Citation: Zan Chen, Yi Wang, Yuxuan Zhou, Yunlang Li, Rong Xiong, Wenting Huang, Huanfeng Jiang, Wanqing Wu. Selective synthesis of [6-6-7]/[6-6-6] core polycyclic heterocycles via Lewis acid-mediated cascade annulation of 1,6-enynols with aminonitriles[J]. Chinese Chemical Letters, ;2026, 37(6): 111718. doi: 10.1016/j.cclet.2025.111718 shu

Selective synthesis of [6-6-7]/[6-6-6] core polycyclic heterocycles via Lewis acid-mediated cascade annulation of 1,6-enynols with aminonitriles

Key Laboratory of Functional Molecular Engineering of Guangdong Province, State Key Laboratory of Luminescent Materials and Devices, School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou 510640, China

cewuwq@scut.edu.cn

Received Date: 8 May 2025
Revised Date: 25 July 2025
Accepted Date: 12 August 2025
Available Online: 13 August 2025

Figures(6)

Polycyclic heterocycles are prevalent in medicines, functional materials and natural products, making their synthesis a significant focus in modern organic chemistry. Herein, we present a Lewis acid-mediated cascade annulation of 1,6-enynols with o-aminobenzonitriles for the chemoselective synthesis of oxepino[3,4,5-de][1,6]naphthyridine and chromeno[2,3,4-de][1,6]naphthyridine derivatives. This reaction design enables selective control over the carbon-heteroatom and carbon-carbon bond formation in an efficient, atom-economical manner, allowing the one-step synthesis of rare [6-6-7] and [6-6-6] core polycyclic heterocycles containing three heteroatoms. Density functional theory (DFT) calculations and control experiments reveal that the reaction's high selectivity is achieved by modulating the reactivity of electron-rich alkenyl groups in the enynols, which selectively directs the intramolecular dehydroaromatization and cyclization processes.
- Polycyclic heterocycles,
- Lewis acid-mediated,
- [4+2] Cycloaddition,
- Dehydroaromatization
1. [1]
  C. Schultz, A. Link, M. Leost, et al., J. Med. Chem. 42 (1999) 2909-2919. doi: 10.1021/jm9900570
2. [2]
  A.N. de Groot, P.W. van Dongen, T.B. Vree, Y.A. Hekster, J. van Roosmalen, Drugs 56 (1998) 523-535. doi: 10.2165/00003495-199856040-00002
3. [3]
  A. Mishra, P. Bäuerle, Angew. Chem. Int. Ed. 51 (2012) 2020-2067. doi: 10.1002/anie.201102326
4. [4]
  W. Liu, B. Hong, J. Wang, X. Lei, Acc. Chem. Res. 53 (2020) 2569-2586. doi: 10.1021/acs.accounts.0c00531
5. [5]
  H. Xin, B. Hou, X. Gao, Acc. Chem. Res. 54 (2021) 1737-1753. doi: 10.1021/acs.accounts.0c00893
6. [6]
  Y. Jiang, R.E. McNamee, P.J. Smith, et al., Chem. Soc. Rev. 50 (2021) 58-71. doi: 10.1039/d0cs00768d
7. [7]
  E. Delfourne, J. Bastide, Med. Res. Rev. 23 (2003) 234-252. doi: 10.1002/med.10032
8. [8]
  K.M. Marshall, L.R. Nat. Prod. Rep. 21 (2004) 731. doi: 10.1039/b401662a
9. [9]
