Research Progress on the Functionalization of [1.1.1]Propellane via Radical Pathways

doi:10.6023/cjoc202512007

Abstract

Bicyclo[1.1.1]pentane (BCP), a three-dimensional bridged ring scaffold, has been widely used in medicinal chemistry due to its role as a bioisostere for groups such as benzene rings, tert-butyl groups, and alkynes. Currently, the radical ring-opening reaction of [1.1.1]propellane has become the most common strategy for constructing BCP derivatives. Traditional radical functionalization of [1.1.1]propellane typically requires harsh conditions and exhibits poor functional group compatibility. In recent years, with the rapid development of photocatalysis in organic synthesis, various photocatalytic functionalizations of [1.1.1]propellane have been reported and successfully applied in the synthesis of drug molecules. Herein, a concise overview of recent advances in radical-based functionalization of [1.1.1]propellane is provided.

Key words: 1.1.1]propellane, bicyclo[1.1.1]pentane, radical, photocatalysis, functionalization

Cite this article

Jianyang Dong, Dong Xue. Research Progress on the Functionalization of [1.1.1]Propellane via Radical Pathways[J]. Chinese Journal of Organic Chemistry, 2026, 46(4): 1464-1480.

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Fig. & Tab. 40

Scheme 1. Bioactive molecules featuring the BCP motif

Scheme 2. Synthesis of BCP derivatives using traditional methods

Scheme 3. Synthesis of [1.1.1]propellane

Scheme 4. Radical functionalization of [1.1.1]propellane

Scheme 5. Manganese-catalyzed hydroamination of [1.1.1]pro- pellane

Scheme 6. Iron-catalyzed carboamination of [1.1.1]propellane

Scheme 7. Functionalization of [1.1.1]propellane for C—S bond formation

Scheme 8. Synthesis and transformation of BCP halides

Scheme 9. Azidoheteroarylation of [1.1.1]propellane

Scheme 10. Diastereoselective synthesis of BCP sulfinamides

Scheme 11. Copper-catalyzed synthesis of acyl-substituted BCP derivatives

Scheme 12. Iron-catalyzed three-component coupling of [1.1.1]- propellane with alkyl halides and aryl Grignard reagents

Scheme 13. Synthesis of pentafluorosulfur-substituted BCP derivatives

Scheme 14. Photo-promoted diacetylation of [1.1.1]propellane

Scheme 15. Synthesis of BCP ketones via synergistic photoredox/nickel catalysis

Scheme 16. Synthesis of BCP ketones via photocatalytic three-component reaction of [1.1.1]propellane with alkyl carboxylic acids and aldehydes

Scheme 17. Synthesis of BCP ketones via synergistic photoredox/NHC catalysis

Scheme 18. Synthesis of BCP ketones via photocatalytic three- component reaction of [1.1.1]propellane with NHPI esters/Katri- tzky salts and aldehydes

Scheme 19. Synthesis of BCP halides under mercury lamp irradiation

Scheme 20. Photocatalytic halogenation of [1.1.1]propellane

Scheme 21. Photocatalytic synthesis of α-chiral and α-quaternary BCP derivatives

Scheme 22. Synthesis of fluoroalkyl-substituted BCPs via a photocatalytic four-component reaction of [1.1.1]propellane

Scheme 23. Photocatalytic synthesis of difluoromethylene- substituted BCP

Scheme 24. Photo-promoted benzylation of [1.1.1]propellane with alkyl hydrocarbons and aldehydes

Scheme 25. Photocatalytic synthesis of alkylamine- and heteroaryl-substituted BCP derivatives

Scheme 26. Photocatalytic three-component reaction of [1.1.1]propellane developed by the Jiang group

Scheme 27. Photo-promoted synthesis of pyridine-substituted BCP derivatives

Scheme 28. Photo-promoted synthesis of perfluoroalkyl- substituted BCP derivatives

Scheme 29. Photo-promoted synthesis of heteroaryl-substituted BCP

Scheme 30. Light-induced difunctionalization of [1.1.1]pro- pellane with heteroaryl sulfones

