Skip to main content
SpringerLink
Log in

Catalytic asymmetric α C(sp3)–H addition of benzylamines to aldehydes

  • Article
  • Published:

From Nature Catalysis

View current issue Submit your manuscript

Abstract

Functionalization of inert C–H bonds has received tremendous attention due to the inherent atom economy and efficiency of the transformations of the starting materials. As compared to transition-metal-catalysed C–H activation, organocatalysis is much less commonly applied for direct functionalization of inert C–H bonds. The α C(sp3)–H bonds of NH2-unprotected benzylamines usually are inert in most reactions due to the extremely low Brønsted acidity. Here we utilize a chiral pyridoxal bearing a quaramide side chain as a bifunctional carbonyl catalyst to activate the α C(sp3)–H bond of NH2-unprotected benzylamines, making it acidic enough to be deprotonated under mild conditions. Based on the carbonyl catalysis strategy, we develop a direct asymmetric α C–H addition of benzylamines to aldehydes, providing one of the most straightforward methods for the synthesis of chiral β-aminoalcohols with excellent diastereo- and enantioselectivities.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1: α C‒H functionalization of benzylamines.
Fig. 2: Catalyst synthesis and screening.
Fig. 3: Substrate investigation.
Fig. 4: Synthetic utility and mechanistic studies.

Similar content being viewed by others

Data availability

The authors declare that the data supporting the findings of this study are available within the Article and its Supplementary Information file, or from the corresponding author upon reasonable request. The X-ray crystallographic coordinates for structures reported in this study have been deposited at the Cambridge Crystallographic Data Centre (CCDC), under deposition numbers CCDC 2121718 ((R,R)-1a) and CCDC 2121753 ((R,R)-4ae). These data can be obtained free of charge from the CCDC via https://www.ccdc.cam.ac.uk/structures/.

References

  1. Campos, K. R. Direct sp3 C–H bond activation adjacent to nitrogen in heterocycles. Chem. Soc. Rev. 36, 1069–1084 (2007).

    Article  CAS  PubMed  Google Scholar 

  2. Mitchell, E. A., Peschiulli, A., Lefevre, N., Meerpoel, L. & Maes, B. U. W. Direct α-functionalization of saturated cyclic amines. Chem. Eur. J. 18, 10092–10142 (2012).

    Article  CAS  PubMed  Google Scholar 

  3. Seidel, D. The azomethine ylide route to amine C–H functionalization: redox-versions of classic reactions and a pathway to new transformations. Acc. Chem. Res. 48, 317–328 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Gonnard, L., Guérinot, A. & Cossy, J. Transition metal-catalyzed α-alkylation of amines by C(sp3)‒H bond activation. Tetrahedron 75, 145–163 (2019).

    Article  CAS  Google Scholar 

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

  6. Gonzalez, A. Z. et al. Selective and potent morpholinone inhibitors of the MDM2–p53 protein–protein interaction. J. Med. Chem. 57, 2472–2488 (2014).

    Article  CAS  PubMed  Google Scholar 

  7. Huang, H. et al. Oxazolidinone-based allosteric modulators of mGluR5: defining molecular switches to create a pharmacological tool box. Bioorg. Med. Chem. Lett. 26, 4165–4169 (2016).

    Article  CAS  PubMed  Google Scholar 

  8. Degnan, A. P. E. A. Oxazolidinones as modulators of mGluR5. Patent WO 2012064603 (2012).

  9. Desimoni, G., Faita, G. & Jørgensen, K. A. Update 1 of: C2-symmetric chiral bis(oxazoline) ligands in asymmetric catalysis. Chem. Rev. 111, PR284–PR437 (2011).

    Article  CAS  PubMed  Google Scholar 

  10. Zhang, Z.-H., Dong, X.-Q., Chen, D. & Wang, C.-J. Fine-tunable organocatalysts bearing multiple hydrogen-bonding donors for construction of adjacent quaternary and tertiary stereocenters via a Michael reaction. Chem. Eur. J. 14, 8780–8783 (2008).

