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:

Oxygen transposition of formamide to α-aminoketone moiety in a carbene-initiated domino reaction

Nature Chemistry (2025)Cite this article

Subjects

Abstract

The carbonyl group is one of the most important functional groups in organic chemistry. C=O cleavage and full transfer of the resulting fragments into final products would be extremely attractive and open up new avenues in retrosynthetic planning. In this context, as an N-containing carbonyl compound, the transformations of formamides, wherein C=O cleavage occurring with simultaneous incorporation of ‘O’ and aminomethine moieties to highly functionalized amines, remain a formidable challenge. Here we disclosed a dirhodium/Xantphos or dirhodium–palladium dual catalysed reaction of diazo compounds and allylic substrates in dimethyl formamide, giving various α-aminoketones and cyclopentenone derivatives efficiently featured with extensively reorganized structure, wherein a carbenic carbon was formally inserted into C=O bond and α-group of the carbene was shifted to the residual aminomethine moiety. Mechanistic studies revealed that three or six domino steps are involved in this catalytic process, including epoxidation, dyotropic type rearrangement, allylic alkylation, Claisen rearrangement, isomerization and Nazarov cyclization.

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: Background and concept.
Fig. 2: The synthesis of α-aminoketone derivatives.
Fig. 3: The synthesis of cyclopentenone derivatives.
Fig. 4: The transformations of the products.
Fig. 5: Mechanistic investigations.
Fig. 6: The possible reaction pathway.

Similar content being viewed by others

Data availability

All data supporting the findings of this study are available within the Article and its Supplementary Information. Crystallographic data for the structures reported in this Article have been deposited at the Cambridge Crystallographic Data Centre (CCDC), under deposition numbers CCDC 2295376 (5a), 2295374 (7d), 2295375 (9f), 2305221 (11e), 2351661 (12p), 2295377 (19), 2350726 (27) and 2305222 (31). These data are available via the Cambridge Crystallographic Data Centre at https://www.ccdc.cam.ac.uk/structures/.

References

  1. Tietze, L. F. Domino reactions in organic synthesis. Chem. Rev. 96, 115–136 (1996).

    Article  CAS  PubMed  Google Scholar 

  2. Lu, L.-Q., Chen, J.-R. & Xiao, W.-J. Development of cascade reactions for the concise construction of diverse heterocyclic architectures. Acc. Chem. Res. 45, 1278–1293 (2012).

    Article  CAS  PubMed  Google Scholar 

  3. Bai, L. & Jiang, X. Catalytic domino reaction: a promising and economic tool in organic synthesis. Chem Catal. 3, 100752 (2023).

    Article  CAS  Google Scholar 

  4. Volkov, A., Tinnis, F., Stagbrand, T., Trillo, P. & Adolfsson, H. Chemoselective reduction of carboxamides. Chem. Soc. Rev. 45, 6685–6697 (2016).

    Article  CAS  PubMed  Google Scholar 

  5. Cabrero-Antonino, J. R., Adam, R., Papa, V. & Beller, M. Homogeneous and heterogeneous catalytic reduction of amides and related compounds using molecular hydrogen. Nat. Commun. 11, 3893–3910 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Huang, P. Direct transformations of amides: tactics and recent progress. Acta Chim. Sinica 76, 357–365 (2018).

    Article  CAS  Google Scholar 

  7. Li, G., Ma, S. & Szostak, M. Amide bond activation: the power of resonance. Trends Chem. 2, 914–928 (2020).

    Article  CAS  Google Scholar 

  8. Kaiser, D., Bauer, A., Lemmerer, M. & Maulide, N. Amide activation: an emerging tool for chemoselective synthesis. Chem. Soc. Rev. 47, 7899–7925 (2018).

    Article  CAS  PubMed  Google Scholar 

  9. Dander, J. E. & Garg, N. K. Breaking amides using nickel catalysis. ACS Catal. 7, 1413–1423 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Feng, M., Zhang, H. & Maulide, N. Challenges and breakthroughs in selective amide activation. Angew. Chem. Int. Ed. 61, e20221221 (2022).