  M.D. Burke, S.L. Schreiber, Angew. Chem. Int. Ed. 43 (2004) 46-58. doi: 10.1002/anie.200300626
10. [10]
  B. Liu, D. Shi, Y. Yang, et al., Eur. J. Org. Chem. 2018 (2018) 869-873. doi: 10.1002/ejoc.201701386
11. [11]
  H.I. Boshoff, N. Malhotra, C.E. Barry, S. Oh, Pharmaceuticals 17 (2024) 211. doi: 10.3390/ph17020211
12. [12]
  L.F. Tietze, S.C. Duefert, J. Clerc, et al., Angew. Chem. Int. Ed. 52 (2013) 3191-3194. doi: 10.1002/anie.201209868
13. [13]
  J. Stanslas, D.J. Hagan, M.J. Ellis, et al., J. Med. Chem. 43 (2000) 1563-1572. doi: 10.1021/jm9909490
14. [14]
  A. Rizzo, S. Iachettini, P. Zizza, et al., J. Exp. Clin. Cancer Res. 33 (2014) 81-88. doi: 10.1186/s13046-014-0081-x
15. [15]
  J. Deguchi, T. Hirahara, S. Oshimi, et al., Org. Lett. 13 (2011) 4344-4347. doi: 10.1021/ol201674a
16. [16]
  A.R.O. Cousins, D. Ritson, P. Sharma, et al., Chem. Commun. 50 (2014) 15202-15205. doi: 10.1039/C4CC07487D
17. [17]
  M. Menna, E. Fattorusso, C. Imperatore, Molecules. 16 (2011) 8694-8732. doi: 10.3390/molecules16108694
18. [18]
  A. Narita, X. Wang, X. Feng, K. Mullen, Chem. Soc. Rev. 44 (2015) 6616-6643.
19. [19]
  H. Ito, K. Ozaki, K. Itami, Angew. Chem. Int. Ed. 56 (2017) 11144-11164. doi: 10.1002/anie.201701058
20. [20]
  S. Zhu, R. Zhang, T. Xia, et al., Org. Lett. 26 (2024) 10746-10751. doi: 10.1021/acs.orglett.4c03692
21. [21]
  W.W. Zhao, M.Y. Tian, Y.L. Zhou, et al., Angew. Chem. Int. Ed. 63 (2024) e202318887. doi: 10.1002/anie.202318887
22. [22]
  K. Fukuzumi, Y. Nishii, M. Miura, Angew. Chem. Int. Ed. 56 (2017) 12746-12750. doi: 10.1002/anie.201707515
23. [23]
  J. Zhang, M. Qiao, L. Chen, et al., Org. Chem. Front. 6 (2019) 2844-2849. doi: 10.1039/c9qo00554d
24. [24]
  I. Kamiyoshi, Y. Kojima, S. Xu, et al., Chem. Sci. 15 (2024) 20413-20420. doi: 10.1039/d4sc05657d
25. [25]
  J. Yin, J. You, Angew. Chem. Int. Ed. (2019) 302-306. doi: 10.1002/anie.201811023
26. [26]
  H. Ito, Y. Segawa, K. Murakami, K. Itami, J. Am. Chem. Soc. 141 (2019) 3-10. doi: 10.1021/jacs.8b09232
27. [27]
  Y. Zhang, S.H. Pun, Q. Miao, Chem. Rev. 122 (2022) 14554-14593. doi: 10.1021/acs.chemrev.2c00186
28. [28]
  A. Narita, X. Wang, X. Feng, K. Mullen, Chem. Soc. Rev. 44 (2015) 6616-6643. doi: 10.1039/C5CS00183H
29. [29]
  M. Ball, Y. Zhong, Y. Wu, et al., Acc. Chem. Res. 48 (2015) 267-276. doi: 10.1021/ar500355d
30. [30]
  X. Yang, R. Sun, Adv. Synth. Catal. 365 (2023) 124-141. doi: 10.1002/adsc.202201172
31. [31]
  G.E. Clarke, J.D. Firth, L.A. Ledingham, et al., Nat. Commun. 15 (2024) 3968. doi: 10.1038/s41467-024-47939-5
32. [32]
  P. Chauhan, S. Mahajan, D. Enders, Acc. Chem. Res. 50 (2017) 2809-2821. doi: 10.1021/acs.accounts.7b00406
33. [33]
  W.J. Kong, Z. Shen, L.H. Finger, L. Ackermann, Angew. Chem. Int. Ed. 59 (2020) 5551-5556. doi: 10.1002/anie.201914775
34. [34]