    Article  CAS  PubMed  Google Scholar 

  11. Park, Y. S., Boys, M. L. & Beak, P. (−)-Sparteine-mediated α-lithiation of N-Boc-N-(p-methoxyphenyl)benzylamine: enantioselective syntheses of (S) and (R) mono- and disubstituted N-Boc-benzylamines. J. Am. Chem. Soc. 118, 3757–3758 (1996).

    Article  CAS  Google Scholar 

  12. Niwa, T., Yorimitsu, H. & Oshima, K. Palladium-catalyzed benzylic arylation of N-benzylxanthone imine. Org. Lett. 10, 4689–4691 (2008).

    Article  CAS  PubMed  Google Scholar 

  13. Chen, Y.-J., Seki, K., Yamashita, Y. & Kobayashi, S. Catalytic carbon–carbon bond-forming reactions of aminoalkane derivatives with imines. J. Am. Chem. Soc. 132, 3244–3245 (2010).

    Article  CAS  PubMed  Google Scholar 

  14. Shibahara, F., Kobayashi, S.-i, Maruyama, T. & Murai, T. Diastereo- and regioselective addition of thioamide dianions to imines and aziridines: synthesis of N-thioacyl-1,2-diamines and N-thioacyl-1,3-diamines. Chem. Eur. J. 19, 304–313 (2013).

    Article  CAS  PubMed  Google Scholar 

  15. Li, M. et al. Transition-metal-free chemo- and regioselective vinylation of azaallyls. Nat. Chem. 9, 997–1004 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Deng, G. et al. Transition-metal-free allylation of 2-azaallyls with allyl ethers through polar and radical mechanisms. Nat. Commun. 12, 3860 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Jun, C.-H. Chelation-assisted alkylation of benzylamine derivatives by Ru0 catalyst. Chem. Commun. 13, 1405–1406 (1998).

    Article  Google Scholar 

  18. Dastbaravardeh, N., Schnürch, M. & Mihovilovic, M. D. Ruthenium(II)-catalyzed sp3 C–H bond arylation of benzylic amines using aryl halides. Org. Lett. 14, 3792–3795 (2012).

    Article  CAS  PubMed  Google Scholar 

  19. Chen, X., Engle, K. M., Wang, D.-H. & Yu, J.-Q. Palladium(II)-catalyzed C−H activation/C–C cross-coupling reactions: versatility and practicality. Angew. Chem. Int. Ed. 48, 5094–5115 (2009).

    Article  CAS  Google Scholar 

  20. Lyons, T. W. & Sanford, M. S. Palladium-catalyzed ligand-directed C–H functionalization reactions. Chem. Rev. 110, 1147–1169 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Wencel-Delord, J., Dröge, T., Liu, F. & Glorius, F. Towards mild metal-catalyzed C−H bond activation. Chem. Soc. Rev. 40, 4740–4761 (2011).

    Article  CAS  PubMed  Google Scholar 

  22. Bordwell, F. G. & Liu, W.-Z. Effects of sulfenyl, sulfinyl and sulfonyl groups on acidities and homolytic bond dissociation energies of adjacent C–H and N–H bonds. J. Phys. Org. Chem. 11, 397–406 (1998).

    Article  CAS  Google Scholar 

  23. Crugeiras, J., Rios, A., Riveiros, E. & Richard, J. P. Substituent effects on electrophilic catalysis by the carbonyl group: anatomy of the rate acceleration for PLP-catalyzed deprotonation of glycine. J. Am. Chem. Soc. 133, 3173–3183 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Chen, J. et al. Carbonyl catalysis enables a biomimetic asymmetric Mannich reaction. Science 360, 1438–1442 (2018).

    Article  CAS  PubMed  Google Scholar 

  25. di Salvo, M. L. et al. On the catalytic mechanism and stereospecificity of Escherichia coli l-threonine aldolase. FEBS J 281, 129–145 (2014).

