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:

Modular alkyl growth in amines via the selective insertion of alkynes into C–C bonds

Nature Chemistry volume 17, pages 1323–1330 (2025)Cite this article

Subjects

Abstract

The site-specific modification of amines has been a highly sought-after objective in organic synthesis. Despite the rapid advancement of carbon–hydrogen (C–H) bond functionalization methods, effective strategies for carbon–carbon (C–C) bond functionalization of amines remain elusive. Here we report a borane-catalysed method for the selective insertion of alkynes into alkyl C–C bonds of amines, resulting in the ring expansion of cyclic amines and chain elongation of acyclic amines. This approach begins with the cleavage of C–H bonds in amines, then transitioning to C–C bond functionalization upon reaction with alkynes. This method is effective with amines lacking an activating or leaving group and is suitable for late-stage functionalization of pharmaceuticals through C–C bond modification. Furthermore, by coupling this reaction with hydrolysis and hydrogenation steps, successive alkyne insertions are achieved, enabling modular and iterative alkyl growth of amines.

Access through your institution
Buy or subscribe

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

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

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

Fig. 1: Development of a method for synthesizing medium-sized cyclic and macrocyclic amines.
Fig. 2: Chain elongation of acyclic amines.
Fig. 3: Synthetic applications.

Similar content being viewed by others

Data availability

The data supporting the findings of this study are available within the article and its Supplementary Information. All crystallographic data are available free of charge from the Cambridge Crystallographic Data Centre under CCDC numbers 2385045 (9), 2385038 (8g), 2385037 (8c), 2385036 (6o), 2385717 (14h), 2385715 (6d), 2417134 (6e), 2385041 (3z) and 2385040 (6b).

References

  1. Jimenez, D. G., Poongavanam, V. & Kihlberg, J. Macrocycles in drug discovery—learning from the past for the future. J. Med. Chem. 66, 5377–5396 (2023).

    Article  Google Scholar 

  2. Hussain, A., Yousufb, S. K. & Mukherjee, D. Importance and synthesis of benzannulated medium-sized and macrocyclic rings (BMRs). RSC Adv. 4, 43241–43257 (2014).

    Article  CAS  Google Scholar 

  3. Driggers, E. M., Hale, S. P., Lee, J. & Terrett, N. K. The exploration of macrocycles for drug discovery—an underexploited structural class. Nat. Rev. Drug Discov. 7, 608–624 (2008).

    Article  CAS  PubMed  Google Scholar 

  4. Yet, L. Metal-mediated synthesis of medium-sized rings. Chem. Rev. 100, 2963–3007 (2000).

    Article  CAS  PubMed  Google Scholar 

  5. Gradillas, A. & Pérez-Castells, J. Macrocyclization by ring-closing metathesis in the total synthesis of natural products: reaction conditions and limitations. Angew. Chem. Int. Ed. 45, 6086–6101 (2006).

    Article  CAS  Google Scholar 

  6. Mortensen, K. T., Osberger, T. J., King, T. A., Sore, H. F. & Spring, D. R. Strategies for the diversity-oriented synthesis of macrocycles. Chem. Rev. 119, 10288–10317 (2019).

    Article  CAS  PubMed  Google Scholar 

  7. Reyes, R. L., Iwai, T. & Sawamura, M. Construction of medium-sized rings by gold catalysis. Chem. Rev. 121, 8926–8947 (2021).

    Article  CAS  PubMed  Google Scholar 

  8. Otevrel, J., Eugui, M., Ričko, S. & Jørgensen, K. A. Enantioselective organocatalytic cycloadditions for the synthesis of medium-sized rings. Nat. Synth. 2, 1142–1158 (2023).

    Article  CAS  Google Scholar 

  9. Rong, Z.-Q. et al. Nine-membered benzofuran-fused heterocycles: enantioselective synthesis by Pd-catalysis and rearrangement via transannular bond formation. J. Am. Chem. Soc. 139, 15304–15307 (2017).

    Article  CAS  PubMed  Google Scholar 

  10. Pan, J., Ho, T. O., Chen, Y.-C., Yang, B.-M. & Zhao, Y. Enantioselective construction of eight-membered N-heterocycles from simple 1,3-dienes via Pd(0) Lewis base catalysis. Angew. Chem. Int. Ed. 63, e202317703 (2024).

    Article  CAS  Google Scholar 

  11. Donald, J. R. & Unsworth, W. P. Ring-expansion reactions in the synthesis of macrocycles and medium-sized rings. Chem. Eur. J. 23, 8780–8799 (2017).

