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Catalytic asymmetric addition of an amine N–H bond across internal alkenes

Abstract

Hydroamination of alkenes, the addition of the N–H bond of an amine across an alkene, is a fundamental, yet challenging, organic transformation that creates an alkylamine from two abundant chemical feedstocks, alkenes and amines, with full atom economy1,2,3. The reaction is particularly important because amines, especially chiral amines, are prevalent substructures in a wide range of natural products and drugs. Although extensive efforts have been dedicated to developing catalysts for hydroamination, the vast majority of alkenes that undergo intermolecular hydroamination have been limited to conjugated, strained, or terminal alkenes2,3,4; only a few examples occur by the direct addition of the N–H bond of amines across unactivated internal alkenes5,6,7, including photocatalytic hydroamination8,9, and no asymmetric intermolecular additions to such alkenes are known. In fact, current examples of direct, enantioselective intermolecular hydroamination of any type of unactivated alkene lacking a directing group occur with only moderate enantioselectivity10,11,12,13. Here we report a cationic iridium system that catalyses intermolecular hydroamination of a range of unactivated, internal alkenes, including those in both acyclic and cyclic alkenes, to afford chiral amines with high enantioselectivity. The catalyst contains a phosphine ligand bearing trimethylsilyl-substituted aryl groups and a triflimide counteranion, and the reaction design includes 2-amino-6-methylpyridine as the amine to enhance the rates of multiple steps within the catalytic cycle while serving as an ammonia surrogate. These design principles point the way to the addition of N–H bonds of other reagents, as well as O–H and C–H bonds, across unactivated internal alkenes to streamline the synthesis of functional molecules from basic feedstocks.

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Fig. 1: Catalytic asymmetric hydroamination of unactivated internal alkenes.
Fig. 2: Development of asymmetric hydroamination of unactivated internal alkenes with 2-amino-6-methylpyridine as an ammonia surrogate.
Fig. 3: Scope of internal alkenes that undergo hydroamination.
Fig. 4: Mechanistic study of the hydroamination.

Data availability

The data that support the findings of this study are available within the article and its Supplementary Information.

References

  1. 1.

    Müller, T. E. & Beller, M. Metal-initiated amination of alkenes and alkynes. Chem. Rev. 98, 675–704 (1998).

    PubMed  Google Scholar 

  2. 2.

    Müller, T. E., Hultzsch, K. C., Yus, M., Foubelo, F. & Tada, M. Hydroamination: direct addition of amines to alkenes and alkynes. Chem. Rev. 108, 3795–3892 (2008).

    PubMed  Google Scholar 

  3. 3.

    Huang, L., Arndt, M., Gooßen, K., Heydt, H. & Gooßen, L. J. Late transition metal-catalyzed hydroamination and hydroamidation. Chem. Rev. 115, 2596–2697 (2015).

    CAS  PubMed  Google Scholar 

  4. 4.

    Reznichenko, A. L. & Hultzsch, K. C. in Organic Reactions 1–554 (Wiley, 2015).

  5. 5.

    Gurak, J. A., Yang, K. S., Liu, Z. & Engle, K. M. Directed, regiocontrolled hydroamination of unactivated alkenes via protodepalladation. J. Am. Chem. Soc. 138, 5805–5808 (2016).

    CAS  PubMed  Google Scholar 

  6. 6.

    Karshtedt, D., Bell, A. T. & Tilley, T. D. Platinum-based catalysts for the hydroamination of olefins with sulfonamides and weakly basic anilines. J. Am. Chem. Soc. 127, 12640–12646 (2005).

    CAS  PubMed  Google Scholar 

  7. 7.

    Zhang, J., Yang, C.-G. & He, C. Gold(i)-catalyzed intra- and intermolecular hydroamination of unactivated olefins. J. Am. Chem. Soc. 128, 1798–1799 (2006).

    CAS  PubMed  Google Scholar 

  8. 8.