    Article  Google Scholar 

  11. Wu, Z., Xu, X., Wang, J. & Dong, G. Carbonyl 1,2-transposition through triflate-mediated α-amination. Science 374, 734–740 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Shennan, B. D. A., Sánchez-Alonso, S., Rossini, G. & Dixon, D. J. 1,2-Redox transpositions of tertiary amides. J. Am. Chem. Soc. 145, 21745–21751 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Li, J., Huang, C.-Y. & Li, C.-J. Deoxygenative functionalizations of aldehydes, ketones and carboxylic acids. Angew. Chem. Int. Ed. 61, e202112770 (2022).

    Article  CAS  Google Scholar 

  14. Muzart, J. N,N-Dimethylformamide: much more than a solvent. Tetrahedron 65, 8313–8323 (2009).

    Article  CAS  Google Scholar 

  15. Ding, S. & Jiao, N. N,N-Dimethylformamide: a multipurpose building block. Angew. Chem. Int. Ed. 51, 9226–9237 (2012).

    Article  CAS  Google Scholar 

  16. Bras, J. L. & Muzart, J. Recent uses of N,N-dimethylformamide and N,N-dimethylacetamide as reagents. Molecules 23, 1939–1969 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  17. Priebbenow, D. L. & Bolm, C. The rhodium-catalysed synthesis of pyrrolidinone substituted (trialkylsilyloxy)acrylic ester. RSC Adv. 3, 10318–10322 (2013).

    Article  CAS  Google Scholar 

  18. Li, Q. et al. Rhodium-catalyzed formal C=O bond insertion and sequential acyl 1,4-N-to‑O migratory rearrangement. J. Org. Chem. 87, 16937–16940 (2022).

    Article  CAS  PubMed  Google Scholar 

  19. Nandra, G. S., Pang, P. S., Porter, M. J. & Elliott, J. M. Synthesis of vinylogous carbamates by rhodium(II)-catalyzed olefination of tertiary formamides with a silylated diazoester. Org. Lett. 7, 3453–3455 (2005).

    Article  CAS  PubMed  Google Scholar 

  20. Jung, D. J., Jeon, H. J., Kim, J. H., Kim, Y. & Lee, S.-G. DMF as a source of oxygen and aminomethine: stereoselective 1,2-insertion of rhodium(II) azavinyl carbenes into the C=O bond of formamides for the synthesis of cis-diamino enones. Org. Lett. 16, 2208–2211 (2014).

    Article  CAS  PubMed  Google Scholar 

  21. Goudedranche, S., Besnard, C., Egger, L. & Lacour, J. Synthesis of pyrrolidines and pyrrolizidines with α-pseudoquaternary centers by copper-catalyzed condensation of α-diazodicarbonyl compounds and aryl γ-lactams. Angew. Chem. Int. Ed. 55, 13775–13779 (2016).

    Article  CAS  Google Scholar 

  22. Tan, F. et al. Chiral Lewis acid catalyzed reactions of α-diazoester derivatives: construction of dimeric polycyclic compounds. Angew. Chem. Int. Ed. 57, 16176–16179 (2018).

    Article  CAS  Google Scholar 

  23. Miura, T., Funakoshi, Y., Tanaka, T. & Murakami, M. Direct production of enaminones from terminal alkynes via rhodium-catalyzed reaction of formamides with N-sulfonyl-1,2,3-triazoles. Org. Lett. 16, 2760–2763 (2014).

    Article  CAS  PubMed  Google Scholar 

  24. Mukherjeea, A. et al. Synthesis of α-amino carbonyl compounds: a brief review. Russ. Chem. Rev. 92, RCR5046 (2023).

    Article  Google Scholar 

  25. Allen, L. A. T., Raclea, R. C., Natho, P. & Parsons, P. J. Recent advances in the synthesis of α-amino ketones. Org. Biomol. Chem. 19, 498–513 (2021).

    Article  CAS  PubMed  Google Scholar 

  26. Fisher, L. E. & Muchowski, J. M. Synthesis of α-aminoaldehydes and α-aminoketones. A review. Org. Prep. Proced. Int. 22, 399–484 (1990).