    Article  PubMed  Google Scholar 

  26. Wang, Q., Gu, Q. & You, S.-L. Enantioselective carbonyl catalysis enabled by chiral aldehydes. Angew. Chem. Int. Ed. 58, 6818–6825 (2019).

    Article  CAS  Google Scholar 

  27. Li, S., Chen, X.-Y. & Enders, D. Aldehyde catalysis: new options for asymmetric organocatalytic reactions. Chem 4, 2026–2028 (2018).

    Article  Google Scholar 

  28. Yin, Q., Shi, Y., Wang, J. & Zhang, X. Direct catalytic asymmetric synthesis of α-chiral primary amines. Chem. Soc. Rev. 49, 6141–6153 (2020).

    Article  PubMed  Google Scholar 

  29. Cheng, A. et al. Efficient asymmetric biomimetic aldol reaction of glycinates and trifluoromethyl ketones by carbonyl catalysis. Angew. Chem. Int. Ed. 60, 20166–20172 (2021).

    Article  CAS  Google Scholar 

  30. Ma, J. et al. Enantioselective synthesis of pyroglutamic acid esters from glycinate via carbonyl catalysis. Angew. Chem. Int. Ed. 60, 10588–10592 (2021).

    Article  CAS  Google Scholar 

  31. Wen, W. et al. Diastereodivergent chiral aldehyde catalysis for asymmetric 1,6-conjugated addition and Mannich reactions. Nat. Commun. 11, 5372 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Wen, W. et al. Chiral aldehyde catalysis for the catalytic asymmetric activation of glycine esters. J. Am. Chem. Soc. 140, 9774–9780 (2018).

    Article  CAS  PubMed  Google Scholar 

  33. Zhu, F. et al. Direct catalytic asymmetric α-allylic alkylation of aza-aryl methylamines by chiral-aldehyde-involved ternary catalysis system. Org. Lett. 23, 1463–1467 (2021).

    Article  CAS  PubMed  Google Scholar 

  34. Ma, J. et al. Asymmetric α-allylation of glycinate with switched chemoselectivity enabled by customized bifunctional pyridoxal catalysts. Angew. Chem. Int. Ed. https://doi.org/10.1002/anie.202200850 (2022).

  35. Xu, B. et al. Catalytic asymmetric direct α-alkylation of amino esters by aldehydes via imine activation. Chem. Sci. 5, 1988–1991 (2014).

    Article  CAS  Google Scholar 

  36. Zhong, X. et al. Chiral Lewis acid-bonded picolinaldehyde enables enantiodivergent carbonyl catalysis in the Mannich/condensation reaction of glycine ester. Chem. Sci. 12, 4353–4360 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Shi, L. et al. Chiral pyridoxal-catalyzed asymmetric biomimetic transamination of α-keto acids. Org. Lett. 17, 5784–5787 (2015).

    Article  CAS  PubMed  Google Scholar 

  38. Liu, Y. E. et al. Enzyme-inspired axially chiral pyridoxamines armed with a cooperative lateral amine chain for enantioselective biomimetic transamination. J. Am. Chem. Soc. 138, 10730–10733 (2016).

    Article  CAS  PubMed  Google Scholar 

  39. Cai, W. et al. Asymmetric biomimetic transamination of α-keto amides to peptides. Nat. Commun. 12, 5174 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Alemán, J., Parra, A., Jiang, H. & Jørgensen, K. A. Squaramides: bridging from molecular recognition to bifunctional organocatalysis. Chem. Eur. J. 17, 6890–6899 (2011).

    Article  PubMed  Google Scholar 

  41. Tang, S., Zhang, X., Sun, J., Niu, D. & Chruma, J. J. 2-Azaallyl anions, 2-azaallyl cations, 2-azaallyl radicals, and azomethine ylides. Chem. Rev. 118, 10393–10457 (2018).

