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Carbonyl cross-metathesis via deoxygenative gem-di-metal catalysis

Nature Chemistry (2023)Cite this article

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Abstract

Carbonyls and alkenes are versatile functional groups, whose reactivities are cornerstones of organic synthesis. The selective combination of two carbonyls to form an alkene—a carbonyl cross-metathesis—would be a valuable tool for their exchange. Yet, this important synthetic challenge remains unsolved. Although alkene/alkene and alkene/carbonyl cross-metathesis reactions are known, there is a lack of analogous methods for deoxygenative cross-coupling of two carbonyl compounds. Here we report a pair of strategies for the cross-metathesis of unbiased carbonyls, allowing an aldehyde to be chemo- and stereoselectively combined with another aldehyde or ketone. These mild, catalytic methods are promoted by earth-abundant metal salts and enable rapid access to an unprecedentedly broad range of either Z- or E-alkenes by two distinct mechanisms—entailing transiently generated (1) carbenes and ylides (via Fe catalysis) or (2) doubly nucleophilic gem-di-metallics (via Cr catalysis).

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Fig. 1: Carbonyl metathesis strategies are rare, and cross-selectivity mechanisms must be developed.
Fig. 2: The Cr-catalysed carbonyl metathesis has wide scope with robust E- and cross-selectivity.
Fig. 3: Cross-metathesis: selectivity probes and mechanism.

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Data availability

The data supporting the findings of this study are included in Supplementary Information.

References

  1. Takeda, T. Modern carbonyl olefination—methods and applications. Synthesis 2004, 1532–1532 (2004).

    Article  Google Scholar 

  2. Hoveyda, A. H. & Zhugralin, A. R. The remarkable metal-catalysed olefin metathesis reaction. Nature 450, 243–251 (2007).

    Article  CAS  PubMed  Google Scholar 

  3. Albright, H. et al. Carbonyl-olefin metathesis. Chem. Rev. 121, 9359–9406 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Griffith, A. K., Vanos, C. M. & Lambert, T. H. Organocatalytic carbonyl-olefin metathesis. J. Am. Chem. Soc. 134, 18581–18584 (2012).

    Article  CAS  PubMed  Google Scholar 

  5. Ludwig, J. R., Zimmerman, P. M., Gianino, J. B. & Schindler, C. S. Iron(III)-catalysed carbonyl-olefin metathesis. Nature 533, 374–379 (2016).

    Article  CAS  PubMed  Google Scholar 

  6. Pitzer, L., Sandfort, F., Strieth‐Kalthoff, F. & Glorius, F. Carbonyl–olefin cross‐metathesis through a visible‐light‐induced 1,3‐diol formation and fragmentation sequence. Angew. Chem. Int. Ed. 57, 16219–16223 (2018).

    Article  CAS  Google Scholar 

  7. McMurry, J. E. Carbonyl-coupling reactions using low-valent titanium. Chem. Rev. 89, 1513–1524 (1989).

    Article  CAS  Google Scholar 

  8. McMurry, J. E. & Fleming, M. P. New method for the reductive coupling of carbonyls to olefins. Synthesis of β-carotene. J. Am. Chem. Soc. 96, 4708–4709 (1974).

    Article  CAS  Google Scholar 

  9. Mukaiyama, T., Sato, T. & Hanna, J. Reductive coupling of carbonyl compounds to pinacols and olefins by using TiCl4 and Zn. Chem. Lett. 2, 1041–1044 (1973).

    Article  Google Scholar 

  10. Asako, S. & Ilies, L. Olefin synthesis by deoxygenative coupling of carbonyl compounds: from stoichiometric to catalytic. Chem. Lett. 49, 1386–1393 (2020).

    Article  CAS  Google Scholar 

  11. Bongso, A., Roswanda, R. & Syah, Y. M. Recent advances of carbonyl olefination via McMurry coupling reaction. RSC Adv. 12, 15885–15909 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. McMurry, J. E., Fleming, M. P., Kees, K. L. & Krepski, L. R. Titanium-induced reductive coupling of carbonyls to olefins. J. Org. Chem. 43, 3255–3266 (1978).

    Article  CAS  Google Scholar 

  13. Mukaiyama, T., Sugimura, H., Ohno, T. & Kobayashi, S. Reductive cross coupling reaction of a glyoxylate with carbonyl compounds. A facile synthesis of α,β-dihydroxycarboxylate based on a low valent titanium compound. Chem. Lett. 18, 1401–1404 (1989).

