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Reversible C–C bond formation using palladium catalysis

Nature Chemistry volume 14, pages 398–406 (2022)Cite this article

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Abstract

A widely appreciated principle is that all reactions are fundamentally reversible. Observing reversible transition metal-catalysed reactions, particularly those that include the cleavage of C–C bonds, is more challenging. The development of palladium- and nickel-catalysed carboiodination reactions afforded access to the cis and trans diastereomers of the iodo-dihydroisoquinolone products. Using these substrates, an extensive study investigating the reversibility of C–C bond formation using a simple palladium catalyst was undertaken. Herein we report a comprehensive investigation of reversible C–C bond formation using palladium catalysis employing diastereomeric neopentyl iodides as the starting point. It was shown that both diastereomers could be converted to a common product under identical catalytic conditions. A combination of experimental and computational studies were used to probe the operative mechanism. A variety of concepts key to understanding the process of reversible C–C bond formations were investigated, including the effect of electronic and steric parameters on the C–C bond-cleavage step.

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Fig. 1: Strategies for β-carbon elimination.
Fig. 2: Initial results and proposed mechanism.
Fig. 3: Mechanistic studies probing alternative pathways.
Fig. 4: DFT analysis of the reaction.
Fig. 5: DFT analysis of the electronic and steric trends of the reaction.

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Data availability

The experimental data, as well as the characterization data for all of the compounds prepared in the course of these studies, are provided in the Supplementary Information. The crystallographic data for the structures reported in this article have been deposited at the Cambridge Crystallographic Data Centre, under accession numbers: 2096025 (2a) and 2123639 (trans-1d) (see the X-ray crystallographic data in the Supplementary Information). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/.

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Acknowledgements

We thank the University of Toronto, the Natural Science and Engineering Research Council (NSERC), and Kennarshore Inc. for financial support. A.D.M. thanks NSERC for an NSERC Vanier fellowship. B.M. thanks the NSERC for a CGS D scholarship. Computational studies were enabled in part through support provided by Compute Ontario (www.computeontario.ca) and Compute Canada (www.computecanada.ca). We thank D. Burns, J. Sheng and K. Demmans (University of Toronto) for their assistance with NMR experiments. We thank I. Franzoni for fruitful discussions and their assistance with the DFT studies. We thank E. M. Larin and D. Armstrong for their helpful discussions about this work. We thank H. Yoon and D. Petrone for their insight on the palladium-catalysed carboiodination reaction. We thank A. Lough (University of Toronto) for obtaining the X-ray crystallographic data.

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Author notes

  1. These authors contributed equally: Austin D. Marchese, Bijan Mirabi.

Authors and Affiliations

  1. Department of Chemistry, Davenport Chemical Laboratories, University of Toronto, Toronto, Ontario, Canada

    Austin D. Marchese, Bijan Mirabi, Colton E. Johnson & Mark Lautens

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Contributions

A.D.M. and B.M. contributed equally to this work. A.D.M. and M.L. conceived the idea for this work. A.D.M. performed the experimental work for this the project, including the mechanistic studies, catalytic reactions, characterization and the majority of the substrate syntheses. B.M. was responsible for all of the DFT calculations and aided in the design of the mechanistic studies and synthesis of the substrates. C.E.J. aided in the synthesis of substrates and characterization. A.D.M, B.M, and M.L prepared the manuscript with feedback from all the authors.

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Correspondence to Mark Lautens.

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Supplementary information

Supplementary Information

General considerations, general procedures 1 and 2, optimization and control studies, X-ray crystallographic data, computational details and results, energies and Cartesian coordinates, spectra.

Supplementary Data 1

Crystallographic data for compound trans-1d; CCDC no. 2123639.

Supplementary Data 2

Crystallographic data for compound 2a; CCDC no. 2096025.

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Marchese, A.D., Mirabi, B., Johnson, C.E. et al. Reversible C–C bond formation using palladium catalysis. Nat. Chem. 14, 398–406 (2022). https://doi.org/10.1038/s41557-022-00898-0

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