Scheme 31. Synthesis of alkynyl-substituted BCPs via synergistic photoredox/copper catalysis

Scheme 32. Synthesis of BCP nitriles via synergistic photoredox/Ni catalysis

Scheme 33. Photo-promoted synthesis of BCP phosphonate

Scheme 34. Photo-promoted functionalization of [1.1.1]propellane for C—P bond formation

Scheme 35. Photo-promoted borylation of [1.1.1]propellane

Scheme 36. Photo-promoted synthesis of phenylseleno-sub- stituted BCP

Scheme 37. Photo/copper-catalyzed three-component cross- coupling of [1.1.1]propellane

Scheme 38. Photocatalytic synthesis of amide-substituted BCPs

Scheme 39. Photocatalytic synthesis of BCP sulfones

Scheme 40. Electrochemically driven functionalization of [1.1.1]propellane

References 78

[1]	Taylor, R. D.; MacCoss, M.; Lawson, A. D. G. J. Med. Chem. 2014, 57, 5845.
[2]	Subbaiah, M. A. M.; Meanwell, N. A. J. Med. Chem. 2021, 64, 14046.
[3]	Ritchie, T. J.; Macdonald, S. J. F. Drug Discovery Today 2009, 14, 1011.
[4]	Lovering, F.; Bikker, J.; Humblet, C. J. Med. Chem. 2009, 52, 6752.
[5]	Mykhailiuk, P. K. Org. Biomol. Chem. 2019, 17, 2839.
[6]	He, F.-S.; Xie, S.; Yao, Y.; Wu, J. Chin. Chem. Lett. 2020, 31, 3065.
[7]	Yang, X.-C.; Wang, J.-J.; Xiao, Y.; Feng, J.-J. Angew. Chem., Int. Ed. 2025, 64, e202505803.
[8]	Xiao, Y.; Tang, L.; Yang, X.-C.; Wang, N.-Y.; Zhang, J.; Deng, W.-P.; Feng, J.-J. CCS Chem. 2025, 7, 1903
[9]	Gao, X.-Y.; Xiao, Y.; Peng, Q.; Yang, F.; Li, D.; Wang, G.; Qian, Y.; Feng, J.-J. Angew. Chem., Int. Ed. 2025, 64, e202513768.
[10]	Che, J.-T.; Zhang, H.-B.; Ding, W.-Y..; Xiang, S.-H.; Tan, B. J. Am. Chem. Soc. 2025, 147, 33879.
[11]	Liu, S.; Ning, Y.; Song, W.; Sivaguru, P.; Wang, Y.; Gan, Y.; Anderson, E. A.; Bi, X. Angew. Chem., Int. Ed. 2025, e202514232.
[12]	Pellicciari, R.; Raimondo, M.; Marinozzi, M.; Natalini, B.; Costantino, G.; Thomsen, C. J. Med. Chem. 1996, 39, 2874.
[13]	Stepan, A. F.; Subramanyam, C.; Efremov, I. V.; Dutra, J. K.; O'Sullivan, T. J.; DiRico, K. J.; McDonald, W. S.; Won, A.; Dorff, P. H.; Nolan, C. E.; Becker, S. L.; Pustilnik, L. R.; Riddell, D. R.; W. Kauffman, G. W.; Kormos, B. L.; Zhang, L.; Lu, Y.; Capetta, S. H.; Green, M. E.; Karki, K.; Sibley, E.; Atchison, K. P.; Hallgren, A. J.; Oborski, C. E.; Robshaw, A. E.; Sneed, Bl.; O'Donnell, C. J. J. Med. Chem. 2012, 55, 3414.
