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:

Base-promoted azaarene and polyazaarene synthesis through C–C bond cleavage and alkyl transfer

Nature Synthesis volume 4, pages 1288–1296 (2025)Cite this article

Subjects

Abstract

Multisubstituted azaarenes and conjugated polyazaarenes are important heterocycles in chemistry and materials science. Here we report the discovery of a carbon–carbon bond cleavage and alkyl transfer approach for the synthesis of azaarenes or conjugated polyazaarenes, which is promoted by potassium tert-butoxide. Neither precious-metal catalysts nor directing groups are required. This strategy is enabled by an alkyl transfer, releasing aryl methanes, such as toluene, as the only by-product. This general and versatile method enables the divergent synthesis of a variety of highly functionalized azaarenes and polyazaarenes. In addition, several azaarenes were found to have visible-light photocatalytic reactivities.

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

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

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

Fig. 1: Azaarene synthesis.
Fig. 2: C–C bond-cleaving, alkyl-transferring synthesis of pyrimidine 4.
Fig. 3: Polyazaarene synthesis.
Fig. 4: Synthesis of dibenzoquinazolines and pyrrolopyrimidines.
Fig. 5: Synthesis of quinolines and PAHs.
Fig. 6: Proposed mechanisms and control experiments.
Fig. 7: Applications in catalysis.

Similar content being viewed by others

Data availability

All data are available in the main text or the Supplementary Information. The crystallographic data for the small molecules have been submitted to the Cambridge Structural Database (https://www.ccdc.cam.ac.uk): 5a (CCDC 2015538), 6a (CCDC 2015536), 8g (CCDC 2016533), 8o (CCDC 2016534), 10o (CCDC 2069031).

References

  1. Maxwell, K. L. Cyclic pyrimidines jump on the anti-phage bandwagon. Cell 184, 5691–5693 (2021).

    Article  CAS  PubMed  Google Scholar 

  2. Becker, S. et al. Unified prebiotically plausible synthesis of pyrimidine and purine RNA ribonucleotides. Science 366, 76–82 (2019).

    Article  CAS  PubMed  Google Scholar 

  3. Hud, N. V. & Fialho, D. M. RNA nucleosides built in one prebiotic pot. Science 366, 32–33 (2019).

    Article  CAS  PubMed  Google Scholar 

  4. Matsumoto, S. et al. DNA damage detection in nucleosomes involves DNA register shifting. Nature 571, 79–84 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Parker, W. B. Enzymology of purine and pyrimidine antimetabolites used in the treatment of cancer. Chem. Rev. 109, 2880–2893 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Hussain, H., Al-Harrasi, A., Al-Rawahi, A., Green, I. R. & Gibbons, S. Fruitful decade for antileishmanial compounds from 2002 to late 2011. Chem. Rev. 114, 10369–10428 (2014).

    Article  CAS  PubMed  Google Scholar 

  7. Wang, M. et al. Revealing the cooperative relationship between spin, energy, and polarization parameters toward developing high-efficiency exciplex light-emitting diodes. Adv. Mater. 31, 1904114 (2019).

    Article  CAS  Google Scholar 

  8. Yang, L. et al. High-performance red quantum-dot light-emitting diodes based on organic electron transporting layer. Adv. Funct. Mater. 31, 2007686 (2021).

    Article  CAS  Google Scholar 

  9. Chen, D., Su, S. J. & Cao, Y. Nitrogen heterocycle-containing materials for highly efficient phosphorescent OLEDs with low operating voltage. J. Mater. Chem. C 2, 9565–9578 (2014).

    Article  CAS  Google Scholar 

  10. Wang, S. F. et al. Highly efficient near-infrared electroluminescence up to 800 nm using platinum(II) phosphors. Adv. Funct. Mater. 30, 2002173 (2020).

    Article  CAS  Google Scholar 

  11. Lipunova, G. N., Nosova, E. V., Charushin, V. N. & Chupakhin, O. N. Functionalized quinazolines and pyrimidines for optoelectronic materials. Curr. Org. Synth. 15, 793–814 (2018).

    Article  CAS  Google Scholar 

  12. Fresta, E. et al. Novel red-emitting copper(I) complexes with pyrazine and pyrimidinyl ancillary ligands for white light-emitting electrochemical cells. Adv. Opt. Mater. 10, 2101999 (2022).

