Synthesis of pyrroles from isoxazoles by an O-to-C skeletal edit

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References

  1. Pandhurnekar, C. P., Pandhurnekar, H. C., Mungole, A. J., Butoliya, S. S. & Yadao, B. G. A review of recent synthetic strategies and biological activities of isoxazole. J. Heterocycl. Chem. 60, 537–565 (2023).

    Article  CAS  Google Scholar 

  2. Ganesh, B. H. et al. Pyrrole: a decisive scaffold for the development of therapeutic agents and structure–activity relationship. ChemMedChem. 19, e202300447 (2024).

    Article  CAS  PubMed  Google Scholar 

  3. Martis, G. J. & Gaonkar, S. L. Advances in isoxazole chemistry and their role in drug discovery. RSC Adv. 15, 8213–8243 (2025).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  4. Joule, J. A. & Mills, K. Heterocyclic Chemistry 5th edn (Wiley-Blackwell, 2010).

  5. Puriņš, M., Elgindy, C. & Levin, M. D. Shape-conserving atom replacements. Chem. Rev. https://doi.org/10.1021/acs.chemrev.5c01009 (2026).

    Article  PubMed  PubMed Central  Google Scholar 

  6. Cheng, G., Lv, W. & Xue, L. Base-promoted ring-closing carbonyl–allene metathesis for the synthesis of 2,4-disubstituted pyrroles. Green Chem. 20, 4414–4417 (2018).

    Article  CAS  Google Scholar 

  7. Newman-Stonebraker, S. H. et al. Univariate classification of phosphine ligation state and reactivity in cross-coupling catalysis. Science 374, 301–308 (2021).

    Article  ADS  CAS  PubMed  Google Scholar 

  8. Pearson, T. J. et al. Aromatic nitrogen scanning by ipso-selective nitrene internalization. Science 381, 1474–1479 (2023).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  9. Puriņš, M., Nakahara, H. & Levin, M. D. Bridging the pyridine-pyridazine synthesis gap by skeletal editing. Science 389, 295–298 (2025).

    Article  ADS  PubMed  Google Scholar 

  10. Wang, Z., Xu, P., Guo, S.-M., Daniliuc, C. G. & Studer, A. C-to-N atom swapping and skeletal editing in indoles and benzofurans. Nature 642, 92–98 (2025).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  11. Choi, W., Jang, A. & Hong, S. Pyridine-to-pyridazine skeletal editing. J. Am. Chem. Soc. 147, 42042–42050 (2025).

    Article  ADS  CAS  PubMed  Google Scholar 

  12. Paschke, A.-S. K., Schiele, S., Pinard, C., Sandrini, F. & Morandi, B. Chemodivergent C-to-N atom swap from benzofurans to benzisoxazoles and benzoxazoles. Chem. Sci. 16, 11464–11467 (2025).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Conboy, A. & Greaney, M. F. Synthesis of benzenes from pyridines via N to C switch. Chem. 10, 1940–1949 (2024).

    Article  CAS  Google Scholar 

  14. Falcone, N. A., He, S., Hoskin, J. F., Mangat, S. & Sorensen, E. J. N-Oxide-to-carbon transmutations of azaarene N-oxides. Org. Lett. 26, 4280–4285 (2024).

    Article  CAS  PubMed  Google Scholar 

  15. Kim, D. et al. Photocatalytic furan-to-pyrrole conversion. Science 386, 99–105 (2024).

    Article  ADS  CAS  PubMed  Google Scholar 

  16. Akram, T., Niu, C., Qiu, W.-J. & Wang, G.-W. An O-to-N swapping reaction via triflic anhydride-mediated lactamization of 3,3-diarylbenzofuranones with nitriles. Adv. Synth. Catal. 368, e70230 (2026).

    Article  CAS  Google Scholar 

  17. Zhang, Y.-Q., Li, S.-H., Zhang, X. & Koh, M. J. Photocatalytic oxygen-atom transmutation of oxetanes. Nature 647, 906–912 (2025).

    Article  ADS  CAS  PubMed  Google Scholar 

  18. Bartholomew, G. L. et al. Cheminformatic analysis of core-atom transformations in pharmaceutically relevant heteroaromatics. J. Med. Chem. 68, 6027–6040 (2025).

