Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Rhodium-catalysed syn-carboamination of alkenes via a transient directing group


Alkenes are the most ubiquitous prochiral functional groups—those that can be converted from achiral to chiral in a single step—that are accessible to synthetic chemists. For this reason, difunctionalization reactions of alkenes (whereby two functional groups are added to the same double bond) are particularly important, as they can be used to produce highly complex molecular architectures1,2. Stereoselective oxidation reactions, including dihydroxylation, aminohydroxylation and halogenation3,4,5,6, are well established methods for functionalizing alkenes. However, the intermolecular incorporation of both carbon- and nitrogen-based functionalities stereoselectively across an alkene has not been reported. Here we describe the rhodium-catalysed carboamination of alkenes at the same (syn) face of a double bond, initiated by a carbon–hydrogen activation event that uses enoxyphthalimides as the source of both the carbon and the nitrogen functionalities. The reaction methodology allows for the intermolecular, stereospecific formation of one carbon–carbon and one carbon–nitrogen bond across an alkene, which is, to our knowledge, unprecedented. The reaction design involves the in situ generation of a bidentate directing group and the use of a new cyclopentadienyl ligand to control the reactivity of rhodium. The results provide a new way of synthesizing functionalized alkenes, and should lead to the convergent and stereoselective assembly of amine-containing acyclic molecules.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Carboamination reactions.
Figure 2: Working hypothesis: tuning of the directing group to influence reactivity.
Figure 3: Applications of the carboamination reaction.
Figure 4: Study and proposed reaction mechanism.


  1. 1

    McDonald, R. I., Liu, G. & Stahl, S. S. Palladium(II)-catalyzed alkene functionalization via nucleopalladation: stereochemical pathways and enantioselective catalytic applications. Chem. Rev. 111, 2981–3019 (2011)

    CAS  Article  Google Scholar 

  2. 2

    Chemler, S. R. & Bovino, M. T. Catalytic aminohalogenation of alkenes and alkynes. Am. Chem. Soc. Catal. 3, 1076–1091 (2013)

    CAS  Google Scholar 

  3. 3

    Berkesell, A. & Gröger, H. Asymmetric Organocatalysis (Wiley-VCH, 2005)

    Book  Google Scholar 

  4. 4

    Jacobsen, E. N. & Wu, M. H. in Comprehensive Asymmetric Catalysis (eds Jacobsen, E. N., Pfaltz, A. & Yamamoto, H. ) 1309–1326 (Springer, 1999)

    Book  Google Scholar 

  5. 5

    Hennecke, U. New catalytic approaches towards the enantioselective halogenation of alkenes. Chem. Asian J. 7, 456–465 (2012)

    CAS  Article  Google Scholar 

  6. 6

    Tan, C. K., Yu, W. Z. & Yeung, Y. Y. Stereoselective bromofunctionalization of alkenes. Chirality 26, 328–343 (2014)

    CAS  Article  Google Scholar 

  7. 7

    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)

    CAS  Article  Google Scholar 

  8. 8

    Zhou, J. & Hartwig, J. F. Intermolecular, catalytic asymmetric hydroamination of bicyclic alkenes and dienes in high yield and enantioselectivity. J. Am. Chem. Soc. 130, 12220–12221 (2008)

    CAS  Article  Google Scholar 

  9. 9

    Shen, X. & Buchwald, S. L. Rhodium-catalyzed asymmetric intramolecular hydroamination of unactivated alkenes. Angew. Chem. Int. Edn 49, 564–567 (2010)

    CAS  Article  Google Scholar 

  10. 10

    Beller, M., Seayad, J., Tillack, A. & Jiao, H. Catalytic Markovnikov and anti-Markovnikov functionalization of alkenes and alkynes: recent developments and trends. Angew. Chem. Int. Edn 43, 3368–3398 (2004)

    CAS  Article  Google Scholar 

  11. 11

    Beletskaya, I. P. & Cheprakov, A. V. The Heck reaction as a sharpening stone of palladium catalysis. Chem. Rev. 100, 3009–3066 (2000)

    CAS  Article  Google Scholar 

  12. 12

    Werner, E. W., Mei, T.-S., Burckle, A. J. & Sigman, M. S. Enantioselective Heck arylations of acyclic alkenyl alcohols using a redox-relay strategy. Science 338, 1455–1458 (2012)