[14]	Nicolaou, K. C.; Vourloumis, D.; Totokotsopoulos, S.; Papageorgiou, C. D.; Karsunky, H.; Fernando, H.; Gavrilyuk, J.; Webb, D.; Stepan, A. F. ChemMedChem 2016, 11, 31.
[15]	Measom, N. D.; Down, K. D.; Hirst, D. J.; Jamieson, C.; Manas, E. S.; Patel, V. K.; Somers, D. O. ACS Med. Chem. Lett. 2017, 8, 43.
[16]	Wiberg, K. B.; Connor, D. S.; Lampman, G. M. Tetrahedron Lett. 1964, 5, 531.
[17]	Applequist, D. E.; Renken, T. L.; Wheeler, J. W. J. Org. Chem. 1982, 47, 4985.
[18]	Wiberg, K. B.; Walker, F. H. J. Am. Chem. Soc. 1982, 104, 5239.
[19]	Semmler, K.; Szeimies, G.; Belzner, J. J. Am. Chem. Soc. 1985, 107, 6410.
[20]	Gianatassio, R.; Lopchuk, J. M.; Wang, J.; Pan, C.-M.; Malins, L. R.; Prieto, L.; Brandt, T. A.; Collins, M. R.; Gallego, G. M.; Sach, N. W.; Spangler, J. E.; Zhu, H.; Zhu, J.; Baran, P. S. Science 2016, 351, 241.
[21]	Bunker, K. D.; Sach, N. W.; Huang, Q.; Raggon, J. W.; Hillier, M. C.; Mesaros, E. F.; Snyder, L. B. Org. Lett. 2011, 13, 4746.
[22]	Kanazawa, J.; Maeda, K.; Uchiyama, M. J. Am. Chem. Soc. 2017, 139, 17791.
[23]	Bär, R. M.; Kirschner, S.; Nieger, M.; Bräse, S. Chem.-Eur. J. 2018, 24, 1373.
[24]	Rout, S. K.; Marghem, G.; Lan, J.; Leyssens, T.; Riant, O. Chem. Commun. 2019, 55, 14976.
[25]	Caputo, D. F. J.; Arroniz, C.; Dürr, A. B.; Mousseau, J. J.; Stepan, A. F.; Mansfield, S. J.; Anderson, E. A. Chem. Sci. 2018, 9, 5295.
[26]	Pickford, H. D.; Nugent, J.; Owen, B.; Smith, R. C.; Anderson, E. A. J. Am. Chem. Soc. 2021, 143, 9729.
[27]	Pickford, H. D.; Ripenko, V.; McNamee, R. E.; Holovchuk, S.; Thompson, A. L.; Smith, R. C.; Mykhailiuk, P. K.; Anderson, E. A. Angew. Chem., Int. Ed. 2023, 62, e202213508.
[28]	Han, H.; Zhu, B.; Du, X.; Zhu, Y.; Yu, C.; Jiang, X. Green Chem. 2021, 23, 10132.
[29]	Shelp, R. A.; Merchant, R. R.; Hughes, J. M. E.; Walsh, P. J. Org. Lett. 2022, 24, 110.
[30]	Li, Q.; Li, L.; Xu, Q.-L.; Pan, F. Org. Lett. 2022, 24, 4292.
[31]	Rentería-Gómez, A.; Lee, W.; Yin, S.; Davis, M.; Gogoi, A., R.; Gutierrez, O. ACS Catal. 2022, 12, 11547.
[32]	Zhao, X.; Shou, J.-Y.; Qing, F.-L. Sci. China: Chem. 2023, 66, 2871.
[33]	Zhao, X.; Li, X.-Y.; Shou, J.-Y.; Qing, F.-L. Chin. J. Chem. 2025, 43, 1523.
[34]	Kaszynski, P.; Michl, J. J. Org. Chem. 1988, 53, 4593.
[35]	Huang, W.; Keess, S.; Molander, G. A. Chem. Sci. 2022, 13, 11936.
[36]	Huang, W.; Keess, S.; Molander, G. A. J. Am. Chem. Soc. 2022, 144, 12961.