    Article  CAS  PubMed  Google Scholar 

  19. Albright, H. et al. Carbonyl–olefin metathesis. Chem. Rev. 121, 9359–9406 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Taishev, A. E., Galenko, E. E., Novikov, M. S. & Khlebnikov, A. F. Azirine-based synthesis of alkynylpyrroles. J. Org. Chem. 91, 767–779 (2026).

    Article  CAS  PubMed  Google Scholar 

  21. Malcor, J.-D. et al. Synthesis and reactivity of pyrrolo[3,2-d][1,3]oxazine-2,4-dione. Access to new pyrrolo[3,2-e][1,4]diazepine-2,5-diones. Tetrahedron 70, 4631–4639 (2014).

    Article  CAS  Google Scholar 

  22. Rostovskii, N. V. et al. Switchable synthesis of pyrroles and pyrazines via Rh(II)-catalyzed reaction of 1,2,3-triazoles with isoxazoles: experimental and DFT evidence for the 1,4-diazahexatriene intermediate. J. Org. Chem. 82, 256–268 (2017).

    Article  CAS  PubMed  Google Scholar 

  23. Agafonova, A. V., Funt, L. D., Novikov, M. S. & Khlebnikov, A. F. An isoxazole strategy for the synthesis of alkyl 5-amino-4-cyano-1H-pyrrole-2-carboxylates—versatile building blocks for assembling pyrrolo-fused heterocycles. Org. Biomol. Chem. 19, 1976–1984 (2021).

    Article  CAS  PubMed  Google Scholar 

  24. Lei, X., Li, L., He, Y.-P. & Tang, Y. Rhodium(II)-catalyzed formal [3 + 2] cycloaddition of N-sulfonyl-1,2,3-triazoles with isoxazoles: entry to polysubstituted 3-aminopyrroles. Org. Lett. 17, 5224–5227 (2015).

    Article  ADS  CAS  PubMed  Google Scholar 

  25. Baltazzi, E. & Krimen, L. I. Recent advances in the chemistry of pyrrole. Chem. Rev. 63, 511–556 (1963).

    Article  CAS  Google Scholar 

  26. van Leusen, A. M., Siderius, H., Hoogenboom, B. E. & van Leusen, D. A new and simple synthesis of the pyrrole ring system from michael acceptors and tosylmethylisocyanides. Tetrahedron Lett. 13, 5337–5340 (1972).

    Article  Google Scholar 

  27. Shi, T. et al. Recent advances in the syntheses of pyrroles. Green Synth. Catal. 4, 20–34 (2023).

    CAS  Google Scholar 

  28. Kanova, N., Dundar, B. A., Kelgokmen, Y. & Zora, M. One-pot synthesis of 2-acetyl-1H-pyrroles from N-propargylic β-enaminones via intermediacy of 1,4-oxazepines. J. Org. Chem. 86, 6289–6304 (2021).

    Article  CAS  PubMed  Google Scholar 

  29. Cacchi, S., Fabrizi, G. & Filisti, E. N-propargylic β-enaminones: common intermediates for the synthesis of polysubstituted pyrroles and pyridines. Org. Lett. 10, 2629–2632 (2008).

    Article  CAS  PubMed  Google Scholar 

  30. Martins, M. A. P. et al. Intramolecular cyclization of N-propargylic β-enaminones catalyzed by silver. Tetrahedron Lett. 54, 847–849 (2013).

    Article  CAS  Google Scholar 

  31. Burton, A. G., Forsythe, P. P., Johnson, C. D. & Katritzky, A. R. The kinetics and mechanism of the electrophilic substitution of heteroaromatic compounds. Part XXVII. The nitration and hydrogen exchange of 1,3,5-trimethylpyrazole, 3,5-dimethylisoxazole, and 3,5-dimethylisothiazole. J. Chem. Soc. B 6, 2365–2371 (1971).

  32. Woodward, R. B. & Olofson, R. A. The reaction of isoxazolium salts with bases. J. Am. Chem. Soc. 83, 1007–1009 (1961).

    Article  ADS  CAS  Google Scholar 

  33. Kashima, C. et al. The ring cleavage of 3,5-disubstituted isoxazolium salts with alkoxides. Heterocycles 7, 241–241 (1977).