    ADS  CAS  Article  Google Scholar 

  13. 13

    Coldham, I. & Hufton, R. Intramolecular dipolar cycloaddition reactions of azomethine ylides. Chem. Rev. 105, 2765–2810 (2005)

    CAS  Article  Google Scholar 

  14. 14

    Nakamura, I. & Yamamoto, Y. Transition-metal-catalyzed reactions in heterocyclic synthesis. Chem. Rev. 104, 2127–2198 (2004)

    CAS  Article  Google Scholar 

  15. 15

    Mai, D. N. & Wolfe, J. P. Asymmetric palladium-catalyzed carboamination reactions for the synthesis of enantiomerically enriched 2-(arylmethyl)- and 2-(alkenylmethyl)pyrrolidines. J. Am. Chem. Soc. 132, 12157–12159 (2010)

    CAS  Article  Google Scholar 

  16. 16

    Wolfe, J. P. Synthesis of saturated heterocycles via metal-catalyzed alkene carboamination or carboalkoxylation reactions. Top. Heterocycl. Chem. 32, 1–37 (2013)

    ADS  CAS  Article  Google Scholar 

  17. 17

    Zeng, W. & Chemler, S. R. Copper(II)-catalyzed enantioselective intramolecular carboamination of alkenes. J. Am. Chem. Soc. 129, 12948–12949 (2007)

    CAS  Article  Google Scholar 

  18. 18

    Weidner, K., Giroult, A., Panchaud, P. & Renaud, P. Efficient carboazidation of alkenes using a radical desulfonylative azide transfer process. J. Am. Chem. Soc. 132, 17511–17515 (2010)

    CAS  Article  Google Scholar 

  19. 19

    Zhang, H. et al. Copper-catalyzed intermolecular aminocyanation and diamination of alkenes. Angew. Chem. Int. Edn 52, 2529–2533 (2013)

    CAS  Article  Google Scholar 

  20. 20

    Piou, T. & Rovis, T. Rh(III)-catalyzed cyclopropanation initiated by C–H activation: ligand development enables a diastereoselective [2 + 1] annulation of N-enoxyphthalimides and alkenes. J. Am. Chem. Soc. 136, 11292–11295 (2014)

    CAS  Article  Google Scholar 

  21. 21

    Mo, J., Wang, L., Liu, Y. & Cui, X. Transition-metal-catalyzed direct C–H functionalization under external-oxidant-free conditions. Synthesis 439–459 (2015)

  22. 22

    Neely, J. M. & Rovis, T. Rh(III)-catalyzed regioselective synthesis of pyridines from alkenes and α,β-unsaturated oxime esters. J. Am. Chem. Soc. 135, 66–69 (2013)

    CAS  Article  Google Scholar 

  23. 23

    Hyster, T. K. & Rovis, T. An improved catalyst architecture for rhodium(III) catalyzed C–H activation and its application to pyridone synthesis. Chem. Sci. (Camb.) 2, 1606–1610 (2011)

    CAS  Article  Google Scholar 

  24. 24

    Webb, N. J., Marsden, S. P. & Raw, S. A. Rhodium(III)-catalyzed C–H activation/annulation with vinyl esters as an acetylene equivalent. Org. Lett. 16, 4718–4721 (2014)

    CAS  Article  Google Scholar 

  25. 25

    Guimond, N., Gorelsky, S. I. & Fagnou, K. Rhodium(III)-catalyzed heterocycle synthesis using an internal oxidant: improved reactivity and mechanistic studies. J. Am. Chem. Soc. 133, 6449–6457 (2011)

    CAS  Article  Google Scholar 

  26. 26

    Rakshit, S., Grohmann, C., Besset, T. & Glorius, F. Rh(III)-catalyzed directed C−H olefination using an oxidizing directing group: mild, efficient, and versatile. J. Am. Chem. Soc. 133, 2350–2353 (2011)

    CAS  Article  Google Scholar 

Download references


We thank the National Institute of General Medical Sciences (grant no. GM80442) for support. We thank Johnson Matthey for rhodium salts, and J. Chu and B. Newell (at Colorado State University) for solving X-ray structures.

Author information




T.P. and T.R. conceived the concept and prepared the manuscript. T.R. directed the investigations. T.P. developed and studied the reaction.

Corresponding author

Correspondence to Tomislav Rovis.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Text and Data and Supplementary References. (PDF 13428 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Piou, T., Rovis, T. Rhodium-catalysed syn-carboamination of alkenes via a transient directing group. Nature 527, 86–90 (2015).

Download citation

Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing