Citation: Tianzhu Qin, Weiwei Zi. Palladium-catalyzed enantioselective [2σ + 2π] cycloadditions of vinyl-carbonyl-bicyclo[1.1.0]butanes with arylidenemalononitriles[J]. Chinese Chemical Letters, ;2026, 37(1): 111072. doi: 10.1016/j.cclet.2025.111072 shu

Palladium-catalyzed enantioselective [2σ + 2π] cycloadditions of vinyl-carbonyl-bicyclo[1.1.0]butanes with arylidenemalononitriles

Tianzhu Qin ^a ,
Weiwei Zi ^{a, b, *,}

a.
State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Frontiers Science Center for New Organic Matter, Nankai University, Tianjin 300071, China
b.
Haihe Laboratory of Sustainable Chemical Transformations, Tianjin 300071, China

zi@nankai.edu.cn

Received Date: 21 February 2025
Revised Date: 7 March 2025
Accepted Date: 11 March 2025
Available Online: 13 March 2025

Figures(5)

Bicyclo[2.1.1]hexanes (BCHs) are structurally unique C(sp³)-rich bicyclic hydrocarbons that are gaining prominence in the field of medicinal chemistry as bioisosteres of benzenoids. The nitrile is an important functionality in drug development due to its ability to improve physicochemical and pharmacokinetic properties and facilitate potential noncovalent interactions with drug targets. Consequently, cyano-arene motifs are commonly found in drug development. The introduction of cyano-BCHs as potential bioisosteres of cyano-arenes shows great promise; however, there are currently no catalytic methods available for their synthesis. Herein, we report a palladium-catalyzed enantioselective [2σ + 2π] cycloadditions of bicyclo[1.1.0]butanes with arylidenemalononitriles for the preparation of chiral cyano-BCHs. This method accommodated a wide range of substrates and tolerated various functional groups. The cyano-BCH products could be transformed to molecules with diverse functionality. Control experiments suggest that the reaction proceeds via a zwitterionic intermediate generated by palladium-mediated ring opening of vinyl-carbonyl bicyclo[1.1.0]butanes followed by stereoselective 1,2-addition and intramolecular allylic substitution reactions.
- Bioisosteres,
- Bicyclo[2.1.1]hexanes,
- Bicyclo[1.1.0]butanes,
- Cycloadditions,
- Palladium catalysis
1. [1]
  P. de Sena M. Pinheiro, D.A. Rodrigues, R. do Couto Maia, et al., Curr. Top. Med. Chem. 19 (2019) 1712–1733. doi: 10.2174/1568026619666190712205025
2. [2]
  P.K. Mykhailiuk, Org. Biomol. Chem. 17 (2019) 2839–2849. doi: 10.1039/c8ob02812e
3. [3]
  M.A.M. Subbaiah, N.A. Meanwell, J. Med. Chem. 64 (2021) 14046–14128. doi: 10.1021/acs.jmedchem.1c01215
4. [4]
  R.D. Taylor, M. MacCoss, A.D.G. Lawson, J. Med. Chem. 57 (2014) 5845–5859. doi: 10.1021/jm4017625
5. [5]
  P. Das, M.D. Delost, M.H. Qureshi, et al., J. Med. Chem. 62 (2019) 4265–4311. doi: 10.1021/acs.jmedchem.8b01610
6. [6]