    Article  CAS  Google Scholar 

  34. Ikeda, R. & Kuwano, R. Asymmetric hydrogenation of isoxazolium triflates with a chiral iridium catalyst. Chem. Eur. J. 22, 8610–8618 (2016).

    Article  CAS  PubMed  Google Scholar 

  35. González-Nogal, A. M. & Calle, M. Silylated azolium salts and their applications in the synthesis of azolines and β-enaminoketones bearing allyl-, vinyl-, and acylsilane or α-silylketone units. Tetrahedron 65, 5472–5483 (2009).

    Article  Google Scholar 

  36. Albertola, A., Antolín, L. F., González, A., Laguna, M. A. & Pulido, F. J. Reaction of isoxazoles and isoxazolium salts with organometallic reagents. Synthesis of dihydroisoxazoles. J. Chem. Soc. Perkin Trans. 1 17, 791–794 (1988).

  37. Nitta, M. & Kobayashi, T. Reductive ring opening of isoxazoles with Mo(CO)6 and water. J. Chem. Soc. Chem. Commun. 18, 877–878 (1982).

  38. Wenkert, E. & Han, A. Nickel-catalyzed reactions of thiazoles, isoxazoles, oxazolines and thiazolines with grignard reagents. Heterocycles 30, 929 (1990).

    Article  CAS  Google Scholar 

  39. Singh, M., Singh, S., Gupta, N., Singh, A. & Singh, M. S. Carbonyl–allene metathesis of S-allenyl-α-oxo-S,S/N,S-ketene acetals: a thermally driven intramolecular tandem [2 + 2] cycloaddition–retro-cyclization. Org. Lett. 28, 1355–1360 (2026).

    Article  CAS  PubMed  Google Scholar 

  40. Wagner, A. M. & Sanford, M. S. Palladium-catalyzed C−H arylation of 2,5-substituted pyrroles. Org. Lett. 13, 288–291 (2011).

    Article  CAS  PubMed  Google Scholar 

  41. Lanzilotti, A. E., Littell, R., Fanshawe, W. J., McKenzie, T. C. & Lovell, F. M. Stereoselective reduction of some indoles with triethylsilane-trifluoroacetic Acid. J. Org. Chem. 44, 4809–4813 (1979).

    Article  CAS  Google Scholar 

  42. Ji, P. et al. Single-site cobalt catalysts at new Zr8(μ2-O)8(μ2-OH)4 metal-organic framework nodes for highly active hydrogenation of alkenes, imines, carbonyls, and heterocycles. J. Am. Chem. Soc. 138, 12234–12242 (2016).

    Article  ADS  CAS  PubMed  Google Scholar 

  43. Doak, K. W. & Corwin, A. H. Kinetics of pyrrole substitutions. The iodination reaction. J. Am. Chem. Soc. 71, 159–163 (1949).

    Article  ADS  CAS  Google Scholar 

  44. Shirley, D. A., Gross, B. H. & Roussel, P. A. Metalation of pyrrole, 1-methylpyrrole, and 1-phenylpyrrole with n-butyllithium. J. Org. Chem. 20, 225–231 (1955).

    Article  CAS  Google Scholar 

  45. Karadeniz, E. & Zora, M. Synthesis of 1-azaspiro[4.5]deca-1,3-dienes from N-propargylic β-enaminones in basic medium. Synthesis 51, 2157–2170 (2019).

    Article  CAS  Google Scholar 

  46. Ge, B., Lv, W., Yu, J., Xiao, S. & Cheng, G. Base-promoted C–C bond cleavage for the synthesis of 2,3,4-trisubstituted pyrroles from N-propargyl β-enaminones. Org. Chem. Front. 5, 3103–3107 (2018).

    Article  CAS  Google Scholar 

  47. Yamauchi, T. et al. Transition metal-free cyclization of N-Boc-N-propargylenamines. Heterocycles 100, 719 (2020).

    Article  Google Scholar 

  48. Yadav, V. K. in Steric and Stereoelectronic Effects in Organic Chemistry (ed. Yadav, V. K.) 107–128 (Springer, 2021).

  49. Malhotra, S. K., Moakley, D. F. & Johnson, F. Steric interference in allylic and pseudo-allylic systems: A(1,2) strain between methyl group and hydrogen. Chem. Commun. 3, 448–449 (1967).

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