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:

Tunable molecular editing of indoles with fluoroalkyl carbenes

Abstract

Building molecular complexity from simple feedstocks through precise peripheral and skeletal modifications is central to modern organic synthesis. Nevertheless, a controllable strategy through which both the core skeleton and the periphery of an aromatic heterocycle can be modified with a common substrate remains elusive, despite its potential to maximize structural diversity and applications. Here we report a carbene-initiated chemodivergent molecular editing of indoles that allows both skeletal and peripheral editing by trapping an electrophilic fluoroalkyl carbene generated in situ from fluoroalkyl N-triftosylhydrazones. A variety of fluorine-containing N-heterocyclic scaffolds have been efficiently achieved through tunable chemoselective editing reactions at the skeleton or periphery of indoles, including one-carbon insertion, C3 gem-difluoroolefination, tandem cyclopropanation and N1 gem-difluoroolefination, and cyclopropanation. The power of this chemodivergent molecular editing strategy has been highlighted through the modification of the skeleton or periphery of natural products in a controllable and chemoselective manner. The reaction mechanism and origins of the chemo- and regioselectivity have been probed by both experimental and theoretical methods.

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

Access options

Buy this article

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

Fig. 1: Molecular editing of heterocycles.
Fig. 2: Skeletal editing of indoles with fluoroalkyl N-triftosylhydrazones.
Fig. 3: Peripheral editing of indoles with fluoroalkyl N-triftosylhydrazones.
Fig. 4: Scale-up synthesis, chemodivergent molecular editing of natural products and mechanistic study.
Fig. 5: Computational investigations.

Similar content being viewed by others

Data availability

The data that support the findings of this study are available in this paper and its Supplementary Information. Crystallographic data for the structures reported in this paper have been deposited at the Cambridge Crystallographic Data Centre under deposition numbers CCDC 2223703 (3), 2220789 (51), 2259107 (72) and 2194938 (127). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/.

References

  1. Corey, E. J. & Cheng, X.-M. The Logic of Chemical Synthesis (Wiley, 1995).

  2. Campos, K. R. et al. The importance of synthetic chemistry in the pharmaceutical industry. Science 363, eaat0805 (2019).

    Article  CAS  PubMed  Google Scholar 

  3. Méndez-Lucio, O. & Medina-Franco, J. L. The many roles of molecular complexity in drug discovery. Drug Discov. Today 22, 120–126 (2017).

    Article  PubMed  Google Scholar 

  4. Jurczyk, J. et al. Single-atom logic for heterocycle editing. Nat. Synth. 1, 352–364 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  5. 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 

  6. Joynson, B. W. & Ball, L. T. Skeletal editing: interconversion of arenes and heteroarenes. Helv. Chim. Acta 106, e202200182 (2023).

    Article  CAS  Google Scholar 

  7. Wang, H. J. et al. Dearomative ring expansion of thiophenes by bicyclobutane insertion. Science 381, 75–81 (2023).

    Article  CAS  PubMed  Google Scholar 

  8. Díaz-Requejo, M. M. & Peréz, P. J. Coinage metal catalyzed C–H bond functionalization of hydrocarbons. Chem. Rev. 108, 3379–3394 (2008).

    Article  PubMed  Google Scholar 

  9. Davies, H. M. L. & Liao, K. Dirhodium tetracarboxylates as catalysts for selective intermolecular C–H functionalization. Nat. Rev. Chem. 3, 347–360 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. 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 

  11. Liao, K., Negretti, S., Musaev, D. G., Bacsa, J. & Davies, H. M. L. Site-selective and stereoselective functionalization of unactivated C–H bonds. Nature 533, 230–234 (2016).

    Article  CAS  PubMed  Google Scholar 

  12. Liao, K. et al. Site-selective and stereoselective functionalization of non-activated tertiary C–H bonds. Nature 551, 609–613 (2017).

    Article  CAS  PubMed  Google Scholar 

  13. Caballero, A. et al. Silver-catalyzed C−C bond formation between methane and ethyl diazoacetate in supercritical CO2. Science 332, 835–838 (2011).

