Cooperative activation of cyclobutanones and olefins leads to bridged ring systems by a catalytic [4 + 2] coupling

Journal name:
Nature Chemistry
Year published:
Published online


Bridged ring systems are widely found in natural products, and successful syntheses of them frequently feature intramolecular Diels–Alder reactions. These reactions are subclassified as either type I or type II depending on how the diene motif is tethered to the rest of the substrate (type I are tethered at the 1-position of the diene and type II at the 2-position). Although the type I reaction has been used with great success, the molecular scaffolds accessible by the type II reactions are limited by the strain inherent in the formation of an sp2 carbon at a bridgehead position. Here, we describe a complementary approach that provides access to these structures through the C–C activation of cyclobutanones and their coupling with olefins. Various alkenes have been coupled with cyclobutanones to provide a range of bridged skeletons. The ketone group of the products serves as a convenient handle for downstream functionalization.

At a glance


  1. The challenge of bridged ring synthesis.
    Figure 1: The challenge of bridged ring synthesis.

    a, Selected alkaloid natural products with bridged-ring substructures. b, Comparison of the type II IMDA reaction, which is synthetically limited by the incipient strain in an unsaturated bridgehead carbon, and the approach described in this work. c, Previous work on metal-catalysed C–C activation of cyclobutanones towards coupling, and potential challenges due to the decarbonylation of the ketones.

  2. Proposed catalytic cycle.
    Figure 2: Proposed catalytic cycle.

    The key features include using metal–ligand cooperative activation of cyclobutanones and in situ carbonyl group protection to avoid decarbonylation.

  3. Potentials and applications in bridged ring synthesis.
    Figure 3: Potentials and applications in bridged ring synthesis.

    a, Construction of fused-bridged tricyclic structures. b, Potentials for developing an enantioselective transformation. c, Use of the carbonyl group in the product as a handle to access ring-contracted and expanded bridged rings.


