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Palladium-catalysed cross-coupling of lithium acetylides

Abstract

The incorporation of alkynes into organic molecules is one of the most valuable transformations for the formation of C–C bonds and provides a versatile handle for further modifications. The Sonogashira cross-coupling of acetylenes holds a prominent position among the suite of catalytic cross-coupling reactions that are key to modern synthesis. Here we present a method that is complementary to the Sonogashira reaction, demonstrating cross-coupling of lithium acetylides with aryl bromides. The reactions take place under ambient conditions with short reaction times, affording the corresponding aryl acetylenes in good to excellent yields while displaying a remarkable functional group tolerance for an organolithium reaction, allowing the presence of a variety of organolithium-sensitive carbonyl functionalities. This developed cross-coupling methodology offers ample opportunities to access a wide variety of acetylenes, as is illustrated by the facile preparation of key intermediates for chemical biology and optoelectronic materials.

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Fig. 1: Catalytic acetylene cross-coupling reactions and product applications.
Fig. 2: One-pot synthesis of an aldehyde via lithium acetylide cross-coupling.
Fig. 3: Potential applications of the cross-coupling methodology.

Data availability

Most data generated or analysed during this study are included in this published article and its Supplementary Information. Actual high-resolution mass spectrometry and gas chromatography–mass spectrometry raw data are available from the corresponding author(s) on reasonable request.

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Acknowledgements

B.L.F. acknowledges financial support from the Netherlands Organisation for Scientific Research, the European ResearchCouncil (ERC Advanced Grant 227897), the Royal Netherlands Academy of Arts and Sciences (KNAW), and the Ministry of Education, Culture and Science (Gravitation program 024.601035). S. Crespi is acknowledged for providing (Z)-6,6'-dibromo-2,2',3,3'-tetrahydro-1,1'-bisindenylidene. M. Hansen is acknowledged for providing 1-(4-bromophenyl)-2-phenyldiazene and W. Danowski is acknowledged for providing tetrakis(4-bromophenyl)methane. R. Sneep is acknowledged for performing the high-resolution mass spectrometry.

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H.H., P.V., J.G.H.H. and J.B. performed the experiments. H.H., P.V., J.G.H.H., J.B. and B.L.F. prepared the manuscript. J.B. and B.L.F. designed and supervised the project.

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Correspondence to Jeffrey Buter or Ben L. Feringa.

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Cross-coupling, Organolithium, Sonogashira reaction, Palladium, Acetylene

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Supplementary Information

Supplementary methods, Tables 1–8, references and spectra.

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Helbert, H., Visser, P., Hermens, J.G.H. et al. Palladium-catalysed cross-coupling of lithium acetylides. Nat Catal 3, 664–671 (2020). https://doi.org/10.1038/s41929-020-0485-2

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