    Article  CAS  Google Scholar 

  27. Wu, W., Chen, C., Peng, J. & Li, Z. Research progress of carbonyl α-position amination. Chin. J. Org. Chem. 43, 2743–2763 (2023).

    Article  CAS  Google Scholar 

  28. Padwa, A. Domino reactions of rhodium(II) carbenoids for alkaloid synthesis. Chem. Soc. Rev. 38, 3072–3081 (2009).

    Article  CAS  PubMed  Google Scholar 

  29. Hashimoto, T. & Maruoka, K. Recent advances of catalytic asymmetric 1,3-dipolar cycloadditions. Chem. Rev. 115, 5366–5412 (2015).

    Article  CAS  PubMed  Google Scholar 

  30. Padwa, A. Catalytic decomposition of diazo compounds as a method for generating carbonyl-ylide dipoles. Helv. Chim. Acta 88, 1357–1374 (2005).

    Article  CAS  Google Scholar 

  31. Padwa, A. Intramolecular cycloaddition of carbonyl ylides as a strategy for natural product synthesis. Tetrahedron 67, 8057–8072 (2011).

    Article  CAS  Google Scholar 

  32. Ning, Y. et al. Rhodium(II) acetate-catalysed cyclization of pyrazol-5-amineand1,3-diketone-2-diazo compounds using N,N-dimethylformamide as a carbon-hydrogen source: access to pyrazolo[3,4-b]pyridines. Adv. Synth. Catal. 361, 3518–3524 (2019).

    Article  CAS  Google Scholar 

  33. Ba, D. et al. Rhodium(II)-catalyzed multicomponent assembly of α,α,α-trisubstituted esters via formal insertion of O–C(sp3)–C(sp2) into C–C bonds. Nat. Commun. 11, 4219–4224 (2020).

  34. Trindade, A. F., Coelho, J. A. S., Afonso, C. A. M., Veiros, L. F. & Gois, P. M. P. Fine tuning of dirhodium(II) complexes: exploring the axial modification. ACS Catal. 2, 370–383 (2012).

    Article  CAS  Google Scholar 

  35. Hong, B., Shi, L., Li, L., Zhan, S. & Gu, Z. Paddlewheel dirhodium(II) complexes with N-heterocyclic carbene or phosphine ligand: new reactivity and selectivity. Green Synth. Catal. 3, 137–149 (2022).

    Article  CAS  Google Scholar 

  36. Wynne, D. C., Olmstead, M. M. & Jessop, P. G. Supercritical and liquid solvent effects on the enantioselectivity of asymmetric cyclopropanation with tetrakis[1-[(4-tert-butylphenyl)-sulfonyl]-(2S)-pyrrolidinecarboxylate]dirhodium(II). J Am Chem Soc 122, 7638–7647 (2000).

  37. Guo, X. & Hu, W. Novel multicomponent reactions via trapping of protic onium ylides with electrophiles. Acc. Chem. Res. 46, 2427–2440 (2013).

    Article  CAS  PubMed  Google Scholar 

  38. Xiao, Q., Zhang, Y. & Wang, J. Diazo compounds and N-tosylhydrazones: novel cross-coupling partners in transition-metal-catalyzed reactions. Acc. Chem. Res. 46, 236–247 (2013).

    Article  CAS  PubMed  Google Scholar 

  39. Xia, Y., Qiu, D. & Wang, J. Transition-metal-catalyzed cross-couplings through carbene migratory insertion. Chem. Rev. 117, 13810–13889 (2017).

    Article  CAS  PubMed  Google Scholar 

  40. Doyle, M. P., McKervey, M. A. & Ye, T. Modern Catalytic Methods for Organic Synthesis with Diazo Compounds (Wiley, 1998).

  41. Davies, H. M. L. & Denton, J. R. Application of donor/acceptor-carbenoids to the synthesis of natural products. Chem. Soc. Rev. 38, 3061–3071 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Ford, A. et al. Modern organic synthesis with α-diazocarbonyl compounds. Chem. Rev. 115, 9981–10080 (2015).

    Article  CAS  PubMed  Google Scholar 

  43. Liu, Z., Sivaguru, P., Ning, Y., Wu, Y. & Bi, X. Skeletal editing of (hetero)arenes using carbenes. Chem. Eur. J. 29, e202301227 (2023).

