Citation: 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[J]. Chinese Chemical Letters, ;2026, 37(4): 111377. doi: 10.1016/j.cclet.2025.111377 shu

Modular synthesis of polyfunctionalized axial-chiral 2-arylpyridines via cobalt-catalyzed asymmetric [2 + 2 + 2] cycloaddition of diynes and nitriles

Zhen-Qi Wang ^{a, 1} ,
Lin-Wen Wei ^{a, 1} ,
Zhao-Qing Wang ^a ,
Yan-Jie Yang ^a ,
Yu Zhao ^{c, *,} ,
Song Liu ^{b, *,} ,
Yuan Huang ^{a, *,}

a.
Department of Medicinal Chemistry, School of Pharmacy, Xi’an Jiaotong University, Xi’an 710061, China
b.
Department of Chongqing Key Laboratory of Environmental Materials and Remediation Technologies College of Chemistry and Environmental Engineering, Chongqing University of Arts and Sciences, Chongqing 402160, China
c.
Department of Chemistry National University of Singapore, Singapore 117543, Singapore

zhaoyu@nus.edu.sg

sliu@cqwu.edu.cn

huangyuan@xjtu.edu.cn

Received Date: 25 January 2025
Revised Date: 18 May 2025
Accepted Date: 26 May 2025
Available Online: 27 May 2025

Figures(6)