38 compounds View all compounds
  1. 4-Methyl-N-((1-methyl-3-oxocyclobutyl)methyl)-N-(2-methylallyl)benzenesulfonamide
    Compound 1a 4-Methyl-N-((1-methyl-3-oxocyclobutyl)methyl)-N-(2-methylallyl)benzenesulfonamide
  2. 4-Methyl-N-((1-methyl-3-oxocyclobutyl)methyl)-N-(2-methylenebutyl)benzenesulfonamide
    Compound 1b 4-Methyl-N-((1-methyl-3-oxocyclobutyl)methyl)-N-(2-methylenebutyl)benzenesulfonamide
  3. N-(2-(((tert-Butyldimethylsilyl)oxy)methyl)allyl)-4-methyl-N-((1-methyl-3-oxocyclobutyl)methyl)benzenesulfonamide
    Compound 1c N-(2-(((tert-Butyldimethylsilyl)oxy)methyl)allyl)-4-methyl-N-((1-methyl-3-oxocyclobutyl)methyl)benzenesulfonamide
  4. 4-Methyl-N-(3-methyl-2-methylenebutyl)-N-((1-methyl-3-oxocyclobutyl)methyl)benzenesulfonamide
    Compound 1d 4-Methyl-N-(3-methyl-2-methylenebutyl)-N-((1-methyl-3-oxocyclobutyl)methyl)benzenesulfonamide
  5. N-(2-Cyclopentylallyl)-4-methyl-N-((1-methyl-3-oxocyclobutyl)methyl)benzenesulfonamide
    Compound 1e N-(2-Cyclopentylallyl)-4-methyl-N-((1-methyl-3-oxocyclobutyl)methyl)benzenesulfonamide
  6. N-Allyl-4-methyl-N-((1-methyl-3-oxocyclobutyl)methyl)benzenesulfonamide
    Compound 1f N-Allyl-4-methyl-N-((1-methyl-3-oxocyclobutyl)methyl)benzenesulfonamide
  7. Methyl allyl((1-methyl-3-oxocyclobutyl)methyl)carbamate
    Compound 1g Methyl allyl((1-methyl-3-oxocyclobutyl)methyl)carbamate
  8. 4-Methyl-N-((1-methyl-3-oxocyclobutyl)methyl)-N-(2-phenylallyl)benzenesulfonamide
    Compound 1h 4-Methyl-N-((1-methyl-3-oxocyclobutyl)methyl)-N-(2-phenylallyl)benzenesulfonamide
  9. N-(2-(4-Methoxyphenyl)allyl)-4-methyl-N-((1-methyl-3-oxocyclobutyl)methyl)benzenesulfonamide
    Compound 1i N-(2-(4-Methoxyphenyl)allyl)-4-methyl-N-((1-methyl-3-oxocyclobutyl)methyl)benzenesulfonamide
  10. N-(2-(4-Fluorophenyl)allyl)-4-methyl-N-((1-methyl-3-oxocyclobutyl)methyl)benzenesulfonamide
    Compound 1j N-(2-(4-Fluorophenyl)allyl)-4-methyl-N-((1-methyl-3-oxocyclobutyl)methyl)benzenesulfonamide
  11. Methyl ((1-ethyl-3-oxocyclobutyl)methyl)(2-methylallyl)carbamate
    Compound 1k Methyl ((1-ethyl-3-oxocyclobutyl)methyl)(2-methylallyl)carbamate
  12. (Z)-N-(But-2-en-1-yl)-4-methyl-N-((1-methyl-3-oxocyclobutyl)methyl)benzenesulfonamide
    Compound 1l (Z)-N-(But-2-en-1-yl)-4-methyl-N-((1-methyl-3-oxocyclobutyl)methyl)benzenesulfonamide
  13. (E)-N-(But-2-en-1-yl)-4-methyl-N-((1-methyl-3-oxocyclobutyl)methyl)benzenesulfonamide
    Compound 1m (E)-N-(But-2-en-1-yl)-4-methyl-N-((1-methyl-3-oxocyclobutyl)methyl)benzenesulfonamide
  14. 4-Methyl-N-((1-methyl-3-oxocyclobutyl)methyl)-N-vinylbenzenesulfonamide
    Compound 1n 4-Methyl-N-((1-methyl-3-oxocyclobutyl)methyl)-N-vinylbenzenesulfonamide
  15. Diethyl 2-((1-methyl-3-oxocyclobutyl)methyl)-2-(2-methylallyl)malonate
    Compound 1o Diethyl 2-((1-methyl-3-oxocyclobutyl)methyl)-2-(2-methylallyl)malonate
  16. 3-(2-Vinylphenyl)cyclobutanone
    Compound 1p 3-(2-Vinylphenyl)cyclobutanone
  17. N-(2-Methylallyl)-N-(2-oxospiro[3.5]nonan-5-yl)benzenesulfonamide
    Compound 1q N-(2-Methylallyl)-N-(2-oxospiro[3.5]nonan-5-yl)benzenesulfonamide
  18. 1,5-Dimethyl-3-tosyl-3-azabicyclo[3.3.1]nonan-7-one