    Article  CAS  PubMed  Google Scholar 

  44. Moebius, D. C., Rendina, V. L. & Kingsbury, J. S. Catalysis of diazoalkane–carbonyl homologation. How new developments in hydrazone oxidation enable a carbon insertion strategy for synthesis. Top. Curr. Chem. 346, 111–162 (2014).

    Article  CAS  PubMed  Google Scholar 

  45. Candeias, N. R., Paterna, R. & Gois, P. M. P. Homologation reaction of ketones with diazo compounds. Chem. Rev. 116, 2937–2981 (2016).

    Article  CAS  PubMed  Google Scholar 

  46. Padwa, A. & Hornbuckle, S. F. Ylide formation from the reaction of carbenes and carbenoids with heteroatom lone pairs. Chem. Rev. 91, 263–309 (1991).

    Article  CAS  Google Scholar 

  47. Li, M. et al. Copper-catalyzed carbene insertion and ester migration for the synthesis of polysubstituted pyrroles. Chem. Commun. 56, 11050–11053 (2020).

    Article  CAS  Google Scholar 

  48. Luo, K. et al. Highly regioselective synthesis of multisubstituted pyrroles via Ag-catalyzed [4+1C]insert cascade. ACS Catal. 10, 3733–3740 (2020).

    Article  CAS  Google Scholar 

  49. Jose, J. & Mathew, T. V. Recent advances in the synthesis of 2-cyclopentenones. Tetrahedron 150, 133747–133770 (2024).

    Article  CAS  Google Scholar 

  50. Zhou, Z., Dixon, D. D., Jolit, A. & Tius, M. A. The evolution of the total synthesis of rocaglamide. Chem. Eur. J. 22, 15929–15936 (2016).

    Article  CAS  PubMed  Google Scholar 

  51. Lu, B. et al. Dirhodium(II)/Xantphos-catalyzed relay carbene insertion and allylic alkylation process: reaction development and mechanistic insights. J. Am. Chem. Soc. 143, 11799–11810 (2021).

    Article  CAS  PubMed  Google Scholar 

  52. Yang, Y., Lu, B., Xu, G. & Wang, X. Overcoming O–H insertion to para-selective C–H functionalization of free phenols: Rh(II)/Xantphos catalyzed geminal difunctionalization of diazo compounds. ACS Cent. Sci. 8, 581–589 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Frontier, A. J. & Hernandez, J. J. New twists in Nazarov cyclization chemistry. Acc. Chem. Res. 53, 1822–1832 (2020).

    Article  CAS  PubMed  Google Scholar 

  54. Wenz, D. R. & Alaniz, J. R. d. The Nazarov cyclization: a valuable method to synthesize fully substituted carbon stereocenters. Eur. J. Org. Chem. 2015, 23–37 (2014).

    Article  Google Scholar 

  55. Grandi, M. J. D. Nazarov-like cyclization reactions. Org. Biomol. Chem. 12, 5331–5345 (2014).

    Article  PubMed  Google Scholar 

  56. Vaidya, T., Eisenberg, R. & Frontier, A. J. Catalytic Nazarov cyclization: the state of the art. ChemCatChem 3, 1531–1548 (2011).

    Article  CAS  Google Scholar 

  57. Tornio, A., Neuvonen, P. J., Niemi, M. & Backman, J. T. Role of gemfibrozil as an inhibitor of CYP2C8 and membrane transporters. Expert Opin. Drug Metab. Toxicol. 13, 83–95 (2017).

    Article  CAS  PubMed  Google Scholar 

  58. Berry, J. The role of three-center/four-electron bonds in superelectrophilic dirhodium carbene and nitrene catalytic intermediates. Dalton Trans. 41, 700–703 (2012).

    Article  CAS  PubMed  Google Scholar 

  59. Werlé, C., Goddard, R., Philipps, P., Farès, C. & Fürstner, A. Structures of reactive donor/acceptor and donor/donor rhodium carbenes in the solid state and their implications for catalysis. J. Am. Chem. Soc. 138, 3797–3805 (2016).