  R. Liang, Y. Jia, Acc. Chem. Res. 55 (2022) 734-745. doi: 10.1021/acs.accounts.1c00781
35. [35]
  T.G. Fan, X.L. Ding, B.X. Sun, et al., Adv. Synth. Catal. 365 (2023) 579-583. doi: 10.1002/adsc.202201368
36. [36]
  J. Han, Y. Yang, Y. Gong, et al., Nat. Commun. 14 (2023) 5148. doi: 10.1038/s41467-023-40801-0
37. [37]
  A. Luo, Y. Bao, X. Liu, et al., J. Am. Chem. Soc. 146 (2024) 6240-6251. doi: 10.1021/jacs.3c14297
38. [38]
  Z. Wang, X. Fu, Q. Li, et al., Molecules. 29 (2024) 2481. doi: 10.3390/molecules29112481
39. [39]
  P. Langer, Eur. J. Org. Chem. 27 (2024) e202400153.
40. [40]
  Y. Fei, Z. Zhou, Z. Ni, et al., Angew. Chem. Int. Ed. 64 (2025) e202414726. doi: 10.1002/anie.202414726
41. [41]
  B.D. Dherange, P.Q. Kelly, J.P. Liles, M.S. Sigman, M.D. Levin, J. Am. Chem. Soc. 143 (2021) 11337-11344. doi: 10.1021/jacs.1c06287
42. [42]
  J.C. Reisenbauer, O. Green, A. Franchino, P. Finkelstein, B. Morandi, Science (1979) 377 (2022) 1104-1109. doi: 10.1126/science.add1383
43. [43]
  S. Liu, X. Cheng, Nat. Commun. 13 (2022) 425.
44. [44]
  C. Ren, B. Han, H. Guo, et al., Angew. Chem. Int. Ed. 63 (2024) e202407222. doi: 10.1002/anie.202407222
45. [45]
  L. Wu, H. Xia, J. Bai, et al., Nat. Chem. 16 (2024) 1951-1959. doi: 10.1038/s41557-024-01668-w
46. [46]
  Z. Liu, P. Sivaguru, Y. Ning, Y. Wu, X. Bi, Chem. Eur. J. 29 (2023) e202301227. doi: 10.1002/chem.202301227
47. [47]
  S. Liu, Y. Yang, Q. Song, et al., Nat. Commun. 15 (2024) 9998.
48. [48]
  S. Liu, Y. Yang, Q. Song, et al., Nat. Chem. 16 (2024) 988-997. doi: 10.1038/s41557-024-01468-2
49. [49]
  X. Zhang, Q. Song, S. Liu, et al., Nat. Chem. 17 (2025) 215-225.
50. [50]
  T.J. Pearson, R. Shimazumi, J.L. Driscoll, et al., Science (1979) 381 (2023) 1474-1479. doi: 10.1126/science.adj5331
51. [51]
  P.Q. Kelly, A.S. Filatov, M.D. Levin, Angew. Chem. Int. Ed. 61 (2022) e202213041.
52. [52]
  S.C. Patel, N.Z. Burns, J. Am. Chem. Soc. 144 (2022) 17797-17802. doi: 10.1021/jacs.2c08464
53. [53]
  J. Wang, H. Lu, Y. He, C. Jing, H. Wei, J. Am. Chem. Soc. 144 (2022) 22433-22439. doi: 10.1021/jacs.2c10570
54. [54]
  H. Li, N. Li, J. Wu, et al., J. Am. Chem. Soc. 145 (2023) 17570-17576. doi: 10.1021/jacs.3c07640
55. [55]
  Y. He, J. Wang, T. Zhu, Z. Zheng, H. Wei, Chem. Sci. 15 (2024) 2612-2617. doi: 10.1039/d3sc05367a
56. [56]
  H. Lu, Y. Zhang, X. Wang, et al., Nat. Commun. 15 (2024) 3772.
57. [57]
  Y. Zhu, L. Sun, P. Lu, Y. Wang, ACS Catal. 4 (2014) 1911-1925. doi: 10.1021/cs400922y
58. [58]
  J. Li, F. Yang, W. Hu, et al., Chem. Commun. 56 (2020) 9154-9157. doi: 10.1039/d0cc03285a
59. [59]
  X. Li, D. Xu, Z. Niu, et al., Org. Lett. 23 (2021) 832-836. doi: 10.1021/acs.orglett.0c04070
60. [60]
  X. Li, X. Kong, C. Wang, et al., Org. Lett. 23 (2021) 9457-9462. doi: 10.1021/acs.orglett.1c03621
61. [61]
