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.

α-Branched amines by catalytic 1,1-addition of C–H bonds and aminating agents to terminal alkenes


α-Branched amines are present in hundreds of pharmaceutical agents and clinical candidates and are important targets for synthesis. Here, we show the convergent synthesis of α-branched amines from three readily accessible starting materials: aromatic C–H bond substrates, terminal alkenes and aminating agents. This reaction proceeds by an intermolecular formation of C–C and C–N bonds at the sp3 carbon branch site through an uncommon 1,1-alkene addition pathway. The reaction is carried out under mild conditions and has high functional group compatibility. Ethylene and propylene feedstock chemicals are effective alkene inputs, with ethylene in particular providing for the one-step synthesis of α-methyl branched amines, a motif prevalent in drug structures. The reaction is scalable and 1% loading of an air-stable dimeric rhodium precatalyst is effective for several different types of products. The use of chiral catalysts also enables the asymmetric synthesis of α-branched amines.

This is a preview of subscription content, access via your institution

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1: α-Branched amines.
Fig. 2: Aminating agent and C–H bond substrate scope for α-branched amine synthesis.
Fig. 3: Alkene scope for the modular synthesis of α-branched amines.
Fig. 4: Use of feedstock alkenes and asymmetric synthesis.
Fig. 5: Proposed catalytic cycle.
Fig. 6: Mechanistic experiments.

Data availability

Much of the data that support the results of this study are available in the Supplementary Information. Additional data are available from the corresponding author upon reasonable request. X-ray crystal data for structure 62 that established its absolute configuration are shown in Supplementary Fig. 9, Supplementary Tables 713 and are available free of charge from the Cambridge Crystallographic Data Centre ( under reference no. CCDC 1903974.


  1. Maciejewski, A. et al. DrugBank 5.0: a major update to the DrugBank database for 2018. Nucleic Acids Res. 46, D1074–D1082 (2017).

    PubMed Central  Google Scholar 

  2. Nugent, T. C. & El-Shazly, M. Chiral amine synthesis—recent developments and trends for enamide reduction, reductive amination and imine reduction. Adv. Synth. Catal. 352, 753–819 (2010).

    Article  CAS  Google Scholar 

  3. Li, W. & Zhang, X. (eds) Stereoselective Formation of Amines Vol. 343 (Topics in Current Chemistry, Springer, 2014).

  4. Yang, Y., Shi, S.-L., Niu, D., Liu, P. & Buchwald, S. L. Catalytic asymmetric hydroamination of unactivated internal olefins to aliphatic amines. Science 349, 62–66 (2015).

    Article  CAS  Google Scholar 

  5. Blakemore, D. C. et al. Organic synthesis provides opportunities to transform drug discovery. Nat. Chem. 10, 383–394 (2018).

    Article  CAS  Google Scholar 

  6. Roizen, J. L., Harvey, M. E. & Du Bois, J. Metal-catalyzed nitrogen-atom transfer methods for the oxidation of aliphatic C–H bonds. Acc. Chem. Res. 45, 911–922 (2012).

    Article  CAS  Google Scholar 

  7. Zhou, Y., Engl, O. D., Bandar, J. S., Chant, E. D. & Buchwald, S. L. CuH-catalyzed asymmetric hydroamidation of vinylarenes. Angew. Chem. Int. Ed. 57, 6672–6675 (2018).

    Article  CAS  Google Scholar 

  8. Lovering, F., Bikker, J. & Humblet, C. Escape from flatland: increasing saturation as an approach to improving clinical success. J. Med. Chem. 52, 6752–6756 (2009).

    Article  CAS  Google Scholar 

  9. Schmidt, F., Stemmler, R. T., Rudolph, J. & Bolm, C. Catalytic asymmetric approaches towards enantiomerically enriched diarylmethanols and diarylmethylamines. Chem. Soc. Rev. 35, 454–470 (2006).

    CAS  PubMed  Google Scholar 

  10. Robak, M. T., Herbage, M. A. & Ellman, J. A. Synthesis and applications of tert-butanesulfinamide. Chem. Rev. 110, 3600–3740 (2010).

