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Palladium-catalysed cross-coupling of lithium acetylides

Nature Catalysis volume 3, pages 664–671 (2020)Cite this article

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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.

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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.

References

  1. Diederich, F., Stang, P. J. & Tykwinski, R. R. Acetylene Chemistry: Chemistry, Biology and Material Science (Wiley-VCH, 2004).

  2. Debets, M. F., van Hest, J. C. M. & Rutjes, F. P. J. T. Bioorthogonal labelling of biomolecules: new functional handles and ligation methods. Org. Biomol. Chem. 11, 6439–6455 (2013).

    Article  CAS  PubMed  Google Scholar 

  3. Bohlmann, F., Burkhardt, H. & Zdero, C. Naturally Occuring Acetylenes (Academic, 1973).

  4. Habrant, D., Rauhala, V. & Koskinen, A. M. P. Conversion of carbonyl compounds to alkynes: general overview and recent developments. Chem. Soc. Rev. 39, 2007–2017 (2010).

    Article  CAS  PubMed  Google Scholar 

  5. Kuang, C., Yang, Q., Senboku, H. & Tokuda, M. Synthesis of (Z)-1-bromo-1-alkenes and terminal alkynes from anti-2,3-dibromoalkanoic acids by microwave-induced reaction. Tetrahedron 61, 4043–4052 (2005).

    Article  CAS  Google Scholar 

  6. Biffis, A., Centomo, P., Del Zotto, A. & Zecca, M. Pd metal catalysts for cross-couplings and related reactions in the 21st century: a critical review. Chem. Rev. 118, 2249–2295 (2018).

    Article  CAS  PubMed  Google Scholar 

  7. Chinchilla, R. & Nájera, C. Recent advances in Sonogashira reactions. Chem. Soc. Rev. 40, 5084–5121 (2011).

    Article  CAS  PubMed  Google Scholar 

  8. Sonogashira, K. in Handbook of Organopalladium Chemistry for Organic Synthesis (ed. Negishi, E.) 493–529 (Wiley, 2002).

  9. Kabalka, G. W. W., Wang, L., Namboodiri, V. & Pagni, R. M. Rapid microwave-enhanced, solventless Sonogashira coupling reaction on alumina. Tetrahedron Lett. 41, 5151–5154 (2000).

    Article  CAS  Google Scholar 

  10. Erdélyi, M. & Gogoll, A. Rapid homogeneous-phase Sonogashira coupling reactions using controlled microwave heating. J. Org. Chem. 66, 4165–4169 (2001).

    Article  PubMed  CAS  Google Scholar 

  11. Gholap, A. R. et al. Copper- and ligand-free Sonogashira reaction catalyzed by Pd(0) nanoparticles at ambient conditions under ultrasound irradiation. J. Org. Chem. 70, 4869–4872 (2005).

    Article  CAS  PubMed  Google Scholar 

  12. He, J., Yang, K., Zhao, J. & Cao, S. LiHMDS-promoted palladium-catalyzed Sonogashira cross-coupling of aryl fluorides with terminal alkynes. Org. Lett. 21, 9714–9718 (2019).

    Article  CAS  PubMed  Google Scholar 

  13. Miyaura, N. & Suzuki, A. Palladium-catalyzed cross-coupling reactions of organoboron compounds. Chem. Rev. 95, 2457–2483 (1995).

    Article  CAS  Google Scholar 

  14. Negishi, E. & Xu, C. in Handbook of Organopalladium Chemistry for Organic Synthesis (ed. Negishi, E.) 531–549 (Wiley, 2002).

  15. Umaña, C. A. & Cabezas, J. A. Palladium-catalyzed one-pot conversion of aldehydes and ketones into 4-substituted homopropargyl alcohols and 5-En-3-yn-1-ols. J. Org. Chem. 82, 9505–9514 (2017).

    Article  PubMed  CAS  Google Scholar 

  16. Cabezas, J. A., Poveda, R. R. & Brenes, J. A. One-pot conversion of aldehydes and ketones into 1-substituted and 1,4-disubstituted 1,3-enynes. Synthesis 50, 3307–3321 (2018).

    Article  CAS  Google Scholar 

  17. Giannerini, M., Fañanás-Mastral, M. & Feringa, B. L. Direct catalytic cross-coupling of organolithium compounds. Nat. Chem. 5, 667–672 (2013).

  18. Heijnen, D. et al. Oxygen activated, palladium nanoparticle catalyzed, ultrafast cross-coupling of organolithium reagents. Angew. Chem. Int. Ed. 56, 3354–3359 (2017).

    Article  CAS  Google Scholar 

  19. Hornillos, V., Giannerini, M., Vila, C., Fañanás-Mastral, M. & Feringa, B. L. Direct catalytic cross-coupling of alkenyllithium compounds. Chem. Sci. 6, 1394–1398 (2015).