    Musacchio, A. J. et al. Catalytic intermolecular hydroaminations of unactivated olefins with secondary alkyl amines. Science 355, 727–730 (2017).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Nguyen, T. M., Manohar, N. & Nicewicz, D. A. anti-Markovnikov hydroamination of alkenes catalyzed by a two-component organic photoredox system: direct access to phenethylamine derivatives. Angew. Chem. Int. Ed. 53, 6198–6201 (2014).

    CAS  Google Scholar 

  10. 10.

    Zhang, Z., Lee, S. D. & Widenhoefer, R. A. Intermolecular hydroamination of ethylene and 1-alkenes with cyclic ureas catalyzed by achiral and chiral gold(i) complexes. J. Am. Chem. Soc. 131, 5372–5373 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Reznichenko, A. L., Nguyen, H. N. & Hultzsch, K. C. Asymmetric intermolecular hydroamination of unactivated alkenes with simple amines. Angew. Chem. Int. Ed. 49, 8984–8987 (2010).

    CAS  Google Scholar 

  12. 12.

    Pan, S., Endo, K. & Shibata, T. Ir(i)-catalyzed intermolecular regio- and enantioselective hydroamination of alkenes with heteroaromatic amines. Org. Lett. 14, 780–783 (2012).

    CAS  PubMed  Google Scholar 

  13. 13.

    Vanable, E. P. et al. Rhodium-catalyzed asymmetric hydroamination of allyl amines. J. Am. Chem. Soc. 141, 739–742 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Nugent, T. C. Chiral Amine Synthesis: Methods, Developments and Applications (Wiley VCH, 2010).

  15. 15.

    Trowbridge, A., Walton, S. M. & Gaunt, M. J. New strategies for the transition-metal catalyzed synthesis of aliphatic amines. Chem. Rev. 120, 2613–2692 (2020).

    CAS  PubMed  Google Scholar 

  16. 16.

    Wang, C. & Xiao, J. in Stereoselective Formation of Amines (eds Li, W. & Zhang, X.) 261–282 (Springer, 2014).

  17. 17.

    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).

    CAS  Google Scholar 

  18. 18.

    Patil, M. D., Grogan, G., Bommarius, A. & Yun, H. Oxidoreductase-catalyzed synthesis of chiral amines. ACS Catal. 8, 10985–11015 (2018).

    CAS  Google Scholar 

  19. 19.

    Xie, J.-H., Zhu, S.-F. & Zhou, Q.-L. Transition metal-catalyzed enantioselective hydrogenation of enamines and imines. Chem. Rev. 111, 1713–1760 (2011).

    CAS  PubMed  Google Scholar 

  20. 20.

    Ellman, J. A., Owens, T. D. & Tang, T. P. N-tert-Butanesulfinyl imines: versatile intermediates for the asymmetric synthesis of amines. Acc. Chem. Res. 35, 984–995 (2002).

    CAS  PubMed  Google Scholar 

  21. 21.

    You, S.-L., Zhu, X.-Z., Luo, Y.-M., Hou, X.-L. & Dai, L.-X. Highly regio- and enantioselective Pd-catalyzed allylic alkylation and amination of monosubstituted allylic acetates with novel ferrocene P,N-ligands. J. Am. Chem. Soc. 123, 7471–7472 (2001).

    CAS  PubMed  Google Scholar 

  22. 22.

    Ohmura, T. & Hartwig, J. F. Regio- and enantioselective allylic amination of achiral allylic esters catalyzed by an iridium−phosphoramidite complex. J. Am. Chem. Soc. 124, 15164–15165 (2002).

    CAS  PubMed  Google Scholar 

  23. 23.

    Löber, O., Kawatsura, M. & Hartwig, J. F. Palladium-catalyzed hydroamination of 1,3-dienes: a colorimetric assay and enantioselective additions. J. Am. Chem. Soc. 123, 4366–4367 (2001).

    PubMed  Google Scholar 

  24. 24.

