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Multimetallic catalysed cross-coupling of aryl bromides with aryl triflates

Nature volume 524, pages 454–457 (2015)Cite this article

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Abstract

The advent of transition-metal catalysed strategies for forming new carbon-carbon bonds has revolutionized the field of organic chemistry, enabling the efficient synthesis of ligands, materials, and biologically active molecules1,2,3. In cases where a single metal fails to promote a selective or efficient transformation, the synergistic cooperation4 of two distinct catalysts—multimetallic catalysis—can be used instead. Many important reactions rely on multimetallic catalysis5,6,7,8,9,10, such as the Wacker oxidation of olefins6,7,8 and the Sonogashira coupling of alkynes with aryl halides9,10, but this approach has largely been limited to the use of metals with distinct reactivities, with only one metal catalyst undergoing oxidative addition11,12. Here, we demonstrate that cooperativity between two group 10 metal catalysts—(bipyridine)nickel and (1,3-bis(diphenylphosphino)propane)palladium—enables a general cross-Ullmann reaction (the cross-coupling of two different aryl electrophiles)13,14,15. Our method couples aryl bromides with aryl triflates directly, eliminating the use of arylmetal reagents and avoiding the challenge of differentiating between multiple carbon–hydrogen bonds that is required for direct arylation methods16,17. Selectivity can be achieved without an excess of either substrate and originates from the orthogonal reactivity of the two catalysts and the relative stability of the two arylmetal intermediates. While (1,3-bis(diphenylphosphino)propane)palladium reacts preferentially with aryl triflates to afford a persistent intermediate, (bipyridine)nickel reacts preferentially with aryl bromides to form a transient, reactive intermediate. Although each catalyst forms less than 5 per cent cross-coupled product in isolation, together they are able to achieve a yield of up to 94 per cent. Our results reveal a new method for the synthesis of biaryls, heteroaryls, and dienes, as well as a general mechanism for the selective transfer of ligands between two metal catalysts. We anticipate that this reaction will simplify the synthesis of pharmaceuticals, many of which are currently made with pre-formed organometallic reagents1,2,3, and lead to the discovery of new multimetallic reactions.

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Figure 1: A general cross-Ullmann reaction catalysed by a combination of nickel and palladium.
Figure 2: Selectivities of nickel and palladium catalysts.
Figure 3: Substrate scope.

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Acknowledgements

This work was supported by the NIH (R01 GM097243). L.K.G.A acknowledges both an NSF Graduate Fellowship (NSF DGE-1419118) and an Elon Huntington Hooker Fellowship (Univ. Rochester). D.J.W is an Alfred P. Sloan Research Fellow and a Camille Dreyfus Teacher Scholar. We thank Z. Melchor (Univ. Rochester) for preliminary exploration of coupling electron-poor aryl halides, and S. Wu for assistance with graphics.

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Authors and Affiliations

  1. Department of Chemistry, University of Rochester, Rochester, 14627-0216, New York, USA

    Laura K. G. Ackerman, Matthew M. Lovell & Daniel J. Weix

Authors
  1. Laura K. G. Ackerman
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  3. Daniel J. Weix
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Contributions

D.J.W. conceived the idea. L.K.G.A. performed experiments and analysed the results with assistance from M.M.L. Both D.J.W. and L.K.G.A. proposed the experiments, discussed the data, and wrote the manuscript.

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Correspondence to Daniel J. Weix.

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The authors declare no competing financial interests.

Extended data figures and tables

Extended Data Figure 1 Varying ligands on the nickel and palladium catalysts.

Several different phosphine ligands for palladium (a) and amine ligands for nickel (b) were investigated. Although selectivity and yield of cross-product were sensitive to the identity of the phosphine ligand (a), a variety of different amine ligands were effective (b). Reactions conducted with L15, L17, and L18 used 5 mol% catalyst loadings, were heated to 40 °C, and were monitored for 64 h. GC, gas chromatography; area per cent, uncorrected.

Extended Data Figure 2 The effect of potassium and fluoride salts on the selectivity of the multimetal-catalysed cross-Ullmann reaction.

The presence of potassium fluoride (KF) in cross-couplings has been demonstrated to improve the product yield and rate of reactions while minimizing the formation of dimeric products. This ‘KF effect’ can be attributed to a variety of different factors, including the formation of ‘ate’ complexes, the removal of a halide from a metal complex, or the formation of a fluoride-bridged complex, which could facilitate an oxidative addition or transmetallation step23,25. a, b, To investigate whether KF could be beneficial for the nickel and palladium multimetallic system, we included various amounts of this additive under standard reaction conditions. The resulting selectivity and rate data are shown. c, d, Once the advantageous role of KF was confirmed, other potassium and fluoride salts were tested. The resulting selectivity and rate data are shown. The presence of potassium resulted in faster reaction rates, while the presence of fluoride reduced the amount of bianisole and biphenyl byproducts, improving the yield of cross-product. (Reactions without additives took 32 h to complete.)

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Ackerman, L., Lovell, M. & Weix, D. Multimetallic catalysed cross-coupling of aryl bromides with aryl triflates. Nature 524, 454–457 (2015). https://doi.org/10.1038/nature14676

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