[37]	Liu, Y.-Z.; Jiang, Y.; Zhang, J.-L.; Mei, Y.; Li, D.-J.; Pan, F. Org. Chem. Front. 2023, 10, 4616.
[38]	Gao, Y.; Zheng, Z.; Zhu, Y.; Li, H.; Yu, C.; Jiang, X. Green Chem. 2023, 25, 3909.
[39]	Li, F.; Dong, J. Y.; Liao, H. J.; Dang, J. Y.; Zhou, X. C.; Wang, Y. Y.; Wang, C. Y.; Jiang, Q.; Li, G.; Xue, D. Sci. China: Chem. 2024, 67, 3389.
[40]	Wang, Y. Y.; Dong, J. Y.; Li, F.; Wang, C. Y.; Zhou, X. C.; Jiang, Q.; Dang, J. Y.; Li, G.; Xue, D. Org. Chem. Front. 2024, 11, 5712.
[41]	Kaszynski, P.; McMurdie, N. D.; Michl, J. J. Org. Chem. 1991, 56, 307.
[42]	Kaszynski, P.; Friedli, A. C.; Michl, J. J. Am. Chem. Soc. 1992, 114, 601.
[43]	Ripenko, V.; Sham, V.; Levchenko, V.; Levchenko, V.; Holovchuk, S.; Vysochyn, D.; Klymov, I.; Kyslyi, D.; Veselovych, S.; Zhersh, S.; Dmytriv, Y.; Tolmachev, A.; Sadkova, I.; Pishel, I.; Horbatok, K.; Kosach, V.; Nikandrova, Y.; Mykhailiuk, P. K. Nat. Synth. 2024, 3, 1538.
[44]	Nugent, J.; Arroniz, C.; Shire, B. R.; Aissa, C.; Rys, A.; Cordes, D. B.; Slawin, A. M. Z.; Molander, G. A.; Anderson, E. A. ACS Catal. 2019, 9, 9568.
[45]	Wong, M. L. J.; Sterling, A. J.; Mousseau, J. J.; Duarte, F.; Anderson, E. A. Nat. Commun. 2021, 12, 1644.
[46]	Nugent, J.; Sterling, A. J.; Frank, N.; Mousseau, J. J.; Leach, A. G.; Anderson, E. A. Org. Lett. 2021, 23, 8628.
[47]	Srinivasu, V.; Das, D.; Chandu, P.; Ghosh, K. G.; Sureshkumar, D. Org. Lett. 2023, 25, 5308.
[48]	Chen, M.; Cui, Y.; Chen, X.; Shang, R.; Zhang, X. Nat. Commun. 2024, 15, 419.
[49]	Cuadros, S.; Goti, G.; Barison, G.; Raulli, A.; Bortolato, T.; Costa, P.; Dell’Amico, L. Angew. Chem., Int. Ed. 2023, 62, e202303585.
[50]	Li, F.; Dong, J. Y.; Wang, C. Y.; Liao, H. J.; Dang, J. Y.; Zhou, J.; Li, G.; Xue, D. Org. Lett. 2024, 26, 9276.
[51]	Dang, X.; Li, Z.; Shang, J.; Zhang, C.; Wang, C.; Xu, Z. Angew. Chem., Int. Ed. 2024, 63, e202400494.
[52]	Huang, W.; Zheng, Y.; Keess, S.; Molander, G. A. J. Am. Chem. Soc. 2023, 145, 5363.
[53]	Huang, W.; Keess, S.; Molander, G. A. Angew. Chem., Int. Ed. 2023, 62, e202302223.
[54]	Yan, B.; Xu, G.; Han, H.; Hong, J.; Xu, W.; Lan, D.; Yu, C.; Jiang, X. Green Chem. 2023, 25, 1948.
[55]	Xu, W.; Zheng, Z.; Bao, G.; Wang, Y.; Gao, Y.; Zhu, H.; Xu, G.; Zhu, Y.; Yu, C.; Jiang, X. Org. Lett. 2023, 25, 4050.
[56]	Zhu, H.; Wu, S.; Zhu, B.; Li, J.; Lan, D.; Xu, W.; Xu, G.; Zhu, Y.; Yu, C.; Jiang, X. Chem. Commun. 2023, 59, 5213.
