, C. E. I. et al. Reductive cross-coupling reactions between two electrophiles. Chem. Eur. J. 20, 6828–6842 (2014).

    Article  CAS  Google Scholar 

  9. Biswas, S. & Weix, D. J. Mechanism and selectivity in nickel-catalyzed cross-electrophile coupling of aryl halides with alkyl halides. J. Am. Chem. Soc. 135, 16192–16197 (2013).

    Article  CAS  Google Scholar 

  10. Jones, G. O., Liu, P., Houk, K. N. & Buchwald, S. L. Computational explorations of mechanisms and ligand-directed selectivities of copper-catalyzed Ullmann-type reactions. J. Am. Chem. Soc. 132, 6205–6213 (2010).

    Article  CAS  Google Scholar 

  11. Everson, D. A., Shrestha, R. & Weix, D. J. Nickel-catalyzed reductive cross-coupling of aryl halides with alkyl halides. J. Am. Chem. Soc. 132, 920–921 (2010).

    Article  CAS  Google Scholar 

  12. Liu, H. & Du, D.-M. Recent advances in the synthesis of 2-imidazolines and their applications in homogeneous catalysis. Adv. Synth. Catal. 351, 489–519 (2009).

    Article  CAS  Google Scholar 

  13. Cui, X. et al. Nickel-catalyzed reductive allylation of aryl bromides with allylic acetates. Org. Biomol. Chem. 11, 3094–3097 (2013).

    Article  CAS  Google Scholar 

  14. Xu, H., Zhao, C., Qian, Q., Deng, W. & Gong, H. Nickel-catalyzed cross-coupling of unactivated alkyl halides using bis(pinacolato)diboron as reductant. Chem. Sci. 4, 4022–4029 (2013).

    Article  CAS  Google Scholar 

  15. Segl′a, P., Koman, M. & Glowiak, T. Formation of 2-pyridinyl-2-oxazolines and pyridine-2-carboxamidine in the coordination sphere of copper(II). J. Coord. Chem. 50, 105–117 (2000).

    Article  Google Scholar 

  16. Milios, C. J., Stamatatos, T. C. & Perlepes, S. P. The coordination chemistry of pyridyl oximes. Polyhedron 25, 134–194 (2006).

    Article  CAS  Google Scholar 

  17. Bacon, E. R., Singh, B. & Lesher, G. Y. 6-Heterocyclyl pyrazolo[3,4-d]pyrimidin-4-ones and compositions and method of use thereof. US patent 5294612 A (1994).

  18. Buonomo, J. A., Everson, D. A. & Weix, D. J. Substituted 2,2ʹ-bipyridines by nickel-catalysis: 4,4ʹ-di-tert-butyl-2,2ʹ-bipyridine. Synthesis 45, 3099–3102 (2013).

    Article  CAS  Google Scholar 

  19. Luman, C. R. & Castellano, F. N. in Comprehensive Coordination Chemistry II (eds McCleverty, J. A. & Meyer, T. J.) 25–39 (Pergamon, 2003).

    Book  Google Scholar 

  20. Czaplik, W. M., Mayer, M. & Jacobi von Wangelin, A. Domino iron catalysis: direct aryl–alkyl cross-coupling. Angew. Chem. Int. Ed. 48, 607–610 (2009).

    Article  CAS  Google Scholar 

  21. Wang, S., Qian, Q. & Gong, H. Nickel-catalyzed reductive coupling of aryl halides with secondary alkyl bromides and allylic acetate. Org. Lett. 14, 3352–3355 (2012).

    Article  CAS  Google Scholar 

  22. Wang, X., Wang, S., Xue, W. & Gong, H. Nickel-catalyzed reductive coupling of aryl bromides with tertiary alkyl halides. J. Am. Chem. Soc. 137, 11562–11565 (2015).

    Article  CAS  Google Scholar 

  23. Blum, J. et al. Palladium-catalyzed methylation of aryl and vinyl halides by stabilized methylaluminum and methylgallium complexes. J. Org. Chem. 62, 8681–8686 (1997).

    Article  CAS  Google Scholar 

  24. Han, C. & Buchwald, S. L. Negishi coupling of secondary alkylzinc halides with aryl bromides and chlorides. J. Am. Chem. Soc. 131, 7532–7533 (2009).

    Article  CAS  Google Scholar 

  25. Gu, J., Wang, X., Xue, W. & Gong, H. Nickel-catalyzed reductive coupling of alkyl halides with other electrophiles: concept and mechanistic considerations. Org. Chem. Front. 2, 1411–1421 (2015).

    Article  CAS  Google Scholar 

  26. Anka-Lufford, L. L., Prinsell, M. R. & Weix, D. J. Selective cross-coupling of organic halides with allylic acetates. J. Org. Chem. 77, 9989–10000 (2012).

    Article  CAS  Google Scholar 

  27. Molander, G. A., Traister, K. M. & O'Neill, B. T. Reductive cross-coupling of nonaromatic, heterocyclic bromides with aryl and heteroaryl bromides. J. Org. Chem. 79, 5771–5780 (2014).

    Article  CAS  Google Scholar 

  28. Molander, G. A., Traister, K. M. & O'Neill, B. T. Engaging nonaromatic, heterocyclic tosylates in reductive cross-coupling with aryl and heteroaryl bromides. J. Org. Chem. 80, 2907–2911 (2015).

    Article  CAS  Google Scholar 

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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.

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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).

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