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Palladium-catalysed carboformylation of alkynes using acid chlorides as a dual carbon monoxide and carbon source

Abstract

Hydroformylation, a reaction that installs both a C–H bond and an aldehyde group across an unsaturated substrate, is one of the most important catalytic reactions in both industry and academia. Given the synthetic importance of creating new C–C bonds, the development of carboformylation reactions, wherein a new C–C bond is formed instead of a C–H bond, would bear enormous synthetic potential to rapidly increase molecular complexity in the synthesis of valuable aldehydes. However, the demanding complexity inherent in a four-component reaction, utilizing an exogenous CO source, has made the development of a direct carboformylation reaction a formidable challenge. Here, we describe a palladium-catalysed strategy that uses readily available aroyl chlorides as a carbon electrophile and CO source, in tandem with a sterically congested hydrosilane, to perform a stereoselective carboformylation of alkynes. An extension of this protocol to four chemodivergent carbonylations further highlights the creative opportunity offered by this strategy in carbonylation chemistry.

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Fig. 1: Comparison between conventional hydroformylation and carboformylation, and the conceptual blueprint for a general intermolecular carboformylation.
Fig. 2: Chemodivergent carbonylation reaction.

Data availability

Crystallographic data for the structures reported in this Article have been deposited at the Cambridge Crystallographic Data Centre, under deposition numbers CCDC 1998285 (10), 2018417 (33), 2000217 (36, minor), 2000218 (53), 2018418 (59), 2018419 (59-Z), 1998290 (62), 1998292 (64), 1998293 (L08) and 1998299 (76). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/. All other data is available in the main text or the Supplementary Information.

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Acknowledgements

We acknowledge ETH Zurich, the European Research Council under the European Union’s Horizon 2020 research and innovation programme (Shuttle Cat, project ID 757608) and LG Chem (fellowship to Y.H.L.) for financial support. We thank the NMR, MS (MoBiAS) and X-ray (SMoCC) service departments at ETH Zurich for technical assistance.

Author information

Affiliations

Authors

Contributions

Y.H.L. designed and discovered the reaction. Y.H.L. and E.H.D. deterimined the scope of the reaction. B.M. supervised the research. All authors contributed to manuscript writing and editing.

Corresponding author

Correspondence to Bill Morandi.

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Competing interests

The authors declare no competing interests.

Additional information

Peer review information Nature Chemistry thanks the anonymous reviewers for their contribution to the peer review of this work.

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Supplementary information

Supplementary Information

Supplementary Figs. 1–25, Tables 1–28, equations 1–40, experimental details for all reactions and analytic details for all products.

Supplementary Data 1

Crystallographic data for compound 10. CCDC reference 1998285.

Supplementary Data 2

Crystallographic data for compound 33. CCDC reference 2018417.

Supplementary Data 3

Crystallographic data for compound 36-alpha-Ar, minor. CCDC reference 2000217.

Supplementary Data 4

Crystallographic data for compound 53. CCDC reference 2000218.

Supplementary Data 5

Crystallographic data for compound 59. CCDC reference 2018418.

Supplementary Data 6

Crystallographic data for compound 59-Z. CCDC reference 2018419.

Supplementary Data 7

Crystallographic data for compound 62. CCDC reference 1998290.

Supplementary Data 8

Crystallographic data for compound 64. CCDC reference 1998292.

Supplementary Data 9

Crystallographic data for compound L08. CCDC reference 1998293.

Supplementary Data 10

Crystallographic data for compound 76. CCDC reference 1998299.

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Lee, Y.H., Denton, E.H. & Morandi, B. Palladium-catalysed carboformylation of alkynes using acid chlorides as a dual carbon monoxide and carbon source. Nat. Chem. 13, 123–130 (2021). https://doi.org/10.1038/s41557-020-00621-x

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