    Adamson, N. J., Hull, E. & Malcolmson, S. J. Enantioselective intermolecular addition of aliphatic amines to acyclic dienes with a Pd–PHOX catalyst. J. Am. Chem. Soc. 139, 7180–7183 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Long, J., Wang, P., Wang, W., Li, Y. & Yin, G. Nickel/Brønsted acid-catalyzed chemo- and enantioselective intermolecular hydroamination of conjugated dienes. iScience 22, 369–379 (2019).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Tran, G., Shao, W. & Mazet, C. Ni-catalyzed enantioselective intermolecular hydroamination of branched 1,3-dienes using primary aliphatic amines. J. Am. Chem. Soc. 141, 14814–14822 (2019).

    CAS  PubMed  Google Scholar 

  27. 27.

    Kawatsura, M. & Hartwig, J. F. Palladium-catalyzed intermolecular hydroamination of vinylarenes using arylamines. J. Am. Chem. Soc. 122, 9546–9547 (2000).

    CAS  Google Scholar 

  28. 28.

    Utsunomiya, M. & Hartwig, J. F. Intermolecular, Markovnikov hydroamination of vinylarenes with alkylamines. J. Am. Chem. Soc. 125, 14286–14287 (2003).

    CAS  PubMed  Google Scholar 

  29. 29.

    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).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Gui, J. et al. Practical olefin hydroamination with nitroarenes. Science 348, 886–891 (2015).

    ADS  CAS  PubMed  Google Scholar 

  31. 31.

    Johns, A. M., Sakai, N., Ridder, A. & Hartwig, J. F. Direct measurement of the thermodynamics of vinylarene hydroamination. J. Am. Chem. Soc. 128, 9306–9307 (2006).

    CAS  PubMed  Google Scholar 

  32. 32.

    Liu, Z. & Hartwig, J. F. Mild, rhodium-catalyzed intramolecular hydroamination of unactivated terminal and internal alkenes with primary and secondary amines. J. Am. Chem. Soc. 130, 1570–1571 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Huang, J.-M., Wong, C.-M., Xu, F.-X. & Loh, T.-P. InBr3 catalyzed intermolecular hydroamination of unactivated alkenes. Tetrahedron Lett. 48, 3375–3377 (2007).

    CAS  Google Scholar 

  34. 34.

    Sevov, C. S., Zhou, J. & Hartwig, J. F. Iridium-catalyzed intermolecular hydroamination of unactivated aliphatic alkenes with amides and sulfonamides. J. Am. Chem. Soc. 134, 11960–11963 (2012).

    CAS  PubMed  Google Scholar 

  35. 35.

    Utsunomiya, M., Kuwano, R., Kawatsura, M. & Hartwig, J. F. Rhodium-catalyzed anti-Markovnikov hydroamination of vinylarenes. J. Am. Chem. Soc. 125, 5608–5609 (2003).

    CAS  PubMed  Google Scholar 

  36. 36.

    Pawlas, J., Nakao, Y., Kawatsura, M. & Hartwig, J. F. A general nickel-catalyzed hydroamination of 1,3-dienes by alkylamines: catalyst selection, scope, and mechanism. J. Am. Chem. Soc. 124, 3669–3679 (2002).

    CAS  PubMed  Google Scholar 

  37. 37.

    Casalnuovo, A. L., Calabrese, J. C. & Milstein, D. Rational design in homogeneous catalysis. Iridium(i)-catalyzed addition of aniline to norbornylene via nitrogen-hydrogen activation. J. Am. Chem. Soc. 110, 6738–6744 (1988).

    CAS  Google Scholar 

  38. 38.

    Dorta, R., Egli, P., Zürcher, F. & Togni, A. The [IrCl(diphosphine)]2/fluoride system. Developing catalytic asymmetric olefin hydroamination. J. Am. Chem. Soc. 119, 10857–10858 (1997).

    CAS  Google Scholar 

  39. 39.

    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  PubMed  Google Scholar 

  40. 40.

    Sevov, C. S., Zhou, J. & Hartwig, J. F. Iridium-catalyzed, intermolecular hydroamination of unactivated alkenes with indoles. J. Am. Chem. Soc. 136, 3200–3207 (2014).