    Compound 2a 1,5-Dimethyl-3-tosyl-3-azabicyclo[3.3.1]nonan-7-one
  19. 1-Ethyl-5-methyl-3-tosyl-3-azabicyclo[3.3.1]nonan-7-one
    Compound 2b 1-Ethyl-5-methyl-3-tosyl-3-azabicyclo[3.3.1]nonan-7-one
  20. 1-(((tert-Butyldimethylsilyl)oxy)methyl)-5-methyl-3-tosyl-3-azabicyclo[3.3.1]nonan-7-one
    Compound 2c 1-(((tert-Butyldimethylsilyl)oxy)methyl)-5-methyl-3-tosyl-3-azabicyclo[3.3.1]nonan-7-one
  21. 1-Isopropyl-5-methyl-3-tosyl-3-azabicyclo[3.3.1]nonan-7-one
    Compound 2d 1-Isopropyl-5-methyl-3-tosyl-3-azabicyclo[3.3.1]nonan-7-one
  22. 1-Cyclopentyl-5-methyl-3-tosyl-3-azabicyclo[3.3.1]nonan-7-one
    Compound 2e 1-Cyclopentyl-5-methyl-3-tosyl-3-azabicyclo[3.3.1]nonan-7-one
  23. 1-Methyl-3-tosyl-3-azabicyclo[3.3.1]nonan-7-one
    Compound 2f 1-Methyl-3-tosyl-3-azabicyclo[3.3.1]nonan-7-one
  24. Methyl 1-methyl-7-oxo-3-azabicyclo[3.3.1]nonane-3-carboxylate
    Compound 2g Methyl 1-methyl-7-oxo-3-azabicyclo[3.3.1]nonane-3-carboxylate
  25. 1-Methyl-5-phenyl-3-tosyl-3-azabicyclo[3.3.1]nonan-7-one
    Compound 2h 1-Methyl-5-phenyl-3-tosyl-3-azabicyclo[3.3.1]nonan-7-one
  26. 1-(4-Methoxyphenyl)-5-methyl-3-tosyl-3-azabicyclo[3.3.1]nonan-7-one
    Compound 2i 1-(4-Methoxyphenyl)-5-methyl-3-tosyl-3-azabicyclo[3.3.1]nonan-7-one
  27. 1-(4-Fluorophenyl)-5-methyl-3-tosyl-3-azabicyclo[3.3.1]nonan-7-one
    Compound 2j 1-(4-Fluorophenyl)-5-methyl-3-tosyl-3-azabicyclo[3.3.1]nonan-7-one
  28. Methyl 1-ethyl-5-methyl-7-oxo-3-azabicyclo[3.3.1]nonane-3-carboxylate
    Compound 2k Methyl 1-ethyl-5-methyl-7-oxo-3-azabicyclo[3.3.1]nonane-3-carboxylate
  29. (1R,5S,6S)-1,6-Dimethyl-3-tosyl-3-azabicyclo[3.3.1]nonan-7-one
    Compound 2l (1R,5S,6S)-1,6-Dimethyl-3-tosyl-3-azabicyclo[3.3.1]nonan-7-one
  30. (1R,5S,6S)-1,6-Dimethyl-3-tosyl-3-azabicyclo[3.3.1]nonan-7-one
    Compound 2m (1R,5S,6S)-1,6-Dimethyl-3-tosyl-3-azabicyclo[3.3.1]nonan-7-one
  31. 1-Methyl-6-tosyl-6-azabicyclo[3.2.1]octan-3-one
    Compound 2n 1-Methyl-6-tosyl-6-azabicyclo[3.2.1]octan-3-one
  32. Diethyl 1,5-dimethyl-7-oxobicyclo[3.3.1]nonane-3,3-dicarboxylate
    Compound 2o Diethyl 1,5-dimethyl-7-oxobicyclo[3.3.1]nonane-3,3-dicarboxylate
  33. 8,9-Dihydro-5H-5,9-methanobenzo[7]annulen-7(6H)-one
    Compound 2p 8,9-Dihydro-5H-5,9-methanobenzo[7]annulen-7(6H)-one
  34. (3R)-3-Methyl-1-(phenylsulfonyl)octahydro-2H-3,6a-methanobenzo[b]azocin-5(6H)-one
    Compound 2q-i (3R)-3-Methyl-1-(phenylsulfonyl)octahydro-2H-3,6a-methanobenzo[b]azocin-5(6H)-one
  35. (3S)-3-Methyl-1-(phenylsulfonyl)octahydro-2H-3,6a-methanobenzo[b]azocin-5(6H)-one
    Compound 2q-ii (3S)-3-Methyl-1-(phenylsulfonyl)octahydro-2H-3,6a-methanobenzo[b]azocin-5(6H)-one
  36. 6-Chloro-1,5-dimethyl-3-tosyl-3-azabicyclo[3.3.1]nonan-7-one
    Compound 5 6-Chloro-1,5-dimethyl-3-tosyl-3-azabicyclo[3.3.1]nonan-7-one
  37. (1S,5S,6R)-Methyl 1,5-dimethyl-3-tosyl-3-azabicyclo[3.2.1]octane-6-carboxylate
    Compound 6 (1S,5S,6R)-Methyl 1,5-dimethyl-3-tosyl-3-azabicyclo[3.2.1]octane-6-carboxylate
  38. 1,6-Dimethyl-8-tosyl-3,8-diazabicyclo[4.3.1]decan-4-one
    Compound 8 1,6-Dimethyl-8-tosyl-3,8-diazabicyclo[4.3.1]decan-4-one