Polyfunctionalized axial-chiral 2-arylpyridines are important class of chiral entities in organic synthesis and drug discovery. However, practical synthesis of such structures remains underdeveloped. Herein, we report a novel synthetic method via simple cobalt-catalyzed [2 + 2 + 2] cycloaddition reactions of easily accessible diynes with nitriles. A wide range of polyfunctionalized axial-chiral 2-arylpyridine derivatives were obtained with high enantioselectivities and atom economy by using 2-methyl tetrahydrofuran (2-MeTHF) as a green solvent. Notably, the axial-chiral 2-arylpyridine N-oxide compounds and chiral bispyridine derivatives have been accessible in high efficiency using this simple protocol. The mechanism and origin of regioselectivity of this reaction was revealed using DFT calculation profiles.
- Axial-chiral 2-arylpyridines,
- Cobalt catalysis,
- [2+2+2] Cycloaddition,
- Asymmetric synthesis,
- DFT calculations
1. [1]
  C.X. Liu, W.W. Zhang, S.Y. Yin, Q. Gu, S.L. You, J. Am. Chem. Soc. 143 (2021) 14025–14040. doi: 10.1021/jacs.1c07635
2. [2]
  T.Z. Li, S.J. Liu, W. Tan, F. Shi, Chem. Eur. J. 26 (2020) 15779–15792. doi: 10.1002/chem.202001397
3. [3]
  G. Liao, T. Zhou, Q.J. Yao, B.F. Shi, Chem. Commun. 55 (2019) 8514–8523. doi: 10.1039/c9cc03967h
4. [4]
  J.E. Smyth, N.M. Butler, P.A. Keller, Nat. Prod. Rep. 32 (2015) 1562–1583. doi: 10.1039/C4NP00121D
5. [5]
  G.J. Mei, W.L. Koay, C.Y. Guan, Y. Lu, Chem. 8 (2022) 1855–1893. doi: 10.1016/j.chempr.2022.04.011
6. [6]
  S.R. LaPlante, P.J. Edwards, L.D. Fader, A. Jakalian, O. Hucke, ChemMedChem 6 (2011) 505–513. doi: 10.1002/cmdc.201000485
7. [7]
  S.R. LaPlante, L.D. Fader, K.R. Fandrick, et al., J. Med. Chem. 54 (2011) 7005–7022. doi: 10.1021/jm200584g
8. [8]
  G. Bringmann, T. Gulder, T.A.M. Gulder, M. Breuning, Chem. Rev. 111 (2011) 563–639. doi: 10.1021/cr100155e
9. [9]
  C.C. Hughes, C.A. Kauffman, P.R. Jensen, W. Fenical, J. Org. Chem. 75 (2010) 3240–3250. doi: 10.1021/jo1002054
10. [10]
  W. Meng, R.P. Brigance, H.J. Chao, et al., J. Med. Chem. 53 (2010) 5620–5628. doi: 10.1021/jm100634a
11. [11]
  J. Clayden, W.J. Moran, P.J. Edwards, S.R. LaPlante, Angew. Chem. Int. Ed. 48 (2009) 6398–6401. doi: 10.1002/anie.200901719
12. [12]
  Y.F. Hallock, K.P. Manfredi, J.W. Blunt, et al., J. Org. Chem. 59 (1994) 6349–6355. doi: 10.1021/jo00100a042
13. [13]
  G. Bringmann, M. Reichert, Y. Hemberger, Tetrahedron. 64 (2008) 515–521. doi: 10.1016/j.tet.2007.11.015
14. [14]
  B.V. Rokade, P.J. Guiry, ACS Catal. 8 (2018) 624–643. doi: 10.1021/acscatal.7b03759
15. [15]
  E. Fernández, P.J. Guiry, K.P.T. Connole, J.M. Brown, J. Org. Chem. 79 (2014) 5391–5400. doi: 10.1021/jo500512s
16. [16]
  B. V. Rokade, J. Barker, P. J. Guiry, Chem. Soc. Rev. 48 (2019) 4766-4790. doi: 10.1039/c9cs00253g
17. [17]
  A.V. Malkov, L. Dufková, L. Farrugia, P. Kočovský, Angew. Chem. Int. Ed. 42 (2003) 3674–3677. doi: 10.1002/anie.200351737
18. [18]
  J.K. Cheng, S.H. Xiang, S. Li, L. Ye, B. Tan, Chem. Rev. 121 (2021) 4805–4902. doi: 10.1021/acs.chemrev.0c01306
19. [19]
