Iron(III)-catalysed carbonyl–olefin metathesis

Journal name:
Nature
Volume:
533,
Pages:
374–379
Date published:
DOI:
doi:10.1038/nature17432
Received
Accepted
Published online

The olefin metathesis reaction of two unsaturated substrates is one of the most powerful carbon–carbon-bond-forming reactions in organic chemistry. Specifically, the catalytic olefin metathesis reaction has led to profound developments in the synthesis of molecules relevant to the petroleum, materials, agricultural and pharmaceutical industries1. These reactions are characterized by their use of discrete metal alkylidene catalysts that operate via a well-established mechanism2. While the corresponding carbonyl–olefin metathesis reaction can also be used to construct carbon–carbon bonds, currently available methods are scarce and severely hampered by either harsh reaction conditions or the required use of stoichiometric transition metals as reagents. To date, no general protocol for catalytic carbonyl–olefin metathesis has been reported. Here we demonstrate a catalytic carbonyl–olefin ring-closing metathesis reaction that uses iron, an Earth-abundant and environmentally benign transition metal, as a catalyst. This transformation accommodates a variety of substrates and is distinguished by its operational simplicity, mild reaction conditions, high functional-group tolerance, and amenability to gram-scale synthesis. We anticipate that these characteristics, coupled with the efficiency of this reaction, will allow for further advances in areas that have historically been enhanced by olefin metathesis.

At a glance

Figures

  1. Olefination and metathesis reactions for the formation of alkenes.
    Figure 1: Olefination and metathesis reactions for the formation of alkenes.

    a, Summary of traditional olefination reactions in organic synthesis. b, Olefin–olefin metathesis catalysed by ruthenium, molybdenum and tungsten complexes. c, Modes of carbonyl–olefin metathesis, including two-step photochemical cycloaddition/thermolysis cycloreversion, stoichiometric transition-metal-mediated, organocatalytic, and the new iron(III)-catalysed processes described herein. R, R1, R2, R3, R4, generic substituent. cat., catalyst.

  2. Initial evaluation of the catalytic carbonyl–olefin metathesis reaction.
    Figure 2: Initial evaluation of the catalytic carbonyl–olefin metathesis reaction.

    a, Stoichiometric Lewis acid evaluation. All reactions were performed using 0.18 mmol β-ketoester 1, 0.18 mmol Lewis acid I dichloromethane (0.1 M) at room temperature (RT) for 24 h. b, Evaluation of electronically differentiated arene substituents in the catalytic carbonyl–olefin metathesis reaction using iron(III) chloride as an Earth-abundant Lewis acid catalyst. Conditions: ketone (1.0 equiv.), FeCl3 (5 mol%) in dichloroethane (0.01 M), room temperature, 1–12 h. 17 and 18 were run at reflux in dichloroethane. For 17 and 18, yields at room temperature were determined by 1H-NMR analysis using naphthalene as internal standard.

  3. Scope of the iron(III)-catalysed carbonyl–olefin metathesis reaction.
    Figure 3: Scope of the iron(III)-catalysed carbonyl–olefin metathesis reaction.

    Conditions: ketone (1.0 equiv.), FeCl3 (5 mol%) in dichloroethane (0.01 M), room temperature, 1–12 h. 25 was stoichiometric in FeCl3. 41 and 42 were run at 60 °C using FeCl3 (5 mol%), 12 h. 30 was obtained as a single alkene isomer in 52% yield using Fe(OTf)3 (5 mol%) at reflux and as a 1.2:1 mixture of alkene isomers in 46% yield using FeCl3 (5 mol%) at room temperature. The yield for both reactions was determined by 1H-NMR analysis using naphthalene as internal standard. 28 and 44 were isolated as a mixture of alkene isomers. See Supplementary Information for details. The tetrasubstituted alkenes 28 and 30 represent the thermodynamically more stable products. For 27, yield was determined by gas chromatography analysis using dodecane as internal standard. For 43, yield was determined by 1H-NMR analysis using naphthalene as internal standard.

  4. Alkene evaluation in the catalytic carbonyl–olefin metathesis reaction.
    Figure 4: Alkene evaluation in the catalytic carbonyl–olefin metathesis reaction.