    Article  CAS  Google Scholar 

  13. Bailey, P. S. The reactions of ozone with organic compounds. Chem. Rev. 58, 925–1010 (1958).

    Article  CAS  Google Scholar 

  14. Liu, J. et al. A metal-free synthesis of pyrimidines from amidines with α,β-unsaturated ketones via tandem [3 + 3] annulation and visible-light-enabled photo-oxidation. Org. Biomol. Chem. 21, 3411–3416 (2023).

    Article  CAS  PubMed  Google Scholar 

  15. Shi, S. H., Liang, Y. & Jiao, N. Electrochemical oxidation induced selective C–C bond cleavage. Chem. Rev. 121, 485–505 (2021).

    Article  CAS  PubMed  Google Scholar 

  16. Chen, F., Wang, T. & Jiao, N. Recent advances in transition-metal-catalyzed functionalization of unstrained carbon–carbon bonds. Chem. Rev. 114, 8613–8661 (2014).

    Article  CAS  PubMed  Google Scholar 

  17. Chan, A. P. Y. & Sergeev, A. G. Metal-mediated cleavage of unsaturated C–C bonds. Coord. Chem. Rev. 413, 213213 (2020).

    Article  CAS  Google Scholar 

  18. Gozin, M. et al. Activation of a carbon–carbon bond in solution by transition-metal insertion. Nature 364, 699–701 (1993).

    Article  CAS  Google Scholar 

  19. Gozin, M. et al. Transfer of methylene groups promoted by metal complexation. Nature 370, 42–44 (1994).

    Article  CAS  Google Scholar 

  20. Smaligo, A. J. et al. Hydrodealkenylative C(sp3)–C(sp2) bond fragmentation. Science 364, 681–685 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Dai, P. F., Wang, H., Cui, X. C., Qu, J. P. & Kang, Y. B. Recent progress in C(aryl)–C(alkyl) bond cleavage of alkylarenes. Org. Chem. Front. 7, 896–904 (2020).

    Article  CAS  Google Scholar 

  22. Dai, P. F. et al. Cleavage of C(aryl)–CH3 bonds in the absence of directing groups under transition metal free conditions. Angew. Chem. Int. Ed. 58, 5392–5395 (2019).

    Article  CAS  Google Scholar 

  23. Shan, X. H. et al. Copper-catalyzed oxidative benzylic C–H cyclization via iminyl radical from intermolecular anion-radical redox relay. Nat. Commun. 10, 908 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  24. Li, Y. W. et al. tBuOK-promoted cyclization of imines with aryl halides. Org. Lett. 22, 4553–4556 (2020).

    Article  CAS  PubMed  Google Scholar 

  25. Shan, X. H., Wang, M. M., Tie, L., Qu, J. P. & Kang, Y. B. CuSO4‑catalyzed tandem C(sp3)–H insertion cyclization of toluenes with isonitriles to form indoles. Org. Lett. 22, 357–360 (2020).

    Article  CAS  PubMed  Google Scholar 

  26. Shan, X. H., Yang, B., Qu, J. P. & Kang, Y. B. CuSO4-catalyzed dual annulation to synthesize O, S or N-containing tetracyclic heteroacenes. Chem. Commun. 56, 4063–4066 (2020).

    Article  CAS  Google Scholar 

  27. Zheng, H. X., Shan, X. H., Qu, J. P. & Kang, Y. B. Strategy for overcoming full reversibility of intermolecular radical addition to aldehydes: tandem C–H and C–O bonds cleaving cyclization of (phenoxymethyl)arenes with carbonyls to benzofurans. Org. Lett. 20, 3310–3313 (2018).

    Article  CAS  PubMed  Google Scholar 

  28. Zheng, H. X. et al. Transition-metal-free self-hydrogen-transferring allylic isomerization. Org. Lett. 17, 6102–6105 (2015).

    Article  CAS  PubMed  Google Scholar 

  29. Li, Q. Q., Xiao, Z. F., Yao, C. Z., Zheng, H. X. & Kang, Y. B. Direct alkylation of amines with alcohols catalyzed by base. Org. Lett. 17, 5328–5331 (2015).

    Article  CAS  PubMed  Google Scholar 

  30. Yao, C. Z., Li, Q. Q., Wang, M. M., Ning, X. S. & Kang, Y. B. (E)-Specific direct Julia-olefination of aryl alcohols without extra reducing agents promoted by bases. Chem. Commun. 51, 7729–7732 (2015).