  A. Nilova, L.C. Campeau, E.C. Sherer, et al., J. Med. Chem. 63 (2020) 13389–13396. doi: 10.1021/acs.jmedchem.0c00915
7. [7]
  N.A. McGrath, M. Brichacek, J.T.A. Njardarson, et al., J. Chem. Ed. 87 (2010) 1348–1349. doi: 10.1021/ed1003806
8. [8]
  F. Lovering, J. Bikker, C. Humblet, J. Med. Chem. 52 (2009) 6752–6756. doi: 10.1021/jm901241e
9. [9]
  T.J. Ritchie, S.J.F. Macdonald, Drug Discov. Today 14 (2009) 1011–1020. doi: 10.1016/j.drudis.2009.07.014
10. [10]
  F. Lovering, MedChemComm 4 (2013) 515–519. doi: 10.1039/c2md20347b
11. [11]
  D. Trauner, Angew. Chem. Int. Ed. 57 (2018) 4177–4191. doi: 10.1002/anie.201708325
12. [12]
  R. Gianatassio, J.M. Lopchuk, J. Wang, et al., Science 351 (2016) 241–246. doi: 10.1126/science.aad6252
13. [13]
  R. T X. Zhang, R.T. Smith, C. Le, et al., Nature 580 (2020) 220–226. doi: 10.1038/s41586-020-2060-z
14. [14]
  M.P. Wiesenfeldt, J.A. Rossi-Ashton, I.B. Perry, et al., Nature 618 (2023) 513–518. doi: 10.1038/s41586-023-06021-8
15. [15]
  Y. Yang, J. Tsien, R. Dykstra, et al., Nat. Chem. 16 (2024) 285–293. doi: 10.1038/s41557-023-01342-7
16. [16]
  J. Tsien, C. Hu, R.R. Merchant, et al., Nat. Rev. Chem. 8 (2024) 605–627. doi: 10.1038/s41570-024-00623-0
17. [17]
  A. Cairncross, E.P. Blanchard, J. Am. Chem. Soc. 88 (1996) 496–504.
18. [18]
  A.D. Meijere, H. Wenck, F. Seyed-Mahdavi, et al., Tetrahedron 42 (1986) 1291–1297. doi: 10.1016/S0040-4020(01)87348-8
19. [19]
  P. Wipf, M.A.A. Walczak, Angew. Chem. Int. Ed. 45 (2006) 4172–4175. doi: 10.1002/anie.200600723
20. [20]
  T.V.T. Nguyen, A. Bossonnet, M.D. Wodrich, et al., J. Am. Chem. Soc. 145 (2023) 25411–25421. doi: 10.1021/jacs.3c09789
21. [21]
  P. Bellotti, F. Glorius, et al., J. Am. Chem. Soc. 145 (2023) 20716–20732. doi: 10.1021/jacs.3c08206
22. [22]
  S.J. Sujansky, X. Ma, Asian J. Org. Chem. 13 (2024) e202400045. doi: 10.1002/ajoc.202400045
23. [23]
  L. Zheng, Y.M. Yang, Z.P. Liu, et al., Org. Lett. 27 (2025) 229–234. doi: 10.1021/acs.orglett.4c04224
24. [24]
  A. Denisenko, P. Garbuz, S.V. Shishkina, et al., Angew. Chem. Int. Ed. 59 (2020) 20515–20521. doi: 10.1002/anie.202004183
25. [25]
  A. Denisenko, P. Garbuz, Y. Makovetska, et al., Chem. Sci. 14 (2023) 14092. doi: 10.1039/d3sc05121h
26. [26]
  R. Kleinmans, T. Pinkert, S. Dutta, S, et al., Nature 605 (2022) 477–483. doi: 10.1038/s41586-022-04636-x
27. [27]
  R. Kleinmans, S. Dutta, K. Ozols, et al., J. Am. Chem. Soc. 145 (2023) 12324–12332. doi: 10.1021/jacs.3c02961
28. [28]
  S. Dutta, Y.L. Lu, J.E. Erchinger, et al., J. Am. Chem. Soc. 146 (2024) 5232–5241. doi: 10.1021/jacs.3c11563
29. [29]
  S. Dutta, D. Lee, K. Ozols, et al., J. Am. Chem. Soc. 146 (2024) 2789–2797. doi: 10.1021/jacs.3c12894
30. [30]
  R. Guo, Y.C. Chang, L. Herter, et al., J. Am. Chem. Soc. 144 (2022) 7988–7994. doi: 10.1021/jacs.2c02976