    Article  CAS  PubMed  Google Scholar 

  20. Pinxterhuis, E. B., Giannerini, M., Hornillos, V. & Feringa, B. L. Fast, greener and scalable direct coupling of organolithium compounds with no additional solvents. Nat. Commun. 7, 11698 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Pinxterhuis, E. B., Visser, P., Esser, I., Gualtierotti, J. B. & Feringa, B. L. Fast, efficient and low E-factor one-pot palladium-catalyzed cross-coupling of (hetero)arenes. Angew. Chem. Int. Ed. 57, 9452–9455 (2018).

    Article  CAS  Google Scholar 

  22. Huang, X. et al. Expanding Pd-catalyzed C–N bond-forming processes: the first amidation of aryl sulfonates, aqueous amination, and complementarity with Cu-catalyzed reactions. J. Am. Chem. Soc. 125, 6653–6655 (2003).

    Article  CAS  PubMed  Google Scholar 

  23. Negishi, E.-i, Akiyoshi, K. & Takahashi, T. Inhibition of reductive elimination of diorganopalladium species by formation of tetraorganopalladates. J. Chem. Soc. Chem. Commun. 6, 477–478 (1987).

    Article  Google Scholar 

  24. Aufiero, M., Scattolin, T., Proutière, F. & Schoenebeck, F. Air-stable dinuclear iodine-bridged Pd(i) complex—catalyst, precursor or parasite? The additive decides. Systematic nucleophile-activity study and application as precatalyst in cross-coupling. Organometallics 34, 5191–5195 (2015).

    Article  CAS  Google Scholar 

  25. Vitaku, E., Smith, D. T. & Njardarson, J. T. Analysis of the structural diversity, substitution patterns, and frequency of nitrogen heterocycles among U.S. FDA approved pharmaceuticals. J. Med. Chem. 57, 10257–10274 (2014).

    Article  CAS  PubMed  Google Scholar 

  26. Majumdar, K. C. & Chattopadhyay, S. Heterocycles in Natural Product Synthesis (Wiley‐VCH, 2011).

  27. Luisi, R. & Capriati, V. Lithium Compounds in Organic Synthesis—From Fundamentals to Applications (Wiley‐VCH, 2014).

  28. Rappoport, Z. & Marek, I. The Chemistry of Organolithium Compounds (John Wiley & Sons, 2004).

  29. Crabtree, R. H. The Organometallic Chemistry of the Transition Metals (John Wiley & Sons, 2019).

  30. Bordwell, F. G. & Drucker, G. E. Acidities of indene and phenyl-, diphenyl-, and triphenylindenes. J. Org. Chem. 45, 3325–3328 (1980).

    Article  CAS  Google Scholar 

  31. Matthews, W. S. et al. Equilibrium acidities of carbon acids. VI. Establishment of an absolute scale of acidities in dimethyl sulfoxide solution. J. Am. Chem. Soc. 97, 7006–7014 (1975).

    Article  CAS  Google Scholar 

  32. Fyfe, J. W. B. & Watson, A. J. B. Recent developments in organoboron chemistry: old dogs, new tricks. Chem 3, 31–55 (2017).

    Article  CAS  Google Scholar 

  33. Suga, S. & Kitamura, M. 4.17 Asymmetric 1,2-addition of organometallics to carbonyl and imine groups. Compr. Chirality 4, 328–342 (2012).

    Article  CAS  Google Scholar 

  34. León, A., Del-Ángel, M., Ávila, J. L. & Delgado, G. in Progress in the Chemistry of Organic Natural Products (eds Kinghorn, A. D. et al.) 127–246 (Springer, 2017).

  35. Oballa, R. M. et al. A generally applicable method for assessing the electrophilicity and reactivity of diverse nitrile-containing compounds. Bioorg. Med. Chem. Lett. 17, 998–1002 (2007).

    Article  CAS  PubMed  Google Scholar 

  36. Nguyen, T. T. T. et al. Chemoselective deprotonative lithiation of azobenzenes: reactions and mechanisms. J. Org. Chem. 79, 2775–2780 (2014).

    Article  CAS  PubMed  Google Scholar 

  37. Haldar, R., Heinke, L. & Wöll, C. Advanced photoresponsive materials using the metal–organic framework approach. Adv. Mater. 32, 1905227 (2019).

  38. Velema, W. A., Szymanski, W. & Feringa, B. L. Photopharmacology: beyond proof of principle. J. Am. Chem. Soc. 136, 2178–2191 (2014).

    Article  CAS  PubMed  Google Scholar 

  39. Dubbaka, S. R., Kienle, M., Mayr, H. & Knochel, P. Copper(i)-mediated oxidative cross-coupling between functionalized alkynyl lithium and aryl magnesium reagents. Angew. Chem. Int. Ed. 46, 9093–9096 (2007).

    Article  CAS  Google Scholar 

  40. Nguyen, M. H., O’Brien, K. T. & Smith, A. B. Design, synthesis, and application of polymer-supported silicon-transfer agents for cross-coupling reactions with organolithium reagents. J. Org. Chem. 82, 11056–11071 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Nagaki, A., Kenmoku, A., Moriwaki, Y., Hayashi, A. & Yoshida, J.-i Cross-coupling in a flow microreactor: space integration of lithiation and murahashi coupling. Angew. Chem. Int. Ed. 49, 7543–7547 (2010).

    Article  CAS  Google Scholar 

  42. Quick, M. et al. Photoisomerization dynamics of stiff-stilbene in solution. J. Phys. Chem. B 118, 1389–1402 (2014).

    Article  CAS  PubMed  Google Scholar 

  43. Qin, L., Xu, G.-j, Yao, C. & Xu, Y.-h Conjugated microporous polymer networks with adjustable microstructures for high CO2 uptake capacity and selectivity. Chem. Commun. 52, 12602–12605 (2016).

    Article  CAS  Google Scholar 

  44. Carlmark, A., Hawker, C., Hult, A. & Malkoch, M. New methodologies in the construction of dendritic materials. Chem. Soc. Rev. 38, 352–362 (2009).

    Article  CAS  PubMed  Google Scholar 

  45. Brown, C. A. & Yamashita, A. Saline hydrides and superbases in organic reactions. IX. Acetylene zipper. Exceptionally facile contrathermodynamic multipositional isomeriazation of alkynes with potassium 3-aminopropylamide. J. Am. Chem. Soc. 97, 891–892 (1975).

    Article  CAS  Google Scholar 

  46. Chowdhury, M. A. & Reissig, H.-U. Syntheses of highly substituted furan and pyrrole derivatives via lithiated 3-aryl-1-methoxyallenes: application to the synthesis of codonopsinine. Synlett 2006, 2383–2386 (2006).

    Article  CAS  Google Scholar 

  47. Alemán, J. et al. Enantioselective synthesis of 4-isoxazolines by 1,3-dipolar cycloadditions of nitrones to alkynals catalyzed by fluorodiphenylmethylpyrrolidines. Adv. Synth. Catal. 354, 1665–1671 (2012).

    Article  CAS  Google Scholar 

  48. Kivrak, A. & Zora, M. A novel synthesis of 1,2,4-oxadiazoles and isoxazoles. Tetrahedron 70, 817–831 (2014).

    Article  CAS  Google Scholar 

  49. Heijnen, D., Helbert, H., Luurtsema, G., Elsinga, P. H. & Feringa, B. L. Synthesis of substituted benzaldehydes via a two-step, one-pot reduction/cross-coupling procedure. Org. Lett. 21, 4087–4091 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Atherton, J. H. H. & Hall, A. Scale-up—how do we get it right the first time? Chem. Today 29, 47–49 (2011).

    CAS  Google Scholar 

  51. Leonard, K. A. et al. 2,4,6-Triarylchalcogenopyrylium dyes related in structure to the antitumor agent AA1 as in vitro sensitizers for the photodynamic therapy of cancer. J. Med. Chem. 42, 3942–3952 (1999).

    Article  CAS  PubMed  Google Scholar 

  52. Jeong, Y., Lee, J. & Ryu, J.-S. Design, synthesis, and evaluation of hinge-binder tethered 1,2,3-triazolylsalicylamide derivatives as Aurora kinase inhibitors. Biorg. Med. Chem. 24, 2114–2124 (2016).

    Article  CAS  Google Scholar 

  53. Abrams, J. N., Zhao, Q., Ghiviriga, I. & Minaruzzaman Palladium(ii)-catalyzed enyne cyclization strategies toward the podophyllotoxin ring system. Tetrahedron 68, 423–428 (2012).

    Article  CAS  Google Scholar 

  54. Fenenko, L. et al. Electrical properties of 1,4-bis(4-(phenylethynyl)phenylethynyl)benzene and its application for organic light emitting diodes. Chem. Commun. 22, 2278–2280 (2007).

    Article  CAS  Google Scholar 

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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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Author notes

  1. These authors contributed equally: Hugo Helbert, Paco Visser.

Authors and Affiliations

  1. Stratingh Institute for Chemistry, University of Groningen, Groningen, The Netherlands

    Hugo Helbert, Paco Visser, Johannes G. H. Hermens, Jeffrey Buter & Ben L. Feringa

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  1. Hugo Helbert
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Contributions

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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