  J.A. Carmona, C. Rodríguez-Franco, R. Fernández, V. Hornillos, J.M. Lassaletta, Chem. Soc. Rev. 50 (2021) 2968–2983. doi: 10.1039/d0cs00870b
20. [20]
  Z.X. Zhang, T.Y. Zhai, L.W. Ye, Chem Catal. 1 (2021) 1378–1412.
21. [21]
  J. Cai, K. Cen, W. Shen, L.G. Bai, W.B. Liu, Chem Catal. 2 (2022) 2889–2897.
22. [22]
  M. Amatore, C. Aubert, Eur. J. Org. Chem. 2015 (2015) 265–286. doi: 10.1002/ejoc.201403012
23. [23]
  A. Pla-Quintana, A. Roglans, Asian J. Org. Chem. 7 (2018) 1706–1718. doi: 10.1002/ajoc.201800291
24. [24]
  K. Cen, M. Usman, W. Shen, et al., Org. Biomol. Chem. 20 (2022) 7391–7404. doi: 10.1039/d2ob01344d
25. [25]
  J. Cai, L.G. Bai, Y. Zhang, et al., Chem. 7 (2021) 799–811. doi: 10.1016/j.chempr.2021.02.013
26. [26]
  K. Li, L. Wei, M. Sun, et al., Angew. Chem. Int. Ed. 60 (2021) 20204–20209. doi: 10.1002/anie.202105452
27. [27]
  A. Gutnov, B. Heller, C. Fischer, et al., Angew. Chem. Int. Ed. 43 (2004) 3795–3797. doi: 10.1002/anie.200454164
28. [28]
  B. Heller, A. Gutnov, C. Fischer, et al., Chem. Eur. J. 13 (2007) 1117–1128. doi: 10.1002/chem.200600826
29. [29]
  F. Fischer, P. Jungk, N. Weding, et al., Eur. J. Org. Chem. 2012 (2012) 5828–5838. doi: 10.1002/ejoc.201200402
30. [30]
  M. Hapke, K. Kral, C. Fischer, et al., J. Org. Chem. 75 (2010) 3993–4003. doi: 10.1021/jo100122d
31. [31]
  K. Kashima, K. Teraoka, H. Uekusa, Y. Shibata, K. Tanaka, Org. Lett. 18 (2016) 2170–2173. doi: 10.1021/acs.orglett.6b00791
32. [32]
  H. Wang, B. Qiao, J. Zhu, et al., Chem 10 (2024) 317–329. doi: 10.1016/j.chempr.2023.09.017
33. [33]
  J.H. Peng, Y.Q. Zheng, L.G. Bai, W.B. Liu, Sci. China Chem. 66 (2023) 3148–3153. doi: 10.1007/s11426-023-1749-x
34. [34]
  Y. Huang, R.Z. Huang, Y. Zhao, J. Am. Chem. Soc. 138 (2016) 6571–6576. doi: 10.1021/jacs.6b02372
35. [35]
  Y. Huang, C. Ma, Y.X. Lee, R. Huang, Y. Zhao, Angew. Chem. Int. Ed. 54 (2015) 13696–13700. doi: 10.1002/anie.201506003
36. [36]
  R.Z. Huang, Z.C. Ma, Y. Huang, Y. Zhao, J. Org. Chem. 88 (2023) 7755–7763. doi: 10.1021/acs.joc.2c01369
37. [37]
  L.W. Wei, Z.C. Ma, Z.Q. Wang, Y. Zhao, Y. Huang, Synthesis (Mass) 55 (2023) 3954–3960. doi: 10.1055/a-2152-0355
38. [38]
  L.J. Li, Y. He, Y. Yang, et al., CCS Chem. 6 (2024) 537–584. doi: 10.31635/ccschem.023.202303412
39. [39]
  J.V. Obligacion, P.J. Chirik, Nat. Rev. Chem. 2(2018) 15–34. doi: 10.1038/s41570-018-0001-2
40. [40]
  N. Yoshikai, Synthesis 51 (2019) 135–145. doi: 10.1055/s-0037-1610397
41. [41]
  P. Gandeepan, C.H. Cheng, Acc. Chem. Res. 48 (2015) 1194–1206. doi: 10.1021/ar500463r
42. [42]
  G. Zhang, Q. Zhang, Chem Catal. 3 (2023) 100526.
43. [43]
  J. Chen, Z. Lu, Org. Chem. Front. 5 (2018) 260–272. doi: 10.1039/c7qo00613f
44. [44]
  T. Du, B. Wang, C. Wang, J. Xiao, W. Tang, Chin. Chem. Lett. 32 (2021) 1241–1244. doi: 10.1016/j.cclet.2020.09.011
45. [45]
  A. Luc, J. Oliveira, P. Boos, et al., Chem Catal. 3 (2023) 100765.
46. [46]
  H. Pellissier, Coordin. Chem. Rev. 360 (2018) 122–168. doi: 10.1016/j.ccr.2018.01.013
47. [47]
  Y. Hu, Y. Zou, H. Yang, et al., Angew. Chem. Int. Ed. 62 (2023) e202217871. doi: 10.1002/anie.202217871
48. [48]
  Y. Zheng, C. Zheng, Q. Gu, S. -L. You, J. Am. Chem. Soc. 14 (2023) 6944–6952.