31. [31]
  M. Yan, Z. Ye, P. Lu, Chin. Chem. Lett. 36 (2025) 110540. doi: 10.1016/j.cclet.2024.110540
32. [32]
  S. Agasti, F. Beltran, E. Pye, et al., Nat. Chem. 15 (2023) 535–541. doi: 10.1038/s41557-023-01135-y
33. [33]
  M. Xu, Z. Wang, Z. Sun, et al., Angew. Chem. Int. Ed. 61 (2022) e202214507. doi: 10.1002/anie.202214507
34. [34]
  Y. Liu, S. Lin, Y. Li, et al., ACS Catal. 13 (2023) 5096–5103. doi: 10.1021/acscatal.3c00305
35. [35]
  J.L. Tyler, F. Schäfer, H. Shao, et al., J. Am. Chem. Soc. 146 (2024) 16237–16247. doi: 10.1021/jacs.4c04403
36. [36]
  N. Radhoff, C.G. Daniliuc, A. Studer, Angew. Chem. Int. Ed. 62 (2023) e202304771. doi: 10.1002/anie.202304771
37. [37]
  L. Tang, Y. Xiao, F. Wu, et al., Angew. Chem. Int. Ed. 62 (2023) e202310066. doi: 10.1002/anie.202310066
38. [38]
  D. Ni, S. Hu, X. Tan, et al., Angew. Chem. Int. Ed. 62 (2023) e202308606. doi: 10.1002/anie.202308606
39. [39]
  J.J. Wang, L. Tang, Y. Xiao, et al., Angew. Chem. Int. Ed. 63 (2024) e202405222. doi: 10.1002/anie.202405222
40. [40]
  S. Hu, Y. Pan, D. Ni, et al., Nat. Commun. 15 (2024) 6128. doi: 10.1038/s41467-024-50434-6
41. [41]
  Q.Q. Hu, L.Y. Wang, X.H. Chen, et al., Angew. Chem. Int. Ed. 63 (2024) e202405781. doi: 10.1002/anie.202405781
42. [42]
  W.H. Brooks, W.C. Guida, K.G. Daniel, et al., Curr. Top. Med. Chem. 11 (2011) 760–770. doi: 10.2174/156802611795165098
43. [43]
  Food and Drug Administration. FDA’s Policy Statement For The Development of New Stereoisomeric Drugs, Chirality 4 (1992) 338–340. doi: 10.1002/chir.530040513
44. [44]
  Agency E.M. Investigation of chiral active substances. 1994.
45. [45]
  J.X. Zhao, Y.X. Chang, C. He, et al., Proc. Natl. Acad. Sci. U. S. A. 118 (2021) e2108881118. doi: 10.1073/pnas.2108881118
46. [46]
  M. De Robichon, T. Kratz, F. Beyer, et al., J. Am. Chem. Soc. 145 (2023) 24466–24470. doi: 10.1021/jacs.3c08404
47. [47]
  Q. Fu, S. Cao, J. Wang, et al., J. Am. Chem. Soc. 146 (2024) 8372–8380. doi: 10.1021/jacs.3c14077
48. [48]
  E.F. Plachinski, R.Z. Qian, R. Villanueva, et al., J. Am. Chem. Soc. 146 (2024) 31400–31404. doi: 10.1021/jacs.4c13596
49. [49]
  X. Wang, Y. Wang, X. Li, et al., RSC Med. Chem. 12 (2021) 1650–1671. doi: 10.1039/d1md00131k
50. [50]
  F.F. Fleming, L. Yao, P.C. Ravikumar, et al., J. Med. Chem. 53 (2021) 7902–7917.
51. [51]
  Y.X. Wang, Y.F. Du, N. Huang, Future Med. Chem. 10 (2018) 2713–2727. doi: 10.4155/fmc-2018-0252
52. [52]
  J.Y. Le Questel, M. Berthelot, C. Laurence, et al., J. Phys. Org. Chem. 13 (2000) 347–358. doi: 10.1002/1099-1395(200006)13:6<347::AID-POC251>3.0.CO;2-E
53. [53]
  V. Bonatto, R.F. Lameiro, F.R. Rocho, et al., RSC Med. Chem. 14 (2023) 201–217. doi: 10.1039/d2md00204c
54. [54]
  H.U. Reissig, Top. Curr. Chem. 144 (1988) 73–135.