[57]	Shin, S.; Lee, S.; Choi, W.; Kim, N.; Hong, S. Angew. Chem., Int. Ed. 2021, 60, 7873.
[58]	Zhu, J.; Guo, Y.; Zhang, Y.; Ni, Z.; Li, W.; Xu, J. Green Chem. 2023, 25, 986.
[59]	Xiao, Y. L.; Dong, J. Y.; Wang, Y. Y.; Liao, H. J.; Dang, J. Y.; Li, G.; Xue, D. Org. Lett. 2024, 26, 7026.
[60]	Jiang, Q.; Dong, J. Y.; Wang, C. Y.; Li, F.; Zhou, X. C.; Wang, Y. Y.; Liao, H. J.; Dang, J. Y.; Li, G.; Xue, D. Org. Lett. 2024, 26, 6230.
[61]	Shi, J.; Xu, Q.-L.; Ni, Y.-Q.; Li, L.; Pan, F. Org. Lett. 2022, 24, 4609.
[62]	Dong, W.; Keess, S.; Molander, G. A. Chem Catal. 2023, 3, 100608.
[63]	Dockery, K. P.; Bentrude, W. G. J. Am. Chem. Soc. 1994, 116, 10332.
[64]	Dockery, K. P.; Bentrude, W. G. J. Am. Chem. Soc. 1997, 119, 1388.
[65]	Ma, Y.; Luo, H.; Lin, L. Org. Lett. 2023, 25, 3492.
[66]	Takano, H.; Katsuyama, H.; Hayashi, H.; Harukawa, M.; Tsurui, M.; Shoji, S.; Hasegawa, Y.; Maeda, S.; Mita, T. Angew. Chem., Int. Ed. 2023, 62, e202303435.
[67]	Kondo, M.; Kanazawa, J.; Ichikawa, T.; Shimokawa, T.; Nagashima, Y.; Miyamoto, K.; Uchiyama, M. Angew. Chem., Int. Ed. 2020, 59, 1970.
[68]	Dong, W.; Yen-Pon, E.; Li, L.; Bhattacharjee, A.; Jolit, A.; Molander, G. A. Nat. Chem. 2022, 14, 1068.
[69]	Kim, S.; Oh, H.; Dong, W. Z.; Majhi, J.; Sharique, M.; Matsuo, B.; Keess, S.; Molander, G. A. ACS Catal. 2023, 13, 9542.
[70]	Wang, Y.; Dong, J.; Xiao, Y.; Wang, Z.; Wu, W.; Xue, D. Org. Chem. Front. 2025, 12, 4050.
[71]	Marinozzi, M.; Fulco, M. C.; Rizzo, R.; Screpanti, C.; Natalini, B.; Pellicciari, R. Synlett 2004, 1027.
[72]	Zhang, X.; Smith, R. T.; Le, C.; McCarver, S. J.; Shireman, B. T.; Carruthers, N. I.; MacMillan, D. W. C. Nature 2020, 580, 220.
[73]	Kim, J. H.; Ruffoni, A.; Al-Faiyz, Y. S. S.; Sheikh, N. S.; Leonori, D. Angew. Chem., Int. Ed. 2020, 59, 8225.
[74]	Zhang, H.; Wang, M.; Wu, X.; Zhu, C. Chin. J. Org. Chem. 2020, 40, 3431 (in Chinese).
	(张红, 王明扬, 吴新鑫, 朱晨, 有机化学, 2020, 40, 3431 )
[75]	Wu, Z.; Xu, Y.; Liu, J.; Zhu, C. Sci. China: Chem. 2020, 63, 1025.
[76]	Wu, Z.; Xu, Y.; Zhang, H.; Wu, X.; Zhu, C. Chem. Commun. 2021, 57, 6066.
[77]	Yan, M.; Kawamata, Y.; Baran, P. S. Chem. Rev. 2017, 117, 13230.
[78]	Liu, J.; Purushothaman, R.; Hinrichs, F.; Surke, M.; Warratz, S.; Ackermann, L. J. Am. Chem. Soc. 2025, 147, 34813.

自由基途径的[1.1.1]螺桨烷官能化研究进展