49. [49]
  Z. Liang, L. Wang, Y. Wang, et al., J. Am. Chem. Soc. 145 (2023) 3588–3598. doi: 10.1021/jacs.2c12475
50. [50]
  M. Zhang, N. Zhang, Q. Zhao, et al., Chin. Chem. Lett. 36 (2025) 110081. doi: 10.1016/j.cclet.2024.110081
51. [51]
  H. Chen, C. Zhu, H. Yue, M. Rueping, ACS Catal. 13 (2023) 6773–6780. doi: 10.1021/acscatal.3c01244
52. [52]
  Y.D. Zhang, X.Y. Li, Q. KM, et al., Angew. Chem. Int. Ed. 61 (2022) e202208473. doi: 10.1002/anie.202208473
53. [53]
  X. Du, Y. Zhang, T. Yang, et al., Chem Catal. 4 (2024) 100999.
54. [54]
  Y. Hu, Z. Zhang, Y. Liu, W. Zhang, Angew. Chem. Int. Ed. 60 (2021) 16989–16993. doi: 10.1002/anie.202106566
55. [55]
  W. Huang, F. Meng, Angew. Chem. Int. Ed. 60 (2021) 2694–2698. doi: 10.1002/anie.202012122
56. [56]
  A. Whyte, J. Bajohr, A. Torelli, M. Lautens, Angew. Chem. Int. Ed. 59 (2020) 16409–16413. doi: 10.1002/anie.202006716
57. [57]
  S. Ghorai, S.S. Chirke, W.B. Xu, J.F. Chen, C. Li, J. Am. Chem. Soc. 141 (2019) 11430–11434. doi: 10.1021/jacs.9b06035
58. [58]
  A. Whyte, A. Torelli, B. Mirabi, et al., J. Am. Chem. Soc. 142 (2020) 9510–9517. doi: 10.1021/jacs.0c03246
59. [59]
  C. Wu, J. Liao, S. Ge, Angew. Chem. Int. Ed. 58 (2019) 8882–8886. doi: 10.1002/anie.201903377
60. [60]
  J. Xiao, Y. Zheng, Y. Zhao, Z. Shi, M. Wang. Chin. Chem. Lett. 36 (2025) 110243. doi: 10.1016/j.cclet.2024.110243
61. [61]
  Z. Cheng, M. Li, X.Y. Zhang, et al., Angew. Chem. Int. Ed. 62 (2023) e202215029. doi: 10.1002/anie.202215029
62. [62]
  Z.L. Zhang, Z. Li, Y.T. Xu, et al., Angew. Chem. Int. Ed. 62 (2023) e202306381. doi: 10.1002/anie.202306381
63. [63]
  S. Zhang, Y. Ouyang, Y. Gao, P. Li, Acc. Chem. Res. 57 (2024) 957–970. doi: 10.1021/acs.accounts.3c00808
64. [64]
  G. Dazinger, M. Torres-Rodrigues, K. Kirchner, M.J. Calhorda, P.J. Costa, J. Organomet. Chem. 691 (2006) 4434–4445. doi: 10.1016/j.jorganchem.2006.03.004
65. [65]
  A.A. Dahy, K. Yamada, N. Koga, Organometallics. 28 (2009) 3636–3649. doi: 10.1021/om900025m
66. [66]
  A.A. Dahy, N. Koga, J. Organomet. Chem. 695 (2010) 2240–2250. doi: 10.1016/j.jorganchem.2010.06.015
67. [67]
  A.M. Rodriguez, C. Cebrián, P. Prieto, et al., Chem. Eur. J. 18 (2012) 6217–6224. doi: 10.1002/chem.201103560
68. [68]
  C.H. Wei, S. Mannathan, C.H. Cheng, J. Am. Chem. Soc. 133 (2011) 6942–6944. doi: 10.1021/ja201827j
69. [69]
  J. Treutwein, G. Hilt, Angew. Chem. Int. Ed. 47 (2008) 6811–6813. doi: 10.1002/anie.200801778
70. [70]
  S. Mannathan, C. -H. Cheng, Chem. Commun. 46 (2010) 1923–1925. doi: 10.1039/b920071a
71. [71]
  W. Ding, N. Yoshikai, Angew. Chem. Int. Ed. 58 (2019) 2500–2504. doi: 10.1002/anie.201813283
72. [72]
  A. Goswami, T. Ito, S. Okamoto, Adv. Synth. Catal. 349 (2007) 2368–2374. doi: 10.1002/adsc.200700188
73. [73]
  L. Fiebig, J. Kuttner, G. Hilt, et al., J. Org. Chem. 78 (2013) 10485–10493. doi: 10.1021/jo402001g
1. [1]
  Hanqing Zhang , Xiaoxia Wang , Chen Chen , Xianfeng Yang , Chungli Dong , Yucheng Huang , Xiaoliang Zhao , Dongjiang Yang . Selective CO2-to-formic acid electrochemical conversion by modulating electronic environment of copper phthalocyanine with defective graphene. Chinese Journal of Structural Chemistry, 2023, 42(10): 100089-100089. doi: 10.1016/j.cjsc.2023.100089