    Article  CAS  PubMed  Google Scholar 

  14. Fan, Z. et al. Molecular editing of aza-arene C–H bonds by distance, geometry and chirality. Nature 610, 87–93 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Lyu, H., Kevlishvili, I., Yu, X., Liu, P. & Dong, G. Boron insertion into alkyl ether bonds via zinc/nickel tandem catalysis. Science 372, 175–182 (2021).

    Article  CAS  PubMed  Google Scholar 

  16. Hyland, E. E., Kelly, P. Q., McKillop, A. M., Dherange, B. D. & Levin, M. D. Unified access to pyrimidines and quinazolines enabled by N–N cleaving carbon atom insertion. J. Am. Chem. Soc. 144, 19258–19264 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Liu, S. & Cheng, X. Insertion of ammonia into alkenes to build aromatic N-heterocycles. Nat. Commun. 13, 425 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Woo, J. et al. Scaffold hopping by net photochemical carbon deletion of azaarenes. Science 376, 527–532 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. 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 

  21. Cao, Z.-C. & Shi, Z.-J. Deoxygenation of ethers to form carbon–carbon bonds via nickel catalysis. J. Am. Chem. Soc. 139, 6546–6549 (2017).

    Article  CAS  PubMed  Google Scholar 

  22. Bartholomew, G. L., Carpaneto, F. & Sarpong, R. Skeletal editing of pyrimidines to pyrazoles by formal carbon deletion. J. Am. Chem. Soc. 144, 22309–22315 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Patel, S. C. & Burns, N. Z. Conversion of aryl azides to aminopyridines. J. Am. Chem. Soc. 144, 17797–17802 (2022).

    Article  CAS  PubMed  Google Scholar 

  24. Sattler, A. & Parkin, G. Cleaving carbon–carbon bonds by inserting tungsten into unstrained aromatic rings. Nature 463, 523–526 (2010).

    Article  CAS  PubMed  Google Scholar 

  25. Liu, X.-Y. & Qin, Y. Indole alkaloid synthesis facilitated by photoredox catalytic radical cascade reactions. Acc. Chem. Res. 52, 1877–1891 (2019).

    Article  CAS  PubMed  Google Scholar 

  26. Wen, J. & Shi, Z. From C4 to C7: innovative strategies for site-selective functionalization of indole C–H bonds. Acc. Chem. Res. 54, 1723–1736 (2021).

    Article  CAS  PubMed  Google Scholar 

  27. Prabagar, B., Yang, Y. & Shi, Z. Site-selective C–H functionalization to access the arene backbone of indoles and quinolines. Chem. Soc. Rev. 50, 11249–11269 (2021).

    Article  CAS  PubMed  Google Scholar 

  28. Zhang, Y.-C., Jiang, F. & Shi, F. Organocatalytic asymmetric synthesis of indole-based chiral heterocycles: strategies, reactions, and outreach. Acc. Chem. Res. 53, 425–446 (2020).

    Article  CAS  PubMed  Google Scholar 

  29. Zhu, M., Zhang, X., Zheng, C. & You, S.-L. Energy-transfer-enabled dearomative cycloaddition reactions of indoles/pyrroles via excited-state aromatics. Acc. Chem. Res. 55, 2510–2525 (2022).

    Article  CAS  PubMed  Google Scholar 

  30. Xu, H. et al. Highly enantioselective copper- and iron-catalyzed intramolecular cyclopropanation of indoles. J. Am. Chem. Soc. 139, 7697–7700 (2017).

    Article  CAS  PubMed  Google Scholar 

  31. Toutov, A. A. et al. Silylation of C–H bonds in aromatic heterocycles by an earth-abundant metal catalyst. Nature 518, 80–84 (2015).

    Article  CAS  PubMed  Google Scholar 

  32. Lv, J. et al. Metal-free directed sp2-C–H borylation. Nature 575, 336–340 (2019).

    Article  CAS  PubMed  Google Scholar 

  33. Légaré, M.-A., Courtemanche, M.-A., Rochette, É. & Fontaine, F.-G. Metal-free catalytic C–H bond activation and borylation of heteroarenes. Science 349, 513–516 (2015).