    Article  CAS  Google Scholar 

  31. Bao, W., Kossen, H. & Schneider, U. Formal allylic C(sp3)–H bond activation of alkenes triggered by a sodium amide. J. Am. Chem. Soc. 139, 4362–4365 (2017).

    Article  CAS  PubMed  Google Scholar 

  32. Toutov, 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 

  33. Müllen, K. & Scherf, U. Conjugated polymers: where we come from, where we stand, and where we might go. Macromol. Chem. Phys. 224, 2200337 (2023).

    Article  Google Scholar 

  34. Allard, S., Forster, M., Souharce, B., Thiem, H. & Scherf, U. Organic semiconductors for solution-processable field-effect transistors (OFETs). Angew. Chem. Int. Ed. 47, 4070–4098 (2008).

    Article  CAS  Google Scholar 

  35. Wang, C., Dong, H., Hu, W., Liu, Y. & Zhu, D. Semiconducting π-conjugated systems in field-effect transistors: a material odyssey of organic electronics. Chem. Rev. 112, 2208–2267 (2012).

    Article  CAS  PubMed  Google Scholar 

  36. Panwar, N. et al. Nanocarbons for biology and medicine: sensing, imaging, and drug delivery. Chem. Rev. 119, 9559–9656 (2019).

    Article  CAS  PubMed  Google Scholar 

  37. Tielens, A. G. G. M. Interstellar polycyclic aromatic hydrocarbon molecules. Annu. Rev. Astron. Astrophys. 46, 289–337 (2008).

    Article  CAS  Google Scholar 

  38. Chen, X. Y. et al. KOt-Bu/DMF promoted intramolecular cyclization of 1,1′-biphenyl aldehydes and ketones: an efficient synthesis of phenanthrenes. RSC Adv. 5, 48046–48049 (2015).

    Article  CAS  Google Scholar 

  39. Luan, Z. H., Qu, J. P. & Kang, Y. B. Discovery of oxygen α-nucleophilic addition to α,β-unsaturated amides catalyzed by redox-neutral organic photoreductant. J. Am. Chem. Soc. 142, 20942–20947 (2020).

    Article  CAS  PubMed  Google Scholar 

  40. Ito, S., Fujimoto, H. & Tobisu, M. Non-stabilized vinyl anion equivalents from styrenes by N-heterocyclic carbene catalysis and its use in catalytic nucleophilic aromatic substitution. J. Am. Chem. Soc. 144, 6714–6718 (2022).

    Article  CAS  PubMed  Google Scholar 

  41. Shan, X. H., Yang, B., Zheng, H. X., Qu, J. P. & Kang, Y. B. Phenanthroline‑tBuOK promoted intramolecular C–H arylation of indoles with ArI under transition-metal-free conditions. Org. Lett. 20, 7898–7901 (2018).

    Article  CAS  PubMed  Google Scholar 

  42. Bhuniaa, S. & Dasb, D. Carbon-based nucleophiles as leaving groups in organic synthesis via cleavage of C–C sigma bonds. Tetrahedron 112, 132738 (2022).

    Article  Google Scholar 

  43. Fabry, D. C., Ronge, M. A. & Rueping, M. Immobilization and continuous recycling of photoredox catalysts in ionic liquids for applications in batch reactions and flow systems: catalytic alkene isomerization by using visible light. Chem. Eur. J. 21, 5350–5354 (2015).

    Article  CAS  PubMed  Google Scholar 

  44. Metternich, J. B. & Gilmour, A. R. Bio-inspired, catalytic E → Z isomerization of activated olefins. J. Am. Chem. Soc. 137, 11254–11257 (2015).

    Article  CAS  PubMed  Google Scholar 

  45. Tlahuext-Aca, A., Garza-Sanchez, R. A. & Glorius, F. Multicomponent oxyalkylation of styrenes enabled by hydrogen-bond-assisted photoinduced electron transfer. Angew. Chem. Int. Ed. 56, 3708–3711 (2017).

    Article  CAS  Google Scholar 

  46. Jiang, M., Yang, H. J. & Fu, H. Visible-light photoredox borylation of aryl halides and subsequent aerobic oxidative hydroxylation. Org. Lett. 18, 5248–5251 (2016).

    Article  CAS  PubMed  Google Scholar 

  47. Wang, S. D., Yang, B., Zhang, H., Qu, J. P. & Kang, Y. B. Reductive cleavage of C–X or N–S bonds catalyzed by super organoreductant CBZ6. Org. Lett. 25, 816–820 (2023).