    Article  PubMed  Google Scholar 

  60. Cao, J., Wu, H., Wang, Q. & Zhu, J. C–C bond activation enabled by dyotropic rearrangement of Pd(IV) species. Nat. Chem. 13, 671–676 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Fernandez, I., Cossio, F. P. & Sierra, M. A. Dyotropic reactions: mechanisms and synthetic applications. Chem. Rev. 109, 6687–6711 (2009).

    Article  CAS  PubMed  Google Scholar 

  62. Bach, R. D. & Domagala, J. M. The effect of Lewis acid and solvent on concerted 1,2-acyl migration. J. Org. Chem. 49, 4181–4188 (1984).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We acknowledge financial support from the National Key Research and Development Programme of China (grant no. 2021YFA1500100), the Strategic Priority Research Programme of the Chinese Academy of Sciences (grant nos XDB0610000 and XDB0590000), the National Natural Science Foundation of China (grant nos 92256303, 22171278, 22122104, 22193012 and 21933004), the Shanghai Science and Technology Committee (grant no. 23ZR1482400), the Natural Science Foundation of Ningbo (grant no. 2023J034), the Chinese Academy of Sciences Project for Young Scientists in Basic Research (grant nos YSBR-052 and YSBR-095), Open Research Fund of School of Chemistry and Chemical Engineering, Henan Normal University and the Research Funds of Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences (2024HIAS-p003). The numerical calculations in this study were carried out on the ORISE Supercomputer.

Author information

Authors and Affiliations

  1. Frontiers Science Center for Transformative Molecules, School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, Shanghai, China

    Yan Luo & Kuiling Ding

  2. State Key Laboratory of Organometallic Chemistry and Shanghai Hongkong Joint Laboratory in Chemical Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China

    Yan Luo, Kuiling Ding & Xiaoming Wang

  3. State Key Laboratory of Fluorine and Nitrogen Chemistry and Advanced Materials and Shanghai Hongkong Joint Laboratory in Chemical Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China

    Guanglong Huang & Xiao-Song Xue

  4. School of Chemistry and Materials Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China

    Xiao-Song Xue & Xiaoming Wang

  5. School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang, China

    Xiaoming Wang

Authors
  1. Yan Luo
    View author publications

    Search author on:PubMed Google Scholar

  2. Guanglong Huang
    View author publications

    Search author on:PubMed Google Scholar

  3. Kuiling Ding
    View author publications

    Search author on:PubMed Google Scholar

  4. Xiao-Song Xue
    View author publications

    Search author on:PubMed Google Scholar

  5. Xiaoming Wang
    View author publications

    Search author on:PubMed Google Scholar

Contributions

K.D. and X.W. conceived the project in collaboration with Y.L., who performed the experimental work and led primary data interpretation and analysis. G.H. and X.-S.X. performed all the computational studies and wrote the section with the calculations.

Corresponding authors

Correspondence to Kuiling Ding, Xiao-Song Xue or Xiaoming Wang.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Chemistry thanks Rosa Adam, Jianbo Wang, Yanying Zhao 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 1–11 and Figs. 1–18, starting material preparation and experimental procedures, synthetic applications, mechanistic studies and product characterization.

Supplementary Data 1

Crystallographic data for compound 5a; CCDC reference 2295376.

Supplementary Data 2

Crystallographic data for compound 7d; CCDC reference 2295374.

Supplementary Data 3

Crystallographic data for compound 9f; CCDC reference 2295375.

Supplementary Data 4

Crystallographic data for compound 11e; CCDC reference 2305221.

Supplementary Data 5

Crystallographic data for compound 12p; CCDC reference 2351661.

Supplementary Data 6

Crystallographic data for compound 19; CCDC reference 2295377.

Supplementary Data 7

Crystallographic data for compound 27; CCDC reference 2350726.

Supplementary Data 8

Crystallographic data for compound 31a; CCDC reference 2305222.

Supplementary Data 9

Computational details and Cartesian coordinates.

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

Luo, Y., Huang, G., Ding, K. et al. Oxygen transposition of formamide to α-aminoketone moiety in a carbene-initiated domino reaction. Nat. Chem. (2025). https://doi.org/10.1038/s41557-025-01834-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41557-025-01834-8

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