    Article  PubMed  Google Scholar 

  34. Liang, Y., Zhang, X. & MacMillan, D. W. C. Decarboxylative sp3 C–N coupling via dual copper and photoredox catalysis. Nature 559, 83–88 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Jiang, R., Ding, L., Zheng, C. & You, S.-L. Iridium-catalyzed Z-retentive asymmetric allylic substitution reactions. Science 371, 380–386 (2021).

    Article  CAS  PubMed  Google Scholar 

  36. Choi, I., Messinis, A. M. & Ackermann, L. C7-Indole amidations and alkenylations by ruthenium(II) catalysis. Angew. Chem. Int. Ed. 59, 12534–12540 (2020).

    Article  CAS  Google Scholar 

  37. Qi, L.-W., Mao, J.-H., Zhang, J. & Tan, B. Organocatalytic asymmetric arylation of indoles enabled by azo groups. Nat. Chem. 10, 58–64 (2018).

    Article  CAS  PubMed  Google Scholar 

  38. Dherange, B. D., Kelly, P. Q., Liles, J. P., Sigman, M. S. & Levin, M. D. Carbon atom insertion into pyrroles and indoles promoted by chlorodiazirines. J. Am. Chem. Soc. 143, 11337–11344 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Reisenbauer, J. C., Green, O., Franchino, A., Finkelstein, P. & Morandi, B. Late-stage diversification of indole skeletons through nitrogen atom insertion. Science 377, 1104–1109 (2022).

    Article  CAS  PubMed  Google Scholar 

  40. Müller, K., Faeh, C. & Diederich, F. Fluorine in pharmaceuticals: looking beyond intuition. Science 317, 1881–1886 (2007).

    Article  PubMed  Google Scholar 

  41. Zhou, Y. et al. Next generation of fluorine-containing pharmaceuticals, compounds currently in phase II–III clinical trials of major pharmaceutical companies: new structural trends and therapeutic areas. Chem. Rev. 116, 422–518 (2016).

    Article  CAS  PubMed  Google Scholar 

  42. Wang, J. et al. Fluorine in pharmaceutical industry: fluorine-containing drugs introduced to the market in the last decade (2001–2011). Chem. Rev. 114, 2432–2506 (2014).

    Article  CAS  PubMed  Google Scholar 

  43. Yu, Y.-J. et al. Sequential C–F bond functionalizations of trifluoroacetamides and acetates via spin-center shifts. Science 371, 1232–1240 (2021).

    Article  CAS  PubMed  Google Scholar 

  44. Tomashenko, O. A. & Grushin, V. V. Aromatic trifluoromethylation with metal complexes. Chem. Rev. 111, 4475–4521 (2011).

    Article  CAS  PubMed  Google Scholar 

  45. Furuya, T., Kamlet, A. S. & Ritter, T. Catalysis for fluorination and trifluoromethylation. Nature 473, 470–477 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Zhang, X. et al. Phosphorus-mediated sp2sp3 couplings for C–H fluoroalkylation of azines. Nature 594, 217–222 (2021).

    Article  CAS  PubMed  Google Scholar 

  47. Fu, X.-P. et al. Controllable catalytic difluorocarbene transfer enables access to diversified fluoroalkylated arenes. Nat. Chem. 11, 948–956 (2019).

    Article  CAS  PubMed  Google Scholar 

  48. Feng, Z., Min, Q.-Q., Fu, X.-P., An, L. & Zhang, X. Chlorodifluoromethane-triggered formation of difluoromethylated arenes catalysed by palladium. Nat. Chem. 9, 918–923 (2017).

    Article  CAS  PubMed  Google Scholar 

  49. Mykhailiuk, P. K. 2,2,2-Trifluorodiazoethane (CF3CHN2): a long journey since 1943. Chem. Rev. 120, 12718–12755 (2020).