    Article  CAS  Google Scholar 

  11. Tsai, A. S., Tauchert, M. E., Bergman, R. G. & Ellman, J. A. Rhodium(iii)-catalyzed arylation of Boc-imines via C−H bond functionalization. J. Am. Chem. Soc. 133, 1248–1250 (2011).

    Article  CAS  Google Scholar 

  12. Li, Y. et al. Rhodium-catalyzed direct addition of aryl C–H bonds to N-sulfonyl aldimines. Angew. Chem. Int. Ed. 50, 2115–2119 (2011).

    Article  CAS  Google Scholar 

  13. Yang, Y., Perry, I. B. & Buchwald, S. L. Copper-catalyzed enantioselective addition of styrene-derived nucleophiles to imines enabled by ligand-controlled chemoselective hydrocupration. J. Am. Chem. Soc. 138, 9787–9790 (2016).

    Article  CAS  Google Scholar 

  14. Hummel, J. R., Boerth, J. A. & Ellman, J. A. Transition-metal-catalyzed C–H bond addition to carbonyls, imines and related polarized π bonds. Chem. Rev. 117, 9163–9227 (2017).

    Article  CAS  Google Scholar 

  15. Heinz, C. et al. Ni-catalyzed carbon–carbon bond-forming reductive amination. J. Am. Chem. Soc. 140, 2292–2300 (2018).

    Article  CAS  Google Scholar 

  16. Trowbridge, A., Reich, D. & Gaunt, M. J. Multicomponent synthesis of tertiary alkylamines by photocatalytic olefin-hydroaminoalkylation. Nature 561, 522–527 (2018).

    Article  CAS  Google Scholar 

  17. McNally, A., Prier, C. K. & MacMillan, D. W. C. Discovery of an α-amino C–H arylation reaction using the strategy of accelerated serendipity. Science 334, 1114–1117 (2011).

    Article  CAS  Google Scholar 

  18. Zuo, Z. et al. Merging photoredox with nickel catalysis: coupling of α-carboxyl sp 3 carbons with aryl halides. Science 345, 437–440 (2014).

    Article  CAS  Google Scholar 

  19. Shaw, M. H., Shurtleff, V. W., Terrett, J. A., Cuthbertson, J. D. & MacMillan, D, W. C. Native functionality in triple catalytic cross-coupling: sp 3 C–H bonds as latent nucleophiles. Science 352, 1304–1308 (2016).

    Article  CAS  Google Scholar 

  20. Jain, P., Verma, P., Xia, G. & Yu, J.-Q. Enantioselective amine α-functionalization via palladium-catalysed C–H arylation of thioamides. Nat. Chem. 9, 140–144 (2017).

    Article  CAS  Google Scholar 

  21. Liao, L., Jana, R., Urkalan, K. B. & Sigman, M. S. A palladium-catalyzed three-component cross-coupling of conjugated dienes or terminal alkenes with vinyl triflates and boronic acids. J. Am. Chem. Soc. 133, 5784–5787 (2011).

    Article  CAS  Google Scholar 

  22. Nelson, H. M., Williams, B. D., Miró, J. & Toste, F. D. Enantioselective 1,1-arylborylation of alkenes: merging chiral anion phase transfer with Pd catalysis. J. Am. Chem. Soc. 137, 3213–3216 (2015).

    Article  CAS  Google Scholar 

  23. 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).

    Article  CAS  Google Scholar 

  24. Patel, P. & Chang, S. N-substituted hydroxylamines as synthetically versatile amino sources in the iridium-catalyzed mild C–H amidation reaction. Org. Lett. 16, 3328–3331 (2014).

    Article  CAS  Google Scholar 

  25. Park, Y., Kim, Y. & Chang, S. Transition metal-catalyzed C–H amination: scope, mechanism and applications. Chem. Rev. 117, 9247–9301 (2017).

    Article  CAS  Google Scholar 

  26. Park, Y., Park, K. T., Kim, J. G. & Chang, S. Mechanistic studies on the Rh(iii)-mediated amido transfer process leading to robust C–H amination with a new type of amidating reagent. J. Am. Chem. Soc. 137, 4534–4542 (2015).

