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A general approach to intermolecular carbonylation of arene C–H bonds to ketones through catalytic aroyl triflate formation

Nature Chemistry volume 10, pages 193–199 (2018)Cite this article

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Abstract

The development of metal-catalysed methods to functionalize inert C–H bonds has become a dominant research theme in the past decade as an approach to efficient synthesis. However, the incorporation of carbon monoxide into such reactions to form valuable ketones has to date proved a challenge, despite its potential as a straightforward and green alternative to Friedel–Crafts reactions. Here we describe a new approach to palladium-catalysed C–H bond functionalization in which carbon monoxide is used to drive the generation of high-energy electrophiles. This offers a method to couple the useful features of metal-catalysed C–H functionalization (stable and available reagents) and electrophilic acylations (broad scope and selectivity), and synthesize ketones simply from aryl iodides, CO and arenes. Notably, the reaction proceeds in an intermolecular fashion, without directing groups and at very low palladium-catalyst loadings. Mechanistic studies show that the reaction proceeds through the catalytic build-up of potent aroyl triflate electrophiles.

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Figure 1: Comparison of the classical approaches to ketone synthesis with the palladium-catalysed carbonylative C–H bond functionalization reaction described here.
Figure 2: Palladium-catalyst development for the intermolecular carbonylative coupling of aryl iodide and benzene into ketones.
Figure 3: Mechanistic studies demonstrate this transformation proceeds through the novel catalytic formation of aroyl triflate electrophiles.
Figure 4: Applications of this general methodology to the synthesis of pharmaceutically relevant molecules, double C–H bond functionalization and low-temperature C–H bond functionalization.

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Acknowledgements

We thank Natural Sciences and Engineering Research Council of Canada, the Canadian Foundation for Innovation and the Centre for Green Chemistry and Catalysis (supported by Fonds de recherche du Québec – Nature et Technologies) for funding this research. We thank L. Kayser for the X-ray crystal structure of 3a and to S. Kelley for the X-ray crystal structure of 4b.

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Authors and Affiliations

  1. Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montreal, H3A 0B8, Quebec, Canada

    R. Garrison Kinney, Jevgenijs Tjutrins, Gerardo M. Torres, Nina Jiabao Liu, Omkar Kulkarni & Bruce A. Arndtsen

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Contributions

B.A.A. and R.G.K. conceived the project. R.G.K. conducted the majority of the experiments. J.T. assisted in the early experiments. G.M.T. conducted the mechanistic experiments with 4b and assisted with Table 1 and Fig. 4b. N.I.L. and O.K. assisted with Table 1. B.A.A. and R.G.K. prepared the manuscript with feedback from all of the authors.

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Correspondence to Bruce A. Arndtsen.

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Crystallographic data for compound 3a (CIF 657 kb)

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Crystallographic data for compound 4b (CIF 4930 kb)

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Garrison Kinney, R., Tjutrins, J., Torres, G. et al. A general approach to intermolecular carbonylation of arene C–H bonds to ketones through catalytic aroyl triflate formation. Nature Chem 10, 193–199 (2018). https://doi.org/10.1038/nchem.2903

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