55. [55]
  H.U. Reissig, R. Zimmer, Chem. Rev. 103 (2003) 1151–1196. doi: 10.1021/cr010016n
56. [56]
  C. Carson, M.A. Kerr, Chem. Soc. Rev. 38 (2009) 3051–3060. doi: 10.1039/b901245c
57. [57]
  T.F. Schneider, J. Kaschel, D.B. Werz, et al., Angew. Chem. Int. Ed. 53 (2014) 5504–5523. doi: 10.1002/anie.201309886
58. [58]
  M.A. Cavitt, L.H. Phun, S. France, Chem. Soc. Rev. 43 (2014) 804–818. doi: 10.1039/C3CS60238A
59. [59]
  F. De Nanteuil, F. De Simone, R. Frei, et al., Chem. Commun. 50 (2014) 10912–10928. doi: 10.1039/C4CC03194F
60. [60]
  H.K. Grover, M.R. Emmett, M.A. Kerr, Org. Biomol. Chem. 13 (2015) 655–671. doi: 10.1039/C4OB02117G
61. [61]
  O.A. Ivanova, I.V. Trushkov, Chem. Rec. 19 (2019) 2189–2208. doi: 10.1002/tcr.201800166
62. [62]
  J. Wang, S.A. Blaszczyk, X. Li, et al., Chem. Rev. 121 (2021) 110. doi: 10.1021/acs.chemrev.0c00160
63. [63]
  Y. Xia, X. Liu, X. Feng, Angew. Chem. Int. Ed. 60 (2021) 9192–9204. doi: 10.1002/anie.202006736
64. [64]
  V. Pirenne, B. Muriel, J. Waser, Chem. Rev. 121 (2021) 227–263. doi: 10.1021/acs.chemrev.0c00109
65. [65]
  T. Qin, M. He, W. Zi, Nat. Synth. 4 (2025) 124–133.
66. [66]
  J. Han, R. Liu, Z. Lin, et al., Angew. Chem. Int. Ed. 62 (2023) e202215714. doi: 10.1002/anie.202215714
67. [67]
  X. Pan, L. Yu, S. Wang, et al., Org. Lett. 24 (2022) 2099–2103. doi: 10.1021/acs.orglett.2c00290
68. [68]
  E.B. Obregón, L.G. Rost, T.R. Kocemba, et al., Angew. Chem. Int. Ed. 63 (2024) e202410524.
69. [69]
  Z.H. Chen, Y.Q. Zheng, H.G. Huang, et al., J. Am. Chem. Soc. 146 (2024) 14445–14452. doi: 10.1021/jacs.4c04495
70. [70]
  M.C. Fu, R. Shang, B. Zhao, et al., Science 363 (2019) 1429–1434. doi: 10.1126/science.aav3200
71. [71]
  C. Yang, Z.X. Yang, C.H. Ding, et al., Chem. Rec. 21 (2021) 1442–1454. doi: 10.1002/tcr.202000177
72. [72]
  B. Xu, Q. Wang, C. Fang, et al., Chem. Soc. Rev. 53 (2024) 883–971. doi: 10.1039/d3cs00489a
73. [73]
  J. Zhou, Y. Xiao, L. He, et al., J. Am. Chem. Soc. 146 (2024) 19621–19628. doi: 10.1021/jacs.4c01851
74. [74]
  X. Wang, R. Gao, X. Li, et al., J. Am. Chem. Soc. 146 (2024) 21069–21077. doi: 10.1021/jacs.4c06436
75. [75]
  F. Wu, W.B. Wu, Y. Xiao, et al., Angew. Chem. Int. Ed. 63 (2024) e202406548. doi: 10.1002/anie.202406548
76. [76]
  M. Zhang, M. Chapman, B.R. Sarode, et al., Nature 633 (2024) 90–95. doi: 10.1038/s41586-024-07865-4
77. [77]
  W.B. Wu, B. Xu, X.C. Yang, et al., Nat. Commun. 15 (2024) 8005. doi: 10.1038/s41467-024-52419-x
78. [78]
  X.G. Zhang, Z.Y. Zhou, J.X. Li, et al., J. Am. Chem. Soc. 146 (2024) 27274–27281. doi: 10.1021/jacs.4c10123
79. [79]
  J. Jeong, S. Cao, H.J. Kang, et al., J. Am. Chem. Soc. 146 (2024) 27830–27842. doi: 10.1021/jacs.4c10153
80. [80]
  T. Li, Y. Wang, Y. Xu, et al., ACS Catal. 14 (2024) 18799–18809. doi: 10.1021/acscatal.4c06660