    Article  CAS  Google Scholar 

  27. Lafrance, M. & Fagnou, K. Palladium-catalyzed benzene arylation: incorporation of catalytic pivalic acid as a proton shuttle and a key element in catalyst design. J. Am. Chem. Soc. 128, 16496–16497 (2006).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  29. Weissermel, K. & Arpel, H. J. in Industrial Organic Chemistry 59–89 (Wiley-VCH, 2003).

  30. Ye, B. & Cramer, N. Chiral cyclopentadienyl ligands as stereocontrolling element in asymmetric C–H functionalization. Science 338, 504–506 (2012).

    Article  CAS  Google Scholar 

  31. Hyster, T. K., Knörr, L., Ward, T. R. & Rovis, T. Biotinylated Rh(iii) complexes in engineered streptavidin for accelerated asymmetric C–H activation. Science 338, 500–503 (2012).

    Article  CAS  Google Scholar 

  32. Trifonova, E. A. et al. A planar-chiral rhodium(iii) catalyst with a sterically demanding cyclopentadienyl ligand and its application in the enantioselective synthesis of dihydroisoquinolones. Angew. Chem. Int. Ed. 57, 7714–7718 (2018).

    Article  CAS  Google Scholar 

  33. Satake, S. et al. Pentamethylcyclopentadienyl rhodium(iii)–chiral disulfonate hybrid catalysis for enantioselective C–H bond functionalization. Nat. Catal. 1, 585–591 (2018).

    Article  CAS  Google Scholar 

  34. Newton, C. G., Kossler, D. & Cramer, N. Asymmetric catalysis powered by chiral cyclopentadienyl ligands. J. Am. Chem. Soc. 138, 3935–3941 (2016).

    Article  CAS  Google Scholar 

  35. Li, L., Jiao, Y., Brennessel, W. W. & Jones, W. D. Reactivity and regioselectivity of insertion of unsaturated molecules into M–C (M = Ir, Rh) bonds of cyclometalated complexes. Organometallics 29, 4593–4605 (2010).

    Article  CAS  Google Scholar 

  36. Simmons, E. M. & Hartwig, J. F. On the interpretation of deuterium kinetic isotope effects in C–H bond functionalizations by transition-metal complexes. Angew. Chem. Int. Ed. 51, 3066–3072 (2012).

    Article  CAS  Google Scholar 

  37. Lei, H. & Rovis, T. Ir-catalyzed intermolecular branch-selective allylic C–H amidation of unactivated terminal olefins. J. Am. Chem. Soc. 141, 2268–2273 (2019).

    Article  CAS  Google Scholar 

  38. Knecht, T., Mondal, S., Ye, J.-H., Das, M. & Glorius, F. Intermolecular, branch-selective and redox-neutral Cp*Ir(iii)-catalyzed allylic C–H amidation. Angew. Chem. Int. Ed. 58, 7117–7121 (2019).

    Article  CAS  Google Scholar 

  39. Burman, J., Harris, R., Farr, C., Bacsa, J. & Blakey, S. B. Rh(iii) and Ir(iii)Cp* complexes provide complementary regioselectivity profiles in intermolecular allylic C–H amidation reactions. ACS Catal. 9, 5474–5479 (2019).

    Article  CAS  Google Scholar 

Download references


This work was supported by the NIH (R35GM122473). The authors thank B. Mercado (Yale University) for solving the crystal structure of 62 and E. Paulson (Yale University) for stereochemical assignment of 64 using NMR methods.

Author information

Authors and Affiliations



S.M. and T.J.P. developed the reaction conditions, completed the scope and designed mechanistic experiments. S.M. co-prepared the manuscript with T.J.P. J.A.E. co-conceived the concept and co-prepared the manuscript with feedback from S.M. and T.J.P.

Corresponding author

Correspondence to Jonathan A. Ellman.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Supplementary Information

Supplementary Tables 1–13, Supplementary Figs, 1–9, Supplementary methods, Supplementary references

compound 62

Crystallographic Data for compound 62.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Maity, S., Potter, T.J. & Ellman, J.A. α-Branched amines by catalytic 1,1-addition of C–H bonds and aminating agents to terminal alkenes. Nat Catal 2, 756–762 (2019).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


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