Direct catalytic cross-coupling of organolithium compounds

Abstract

Catalytic carbon–carbon bond formation based on cross-coupling reactions plays a central role in the production of natural products, pharmaceuticals, agrochemicals and organic materials. Coupling reactions of a variety of organometallic reagents and organic halides have changed the face of modern synthetic chemistry. However, the high reactivity and poor selectivity of common organolithium reagents have largely prohibited their use as a viable partner in direct catalytic cross-coupling. Here we report that in the presence of a Pd-phosphine catalyst, a wide range of alkyl-, aryl- and heteroaryl-lithium reagents undergo selective cross-coupling with aryl- and alkenyl-bromides. The process proceeds quickly under mild conditions (room temperature) and avoids the notorious lithium halogen exchange and homocoupling. The preparation of key alkyl-, aryl- and heterobiaryl intermediates reported here highlights the potential of these cross-coupling reactions for medicinal chemistry and material science.

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Figure 1: Catalytic cross-coupling reactions.
Figure 2: Cross-coupling of phenyllithium and 4-methoxy-bromobenzene.
Figure 3: Comparison of established methods and the present cross-coupling protocol with organolithium reagents.

Change history

  • 17 June 2013

    In the version of this Article originally published online, there are three instances where the compound 2u should have been 2x: twice in Table 1, and once in the section 'Pd-catalysed cross-coupling with alkyllithium reagents.' Also in that section, 2s-2v should have been 2v-2y. These errors have been corrected in the HTML and PDF versions of the Article.

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Acknowledgements

The authors thank the Netherlands Organization for Scientific Research (NWO-CW), the National Research School Catalysis (NRSC-C) and the European Research Council (ERC advanced grant 227897 to B.L.F.) for financial support.

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M.G. and M.F.-M. performed the experiments. M.G., M.F.-M. and B.L.F. designed the experiments, analysed the data and wrote the manuscript. B.L.F. guided the research.

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Correspondence to Ben L. Feringa.

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The authors declare no competing financial interests.

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Giannerini, M., Fañanás-Mastral, M. & Feringa, B. Direct catalytic cross-coupling of organolithium compounds. Nature Chem 5, 667–672 (2013). https://doi.org/10.1038/nchem.1678

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