    Article  CAS  PubMed  Google Scholar 

  48. Wang, H., Qu, J. P. & Kang, Y. B. CBZ6 as a recyclable organic photoreductant for pinacol coupling. Org. Lett. 23, 2900–2903 (2021).

    Article  CAS  PubMed  Google Scholar 

  49. Okamoto, S., Kojiyama, K., Tsujioka, H. & Sudo, A. Metal-free reductive coupling of C=O and C=N bonds driven by visible light: use of perylene as a simple photoredox catalyst. Chem. Commun. 52, 11339–11342 (2016).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank the National Key R&D Program of China (2021YFA1500100, Y.-B.K.) and the National Natural Science Foundation of China (22271268, Y.-B.K.) for financial support. We thank S. Zhou for helping with X-ray molecular structure analysis.

Author information

Author notes

  1. These authors contributed equally: Yong-Ze Chen, Xiang-Huan Shan.

Authors and Affiliations

  1. Hefei National Research Center for Physical Sciences at the Microscale, Department of Chemistry, University of Science and Technology of China, Hefei, China

    Yong-Ze Chen, Xiang-Huan Shan, Bo Yang, Lin Tie, Yu Liu, Jia-Le Fu & Yan-Biao Kang

  2. School of Chemistry and Molecular Engineering, Nanjing Tech University, Nanjing, China

    Jian-Ping Qu

Authors
  1. Yong-Ze Chen
    View author publications

    Search author on:PubMed Google Scholar

  2. Xiang-Huan Shan
    View author publications

    Search author on:PubMed Google Scholar

  3. Bo Yang
    View author publications

    Search author on:PubMed Google Scholar

  4. Lin Tie
    View author publications

    Search author on:PubMed Google Scholar

  5. Yu Liu
    View author publications

    Search author on:PubMed Google Scholar

  6. Jia-Le Fu
    View author publications

    Search author on:PubMed Google Scholar

  7. Jian-Ping Qu
    View author publications

    Search author on:PubMed Google Scholar

  8. Yan-Biao Kang
    View author publications

    Search author on:PubMed Google Scholar

Contributions

Y.-Z.C. and X.-H.S. performed the experiments for compounds 1–9 and PM and analysed the data, unless otherwise stated. B.Y. tested the applications of 6a, 6f, 6i and 7 in photocatalysis. L.T. performed experiments for the synthesis of 1C and 10 and analysed the data. Y.L. performed the characterization of 6a, 6f, 6i, 7 and 8a. J.-L.F. synthesized substrates 1a, 1b, 1l, 2m and 2n. Y.-B.K. and J.-P.Q. conceived the research, designed the experiments, supervised experiments and analyses, interpreted the data, generated figures and wrote the manuscript.

Corresponding author

Correspondence to Yan-Biao Kang.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Synthesis thanks the anonymous reviewers for their contribution to the peer review of this work. Primary Handling Editor: Peter Seavill, 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

Supplementary Information

Experimental details, Supplementary sections 1–20, Figs. 1–51 and Tables 1 and 2.

Supplementary Data 1

Supplementary NMR spectra.

Supplementary Data 2

X-ray crystallographic data for 5a, CCDC 2015538.

Supplementary Data 3

Structure factors for 5a, CCDC 2015538.

Supplementary Data 4

X-ray crystallographic data for 6a, CCDC 2015536.

Supplementary Data 5

Structure factors for 6a, CCDC 2015536.

Supplementary Data 6

X-ray crystallographic data for 8g, CCDC 2016533.

Supplementary Data 7

Structure factors for 8g, CCDC 2016533.

Supplementary Data 8

X-ray crystallographic data for 8o, CCDC 2016534.

Supplementary Data 9

Structure factors for 8o, CCDC 2016534.

Supplementary Data 10

X-ray crystallographic data for 10o, CCDC 2069031.

Supplementary Data 11

Structure factors for 10o, CCDC 2069031.

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

Chen, YZ., Shan, XH., Yang, B. et al. Base-promoted azaarene and polyazaarene synthesis through C–C bond cleavage and alkyl transfer. Nat. Synth 4, 1288–1296 (2025). https://doi.org/10.1038/s44160-025-00833-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Version of record:

  • Issue date:

  • DOI: https://doi.org/10.1038/s44160-025-00833-4

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