1. [1]
  Yunqiang Li , Yongxian Huang , Sinuo Li , He Huang , Zhiwei Jiao . Elaborating azaaryl alkanes enabled by photoredox/palladium dual catalyzed dialkylation of azaaryl alkenes. Chinese Chemical Letters, 2025, 36(4): 110051-. doi: 10.1016/j.cclet.2024.110051
2. [2]
  Min Yan , Zihao Ye , Ping Lu . Catalyst-free, visible-light-induced [2π + 2σ] cycloaddition towards azabicyclohexanes. Chinese Chemical Letters, 2025, 36(6): 110540-. doi: 10.1016/j.cclet.2024.110540
3. [3]
  Baokang Geng , Xiang Chu , Li Liu , Lingling Zhang , Shuaishuai Zhang , Xiao Wang , Shuyan Song , Hongjie Zhang . High-efficiency PdNi single-atom alloy catalyst toward cross-coupling reaction. Chinese Chemical Letters, 2024, 35(7): 108924-. doi: 10.1016/j.cclet.2023.108924
4. [4]
  Mengyu Wu , Kewei Ren , Chengyu Zou , Jiacheng Chen , Rui Ma , Chuan Zhu , Chao Feng . A general synthesis of gem–difluorobicyclo[2.1.1]hexanes. Chinese Chemical Letters, 2025, 36(5): 110213-. doi: 10.1016/j.cclet.2024.110213
5. [5]
  Xiyuan Zhang , Rui Dong , Yang Yang , Jiapeng Ding , Zhiwei Miao . Palladium-Catalyzed Tandem Cyclization of 4-Vinylbenzoxazinone and Indene-2-carbaldehyde: A Comprehensive Organic Chemistry Experiment. University Chemistry, 2025, 40(9): 361-367. doi: 10.12461/PKU.DXHX202410062
6. [6]
  Zhao Gu , Yunhui Yang , Song Ye , Congyang Wang . 2,3-Arylacylation of allenes through synergetic catalysis of palladium and N-heterocyclic carbene. Chinese Chemical Letters, 2025, 36(5): 110334-. doi: 10.1016/j.cclet.2024.110334
7. [7]
  Ji-Ping Liao , Jiang Li , Wen-Jie Qin , Xiu-Mei Duan , Peng-Fei Wang , Jin-Ying Tian , Xiang Yuan , Pei-Cheng Zhang , Fei Ye , Ya-Nan Yang . Two racemic pairs of benzo bicyclo[3.3.1]/[4.2.1] nonene stilbenoid dimers from Heterosmilax yunnanensis and structural revision of syagrusin A. Chinese Chemical Letters, 2025, 36(9): 110687-. doi: 10.1016/j.cclet.2024.110687
8. [8]
  Jun Liu , Zhaoyu Feng , Renming Pan , Xiaolong Yu , Meijuan Zhou , Gang Zhao , Hongyu Wang . Enantioselective regulation to coronal polyheterocyclic compounds via phosphonium salt-catalyzed cycloadditions of azomethine imines with γ-butenolides. Chinese Chemical Letters, 2025, 36(8): 110647-. doi: 10.1016/j.cclet.2024.110647
9. [9]
  Rong-Nan Yi , Wei-Min He . Photocatalytic Minisci-type multicomponent reaction for the synthesis of 1-(halo)alkyl-3-heteroaryl bicyclo[1.1.1]pentanes. Chinese Chemical Letters, 2024, 35(10): 110115-. doi: 10.1016/j.cclet.2024.110115
10. [10]
  Wu-Yang Liu , Xin-Xiang Lei , Wen-Ji Wang , Jun-Mian Tian , Yu-Qi Gao , Jin-Ming Gao . Hyperforatone A, the 1,8-seco rearranged polycyclic polyprenylated acylphloroglucinol with a unique bicyclo[5.4.0]undecane core from Hypericum perforatum. Chinese Chemical Letters, 2025, 36(4): 110478-. doi: 10.1016/j.cclet.2024.110478
