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:

Ring expansion of indene by photoredox-enabled functionalized carbon-atom insertion

Nature Catalysis volume 7, pages 242–251 (2024)Cite this article

Subjects

Abstract

Skeletal editing has received unprecedented attention as an emerging technology for the late-stage manipulation of molecular scaffolds. The direct achievement of functionalized carbon-atom insertion in aromatic rings is challenging. Despite ring-expanding carbon-atom insertion reactions, such as the Ciamician–Dennstedt re-arrangement, being performed for more than 140 years, only a few relevant examples of such transformations have been reported, with these limited to the installation of halogen, ester and phenyl groups. Here we describe a photoredox-enabled functionalized carbon-atom insertion reaction into indene. We disclose the utilization of a radical carbyne precursor that facilitates the insertion of carbon atoms bearing a variety of functional groups, including trifluoromethyl, ester, phosphate ester, sulfonate ester, sulfone, nitrile, amide, aryl ketone and aliphatic ketone fragments to access a library of 2-substituted naphthalenes. The application of this methodology to the skeletal editing of molecules of pharmaceutical relevance highlights its utility.

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: Skeletal editing via single-atom insertion.
Fig. 2: Development of the functionalized carbon-atom insertion reaction.
Fig. 3: Substrate scope for the functionalized carbon-atom insertion reaction.
Fig. 4: α-Iodonium diazo compounds scope for the functionalized carbon-atom insertion reaction.
Fig. 5: Synthetic applications of the functionalized carbon-atom insertion reaction.
Fig. 6: Mechanistic studies.
Fig. 7: Proposed reaction mechanism and DFT calculations.

Similar content being viewed by others

Data availability

The data that support the findings of this study are available within the main text and its Supplementary Information file. Source data are provided as Source Data file. Data are also available from the corresponding author upon request. Crystallographic information data files and xyz coordinates of the optimized structures are available as supplementary files. The X-ray crystallographic coordinates for structures reported in this study have been deposited at the Cambridge Crystallographic Data Centre under deposition no. CCDC 2262556 (3y). These data can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.

References

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

    PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Haut, F. L. et al. Synthesis of pyrroles via consecutive 6π-electrocyclization/ring-contraction of sulfilimines. J. Am. Chem. Soc. 143, 9002–9008 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Morofuji, T., Nagai, S., Watanabe, A., Inagawa, K. & Kano, N. Streptocyanine as an activation mode of amine catalysis for the conversion of pyridine rings to benzene rings. Chem. Sci. 14, 485–490 (2023).

    CAS  PubMed  Google Scholar 

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

  6. Hui, C., Wang, Z., Wang, S. & Xu, C. Molecular editing in natural product synthesis. Org. Chem. Front. 9, 1451–1457 (2022).

    CAS  Google Scholar 

  7. 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).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 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).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  11. 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).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Kelly, P. Q., Filatov, A. S. & Levin, M. D. A synthetic cycle for heteroarene synthesis by nitride insertion. Angew. Chem. Int. Ed. 61, e202213041 (2022).

  14. Finkelstein, P. et al. Nitrogen atom insertion into indenes to access isoquinolines. Chem. Sci. 14, 2954–2959 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Morofuji, T., Kinoshita, H. & Kano, N. Connecting a carbonyl and a pi-conjugated group through a p-phenylene linker by (5+1) benzene ring formation. Chem. Commun. 55, 8575–8578 (2019).

    CAS  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  17. Ciamician, G. L. & Dennstedt, M. Ueber die Einwirkung des Chloroforms auf die Kaliumverbindung Pyrrols. Ber. Dtsch. Chem. Ges. 14, 1153–1163 (1881).

    Google Scholar 

  18. Ma, D., Martin, B. S., Gallagher, K. S., Saito, T. & Dai, M. One-carbon insertion and polarity inversion enabled a pyrrole strategy to the total syntheses of pyridine-containing lycopodium alkaloids: complanadine a and lycodine. J. Am. Chem. Soc. 143, 16383–16387 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Wynberg, H. The Reimer–Tiemann reaction. Chem. Rev. 60, 169–184 (1960).

    CAS  Google Scholar 

  20. Morten, M., Hennum, M. & Bonge-Hansen, T. Synthesis of quinoline-3-carboxylates by a Rh(II)-catalyzed cyclopropanation–ring expansion reaction of indoles with halodiazoacetates. Beilstein J. Org. Chem. 11, 1944–1949 (2015).

  21. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Gabriele, B., Mancuso, R. & Veltri, L. Recent advances in the synthesis of indanes and indenes. Chem. Eur. J. 22, 5056–5094 (2016).

    CAS  PubMed  Google Scholar 

  24. Prasher, P. & Sharma, M. Medicinal chemistry of indane and its analogues: a mini review. ChemistrySelect 6, 2658–2677 (2021).

    CAS  Google Scholar 

  25. Unzner, T. A., Grossmann, A. S. & Magauer, T. Rapid access to orthogonally functionalized naphthalenes: application to the total synthesis of the anticancer agent chartarin. Angew. Chem. Int. Ed. 55, 9763–9767 (2016).

    CAS  Google Scholar 

  26. Banerjee, S. et al. Recent advances in the development of 1,8-naphthalimide based DNA targeting binders, anticancer and fluorescent cellular imaging agents. Chem. Soc. Rev. 42, 1601–1618 (2013).

    CAS  PubMed  Google Scholar 

  27. Parham, W. E. & Reiff, H. E. Ring expansion during the reaction of indenylsodium and chloroform. J. Am. Chem. Soc. 77, 1177–1178 (1955).

    CAS  Google Scholar 

  28. Parham, W. E., Reiff, H. E. & Swartzentruhe, P. The formation of naphthalenes from indenes. J. Am. Chem. Soc. 78, 1437–1440 (1956).

    CAS  Google Scholar 

  29. Weiss, R., Seubert, J. & Hampel, F. α-Aryliodonio diazo compounds: SN reactions at the α-C atom as a novel reaction type for diazo compounds. Angew. Chem. Int. Ed. 33, 1952–1953 (1994).

    Google Scholar 

  30. Wang, Z., Herraiz, A. G., Del Hoyo, A. M. & Suero, M. G. Generating carbyne equivalents with photoredox catalysis. Nature 554, 86–91 (2018).

    CAS  PubMed  Google Scholar 

  31. Wang, X. et al. Convergent synthesis of 1,4-dicarbonyl Z-alkenes through three-component coupling of alkynes, α-diazo sulfonium triflate, and water. J. Am. Chem. Soc. 144, 4952–4965 (2022).

    CAS  PubMed  Google Scholar 

  32. Ansari, M. A., Kumar, G. & Singh, M. S. Base mediated diazirination via iodine(III) reagents. Org. Lett. 24, 2815–2820 (2022).

    CAS  PubMed  Google Scholar 

  33. Jiang, L., Wang, Z., Armstrong, M. & Suero, M. G. β-Diazocarbonyl compounds: synthesis and their Rh(II)-catalyzed 1,3 C–H insertions. Angew. Chem. Int. Ed. 60, 6177–6184 (2021).

    CAS  Google Scholar 

  34. Taylor, M. T., Nelson, J. E., Suero, M. G. & Gaunt, M. J. A protein functionalization platform based on selective reactions at methionine residues. Nature 562, 563–568 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Tu, H. F., Jeandin, A. & Suero, M. G. catalytic synthesis of cyclopropenium cations with Rh-carbynoids. J. Am. Chem. Soc. 144, 16737–16743 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Wang, Z., Jiang, L., Sarro, P. & Suero, M. G. Catalytic cleavage of C(sp2)–C(sp2) bonds with Rh-carbynoids. J. Am. Chem. Soc. 141, 15509–15514 (2019).

    CAS  PubMed  Google Scholar 

  37. Palomo, E. et al. Generating Fischer-type Rh-carbenes with Rh-carbynoids. J. Am. Chem. Soc. 145, 4975–4981 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Bonge, H. T., Pintea, B. & Hansen, T. Highly efficient formation of halodiazoacetates and their use in stereoselective synthesis of halocyclopropanes. Org. Biomol. Chem. 6, 3670–3672 (2008).