    Article  Google Scholar 

  14. Wang, H., Dai, X. J. & Li, C. J. Aldehydes as alkyl carbanion equivalents for additions to carbonyl compounds. Nat. Chem. 9, 374–378 (2017).

    Article  CAS  PubMed  Google Scholar 

  15. Wei, W. et al. Ruthenium(II)-catalyzed olefination: via carbonyl reductive cross-coupling. Chem. Sci. 8, 8193–8197 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Esfandiarfard, K., Mai, J. & Ott, S. Unsymmetrical E-alkenes from the stereoselective reductive coupling of two aldehydes. J. Am. Chem. Soc. 139, 2940–2943 (2017).

    Article  CAS  PubMed  Google Scholar 

  17. Wang, S., Lokesh, N., Hioe, J., Gschwind, R. M. & König, B. Photoinitiated carbonyl-metathesis: deoxygenative reductive olefination of aromatic aldehydes via photoredox catalysis. Chem. Sci. 10, 4580–4587 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Wang, L., Lear, J. M., Rafferty, S. M., Fosu, S. C. & Nagib, D. A. Ketyl radical reactivity via atom transfer catalysis. Science 362, 225–229 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Yang, Z. P. & Fu, G. C. Convergent catalytic asymmetric synthesis of esters of chiral dialkyl carbinols. J. Am. Chem. Soc. 142, 5870–5875 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Rafferty, S. M., Rutherford, J. E., Zhang, L., Wang, L. & Nagib, D. A. Cross-selective aza-pinacol coupling via atom transfer catalysis. J. Am. Chem. Soc. 143, 5622–5628 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Huang, H.-M., Bellotti, P., Kim, S., Zhang, X. & Glorius, F. Catalytic multicomponent reaction involving a ketyl-type radical. Nat. Synth. 1, 464–474 (2022).

    Article  Google Scholar 

  22. Huang, H. M., Bellotti, P., Erchinger, J. E., Paulisch, T. O. & Glorius, F. Radical carbonyl umpolung arylation via dual nickel catalysis. J. Am. Chem. Soc. 144, 1899–1909 (2022).

    Article  CAS  PubMed  Google Scholar 

  23. Zhu, C., Lee, S. C., Chen, H., Yue, H. & Rueping, M. Reductive cross-coupling of α-oxy halides enabled by thermal catalysis, photocatalysis, electrocatalysis, or mechanochemistry. Angew. Chem. Int. Ed. 61, e202204212 (2022).

    Article  CAS  Google Scholar 

  24. Kennedy, S. H., Dherange, B. D., Berger, K. J. & Levin, M. D. Skeletal editing through direct nitrogen deletion of secondary amines. Nature 593, 223–227 (2021).

    Article  CAS  PubMed  Google Scholar 

  25. Dong, Z. & MacMillan, D. W. C. Metallaphotoredox-enabled deoxygenative arylation of alcohols. Nature 598, 451–456 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Zhang, L., DeMuynck, B. M., Paneque, A. N., Rutherford, J. E. & Nagib, D. A. Carbene reactivity from alkyl and aryl aldehydes. Science 377, 649–654 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Aggarwal, V. K. & Winn, C. L. Catalytic, asymmetric sulfur ylide-mediated epoxidation of carbonyl compounds: scope, selectivity, and applications in synthesis. Acc. Chem. Res. 37, 611–620 (2004).

    Article  CAS  PubMed  Google Scholar 

  28. Ledford, B. E. & Carreira, E. M. Synthesis of unsaturated esters from aldehydes: an inexpensive, practical alternative to the Horner–Emmons reaction under neutral conditions. Tetrahedron Lett. 38, 8125–8128 (1997).

    Article  CAS  Google Scholar 

  29. Lebel, H., Paquet, V. & Proulx, C. Methylenation of aldehydes: transition metal catalyzed formation of salt-free phosphorus ylides. Angew. Chem. Int. Ed. 40, 2887–2890 (2001).

    Article  CAS  Google Scholar 

  30. Aggarwal, V. K., Fulton, J. R., Sheldon, C. G. & De Vicente, J. Generation of phosphoranes derived from phosphites. A new class of phosphorus ylides leading to high E selectivity with semi-stabilizing groups in Wittig olefinations. J. Am. Chem. Soc. 125, 6034–6035 (2003).