11. [11]
  Ze-Hong Zheng , Mu-Qiu Chen , Jin Zhou , Jie Wang , Yan-Rong Wei , Cheng Peng , Gu Zhan , Qian-Qian Yang , Bo Han . Diverse synthesis of bridged bicyclo[3.2.1]octa-2,6-diene and tricyclo[3.2.1.0^2,7]oct-3-ene frameworks via stepwise cascade reactions. Chinese Chemical Letters, 2025, 36(12): 111202-. doi: 10.1016/j.cclet.2025.111202
12. [12]
  Conghui Wang , Lei Xu , Zhenhua Jia , Teck-Peng Loh . Recent applications of macrocycles in supramolecular catalysis. Chinese Chemical Letters, 2024, 35(4): 109075-. doi: 10.1016/j.cclet.2023.109075
13. [13]
  Wei Chen , Pieter Cnudde . A minireview to ketene chemistry in zeolite catalysis. Chinese Journal of Structural Chemistry, 2024, 43(11): 100412-100412. doi: 10.1016/j.cjsc.2024.100412
14. [14]
  Lin Zhang , Chaoran Li , Thongthai Witoon , Xingda An , Le He . Nano-thermometry in photothermal catalysis. Chinese Journal of Structural Chemistry, 2025, 44(4): 100456-100456. doi: 10.1016/j.cjsc.2024.100456
15. [15]
  Hailong He , Wenbing Wang , Wenmin Pang , Chen Zou , Dan Peng . Double stimulus-responsive palladium catalysts for ethylene polymerization and copolymerization. Chinese Chemical Letters, 2024, 35(7): 109534-. doi: 10.1016/j.cclet.2024.109534
16. [16]
  Gongcheng Ma , Qihang Ding , Yuding Zhang , Yue Wang , Jingjing Xiang , Mingle Li , Qi Zhao , Saipeng Huang , Ping Gong , Jong Seung Kim . Palladium-free chemoselective probe for in vivo fluorescence imaging of carbon monoxide. Chinese Chemical Letters, 2024, 35(9): 109293-. doi: 10.1016/j.cclet.2023.109293
17. [17]
  Junlong Tang , Yuhan Zhao , Yangbin Jin , Liren Zhang , Yuanfang Wang , Wanqing Wu , Huanfeng Jiang . Palladium-catalyzed modular biomimetic synthesis of lignans derivatives. Chinese Chemical Letters, 2025, 36(7): 110969-. doi: 10.1016/j.cclet.2025.110969
18. [18]
  Yu Mao , Yilin Liu , Xiaochen Wang , Shengyang Ni , Yi Pan , Yi Wang . Acylfluorination of enynes via phosphine and silver catalysis. Chinese Chemical Letters, 2024, 35(8): 109443-. doi: 10.1016/j.cclet.2023.109443
19. [19]
  Jiaqi Jia , Kathiravan Murugesan , Chen Zhu , Huifeng Yue , Shao-Chi Lee , Magnus Rueping . Multiphoton photoredox catalysis enables selective hydrodefluorinations. Chinese Chemical Letters, 2025, 36(2): 109866-. doi: 10.1016/j.cclet.2024.109866
20. [20]
  Shuai Zhu , Mingjie Chen , Haichao Shen , Hanming Ding , Wenbo Li , Junliang Zhang . Palladium/Xu-Phos-catalyzed enantioselective arylalkoxylation reaction of γ-hydroxyalkenes at room temperature. Chinese Chemical Letters, 2024, 35(11): 109879-. doi: 10.1016/j.cclet.2024.109879

Get Citation

PDF

XML

Metrics

PDF Downloads(0)
Abstract views(8)
HTML views(1)

通讯作者: 陈斌, bchen63@163.com

1.
沈阳化工大学材料科学与工程学院沈阳 110142