Skip to main content

Thank you for visiting nature.com. 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.

  • Article
  • Published:

Enantioselective synthesis of β- and α-amino ketones through reversible alkane carbonylation

Nature Synthesis volume 3, pages 507–516 (2024)Cite this article

Subjects

Abstract

The direct incorporation of alkanes and CO into value-added chiral products through alkane carbonylation is a desirable transformation; however, it remains inefficient. The carbonylation of alkanes via photoirradiated radical addition to CO requires mild reaction conditions but suffers from low conversion due to equilibrium constraints. Here an equilibrium-leveraging strategy that combines alkane carbonylation with various enantioselective transformations is reported. The combination of tetra-n-butylammonium decatungstate and chiral sodium phosphate catalysts enables alkane carbonylation/enantioselective Mannich reaction and alkane carbonylation/enantioselective radical addition cascade processes for the enantioselective synthesis of β-amino and α-amino ketones from alkanes, CO and anilines by breaking the equilibrium of reversible photocatalytic C–H carbonylation. While both reactions can tolerate a broad scope of cyclic alkanes and anilines, the synthetic method to synthesize β-amino ketones can use a range of aliphatic ketones as substrates. The synthetic process to form β-amino ketones can be readily scaled-up through use of an integrated continuous-flow and batch set-up, providing efficient gram-scale synthesis. Mechanistic studies reveal that the synthesis of α-amino ketones proceeds through the asymmetric addition of an acyl radical to an imine intermediate.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Equilibrium-leveraging strategy for the conversion of alkanes, CO and other simple reactants to chiral amino ketones.
Fig. 2: Scope of the cascade carbonylation/asymmetric Mannich reactiona, b.
Fig. 3: Synthesis of α-amino ketones via the asymmetric cascade reactions based on alkane carbonylationa.
Fig. 4: Synthesis of α-amino ketones via the asymmetric cascade reactions of the addition of external aldehydea.
Fig. 5: Synthetic applications.
Fig. 6: Proposed reaction pathways of the dual catalytic asymmetric cascade reactions.

Similar content being viewed by others

Data availability

Full experimental procedures and the data supporting the findings of this study are available within the Article and its Supplementary Information.

References

  1. Ryu, I., Sonoda, N. & Curran, D. P. Tandem radical reactions of carbon monoxide, isonitriles, and other reagent equivalents of the geminal radical acceptor/radical precursor synthon. Chem. Rev. 96, 177–194 (1996).

    Article  CAS  PubMed  Google Scholar 

  2. Peng, J.-B., Geng, H.-Q. & Wu, X.-F. The chemistry of CO: carbonylation. Chem 5, 526–552 (2018).

    Article  Google Scholar 

  3. Cai, B., Cheo, H. W., Liu, T. & Wu, J. Light-promoted organic transformations utilizing carbon-based gas molecules as feedstocks. Angew. Chem. Int. Ed. 60, 18950–18980 (2021).

    Article  CAS  Google Scholar 

  4. Faisca Phillips, A. M. & Pombeiro, A. In Alkane Functionalization (eds Pombeiro, A. J. L. & da Silva, M. F. C. G.) Ch. 18, 476–513 (Wiley, 2019).

  5. Liu, C., Liu, D. & Lei, A. Recent advances of transition-metal catalyzed radical oxidative cross-couplings. Acc. Chem. Res. 47, 3459–3470 (2014).

    Article  CAS  PubMed  Google Scholar 

  6. Sumino, S., Fusano, A., Fukuyama, T. & Ryu, I. Carbonylation reactions of alkyl iodides through the interplay of carbon radicals and Pd catalysts. Acc. Chem. Res. 47, 1563–1574 (2014).

    Article  CAS  PubMed  Google Scholar 

  7. Yoo, E. J., Wasa, M. & Yu, J.-Q. Pd(II)-catalyzed carbonylation of C(sp3)–H bonds: a new entry to 1,4-dicarbonyl compounds. J. Am. Chem. Soc. 132, 17378–17380 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Xie, P. et al. Palladium-catalyzed oxidative carbonylation of benzylic C–H bonds via nondirected C(sp3)–H activation. J. Am. Chem. Soc. 134, 9902–9905 (2012).

    Article  CAS  PubMed  Google Scholar 

  9. Lu, L., Qiu, F., Alhumade, H., Zhang, H. & Lei, A. Tuning the oxidative mono- or double-carbonylation of alkanes with CO by choosing a Co or Cu catalyst. ACS Catal. 12, 9664–9669 (2022).

    Article  CAS  Google Scholar 

  10. Li, Y., Dong, K., Zhu, F., Wang, Z. & Wu, X. F. Copper-catalyzed carbonylative coupling of cycloalkanes and amides. Angew. Chem. Int. Ed. 55, 7227–7230 (2016).

    Article  CAS  Google Scholar 

  11. Bai, S.-T., Wen, J. & Zhang, X. in The Chemical Transformations of C1 Compounds (eds Wu, X.-F., Han, B., Ding, K. & Liu, Z.) 611–666 (Wiley, 2022).

  12. Boese, W. T. & Goldman, A. S. Alkane carbonylation photocatalyzed by aromatic ketones under high CO pressure. Tetrahedron Lett. 33, 2119–2122 (1992).

    Article  CAS  Google Scholar 

  13. Boese, W. T. & Goldman, A. S. Photochemical cyclohexane carbonylation cocatalyzed by d8 transition metal carbonyls and aromatic ketones and aldehydes. J. Am. Chem. Soc. 114, 350–351 (1992).

    Article  CAS  Google Scholar 

  14. Jaynes, B. S. & Hill, C. L. Radical carbonylation of alkanes via polyoxotungstate photocatalysis. J. Am. Chem. Soc. 117, 4704–4705 (1995).

    Article  CAS  Google Scholar 

  15. Ravelli, D., Protti, S. & Fagnoni, M. Decatungstate anion for photocatalyzed “window ledge” reactions. Acc. Chem. Res. 49, 2232–2242 (2016).

    Article  CAS  PubMed  Google Scholar 

  16. Hill, C. L. Introduction of functionality into unactivated carbon-hydrogen bonds. Catalytic generation and nonconventional utilization of organic radicals. Synlett 1995, 127–132 (1995).

    Article  Google Scholar 

  17. Perry, I. B. et al. Direct arylation of strong aliphatic C–H bonds. Nature 560, 70–75 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Ravelli, D. et al. Functionalization by decatungstate anion photocatalysis: synergistic control by polar and steric effects expands the reaction scope. ACS Catal. 8, 701–713 (2018).

    Article  CAS  Google Scholar 

  19. Abrams, D. J., West, J. G. & Sorensen, E. J. Toward a mild dehydroformylation using base-metal catalysis. Chem. Sci. 8, 1954–1959 (2017).

    Article  CAS  PubMed  Google Scholar 

  20. Ryu, I. et al. Atom-economical synthesis of unsymmetrical ketones through photocatalyzed C–H activation of alkanes and coupling with CO and electrophilic alkenes. Angew. Chem. Int. Ed. 50, 1869–1872 (2011).

    Article  CAS  Google Scholar 

  21. Ryu, I. et al. Efficient C–H/C–N and C–H/C–CO–N conversion via decatungstate-photoinduced alkylation of diisopropyl azodicarboxylate. Org. Lett. 15, 2554–2557 (2013).

    Article  CAS  PubMed  Google Scholar 

  22. Raymenants, F., Masson, T. M., Sanjosé-Orduna, J. & Noël, T. Efficient C(sp3)–H carbonylation of light and heavy hydrocarbons with carbon monoxide via hydrogen atom transfer photocatalysis in flow. Angew. Chem. Int. Ed. 62, e202308563 (2023).

    Article  CAS  Google Scholar 

  23. Mayer, J. M. Understanding hydrogen atom transfer: from bond strengths to Marcus theory. Acc. Chem. Res. 44, 36–46 (2011).

    Article  CAS  PubMed  Google Scholar 

  24. Liu, W. et al. Oxidative aliphatic C–H fluorination with fluoride ion catalyzed by a manganese porphyrin. Science 337, 1322–1325 (2012).

    Article  CAS  PubMed  Google Scholar 

  25. Jeffrey, J. L., Terrett, J. A. & MacMillan, D. W. C. O–H hydrogen bonding promotes H-atom transfer from α-C–H bonds for C-alkylation of alcohols. Science 349, 1532–1536 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Chu, J. C. & Rovis, T. Amide-directed photoredox-catalysed C–C bond formation at unactivated sp3 C–H bonds. Nature 539, 272–275 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  27. Choi, G. J., Zhu, Q., Miller, D. C., Gu, C. J. & Knowles, R. R. Catalytic alkylation of remote C–H bonds enabled by proton-coupled electron transfer. Nature 539, 268–271 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Capaldo, L., Ravelli, D. & Fagnoni, M. Direct photocatalyzed hydrogen atom transfer (HAT) for aliphatic C–H bonds elaboration. Chem. Rev. 122, 1875–1924 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  29. Wang, P. S., Chen, D. F. & Gong, L. Z. Recent progress in asymmetric relay catalysis of metal complex with chiral phosphoric acid. Top. Curr. Chem. 378, 9 (2020).

    Article  Google Scholar 

  30. Zhou, Q. L. Transition-metal catalysis and organocatalysis: where can progress be expected? Angew. Chem. Int. Ed. 55, 5352–5353 (2016).

    Article  CAS  Google Scholar 

  31. Du, Z. & Shao, Z. Combining transition metal catalysis and organocatalysis—an update. Chem. Soc. Rev. 42, 1337–1378 (2013).

    Article  CAS  PubMed  Google Scholar 

  32. Uraguchi, D. & Terada, M. Chiral Brønsted acid-catalyzed direct Mannich reactions via electrophilic activation. J. Am. Chem. Soc. 126, 5356–5357 (2004).

    Article  CAS  PubMed  Google Scholar 

  33. Akiyama, T., Itoh, J., Yokota, K. & Fuchibe, K. Enantioselective Mannich-type reaction catalyzed by a chiral Brønsted acid. Angew. Chem. Int. Ed. 43, 1566–1568 (2004).

    Article  CAS  Google Scholar 

  34. Guo, Q.-X. et al. Chiral Brønsted acid-catalyzed direct asymmetric Mannich. reaction. J. Am. Chem. Soc. 129, 3790–3791 (2007).

    Article  CAS  PubMed  Google Scholar 

  35. List, B., Pojarliev, P., Biller, W. T. & Martin, H. J. The proline-catalyzed direct asymmetric three-component Mannich reaction: scope, optimization, and application to the highly enantioselective synthesis of 1,2-amino alcohols. J. Am. Chem. Soc. 124, 827–833 (2002).

    Article  CAS  PubMed  Google Scholar 

  36. Parmar, D., Sugiono, E., Raja, S. & Rueping, M. Complete field guide to asymmetric BINOL-phosphate derived Brønsted acid and metal catalysis: history and classification by mode of activation; bronsted acidity, hydrogen bonding, ion pairing, and metal phosphates. Chem. Rev. 114, 9047–9153 (2014).

    Article  CAS  PubMed  Google Scholar 

  37. Kampen, D., Reisinger, C. M. & List, B. Chiral Brønsted acids for asymmetric organocatalysis. Top. Curr. Chem. 291, 395–456 (2010).

    Article  CAS  PubMed  Google Scholar 

  38. Akiyama, T. Stronger Brønsted acids. Chem. Rev. 107, 5744–5758 (2007).

    Article  CAS  PubMed  Google Scholar 

  39. Du, Y. et al. Aromatic β-amino-ketone derivatives as novel selective non-steroidal progesterone receptor antagonists. Bioorg. Med. Chem. 18, 4255–4268 (2010).

    Article  CAS  PubMed  Google Scholar 

  40. Shen, K., Liu, X. H., Cai, Y. F., Lin, L. L. & Feng, X. M. Facile and efficient enantioselective Strecker reaction of ketimines by chiral sodium phosphate. Chem. Eur. J. 15, 6008–6014 (2009).

    Article  CAS  PubMed  Google Scholar 

  41. Hatano, M., Ikeno, T., Matsumura, T., Torii, S. & Ishihara, K. Chiral lithium salts of phosphoric acids as Lewis acid–base conjugate catalysts for the enantioselective cyanosilylation of ketones. Adv. Synth. Catal. 350, 1776–1780 (2008).

    Article  CAS  Google Scholar 

  42. Klussmann, M. et al. Synthesis of TRIP and analysis of phosphate salt impurities. Synlett 21, 2189–2192 (2010).

  43. Mondal, S. et al. Enantioselective radical reactions using chiral catalysts. Chem. Rev. 122, 5842–5976 (2022).

    Article  CAS  PubMed  Google Scholar 

  44. Uchikura, T., Kamiyama, N., Mouri, T. & Akiyama, T. Visible-light-driven enantioselective radical addition to imines enabled by the excitation of a chiral phosphoric acid–imine complex. ACS Catal. 12, 5209–5216 (2022).