    Article  CAS  PubMed  Google Scholar 

  12. Clarke, A. K. & Unsworth, W. P. A happy medium: the synthesis of medicinally important medium-sized rings via ring expansion. Chem. Sci. 11, 2876–2881 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Roque, J. B., Kuroda, Y., Göttemann, L. T. & Sarpong, R. Deconstructive fluorination of cyclic amines by carbon-carbon cleavage. Science 361, 171–174 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Roque, J. B., Kuroda, Y., Göttemann, L. T. & Sarpong, R. Deconstructive diversification of cyclic amines. Nature 564, 244–248 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Kennedy, S. H., Dherange, B. D., Berger, K. J. & Levin, M. D. Skeletal editing through direct nitrogen deletion of secondary amines. Nature 593, 223–227 (2021).

    Article  CAS  PubMed  Google Scholar 

  16. Jurczyk, J. et al. Photomediated ring contraction of saturated heterocycles. Science 373, 1004–1012 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Mendoza-Sanchez, R. et al. Cyclols revisited: facile synthesis of medium-sized cyclic peptides. Chem. Eur. J. 23, 13319–13322 (2017).

    Article  CAS  PubMed  Google Scholar 

  18. Hall, J. E., Matlock, J. V., Ward, J. W., Gray, K. V. & Clayden, J. Medium-ring nitrogen heterocycles through migratory ring expansion of metalated ureas. Angew. Chem. Int. Ed. 55, 11153–11157 (2016).

    Article  CAS  Google Scholar 

  19. Lawer, A. et al. Internal nucleophilic catalyst mediated cyclisation/ring expansion cascades for the synthesis of medium-sized lactones and lactams. Angew. Chem. Int. Ed. 58, 13942–13947 (2019).

    Article  CAS  Google Scholar 

  20. Zhao, W., Qian, H., Li, Z. & Sun, J. Catalytic ring expansion of cyclic hemiaminals for the synthesis of medium-ring lactams. Angew. Chem. Int. Ed. 54, 10005–10008 (2015).

    Article  CAS  Google Scholar 

  21. Guney, T., Wenderski, T. A., Boudreau, M. W. & Tan, D. S. Synthesis of benzannulated medium-ring lactams via a tandem oxidative dearomatization-ring expansion reaction. Chem. Eur. J. 24, 13150–13157 (2018).

    Article  CAS  PubMed  Google Scholar 

  22. Li, L. et al. Radical aryl migration enables diversity-oriented synthesis of structurally diverse medium/macro- or bridged-rings. Nat. Commun. 7, 13852 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  23. Wang, N. et al. Direct photocatalytic synthesis of medium-sized lactams by C−C bond cleavage. Angew. Chem. Int. Ed. 57, 14225–14229 (2018).

    Article  CAS  Google Scholar 

  24. Zalessky, I. et al. A modular strategy for the synthesis of macrocycles and medium-sized rings via cyclization/ring expansion cascade reactions. J. Am. Chem. Soc. 146, 5702–5711 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Wu, L. et al. Diversified ring expansion of saturated cyclic amines enabled by azlactone insertion. Nat. Chem. 16, 1951–1959 (2024).

    Article  CAS  PubMed  Google Scholar 

  26. Millot, N., Santini, C. C., Fenet, B. & Basset, J. M.Formation and characterization of zwitterionic stereoisomers from the reaction of B(C6F5)3 and NEt2Ph: (E)- and (Z)-[EtPhN+=CHCH2-B−(C6F5)3]. Eur. J. Inorg. Chem. 20023328–3335 (2002).

    Article  Google Scholar 

  27. Basak, S. et al. Electron deficient borane-mediated hydride abstraction in amines: stoichiometric and catalytic processes. Chem. Soc. Rev. 50, 3720–3737 (2021).

    Article  CAS  PubMed  Google Scholar 

  28. Saridakis, I., Klose, I., Jones, B. T. & Maulide, N. Hydride shuttle catalysis: from conventional to inverse mode. JACS Au 4, 3358–3369 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Shang, M. et al. C–H functionalization of amines via alkene-derived nucleophiles through cooperative action of chiral and achiral Lewis acid catalysts: applications in enantioselective synthesis. J. Am. Chem. Soc. 140, 10593–10601 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Maier, A. F. G. et al. Borane-catalyzed synthesis of quinolines bearing tetrasubstituted stereocenters by hydride abstraction-induced electrocyclization. Chem. Eur. J. 24, 16287–16291 (2018).

    Article  CAS  PubMed  Google Scholar 

  31. Tian, J.-J., Zeng, N.-N., Liu, N., Tu, X.-S. & Wang, X.-C. Intramolecular cyclizations of vinyl-substituted N,N‑dialkyl arylamines enabled by borane-assisted hydride transfer. ACS Catal. 9, 295–300 (2019).

    Article  CAS  Google Scholar 

  32. Basak, S. et al. B(C6F5)3-catalyzed direct C3 alkylation of indoles and oxindoles. ACS Catal. 10, 4835–4840 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Zhang, J., Park, S. & Chang, S. Catalytic access to bridged sila-N-heterocycles from piperidines via cascade sp3 and sp2 C–Si bond formation. J. Am. Chem. Soc. 140, 13209–13213 (2018).

    Article  CAS  PubMed  Google Scholar 

  34. Fang, H., Xie, K., Kemper, S. & Oestreich, M. Consecutive β,β′-selective C(sp3)–H silylation of tertiary amines with dihydrosilanes catalyzed by B(C6F5)3. Angew. Chem. Int. Ed. 60, 8542–8546 (2021).

    Article  CAS  Google Scholar 

  35. Chang, Y. et al. Enantioselective synthesis of N-alkylamines through β-amino C–H functionalization promoted by cooperative actions of B(C6F5)3 and a chiral Lewis acid co-catalyst. J. Am. Chem. Soc. 143, 2441–2455 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Klose, I., Mauro, G. D., Kaldre, D. & Maulide, N. Inverse hydride shuttle catalysis enables the stereoselective one-step synthesis of complex frameworks. Nat. Chem. 14, 1306–1310 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Zhang, M., Tang, Z.-L., Luo, H. & Wang, X.-C. β-C–H allylation of trialkylamines with allenes promoted by synergistic borane/palladium catalysis. Angew. Chem. Int. Ed. 63, e202317610 (2024).

    Article  CAS  Google Scholar 

  38. Zhou, X.-Y. et al. B(C6F5)3‑catalyzed C(sp3)−H alkylation of tertiary amines with electron-deficient olefins: determinants of site selectivity. ACS Catal. 14, 8041–8049 (2024).

    Article  CAS  Google Scholar 

  39. Liu, B., Romine, A. M., Rubel, C. Z., Engle, K. M. & Shi, B.-F. Transition-metal-catalyzed, coordination-assisted functionalization of nonactivated C(sp3)–H bonds. Chem. Rev. 121, 14957–15074 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Holmberg-Douglas, N. & Nicewicz, D. A. Photoredox-catalyzed C–H functionalization reactions. Chem. Rev. 122, 1925–2016 (2022).

    Article  CAS  PubMed  Google Scholar 

  41. Zhang, Z., Chen, P. & Liu, G. Copper-catalyzed radical relay in C(sp3)–H functionalization. Chem. Soc. Rev. 51, 1640–1658 (2022).

    Article  CAS  PubMed  Google Scholar 

  42. Mariano, P. S., Osborn, M. E., Dunaway-Mariano, D., Gunn, B. C. & Pettersen, R. C. The chemistry of azocines. Intermediates for the synthesis of pyrrolizidines. J. Org. Chem. 42, 2903–2910 (1977).

    Article  CAS  Google Scholar 

  43. Takahata, H., Tomiguchi, A., Hagiwara, A. & Yamazaki, T. Activated lactams. VI. The cycloaddition reaction of cyclic ketene-S,N-acetals with dimethyl acetylenedicarboxylate. Chem. Pharm. Bull. 30, 3959–3964 (1982).

    Article  CAS  Google Scholar 

  44. Reinhoudt, D. N. et al. Reactivity of cis-fused 3-(dialkylamino)cyclobutenes in polar and apolar solvents. Synthesis, X-ray structures, and reactions of cis,cis- and cis,trans-1,3-cycloalkadienes. J. Am. Chem. Soc. 106, 1341–1350 (1984).

    Article  CAS  Google Scholar 

  45. Xu, G.-Q. et al. Dual C(sp3)–H bond functionalization of N-heterocycles through sequential visible-light photocatalyzed dehydrogenation/[2+2] cycloaddition reactions. Angew. Chem. Int. Ed. 57, 5110–5114 (2018).

    Article  CAS  Google Scholar 

  46. Li, X. et al. Temperature-controlled divergent hydroamination cyclization [2+2]-cycloaddition cascade reactions of homopropargylic amines with 2-butynedioates: direct access to pyrrolo-b-cyclobutene and dihydro-1H-azepines. J. Org. Chem. 84, 1288–1298 (2019).

    Article  CAS  PubMed  Google Scholar 

  47. Efimov, I. V., Zhilyaev, D. I., Kulikova, L. N. & Voskressensky, L. G. Cycloaddition reactions of enamines. Eur. J. Org. Chem. 26, e202201450 (2023).

    Article  CAS  Google Scholar 

  48. López, C. S., Faza, O. N. & de Lera, Á. R. Electrocyclic ring opening of cis-bicyclo[m.n.0]alkenes: the anti-Woodward–Hoffmann quest. Chem. Eur. J. 13, 5009–5017 (2007).

    Article  Google Scholar 

  49. Guillemard, L., Kaplaneris, N., Ackermann, L. & Johansson, M. J. Late-stage C–H functionalization offers new opportunities in drug discovery. Nat. Rev. Chem. 5, 522–545 (2021).

    Article  CAS  PubMed  Google Scholar 

  50. Zhang, L. & Ritter, T. A perspective on late-stage aromatic C–H bond functionalization. J. Am. Chem. Soc. 144, 2399–2414 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Liang, Y.-F. et al. Carbon–carbon bond cleavage for late-stage functionalization. Chem. Rev. 123, 12313–12370 (2023).

    Article  CAS  PubMed  Google Scholar 

  52. Yu, X.-Y., Chen, J.-R. & Xiao, W.-J. Visible light-driven radical-mediated C–C bond cleavage/functionalization in organic synthesis. Chem. Rev. 121, 506–561 (2021).

    Article  CAS  PubMed  Google Scholar 

  53. Xia, Y. & Dong, G. Temporary or removable directing groups enable activation of unstrained C–C bonds. Nat. Rev. Chem. 4, 600–614 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank F. Wang for helpful discussions. We acknowledge support from National Natural Science Foundation of China (grant nos. 22461160280, 22371141, 22221002 and 22188101 to X.-C.W.), National Key R&D Program of China (grant no. 2021YFA1500200 to X.-C.W.), National Natural Science Foundation of China/RGC Joint Research Scheme (grant no. N_CUHK452-24 to H.L.) and China Postdoctoral Science Foundation (grant no. 2024M751519 to X.-Y.Z.).

Author information

Authors and Affiliations

  1. State Key Laboratory and Institute of Elemento-Organic Chemistry, Haihe Laboratory of Sustainable Chemical Transformations, Frontiers Science Center for New Organic Matter, College of Chemistry, Nankai University, Tianjin, China

    Xin-Yue Zhou, Lu Liu & Xiao-Chen Wang

  2. Department of Chemistry, The Chinese University of Hong Kong, Hong Kong SAR, China

    Hairong Lyu

Authors
  1. Xin-Yue Zhou
    View author publications

    Search author on:PubMed Google Scholar

  2. Lu Liu
    View author publications

    Search author on:PubMed Google Scholar

  3. Hairong Lyu
    View author publications

    Search author on:PubMed Google Scholar

  4. Xiao-Chen Wang
    View author publications

    Search author on:PubMed Google Scholar

Contributions

X.-C.W. conceived the concept and supervised the study. X.-Y.Z. performed the experiments and analysed the data. L.L. performed the DFT calculations. X.-C.W. and H.L. proposed the research direction and wrote the paper with input from all authors.

Corresponding author

Correspondence to Xiao-Chen Wang.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Chemistry thanks Alexander Pulis, Donghui Wei 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 Tables 1–7, Figs. 1–11, experimental procedures, computational details, data and spectra.

Supplementary Data 1

Crystallographic data for compound 3z; CCDC reference 2385041.

Supplementary Data 2

Crystallographic data for compound 6b; CCDC reference 2385040.

Supplementary Data 3

Crystallographic data for compound 6d; CCDC reference 2385715.

Supplementary Data 4

Crystallographic data for compound 6e; CCDC reference 2417134.

Supplementary Data 5

Crystallographic data for compound 6o; CCDC reference 2385036.

Supplementary Data 6

Crystallographic data for compound 8c; CCDC reference 2385037.

Supplementary Data 7

Crystallographic data for compound 8g; CCDC reference 2385038.

Supplementary Data 8

Crystallographic data for compound 9; CCDC reference 2385045.

Supplementary Data 9

Crystallographic data for compound 14h; CCDC reference 2385717.

Supplementary Data 10

Cartesian coordinates raw file for all computations.

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

Zhou, XY., Liu, L., Lyu, H. et al. Modular alkyl growth in amines via the selective insertion of alkynes into C–C bonds. Nat. Chem. 17, 1323–1330 (2025). https://doi.org/10.1038/s41557-025-01849-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue date:

  • DOI: https://doi.org/10.1038/s41557-025-01849-1

This article is cited by

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