    CAS  PubMed  Google Scholar 

  41. 41.

    Hanley, P. S. & Hartwig, J. F. Migratory insertion of alkenes into metal–oxygen and metal–nitrogen bonds. Angew. Chem. Int. Ed. 52, 8510–8525 (2013).

    CAS  Google Scholar 

  42. 42.

    Thompson, W. H. & Sears, C. T. Kinetics of oxidative addition to iridium(i) complexes. Inorg. Chem. 16, 769–774 (1977).

    CAS  Google Scholar 

  43. 43.

    Smout, V. et al. Removal of the pyridine directing group from α-substituted N-(pyridin-2-yl)piperidines obtained via directed Ru-catalyzed sp3 C–H functionalization. J. Org. Chem. 78, 9803–9814 (2013).

    CAS  PubMed  Google Scholar 

  44. 44.

    Hanley, P. S. & Hartwig, J. F. Intermolecular migratory insertion of unactivated olefins into palladium–nitrogen bonds. Steric and electronic effects on the rate of migratory insertion. J. Am. Chem. Soc. 133, 15661–15673 (2011).

    CAS  PubMed  Google Scholar 

  45. 45.

    Zhang, M., Hu, L., Lang, Y., Cao, Y. & Huang, G. Mechanism and origins of regio- and enantioselectivities of iridium-catalyzed hydroarylation of alkenyl ethers. J. Org. Chem. 83, 2937–2947 (2018).

    CAS  PubMed  Google Scholar 

  46. 46.

    Xing, D., Qi, X., Marchant, D., Liu, P. & Dong, G. Branched-selective direct α-alkylation of cyclic ketones with simple alkenes. Angew. Chem. Int. Ed. 58, 4366–4370 (2019).

    CAS  Google Scholar 

  47. 47.

    Xi, Y., Butcher, T. W., Zhang, J. & Hartwig, J. F. Regioselective, asymmetric formal hydroamination of unactivated internal alkenes. Angew. Chem. Int. Ed. 55, 776–780 (2016).

    CAS  Google Scholar 

  48. 48.

    Mei, T.-S., Werner, E. W., Burckle, A. J. & Sigman, M. S. Enantioselective redox-relay oxidative heck arylations of acyclic alkenyl alcohols using boronic acids. J. Am. Chem. Soc. 135, 6830–6833 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49.

    Morandi, B., Wickens, Z. K. & Grubbs, R. H. Regioselective Wacker oxidation of internal alkenes: rapid access to functionalized ketones facilitated by cross-metathesis. Angew. Chem. Int. Ed. 52, 9751–9754 (2013).

    CAS  Google Scholar 

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Acknowledgements

The enantioselective aspects of the work were supported by the National Institutes of Health under grant R35GM130387 and the catalyst development was supported by the Director, Office of Science, of the US Department of Energy under contract number DE-AC02-05CH11231. Calculations were performed at the Molecular Graphics and Computation Facility at UC Berkeley funded by the NIH (S10OD023532). We gratefully acknowledge Takasago for gifts of (S)-DTBM-SEGPHOS, and H. Celik for assistance with nuclear magnetic resonance (NMR) experiments. Instruments in the College of Chemistry NMR facility are supported in part by NIH S10OD024998. We thank R. G. Bergman, B. Su and T. Butcher for discussions. Y.X. thanks Bristol-Myers Squibb for a graduate fellowship, S. Pedram for supply of NaBARF and D. Small for assistance with DFT calculations.

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Y.X. and J.F.H. conceived the project. Y.X. discovered the reaction and performed experiments and DFT calculations. S.M. performed experiments for revision. Y.X. and J.F.H. wrote the manuscript.

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Correspondence to John F. Hartwig.

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Xi, Y., Ma, S. & Hartwig, J.F. Catalytic asymmetric addition of an amine N–H bond across internal alkenes. Nature 588, 254–260 (2020). https://doi.org/10.1038/s41586-020-2919-z

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