  1. Oppolzer, W. Intramolecular [4+2] and [3+2] cycloadditions in organic synthesis. Angew. Chem. Int. Ed. 16, 1023 (1977).
  2. Brieger, G. & Bennett, J. N. The intramoecular Diels–Alder reaction. Chem. Rev. 80, 6397 (1980).
  3. Fallis, A. G. The intramolecular Diels–Alder reaction: recent advances and synthetic applications. Can. J. Chem. 62, 183234 (1984).
  4. Craig, D. Sterochemical aspects of the intrmolecular Diels–Alder reaction. Chem. Soc. Rev. 16, 187238 (1987).
  5. Roush, W. R. in Comprehensive Organic Synthesis Vol. 5 (eds Trost, B. M., Fleming, I. & Paquette, L. A.) 513550 (Pergamon, 1991).
  6. Fallis, A. G. Harvesting Diels and Alder's garden: synthetic investigations of intramolecular [4+2] cycloadditions. Acc. Chem. Res. 32, 464474 (1999).
  7. Bear, B. R., Sparks, S. M. & Shea, K. J. The type 2 intramolcular Diels–Alder reaction: synthesis and chemistry of bridgehead alkene. Angew. Chem. Int. Ed. 40, 820849 (2001).
  8. Marsault, E., Toro, A., Nowak, P. & Deslongchamps, P. The transannular Diels–Alder strategy: applications to total synthesis. Tetrahedron 57, 42434260 (2001).
  9. Suzuki, Y., Murata, T., Takao, K. & Tadano, K. The intramolecular Diels–Alder strategy: applications to total synthesis of natural products. J. Synth. Org. Chem. Jpn 60, 679690 (2002).
  10. Ciganek, E. 2004. The intramolecular Diels–Alder reaction. Organic Reactions (Wiley, 2004).
  11. Bredt, J. Über sterische Hinderung in Brückenringen (Bredtsche Regel) und über die meso-trans-Stellung in kondensierten Ringsystemen des Hexamethylens. Liebigs Ann. Chem. 437, 113 (1924).
  12. Shea, K. J. & Wise, S. Intramolecular Diels–Alder reacition. A new entry into brigehead bicyclo[3.n.1]alkenes. J. Am. Chem. Soc. 100, 65196521 (1978).
  13. Shea, K. J. & Wise, S. Intramolecular Diels–Alder cycloadditions. Synthesis of substituted derivatives of bicyclo[3.n.1]bridgehead alkenes. Tetrahedron Lett. 20, 10111014 (1979).
  14. Shea, K. J. et al. Applications of the intramolecular Diels–Alder reaction to the formation of strained molecules. Synthesis of bridgehead alkenes. J. Am. Chem. Soc. 104, 57085715 (1982).
  15. Jones, W. D. The fall of the C–C bond. Nature 364, 676677 (1993).
  16. Murakami, M. & Ito, Y. Cleavage of carbon–carbon single bonds by transition metals. Top. Organomet. Chem. 3, 97129 (1999).
  17. Rybtchiski, B. & Milstein, D. Metal insertion into C–C bonds in solution. Angew. Chem. Int. Ed. 38, 870883 (1999).
  18. Perthuisot, C. et al. Cleavage of the carbon–carbon bond in biphenylene using transition metals. J. Catal. Mol. A 189, 157168 (2002).
  19. Van der Boom, M. E. & Milstein, D. Cyclometalated phosphine-based pincer complexes: mechanistic insight in catalysis, coordination, and bond activation. Chem. Rev. 103, 17591792 (2003).
  20. Jun, C-H. Transition metal-catalyzed carbon–carbon bond activation. Chem. Soc. Rev. 33, 610618 (2004).
  21. Miura, M. & Satoh, T. Catalytic processes involving β-carbon elimination. Top. Organomet. Chem. 14, 120 (2005).
  22. Jun, C-H. & Park, J. W. Directed C–C bond activation by transition metal complexes. Top. Organomet. Chem. 24, 117143 (2007).
  23. Necas, D. & Kotora, M. Rhodium-catalysed C–C bond cleavage reactions. Curr. Org. Chem. 11, 15661592 (2007).
  24. Crabtree, R. H. The organometallic chemistry of alkanes. Chem. Rev. 85, 245269 (1985).
  25. Kondo, T. & Mitsudo, T. A. Ruthenium-catalyzed reconstructive synthesis of functional organic molecules via cleavage of carbon–carbon bonds. Chem. Lett. 34, 14621467 (2005).
  26. Ruhland, K. Transition-metal-mediated cleavage and activation of C–C single bonds. Eur. J. Org. Chem. 2012, 26832706 (2012).
  27. Korotvicka, A., Necas, D. & Kotora, M. Rhodium-catalyzed C–C bond cleavage reactions—an update. Curr. Org. Chem. 16, 11701214 (2012).
