Homocoupling-free iron-catalysed twofold C–H activation/cross-couplings of aromatics via transient connection of reactants

Abstract

Twofold C–H activation/cross-coupling of stoichiometric amounts of organic molecules, R1–H and R2–H, to form an R1–R2 product free of homocoupling products is a goal in the activation of unreactive C–H bonds, as it will dramatically simplify organic synthesis. No reliable strategy to eliminate the homocoupling side products effectively without recourse to the use of an excess of one reactant over another is known. We report herein that a transient connection of two reactants by an anionic group appended to one reactant achieves this goal under mildly oxidative iron-catalysed conditions, through the formation of a productive heteroleptic R1–M–R2 intermediate. We utilized an N-(quinolin-8-yl)amide anion for the temporary connection and cross-coupled a stoichiometric mixture of aromatics in high yield without any trace of homocoupling products. A short-step synthesis of several donor/acceptor thiophene compounds and carbon/sulfur-bridged flat conjugated systems illustrates the utility of this method to streamline organic synthesis.

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Fig. 1
Fig. 2: Iron-catalysed twofold C–H activation/cross-coupling and its application to material synthesis.
Fig. 3: Reaction scope of iron-catalysed twofold C–H activation/cross-coupling of heteroarenes with (hetero)aryl and alkenyl carboxamides.
Fig. 4: Reaction scope of iron-catalysed twofold C–H activation/cross-coupling of carboxamides with arenes.
Fig. 5: Iron-catalysed twofold C–H activation/cross-coupling using heteroarenes of interest in materials science.
Fig. 6: Mechanistic investigation.

Data availability

All data supporting the findings of this study, including experimental procedures and compound characterization, are available within the paper and its Supplementary Information, or from the authors upon reasonable request.

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Acknowledgements

The authors thank MEXT for financial support (KAKENHI Grant-in-Aid for Scientific Research (S) 15H05754 to E.N., JP18H04238 in Precisely Designed Catalysts with Customized Scaffolding to L.I. and KAKENHI Grant-in-Aid for Young Scientists (B) JP17K14480 to R.S.).

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E.N. and R.S. guided the research and wrote the manuscript. T.D. performed the experiments to study the scope, application and mechanism. All authors contributed to designing the experiments, analysing the data and editing the manuscript.

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Correspondence to Rui Shang or Eiichi Nakamura.

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Supplementary Methods, Supplementary Figures 1–4, Supplementary References

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Doba, T., Matsubara, T., Ilies, L. et al. Homocoupling-free iron-catalysed twofold C–H activation/cross-couplings of aromatics via transient connection of reactants. Nat Catal 2, 400–406 (2019). https://doi.org/10.1038/s41929-019-0245-3

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