    Article  CAS  Google Scholar 

  45. Garrido-Castro, A. F., Maestro, M. C. & Alemán, J. α-Functionalization of imines via visible light photoredox catalysis. Catalysts 10, 562 (2020).

  46. Ermanis, K. et al. A computational and experimental investigation of the origin of selectivity in the chiral phosphoric acid catalyzed enantioselective Minisci reaction. J. Am. Chem. Soc. 142, 21091–21101 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Proctor, R. S. J., Davis, H. J. & Phipps, R. J. Catalytic enantioselective Minisci-type addition to heteroarenes. Science 360, 419–422 (2018).

    Article  CAS  PubMed  Google Scholar 

  48. Qi, X. K. et al. Multicomponent synthesis of α-branched tertiary and secondary amines by photocatalytic hydrogen atom transfer strategy. Org. Lett. 23, 4473–4477 (2021).

    Article  CAS  PubMed  Google Scholar 

  49. Zhang, X., Staples, R. J., Rheingold, A. L. & Wulff, W. D. Catalytic asymmetric α-iminol rearrangement: new chiral platforms. J. Am. Chem. Soc. 136, 13971–13974 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Cao, J., Su, Y. X., Zhang, X. Y. & Zhu, S. F. Highly enantioselective Brønsted acid catalyzed Heyns rearrangement. Angew. Chem. Int. Ed. 62, e202212976 (2023).

    Article  CAS  Google Scholar 

  51. Mennen, S. M., Gipson, J. D., Kim, Y. R. & Miller, S. J. Thiazolylalanine-derived catalysts for enantioselective intermolecular aldehyde–imine cross-couplings. J. Am. Chem. Soc. 127, 1654–1655 (2005).

    Article  CAS  PubMed  Google Scholar 

  52. DiRocco, D. A. & Rovis, T. Catalytic asymmetric cross-aza-benzoin reactions of aliphatic aldehydes with N-Boc-protected imines. Angew. Chem. Int. Ed. 51, 5904–5906 (2012).

    Article  CAS  Google Scholar 

  53. Weinberg, D. R. et al. Proton-coupled electron transfer. Chem. Rev. 112, 4016–4093 (2012).

    Article  CAS  PubMed  Google Scholar 

  54. Uraguchi, D., Kinoshita, N., Kizu, T. & Ooi, T. Synergistic catalysis of ionic Brønsted acid and photosensitizer for a redox neutral asymmetric α-coupling of N-arylaminomethanes with aldimines. J. Am. Chem. Soc. 137, 13768–13771 (2015).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by the National Natural Science Foundation of China (22188101, 21831007, 21971231).

Author information

Authors and Affiliations

  1. Department of Chemistry, University of Science and Technology of China, Hefei, China

    Wei-Wei Ding, Zhi-Yuan He, Mostafa Sayed, Yu Zhou, Zhi-Yong Han & Liu-Zhu Gong

  2. Hefei National Research Center for Physical Sciences at the Microscale, Hefei, China

    Zhi-Yong Han & Liu-Zhu Gong

Authors
  1. Wei-Wei Ding
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zhi-Yuan He
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mostafa Sayed
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yu Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Zhi-Yong Han
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Liu-Zhu Gong
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

W.-W.D. carried out most of the experimental and data analysis work. Z.-Y.H., M.S. and Y.Z. contributed to the synthesis of catalysts and the synthetic applications. Z.-Y.H. and L.-Z.G. designed the reaction and directed the project. The paper was written by Z.-Y.H. and L.-Z.G. All authors contributed to discussions.

Corresponding authors

Correspondence to Zhi-Yong Han or Liu-Zhu Gong.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Synthesis thanks Bin Tan, Julian West and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Thomas West, in collaboration with the Nature Synthesis team.

Additional information

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

Supplementary information

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

Ding, WW., He, ZY., Sayed, M. et al. Enantioselective synthesis of β- and α-amino ketones through reversible alkane carbonylation. Nat. Synth 3, 507–516 (2024). https://doi.org/10.1038/s44160-023-00476-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s44160-023-00476-3

Search

Advanced search

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