  28. Seiser, T., Saget, T., Tran, D. N. & Cramer, N. Cyclobutanes in catalysis. Angew. Chem. Int. Ed. 50, 77407752 (2011).
  29. Dermenci, A. & Dong, G. Decarbonylative C–C bond forming reactions mediated by transition metals. Sci. China Chem. 56, 685701 (2013).
  30. South, M. S. & Liebeskind, L. S. Regiospecific total synthesis of (±)-nanaomycin A using phthaloylcobalt complexes. J. Am. Chem. Soc. 106, 41814185 (1984).
  31. Murakami, M., Itahashi, T. & Ito, Y. Catalyzed intramolecular olefin insertion into a carbon–carbon single bond. J. Am. Chem. Soc. 124, 1397613977 (2002).
  32. Murakami, M., Ishida, N. & Miura, T. Solvent and ligand partition reaction pathways in nickel-mediated carboxylation of methylenecyclopropanes. Chem. Commun. 643645 (2006).
  33. Murakami, M., Ashida, S. & Matsuda, T. Two-carbon ring expansion of cyclobutanone skeletons by nickel-catalyzed intermolecular alkyne insertion. Tetrahedron 62, 75407546 (2006).
  34. Murakami, M., Ashida, S. & Matsuda, T. Nickel-catalyzed intermolecular alkyne insertion into cyclobutanones. J. Am. Chem. Soc. 127, 69326933 (2005).
  35. Murakami, M. & Ashida, S. Nickel-catalysed intramolecular alkene insertion into cyclobutanones. Chem. Commun. 45994601 (2006).
  36. Ashida, S. & Murakami, M. Nickel-catalyzed [4+2+2]-type annulation reaction of cyclobutanones with diynes and enynes. Bull. Chem. Soc. Jpn 81, 885893 (2008).
  37. Liu, L., Ishida, N. & Murakami, M. Atom- and step-economical pathway to chiral benzobicyclo[2.2.2]octenones through carbon–carbon bond cleavage. Angew. Chem. Int. Ed. 51, 24852488 (2012).
  38. Kumar, P. & Louie, J. A single step approach to piperidines via Ni-catalyzed β-carbon elimination. Org. Lett. 14, 20262029 (2012).
  39. Ishida, N., Yuhki, T. & Murakami, M. Synthesis of enantiopure dehydropiperidinones from α-amino acids and alkynes via azetidin-3-ones. Org. Lett. 14, 38983901 (2012).
  40. Lee, H. & Jun, C-H. Catalytic carbon–carbon bond activation of unstrained ketone by soluble transition-metal complex. J. Am. Chem. Soc. 121, 880881 (1999).
  41. Park, Y. J., Park, J-W. & Jun, C-H. Metal–organic cooperative catalysis in C–H and C–C bond activation and its concurrent recovery. Acc. Chem. Res. 41, 222234 (2008).
  42. Jun, C-H., Lee, H. & Lim, S-G. The C–C bond activation and skeletal rearrangement of cycloalkanone imine by Rh(I) catalysts. J. Am. Chem. Soc. 123, 751752 (2001).
  43. Luo, S-P., Guo, L-D., Gao, L-H., Li, S. & Huang, P-Q. Toward the total synthesis of haliclonin A: construction of a tricyclic substructure. Chem. Eur. J. 19, 8791 (2013).
  44. Mazurov, A. A. et al. Novel nicotinic acetylcholine receptor agonists containing carbonyl moiety as a hydrogen bond acceptor. Bioorg. Med. Chem. Lett. 23, 39273934 (2013).
  45. Cheng, X. & Waters, S. P. Pyridone annulation via tandem curtius rearrangement/6π-electrocyclization: total synthesis of (–)-lyconadin C. Org. Lett. 15, 42264229 (2013).
  46. Breining, S. R. et al. Structure-activity studies of 7-heteroaryl-3-azabicyclo[3.3.1]non-6-enes: a novel class of highly potent nicotinic receptor ligands. J. Med. Chem. 55, 99299945 (2012).
  47. Jirgensons, A., Kauss, V., Mishnev, A. F. & Kalvinsh, I. The synthesis of 3-amino-methylbicyclo[3.3.1]nonanes: endo-selectivity in the Ritter reaction of 1,3,5,7α-tetramethylbicyclo[3.3.1]nonan-3-ol. J. Chem. Soc. Perkin Trans. 1, 35273530 (1999).
  48. Parker, E. & Cramer, N. Asymmetric rhodium(I)-catalyzed C–C activations with zwitterionic bis-phospholane ligands. Organometallics 33, 780787 (2014).
  49. Souillart, L., Parker, E. & Cramer, N. Highly enantioselective rhodium(I)-catalyzed activation of enantiotopic cyclobutanone C–C bonds. Angew. Chem. Int. Ed. 53, 30013005 (2014).