    Article  CAS  PubMed  Google Scholar 

  42. Crugeiras, J., Rios, A., Riveiros, E., Amyes, T. L. & Richard, J. P. Glycine enolates: the effect of formation of iminium ions to simple ketones on α-amino carbon acidity and a comparison with pyridoxal iminium ions. J. Am. Chem. Soc. 130, 2041–2050 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. 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 

  44. Hansch, C., Leo, A. & Taft, R. W. A survey of Hammett substituent constants and resonance and field parameters. Chem. Rev. 91, 165–195 (1991).

    Article  CAS  Google Scholar 

  45. Doyle, A. G. & Jacobsen, E. N. Small-molecule H-bond donors in asymmetric catalysis. Chem. Rev. 107, 5713–5743 (2007).

    Article  CAS  PubMed  Google Scholar 

  46. Lu, L.-Q., An, X.-L., Chen, J.-R. & Xiao, W.-J. Dual activation in organocatalysis: design of tunable and bifunctional organocatalysts and their applications in enantioselective reactions. Synlett 2012, 490–508 (2012).

    Google Scholar 

  47. Breslow, R. Biomimetic chemistry and artificial enzymes: catalysis by design. Acc. Chem. Res. 28, 146–153 (1995).

    Article  CAS  Google Scholar 

  48. Chen, J., Liu, Y. E., Gong, X., Shi, L. & Zhao, B. Biomimetic chiral pyridoxal and pyridoxamine catalysts. Chin. J. Chem. 37, 103–112 (2019).

    Article  CAS  Google Scholar 

  49. Dalko, P. I. & Moisan, L. Enantioselective organocatalysis. Angew. Chem. Int. Ed. 40, 3726–3748 (2001).

    Article  CAS  Google Scholar 

  50. List, B. Introduction: organocatalysis. Chem. Rev. 107, 5413–5415 (2007).

    Article  CAS  Google Scholar 

  51. MacMillan, D. W. C. The advent and development of organocatalysis. Nature 455, 304–308 (2008).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We are grateful for the generous financial support from the National Natural Science Foundation of China (21871181, 22271192), the Shanghai Municipal Education Commission (2019-01-07-00-02-E00029), the Shanghai Municipal Committee of Science and Technology (20JC1416800) and Shanghai Engineering Research Center of Green Energy Chemical Engineering (18DZ2254200).

Author information

Authors and Affiliations

  1. The Education Ministry Key Lab of Resource Chemistry, Shanghai Key Laboratory of Rare Earth Functional Materials, and Shanghai Frontiers Science Center of Biomimetic Catalysis, Shanghai Normal University, Shanghai, China

    Chengkang Hou, Bingfei Peng, Shen Ye, Zeyang Yin, Jing Cao, Xiao Xiao & Baoguo Zhao

Authors
  1. Chengkang Hou
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bingfei Peng
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shen Ye
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Zeyang Yin
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jing Cao
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Xiao Xiao
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Baoguo Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

B.Z. conceived and directed the project and wrote the paper. C.H. conducted most of the experiments including the synthesis of the chiral pyridoxamine catalysts and the development of the reaction. B.P., S.Y. and Z.Y. performed pyridoxal catalyst development. J.C. performed MS analysis for the project. X.X. revised the manuscript.

Corresponding author

Correspondence to Baoguo Zhao.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Catalysis thanks Weiwei Zi and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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 Methods, References, Figs. 1–26, Tables 1–12 and Equations (1)–(7).

Supplementary Data 1

The .cif file of compound (R,R)-1a (CCDC 2121718).

Supplementary Data 2

The .cif file of compound (R,R)-4ae (CCDC 2121753).

Supplementary Data 3

The computational data for pKa determination.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hou, C., Peng, B., Ye, S. et al. Catalytic asymmetric α C(sp3)–H addition of benzylamines to aldehydes. Nat Catal 5, 1061–1068 (2022). https://doi.org/10.1038/s41929-022-00875-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41929-022-00875-3

  • Springer Nature Limited

This article is cited by

Search

Navigation