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Remote C−H alkylation and C−C bond cleavage enabled by an in situ generated palladacycle

Nature Chemistry volume 9, pages 361–368 (2017)Cite this article

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Abstract

The direct and selective functionalization of C−H bonds of arenes is one of the most challenging yet valuable aims in organic synthesis. Despite notable recent achievements, a pre-installed directing group proved to be essential in most of the methodologies reported so far. In this context, the use of a transient directing group that can be generated in situ has attracted attention and demonstrated the great potential of this strategy. Here we report the use of an in situ generated palladacycle to accomplish remote-selective C−H alkylation reactions of arenes. Following the C−H functionalization event, the alkylated aryl ring undergoes a formal migration to provide diversely substituted benzofuran and indole scaffolds. Computational studies revealed that a palladium(IV) intermediate is not involved in the alkylation step. The aryl migration was found to proceed through a sequential C−C bond cleavage, insertion and β-hydride-elimination process. The increasing steric bulk that builds up during the C−H functionalization step drives the unusual C−C bond cleavage in a non-strained system.

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Figure 1: Previous strategies for C−H functionalization of arenes and the current work.
Figure 2: Computational studies to elucidate the mechanism of the reaction.
Figure 3: Mechanistic studies to support the calculations and synthetic manipulations of the benzofuran product.

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Acknowledgements

We are grateful for financial support from the Natural Sciences and Engineering Research Council (NSERC), the University of Toronto (U of T) and Alphora Research Inc. M.L. thanks the Canada Council for the Arts for a Killam Fellowship. A. Lough (U of T) is acknowledged for X-ray analysis. Z.S. is a visiting scholar from China Pharmaceutical University and thanks the China Scholarship Council. F.S. and T.S. thank the RWTH Aachen and the Evonik Foundation (scholarship to T.S.) for funding. Y.Y. thanks the Osaka University Scholarship for Overseas Research Activities 2015. C.K. is grateful for the award of a Synthesis and Solid State Pharmaceutical Centre PhD Scholarship. D. Schmidmeier is acknowledged for the synthesis of some substrates. We also thank T. Rovis (Columbia University) for suggestions on the mechanism of the reaction and providing chemicals and equipment during the revision of this manuscript, S. S. Stahl (University of Wisconsin-Madison), M. S. Taylor (U of T), D. A. Petrone (U of T), C. C. J. Loh (Max-Planck-Institut für Molekulare Physiologie, Abteilung Chemische Biologie) and I. A. Sanhueza (RWTH Aachen) for helpful discussions. M. Sickert (University of Leipzig) is acknowledged for his initial exploration in this area. This paper is dedicated to Professor Barry M. Trost on the occasion of his 75th birthday.

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Authors and Affiliations

  1. Department of Chemistry, Davenport Laboratories, University of Toronto, 80 St George Street, Toronto, M5S 3H6, Ontario, Canada

    Juntao Ye, Zhihao Shi, Yoshifumi Yasukawa, Cian Kingston & Mark Lautens

  2. Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, Aachen, 52074, Germany

    Theresa Sperger & Franziska Schoenebeck

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  1. Juntao Ye
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Contributions

J.Y. and M.L. conceived the idea. J.Y. and Z.S. conducted the majority of the experimental work and analysed data. T.S. and F.S. carried out the computational studies. Y.Y. and C.K. performed some preliminary screening reactions and substrate synthesis. J.Y., M.L., T.S. and F.S. prepared the manuscript with feedback from all the authors.

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Correspondence to Franziska Schoenebeck or Mark Lautens.

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Crystallographic data for compound 4b (CIF 945 kb)

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Crystallographic data for compound 4n (CIF 1397 kb)

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Ye, J., Shi, Z., Sperger, T. et al. Remote C−H alkylation and C−C bond cleavage enabled by an in situ generated palladacycle. Nature Chem 9, 361–368 (2017). https://doi.org/10.1038/nchem.2631

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