Download references

Author information


  1. Department of Chemistry, University of Texas at Austin, Austin, Texas 78712, USA

    • Haye Min Ko &
    • Guangbin Dong


H.M.K. and G.D. conceived and designed the experiments. H.M.K. performed the experiments. H.M.K and G.D. analysed the data. H.M.K. and G.D. co-wrote the manuscript.

Competing financial interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to:

Author details

Supplementary information

PDF files

  1. Supplementary information (5,842 KB)

    Supplementary information

Crystallographic information files

  1. Supplementary information (18 KB)

    Crystallographic data for compound 2a

  2. Supplementary information (5,842 KB)

    Crystallographic data for compound 2f

  3. Supplementary information (5,842 KB)

    Crystallographic data for compound 2i

  4. Supplementary information (5,842 KB)

    Crystallographic data for compound 2n

  5. Supplementary information (5,842 KB)

    Crystallographic data for compound 2q-i

  6. Supplementary information (5,842 KB)

    Crystallographic data for compound 2q-ii

  7. Supplementary information (5,842 KB)

    Crystallographic data for compound 8

  8. Supplementary information (5,842 KB)

    Crystallographic data for compound 2o-i

  9. Supplementary information (5,842 KB)

    Crystallographic data for Rh[P(C6H3(CF3)2)3]2COCl

Additional data