  Dattatri, M.K.R. Singam, S. Vavilapalli, J.B. Nanubolu, M.S. Reddy, Angew. Chem. Int. Ed. 62 (2023) e202215825.
62. [62]
  W. Chen, Y. Li, Y. Chen, C.Y. Ho, Angew. Chem. Int. Ed. 57 (2018) 2677-2681. doi: 10.1002/anie.201712693
63. [63]
  C. Chen, C. Shi, Y. Yang, B. Zhou, Chem. Sci. 11 (2020) 12124-12129. doi: 10.1039/d0sc04007j
64. [64]
  M. Slivka, M. Onysko, Synthesis 53 (2021) 3497-3512. doi: 10.1055/s-0040-1706036
65. [65]
  Q. Huang, S.R. Suravarapu, P. Renaud, Chem. Sci. 12 (2021) 2225-2230. doi: 10.1039/d0sc06341j
66. [66]
  H. Jiang, X. Yu, C.G. Daniliuc, A. Studer, Angew. Chem. Int. Ed. 60 (2021) 14399-14404. doi: 10.1002/anie.202101775
67. [67]
  M. Luo, Q. Xiao, J. Li, Chem. Soc. Rev. 51 (2022) 726-7237. doi: 10.3390/land11050726
68. [68]
  Y. Gao, S. Yang, M. She, et al., Chem. Sci. 13 (2022) 2105-2114. doi: 10.1039/d1sc06565c
69. [69]
  L. Ouyang, J. Li, J. Zheng, et al., Angew. Chem. Int. Ed. 56 (2017) 15926-15930. doi: 10.1002/anie.201709285
70. [70]
  F. Zhou, M. Li, H. Jiang, W. Wu, Adv. Synth. Catal. 363 (2021) 4841-4855. doi: 10.1002/adsc.202100585
71. [71]
  Z. Wu, M. Hu, Y. Jin, et al., Sci. Adv. 7 (2021) eabh4088.
72. [72]
  F. Zhou, C. Li, M. Li, et al., Chem. Commun. 57 (2021) 4799-4802. doi: 10.1039/d1cc00709b
73. [73]
  Z. Chen, W. Huang, Y. Su, H. Jiang, W. Wu, Chem. Commun. 59 (2023) 4523-4526. doi: 10.1039/d3cc00787a
74. [74]
  Y. Zheng, Y. Wu, J. Li, et al., Green Chem. 27 (2025) 1018-1022. doi: 10.1039/d4gc05771f
75. [75]
  L.J. Du, Y.P. Han, H.Y. Zhang, et al., Adv. Synth. Catal. 362 (2020) 1399-1404. doi: 10.1002/adsc.201901409
76. [76]
  X.Y. Liu, Y.L. Liu, L. Chen, Adv. Synth. Catal. 362 (2020) 5170-5195. doi: 10.1002/adsc.202000930
77. [77]
  X.R. Song, R. Yang, Q. Xiao, Adv. Synth. Catal. 363 (2021) 852-876. doi: 10.1002/adsc.202001142
78. [78]
  M. Shankar, K.C.K. Swamy, Org. Lett. 25 (2023) 3397-3401. doi: 10.1021/acs.orglett.3c00925
79. [79]
  X. Ren, X. Feng, H. Zhang, et al., J. Org. Chem. 88 (2023) 16007-16017. doi: 10.1021/acs.joc.3c01813
80. [80]
  S. De, C. Chowdhury, Chem. Eur. J. 29 (2023) e202203993.
81. [81]
  X. You, X. Xie, H. Chen, Y. Li, Y. Liu, Chem. Eur. J. 21 (2015) 18699-18705. doi: 10.1002/chem.201503374
82. [82]
  T. Wang, R.R. Naredla, S.K. Thompson, T.R. Hoye, Nature 532 (2016) 484-488. doi: 10.1038/nature17429
83. [83]
  Z.Y. Tian, Q. Cui, C.H. Liu, Z.X. Yu, Angew. Chem. Int. Ed. 57 (2018) 15544-15548. doi: 10.1002/anie.201805908
84. [84]
  S.K. Thompson, T.R. Hoye, J. Am. Chem. Soc. 141 (2019) 19575-19580. doi: 10.1021/jacs.9b11243
85. [85]
  Q. Xu, T.R. Hoye, Angew. Chem. Int. Ed. 61 (2022) e202207510.
86. [86]
  N. Kraemer, R.R. Naredla, T.R. Hoye, Org. Lett. 24 (2022) 2327-2331. doi: 10.1021/acs.orglett.2c00491
1. [1]
  Feng Wu , Yuanjiu Xiao , Mengran Wei , Guoqiang Wang , Jian-Jun Feng . Lewis acid catalyzed enantioselective dearomative (3+2) cycloaddition of aromatic N-heterocycles with bicyclobutanes. Chinese Chemical Letters, 2026, 37(3): 111963-. doi: 10.1016/j.cclet.2025.111963
2. [2]
  Guo-Cai Yuan , Ming-Gang Li , Sha Yang , Kanghui Song , Chen-Xu Gong , Shuang-Jun Zhu , Yuanming Li , Ke-Yin Ye . Electrophotocatalytic decarbonylative [4+2] cyclization of indenones. Chinese Chemical Letters, 2026, 37(6): 111709-. doi: 10.1016/j.cclet.2025.111709
3. [3]
  Saima Perveen , Lulu Qin , Min Zhao , Zhengwei Ding , Yingying Wang , Zaicheng Nie , Pengfei Li . Recent development in radical cycloaddition reactions for the synthesis of carbo- and heterocycles. Chinese Chemical Letters, 2026, 37(1): 111886-. doi: 10.1016/j.cclet.2025.111886
4. [4]
  Meixin Wang , Yizhi Zhang , Shanshan Liu , Xiao Shen . Synthesis of rigidified cyclohexanes enabled by visible-light-induced trifluoroacetylsilane-mediated [2 + 2] cycloaddition of cyclopropenes. Chinese Chemical Letters, 2025, 36(8): 110758-. doi: 10.1016/j.cclet.2024.110758
5. [5]
  Gangsheng Li , Xiang Yuan , Fu Liu , Zhihua Liu , Xujie Wang , Yuanyuan Liu , Yanmin Chen , Tingting Wang , Yanan Yang , Peicheng Zhang . Three-step synthesis of flavanostilbenes with a 2-cyclohepten-1-one core by Cu-mediated [5 + 2] cycloaddition/decarboxylation cascade. Chinese Chemical Letters, 2025, 36(2): 109880-. doi: 10.1016/j.cclet.2024.109880
6. [6]
  Zheng-Yi Li , Tao Li , Zuquan Wang , Yi Zhao , Jing Shi , Xiaoqiang Sun , Ke Yang . Cycloaddition of epoxides and atmospheric CO₂ in aqueous catalyzed by an upper-rim functionalized calix[4]arene organocatalyst. Chinese Chemical Letters, 2026, 37(4): 111352-. doi: 10.1016/j.cclet.2025.111352
7. [7]
  Junhua Li , Yu Fu , Yian Shi . A rapid access to fused polycyclic indolo[2,1-a]isoquinolins via Pd-catalyzed sequential Heck/C-H activation/amination reaction with diaziridinone. Chinese Chemical Letters, 2026, 37(3): 111376-. doi: 10.1016/j.cclet.2025.111376
8. [8]
  Fangxiang SUN , Qing ZHANG , Yifan ZHANG , Haoyi SUN , Akim V. Shmal′ko , Sergey A. Anufriev , Igor B. Sivaev , Deshuang TU , Hong YAN . Pd-catalyzed B—H bond activation and annulation of nido-carborane with terminal olefins: Facile construction of 2D-3D fused polycyclic compounds. Chinese Journal of Inorganic Chemistry, 2026, 42(3): 467-478. doi: 10.11862/CJIC.20250347
9. [9]
  Jiajun Lu , Zhehui Liao , Tongxiang Cao , Shifa Zhu . Synergistic Brønsted/Lewis acid catalyzed atroposelective synthesis of aryl-β-naphthol. Chinese Chemical Letters, 2025, 36(1): 109842-. doi: 10.1016/j.cclet.2024.109842
10. [10]
  Ruofan Qi , Jing Zhang , Wang Sun , Bai Yu , Zhenhua Wang , Kening Sun . Solid-acid-Lewis-base interaction accelerates lithium ion transport for uniform lithium deposition. Chinese Chemical Letters, 2025, 36(6): 110009-. doi: 10.1016/j.cclet.2024.110009
11. [11]
  Jun Li , Shi-Hu Du , Yao Zhang , Jia Liu , Jing Chen , Shi-Bo Cheng . Shell-independent superhalogen formation in aluminum-based clusters via boron Lewis acid ligands functionalization. Chinese Chemical Letters, 2026, 37(1): 111177-. doi: 10.1016/j.cclet.2025.111177
12. [12]
  Peipei CUI , Yawen ZHENG , Pan LI , Peiyan GUAN , Zhaohong QIAN . Praseodymium-organic framework with 4, 4′-oxybis(benzoic acid): Rare broken layer structure, antibacterial activity, and sensing for Cd²⁺ ions. Chinese Journal of Inorganic Chemistry, 2025, 41(8): 1641-1649. doi: 10.11862/CJIC.20250152
13. [13]
  Uttam Pandurang Patil . Porous carbon catalysis in sustainable synthesis of functional heterocycles: An overview. Chinese Chemical Letters, 2024, 35(8): 109472-. doi: 10.1016/j.cclet.2023.109472
14. [14]
  Yan-Yan Zeng , Jun Jiang , Yan-Cui Wen , Chun-Lin Zhuang , Li-Juan Ou , Zi Yang , Hai-Tao Zhu , Zu-Li Wang , Wei-Min He . Decatungstate-photocatalyzed heterogeneous direct benzylation of N-heterocycles with benzaldehydes. Chinese Chemical Letters, 2026, 37(4): 111776-. doi: 10.1016/j.cclet.2025.111776
15. [15]
  Jingyuan Yang , Xinyu Tian , Liuzhong Yuan , Yu Liu , Yue Wang , Chuandong Dou . Enhancing stability of diradical polycyclic hydrocarbons via P=O-attaching. Chinese Chemical Letters, 2024, 35(8): 109745-. doi: 10.1016/j.cclet.2024.109745
16. [16]
  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
17. [17]
  Fujie Liu , Yuzhu Yan , Xi Wang , Lingfei Hu , Gang Lu , Tao Xu . Retro aza-[2+2] cycloaddition as stereochemical editing logic for multi-substituted azacyclobutanes. Chinese Chemical Letters, 2026, 37(3): 111498-. doi: 10.1016/j.cclet.2025.111498
18. [18]
  Yan Luo , Yan-Jiao Lu , Mei-Mei Pan , Yu-Feng Liang , Wei-Min Shi , Chun-Hua Chen , Cui Liang , Gui-Fa Su , Dong-Liang Mo . Rapidly diastereoselective assembly of ten-membered N-heterocycles between two 1,3-dipoles and their diversity to access fused N-heterocycles. Chinese Chemical Letters, 2025, 36(5): 110207-. doi: 10.1016/j.cclet.2024.110207
19. [19]
  Zhen-Qi Wang , Lin-Wen Wei , Zhao-Qing Wang , Yan-Jie Yang , Yu Zhao , Song Liu , Yuan Huang . Modular synthesis of polyfunctionalized axial-chiral 2-arylpyridines via cobalt-catalyzed asymmetric [2 + 2 + 2] cycloaddition of diynes and nitriles. Chinese Chemical Letters, 2026, 37(4): 111377-. doi: 10.1016/j.cclet.2025.111377
20. [20]
  Ruolin CHENG , Yue WANG , Fei YANG , Huagen LIANG , Shijian LU . Application of metal-organic frameworks (MOFs) in photocatalytic CO₂ cycloaddition reaction: A mini review. Chinese Journal of Inorganic Chemistry, 2025, 41(12): 2429-2440. doi: 10.11862/CJIC.20250242

Get Citation

PDF

XML

Metrics

PDF Downloads(0)
Abstract views(14)
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