2. [2]
  Xue Du , Ze-Hua Sun , Penglei Zhang , Li-Ping Xu , Xiaodong Xiong . Asymmetric chloro– and selenocyclization of 2-alkenyl anilides enabled by tertiary ammonium salt catalysis. Chinese Chemical Letters, 2026, 37(4): 111259-. doi: 10.1016/j.cclet.2025.111259
3. [3]
  Saima Perveen , Xicheng Wang , Tao Li , Linghua Wang , Shuai Zhang , Yizhao Ouyang , Xue Zhao , Liang Xu , Pengfei Li . Enantioconvergent reductive amidation of benzyl ammonium salts for synthesis of α-chiral amides. Chinese Chemical Letters, 2026, 37(1): 111779-. doi: 10.1016/j.cclet.2025.111779
4. [4]
  Jieshuai Xiao , Yuan Zheng , Yue Zhao , Zhuangzhi Shi , Minyan Wang . Asymmetric Nozaki-Hiyama-Kishi (NHK)-type reaction of isatins with aromatic iodides by cobalt catalysis. Chinese Chemical Letters, 2025, 36(5): 110243-. doi: 10.1016/j.cclet.2024.110243
5. [5]
  Deng Pan , Chuan He , Genping Huang . Mechanism and origins of enantioselectivity of iridium-catalyzed atroposelective intermolecular C(sp²)-H silylation: A ligand-enabled axial chirality transfer strategy. Chinese Chemical Letters, 2026, 37(4): 111217-. doi: 10.1016/j.cclet.2025.111217
6. [6]
  Guie Li , Chunyan Yang , Qiu Yang , Qingzhu Zheng , Menghan Li , Jianhua Qu , Guangshan Zhang . A magnetically recyclable CoFe₂O₄/BiOBr S-scheme heterojunction for efficient photocatalytic degradation of diuron: Performance, durability and mechanism exploration. Chinese Chemical Letters, 2026, 37(1): 111207-. doi: 10.1016/j.cclet.2025.111207
7. [7]
  Zhihua Wang , Xiang-Zhao Zhu , Xinglei He , Chen-Xu Gong , Wang-Fu Liang , Wenfeng Wang , Yuqi Lin , Ke-Yin Ye . Deoxygenative hydrohalogenation of propargyl alcohols: Regio- and stereoselective synthesis of unsaturated distal dihalides. Chinese Chemical Letters, 2025, 36(12): 111067-. doi: 10.1016/j.cclet.2025.111067
8. [8]
  Yutong Xiong , Ting Meng , Wendi Luo , Bin Tu , Shuai Wang , Qingdao Zeng . Molecular conformational effects on co-assembly systems of low-symmetric carboxylic acids investigated by scanning tunneling microscopy. Chinese Journal of Structural Chemistry, 2025, 44(2): 100511-100511. doi: 10.1016/j.cjsc.2025.100511
9. [9]
  Minghui Zhang , Na Zhang , Qian Zhao , Chao Wang , Alexander Steiner , Jianliang Xiao , Weijun Tang . Cobalt pincer complex-catalyzed highly enantioselective hydrogenation of quinoxalines. Chinese Chemical Letters, 2025, 36(4): 110081-. doi: 10.1016/j.cclet.2024.110081
10. [10]
  Wen-Rui Li , Ru-Bing Wang , Huiqiang Wang , Jin-Yao Yong , Yu-Huan Li , Shi-Shan Yu , Shuang-Gang Ma . Ring-reorganization strategy for asymmetric synthesis of sesquiterpenoid illihenin A and its antiviral activity evaluation. Chinese Chemical Letters, 2025, 36(11): 110945-. doi: 10.1016/j.cclet.2025.110945
11. [11]
  Pan Hu , Xiaofan Wu , Yi An , Xianjing Zheng , Liang Gao , Yuan Tao , Yajiao Zhang , Zedu Huang , Fener Chen . Batch and continuous-flow asymmetric synthesis of D-pantothenic acid precursor enabled by immobilized ketoreductase mutant. Chinese Chemical Letters, 2026, 37(2): 111945-. doi: 10.1016/j.cclet.2025.111945