    CAS  PubMed  Google Scholar 

  39. Li, X., Golz, C. & Alcarazo, M. α-Diazo sulfonium triflates: synthesis, structure, and application to the synthesis of 1-(dialkylamino)-1,2,3-triazoles. Angew. Chem. Int. Ed. 60, 6943–6948 (2021).

    CAS  Google Scholar 

  40. Schnaars, C., Hennum, M. & Bonge-Hansen, T. Nucleophilic halogenations of diazo compounds, a complementary principle for the synthesis of halodiazo compounds: experimental and theoretical studies. J. Org. Chem. 78, 7488–7497 (2013).

    CAS  PubMed  Google Scholar 

  41. Mejía, E. & Togni, A. Rhenium-catalyzed trifluoromethylation of arenes and heteroarenes by hypervalent iodine reagents. ACS Catal. 2, 521–527 (2012).

    Google Scholar 

  42. Keaveney, S. T. & Schoenebeck, F. Palladium-catalyzed decarbonylative trifluoromethylation of acid fluorides. Angew. Chem. Int. Ed. 57, 4073–4077 (2018).

    CAS  Google Scholar 

  43. Shroot, B. & Michel, S. Pharmacology and chemistry of adapalene. J. Am. Acad. Dermatol. 97, 96–103 (1997).

    Google Scholar 

  44. Prier, C. K., Rankic, D. A. & MacMillan, D. W. Visible light photoredox catalysis with transition metal complexes: applications in organic synthesis. Chem. Rev. 113, 5322–5363 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

Generous financial support by the Deutsche Forschungsgemeinschaft (Leibniz Award) and the Alexander von Humboldt Foundation (C.C.C. and J.T.) is gratefully acknowledged. O.G. gratefully acknowledges financial support from the National Institutes of Health (R35GM137797), the Camille and Henry Dreyfus Foundation and the Welch Foundation (A-2102-20220331) for supporting this work. O.G. also acknowledges the Texas A&M University HPRC resources (https://hprc.tamu.edu) for computational resources. We sincerely thank G. Tan, H. Wang, R. Kleinmans and A. Heusler for help in preparing the manuscript and many helpful discussions.

Author information

Author notes

  1. These authors contributed equally: Remy Lalisse, Poulami Mukherjee.

Authors and Affiliations

  1. Organisch-Chemisches Institut, Universität Münster, Münster, Germany

    Fu-Peng Wu, Chetan C. Chintawar, Subhabrata Dutta, Jasper Tyler, Constantin G. Daniliuc & Frank Glorius

  2. Department of Chemistry, Texas A&M University, College Station, TX, USA

    Remy Lalisse, Poulami Mukherjee & Osvaldo Gutierrez

Authors
  1. Fu-Peng Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chetan C. Chintawar
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Remy Lalisse
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Poulami Mukherjee
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Subhabrata Dutta
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jasper Tyler
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Constantin G. Daniliuc
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Osvaldo Gutierrez
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Frank Glorius
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

F.G. and F.-P.W. conceived the project. F.-P.W. performed the initial screening experiments. F.-P.W. and C.C.C. performed synthetic experiments. R.L. and P.M. conducted computations. C.G.D. analysed X-ray structures. F.-P.W. and F.G. supervised research. F.-P.W., J.T. and F.G. wrote the manuscript with contributions from all authors.

Corresponding authors

Correspondence to Osvaldo Gutierrez or Frank Glorius.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Catalysis thanks Lei Shi, Andrius Merkys 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 discussion, note, Figs. 1–265 and Tables 1–4.

Supplementary Data 1

Cartesian coordinates for all calculated structures.

Supplementary Data 2

Crystallographic data of compound 3y.

Supplementary Data 3

CheckCIF data of compound 3y.

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

Wu, FP., Chintawar, C.C., Lalisse, R. et al. Ring expansion of indene by photoredox-enabled functionalized carbon-atom insertion. Nat Catal 7, 242–251 (2024). https://doi.org/10.1038/s41929-023-01089-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41929-023-01089-x

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