    Conditions: ketone (1.0 equiv.), FeCl3 (5 mol%) in dichloroethane (0.01 M) at room temperature. See Supplementary Information for additional experimental details. Terminal alkenes and tetrasubstituted alkenes were found to be unreactive under the optimized reaction conditions. 4749 were run at reflux in dichloroethane.

  5. Mechanistic hypothesis for the iron(III)-chloride-catalysed carbonyl–olefin metathesis reaction.
    Figure 5: Mechanistic hypothesis for the iron(III)-chloride-catalysed carbonyl–olefin metathesis reaction.

    a, Two possible pathways of product formation relying on either a concerted or a carbocation mechanism. b, Design of mechanistic probe molecules to trap potential carbocation intermediates C and F. c, Enthalpic profile and reaction pathway of the computationally proposed reaction mechanism for carbonyl–olefin metathesis using iron(III) chloride. Ar, generic aryl substituent; R, R1, R2, generic substituent.

References

  1. Hoveyda, A. H. & Zhugralin, A. R. The remarkable metal-catalysed olefin metathesis reaction. Nature 450, 243251 (2007)
  2. Grubbs, R. H. & Wenzel, A. G. Handbook of Metathesis 2nd edn, Vols 1–3 (Wiley, 2015)
  3. Katz, T. J. & McGinnis, J. The mechanism of the olefin metathesis reaction. J. Am. Chem. Soc. 97, 15921594 (1975)
  4. Grubbs, R. H., Carr, D. D., Hoppin, C. & Burk, P. L. Consideration of the mechanism of the metal catalyzed olefin metathesis reaction. J. Am. Chem. Soc. 98, 34783483 (1976)
  5. Chauvin, Y. Olefin metathesis: the early days. Angew. Chem. Int. Ed. 45, 37403747 (2006)
  6. Fürstner, A. Olefin metathesis and beyond. Angew. Chem. Int. Ed. 39, 30123043 (2000)
  7. Maryanoff, B. E. & Reitz, A. B. The Wittig olefination reaction and modifications involving phosphoryl-stabilized carbanions. Stereochemistry, mechanism, and selected synthetic aspects. Chem. Rev. 89, 863927 (1989)
  8. Petasis, N. A. & Bzowej, E. I. Titanium-mediated carbonyl olefinations. 1. Methylenations of carbonyl compounds with dimethyltitanocene. J. Am. Chem. Soc. 112, 63926394 (1990)
  9. Takeda, T. & Tsubouchi, A. in Modern Carbonyl Olefination (ed. Takeda, T.) 151199 (Wiley, 2003)
  10. Jones, G. II, Acquadro, M. A. & Carmody, M. A. Long-chain enals via carbonyl–olefin metathesis. An application in pheromone synthesis. J. Chem. Soc. Chem. Commun. 6, 206207 (1975)
  11. Pérez-Ruiz, R., Miranda, M. A., Alle, R., Meerholz, K. & Griesbeck, A. G. An efficient carbonyl-alkene metathesis of bicyclic oxetanes: photoinduced electron transfer reduction of the Paternò–Büchi adducts from 2,3-dihydrofuran and aromatic aldehydes. Photochem. Photobiol. Sci. 5, 5155 (2006)
  12. Valiulin, R. A. & Kutateladze, A. G. Harvesting the strain installed by a Paternò−Büchi step in a synthetically useful way: high-yielding photoprotolytic oxametathesis in polycyclic systems. Org. Lett. 11, 38863889 (2009)
  13. Fu, G. C. & Grubbs, R. H. Synthesis of cycloalkenes via alkylidene-mediated olefin metathesis and carbonyl olefination. J. Am. Chem. Soc. 115, 38003801 (1993)
  14. Stille, J. R., Santarsiero, B. D. & Grubbs, R. H. Rearrangement of bicyclo[2.2.1]heptane ring systems by titanocene alkylidene complexes to bicyclo[3.2.0]heptane enol ethers. Total synthesis of (±)-Δ9(12)-capnellene. J. Org. Chem. 55, 843862 (1990)
  15. Iyer, K. & Rainier, J. D. Olefinic ester and diene ring-closing metathesis using a reduced titanium alkylidene. J. Am. Chem. Soc. 129, 1260412605 (2007)
  16. Soicke, A., Slavov, N., Neudörfl, J.-M. & Schmalz, H.-G. Metal-free intramolecular carbonyl–olefin metathesis of ortho-prenylaryl ketones. Synlett 17, 24872490 (2011)