    Article  CAS  PubMed  Google Scholar 

  31. Filippini, D. & Silvi, M. Visible light-driven conjunctive olefination. Nat. Chem. 14, 66–70 (2022).

    Article  CAS  PubMed  Google Scholar 

  32. Takai, K., Hotta, Y., Oshima, K. & Nozaki, H. Effective methods of carbonyl methylenation using CH2I2–Zn–Me3Al and CH2Br2–Zn–TiCl4 system. Tetrahedron Lett. 19, 2417–2420 (1978).

    Article  Google Scholar 

  33. Okazoe, T., Takai, K. & Utimoto, K. E-selective olefination of aldehydes by means of gem-dichromium reagents derived by reduction of gem-diiodoalkanes with chromium(II) chloride.J. Am. Chem. Soc. 109, 951–953 (1987).

    Article  CAS  Google Scholar 

  34. Kochi, J. K. & Mocadlo, P. E. Facile reduction of alkyl halides with chromium(II) complexes. Alkylchromium species as intermediates. J. Am. Chem. Soc. 88, 4094–4096 (1966).

    Article  CAS  Google Scholar 

  35. Marek, I. & Normant, J. F. Synthesis and reactivity of sp3-geminated organodimetallics. Chem. Rev. 96, 3241–3267 (1996).

    Article  CAS  PubMed  Google Scholar 

  36. Nallagonda, R., Padala, K. & Masarwa, A. gem-Diborylalkanes: recent advances in their preparation, transformation and application. Org. Biomol. Chem. 16, 1050–1064 (2018).

    Article  CAS  PubMed  Google Scholar 

  37. Banerjee, A. K., Sulbaran De Carrasco, M. C., Frydrych-Houge, C. S. V. & Motherwell, W. B. Observations on the reductive deoxygenation of aryl and α,β-unsaturated carbonyl compounds with chlorotrimethylsilane and zinc. J. Chem. Soc. Chem.Commun. 1986, 1803–1805 (1986).

    Article  Google Scholar 

  38. Knecht, M. & Boland, W. E-selective alkylidenation of aldehydes with reagents derived from α-acetoxy bromides, zinc and CrCl3. Synlett 1993, 837–838 (1993).

    Article  Google Scholar 

  39. Fürstner, A. & Shi, N. Nozaki–Hiyama–Kishi reactions catalytic in chromium. J. Am. Chem. Soc. 118, 12349–12357 (1996).

    Article  Google Scholar 

  40. Zhao, K. & Knowles, R. R. Contra-thermodynamic positional isomerization of olefins. J. Am. Chem. Soc. 144, 137–144 (2022).

    Article  CAS  PubMed  Google Scholar 

  41. Zhang, C., Lin, Z., Zhu, Y. & Wang, C. Chromium-catalyzed allylic defluorinative ketyl olefin coupling. J. Am. Chem. Soc. 143, 11602–11610 (2021).

    Article  CAS  PubMed  Google Scholar 

  42. Schwarz, J. L., Schäfers, F., Tlahuext-Aca, A., Lückemeier, L. & Glorius, F. Diastereoselective allylation of aldehydes by dual photoredox and chromium catalysis. J. Am. Chem. Soc. 140, 12705–12709 (2018).

    Article  CAS  PubMed  Google Scholar 

  43. Ruffoni, A., Hampton, C., Simonetti, M. & Leonori, D. Photoexcited nitroarenes for the oxidative cleavage of alkenes. Nature 610, 81–86 (2022).

    Article  CAS  PubMed  Google Scholar 

  44. Wise, D. E. et al. Photoinduced oxygen transfer using nitroarenes for the anaerobic cleavage of alkenes. J. Am. Chem. Soc. 144, 15437–15442 (2022).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank the National Institutes of Health (R35 GM119812), National Science Foundation (CAREER 1654656) and Brown Science Foundation (BIA) for funding (to D.A.N.), and we are grateful to T. Bednar for independent verification of the robustness of this method.

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Authors and Affiliations

  1. Department of Chemistry and Biochemistry, The Ohio State University, Columbus, OH, USA

    Lumin Zhang & David A. Nagib

  2. Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China

    Lumin Zhang

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  1. Lumin Zhang
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L.Z. and D.A.N. designed these strategies and wrote the manuscript. L.Z. performed all experiments and analysis.

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Correspondence to Lumin Zhang or David A. Nagib.

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Zhang, L., Nagib, D.A. Carbonyl cross-metathesis via deoxygenative gem-di-metal catalysis. Nat. Chem. (2023). https://doi.org/10.1038/s41557-023-01333-8

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