12. [12]
  Hanqi Zhang , Biao Gao , Yuanyuan Feng , Guijuan Zheng , Zhijun Liu , Lichun Kong , Junjun Liu , Haji Akber Aisa , Guangmin Yao . DFT calculations and dynamic NMR revealed the coalescent NMR phenomena of the 6/6/6/9 tetracyclic merosesquiterpenoids with an unprecedented 9,15-dioxatetracyclo[8.5.3.0^4,17.0^14,18]octadecane core skeleton. Chinese Chemical Letters, 2025, 36(9): 111234-. doi: 10.1016/j.cclet.2025.111234
13. [13]
  Huiyuan Deng , Na Zhao , Junjie You , Zhicheng Pan , Bo Xing , Yuling Ye , Bo Lai , Yuxi Wang , Tongrui Lu , Xiaonan Liu . Removal of bisphenol a through peroxymonosulfate activation with N-doped graphite carbon spheres coated cobalt nanoparticles catalyst: Synergy of nonradicals. Chinese Chemical Letters, 2025, 36(8): 110650-. doi: 10.1016/j.cclet.2024.110650
14. [14]
  Xu-Hui Yue , Xiang-Wen Zhang , Hui-Min He , Lei Qiao , Zhong-Ming Sun . Synthesis, chemical bonding and reactivity of new medium-sized polyarsenides. Chinese Chemical Letters, 2024, 35(7): 108907-. doi: 10.1016/j.cclet.2023.108907
15. [15]
  Fengqing Wang , Changxing Qi , Chunmei Chen , Qin Li , Qingyi Tong , Weiguang Sun , Zhengxi Hu , Minyan Wang , Hucheng Zhu , Lianghu Gu , Yonghui Zhang . Discovery and enantioselective total synthesis of antitumor agent asperfilasin A via a regio- and diastereoselective Nazarov cyclization. Chinese Chemical Letters, 2025, 36(6): 110252-. doi: 10.1016/j.cclet.2024.110252
16. [16]
  Kun Wang , Tianxue Gong , Yaohuang Huang , Boyang Han , Hanxiao Yang , Pavlo O. Dral , Weiwei Fang . Bornylimidazo[1,5–a]pyridin-3-ylidene allylic Pd catalyst with optimal electronic and steric properties for synthesis of 3,3′-disubstituted oxindoles. Chinese Chemical Letters, 2025, 36(7): 110539-. doi: 10.1016/j.cclet.2024.110539
17. [17]
  Min Liu , Di Wang , Zenghui Ye , Donghao Jiang , Bencan Tang , Yanqi Wu , Fengzhi Zhang . Highly stereo- and enantio-selective synthesis of spiro cyclopropyl oxindoles via organic catalyst-mediated cyclopropanation. Chinese Chemical Letters, 2025, 36(10): 110923-. doi: 10.1016/j.cclet.2025.110923
18. [18]
  Tao Yu , Vadim A. Soloshonok , Zhekai Xiao , Hong Liu , Jiang Wang . Probing the dynamic thermodynamic resolution and biological activity of Cu(Ⅱ) and Pd(Ⅱ) complexes with Schiff base ligand derived from proline. Chinese Chemical Letters, 2024, 35(4): 108901-. doi: 10.1016/j.cclet.2023.108901
19. [19]
  Qian Wang , Yeping Bian , Gagan Dhawan , Wei Zhang , Alexander E. Sorochinsky , Ata Makarem , Vadim A. Soloshonok , Jianlin Han . FDA approved fluorine-containing drugs in 2023. Chinese Chemical Letters, 2024, 35(11): 109780-. doi: 10.1016/j.cclet.2024.109780
20. [20]
  Youxiang He , Yongfa Zhu , Ming Luo , Haiping Xia . A nonalternant analogue of pentacene incorporating a non-terminal azulene unit. Chinese Chemical Letters, 2025, 36(7): 110463-. doi: 10.1016/j.cclet.2024.110463

Get Citation

PDF

XML

Metrics

PDF Downloads(0)
Abstract views(83)
HTML views(7)

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