    Article  CAS  PubMed  Google Scholar 

  50. Liu, Z., Sivaguru, P., Zanoni, G. & Bi, X. N-Triftosylhydrazones: a new chapter for diazo-based carbene chemistry. Acc. Chem. Res. 55, 1763–1781 (2022).

    Article  CAS  PubMed  Google Scholar 

  51. Sivaguru, P. & Bi, X. Fluoroalkyl N-sulfonyl hydrazones: an efficient reagent for the synthesis of fluoroalkylated compounds. Sci. China Chem. 64, 1614–1629 (2021).

    Article  CAS  Google Scholar 

  52. Arredondo, V., Hiew, S. C., Gutman, E. S., Premachandra, I. D. U. A. & Vranken, D. L. V. Enantioselective palladium-catalyzed carbene insertion into the N–H bonds of aromatic heterocycles. Angew. Chem. Int. Ed. 56, 4156–4159 (2017).

    Article  CAS  Google Scholar 

  53. Delgado-Rebollo, M., Prieto, A. & Pérez, P. J. Catalytic functionalization of indoles by copper-mediated carbene transfer. ChemCatChem 6, 2047–2052 (2014).

    Article  CAS  Google Scholar 

  54. Yang, Z., Möller, M. & Koenigs, R. M. Synthesis of gem-difluoro olefins through C–H functionalization and β-fluoride elimination reactions. Angew. Chem. Int. Ed. 59, 5572–5576 (2020).

    Article  CAS  Google Scholar 

  55. Dohm, S., Hansen, A., Steinmetz, M., Grimme, S. & Checinski, M. P. Comprehensive thermochemical benchmark set of realistic closed-shell metal organic reactions. J. Chem. Theory Comput. 14, 2596–2608 (2018).

    Article  CAS  PubMed  Google Scholar 

  56. Minenkov, Y., Chermak, E. & Cavallo, L. Accuracy of DLPNO–CCSD(T) method for noncovalent bond dissociation enthalpies from coinage metal cation complexes. J. Chem. Theory Comput. 11, 4664–4676 (2015).

    Article  CAS  PubMed  Google Scholar 

  57. Yang, W. & Parr, R. G. Hardness, softness, and the Fukui function in the electronic theory of metals and catalysis. Proc. Natl Acad. Sci. USA 82, 6723–6726 (1985).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Lu, T. & Chen, F. Multiwfn: a multifunctional wavefunction analyzer. J. Comput. Chem. 33, 580–592 (2012).

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

This work was financially supported by the National Natural Science Foundation of China (grant nos. 22331004, 21871043 and 21961130376 to X.B., and grant no. 22371035 to Z.L.) and the Department of Science and Technology of Jilin Province (grant no. 20230508054RC to Z.L.). We thank W. Guan of Northeast Normal University for assistance with the computational studies.

Author information

Authors and Affiliations

Authors

Contributions

S.L. and Y.Y. conducted and analysed the experiments described in this paper. Y.L. and Z.W. helped with substrate synthesis and data collection. Q.S. carried out the DFT calculations. Z.L. and X.B. conceived the concept, supervised the experiments and prepared the paper with P.S. All authors discussed the results and commented on the manuscript.

Corresponding authors

Correspondence to Zhaohong Liu or Xihe Bi.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Chemistry thanks Yu-hong Lam 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

Materials and Methods, Supplementary Figs. 1–586, Tables 1–4 and spectral data for all new compounds.

Supplementary Data 1

Crystallographic data for compound 3; CCDC reference 2223703.

Supplementary Data 2

Crystallographic data for compound 51; CCDC reference 2220789.

Supplementary Data 3

Crystallographic data for compound 72; CCDC reference 2259107.

Supplementary Data 4

Crystallographic data for compound 127; CCDC reference 2194938.

Supplementary Data 5

Computational data for DFT calculations.

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

Liu, S., Yang, Y., Song, Q. et al. Tunable molecular editing of indoles with fluoroalkyl carbenes. Nat. Chem. 16, 988–997 (2024). https://doi.org/10.1038/s41557-024-01468-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41557-024-01468-2

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