  17. van Schaik, H.-P., Vijn, R.-J. & Bickelhaupt, F. Acid-catalyzed olefination of benzaldehyde. Angew. Chem. Int. Edn Engl. 33, 16111612 (1994)
  18. Bah, J., Franzén, J. & Naidu, V. R. Direct organocatalytic oxo-metathesis, a trans-selective carbocation-catalyzed olefination of aldehydes. Eur. J. Org. Chem. 2015, 18341839 (2015)
  19. Jossifov, C., Kalinova, R. & Demonceau, A. Carbonyl olefin metathesis. Chim. Oggi 26, 8587 (2008)
  20. Griffith, A. K., Vanos, C. M. & Lambert, T. H. Organocatalytic carbonyl-olefin metathesis. J. Am. Chem. Soc. 134, 1858118584 (2012)
  21. Hong, B., Li, H., Wu, J., Zhang, J. & Lei, X. Total syntheses of (−)-huperzine Q and (+)-lycopladines B and C. Angew. Chem. Int. Ed. 54, 10111015 (2015)
  22. Heller, S. T., Kiho, T., Narayan, A. R. H. & Sarpong, R. Protic-solvent-mediated cycloisomerization of quinoline and isoquinoline propargylic alcohols: syntheses of (±)-3-demethoxyerythratidinone and (±)-cocculidine. Angew. Chem. Int. Ed. 52, 1112911133 (2013)
  23. Clarke, M. L. & France, M. B. The carbonyl ene reaction. Tetrahedron 64, 90039031 (2008)
  24. Miles, R. B., Davis, C. E. & Coates, R. M. Syn- and anti-selective Prins cyclizations of δ,ε-unsaturated ketones to 1,3-halohydrins with Lewis acids. J. Org. Chem. 71, 14931501 (2006)
  25. Jackson, A. C., Goldman, B. E. & Snider, B. B. Intramolecular and intermolecular Lewis acid catalyzed ene reactions using ketones as enophiles. J. Org. Chem. 49, 39883994 (1984)
  26. Reetz, M. T. Lewis acid induced α-alkylation of carbonyl compounds. Angew. Chem. Int. Edn Engl. 21, 96108 (1982)
  27. Demole, E., Enggist, P. & Borer, M. C. Applications synthétiques de la cyclisation d’alcools tertiaires γ-éthyléniques en α-bromotétrahydrofurannes sous l’action du N-bromosuccinimide. II. Cyclisation du (±)-nérolidol en diméthyl-2,5-(méthyl-4-pentène-3-yl)-2-cycloheptène-4-one, tétraméthyl-3, 3, 7, 10-oxa-2-tricyclo[5.5.0.01,4]-dodécène-9, β-acoratriène, cédradiène-2,8, épi-2-α-cédrène et α-cédrène. Helv. Chim. Acta 54, 18451864 (1971)
  28. Carless, H. A. J. & Trivedi, H. S. New ring expansion reaction of 2-t-butyloxetans. J. Chem. Soc. Chem. Commun. 382383 (1979)
  29. Zimmerman, P. M. Automated discovery of chemically reasonable elementary reaction steps. J. Comput. Chem. 34, 13851392 (2013)
  30. Zimmerman, P. M. Reliable transition state searches integrated with the growing string method. J. Chem. Theory Comput. 9, 30433050 (2013)

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Author information

Affiliations

  1. Department of Chemistry, University of Michigan, Willard Henry Dow Laboratory, 930 North University Avenue, Ann Arbor, Michigan 48109, USA

    • Jacob R. Ludwig,
    • Paul M. Zimmerman,
    • Joseph B. Gianino &
    • Corinna S. Schindler

Contributions

J.R.L., J.B.G. and C.S.S. devised the experiments, prepared the starting materials and the products. P.M.Z. conducted the theoretical investigations. J.R.L., J.B.G., P.M.Z. and C.S.S. prepared this manuscript for publication.

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The authors declare no competing financial interests.

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Supplementary information

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  1. Supplementary Information (33.3 MB)

    This file contains Supplementary Tables 1-8 and 6 Supplementary Figures. Also included are Supplementary Methods and Materials, Supplementary Results, X-Ray crystallographic data and NMR Spectral data, which contains 1H and 13C NMR data for all new compounds.

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