Citation: 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[J]. Chinese Chemical Letters, ;2026, 37(1): 111779. doi: 10.1016/j.cclet.2025.111779 shu

Enantioconvergent reductive amidation of benzyl ammonium salts for synthesis of α-chiral amides

Saima Perveen ^{a, 1,*,} ,
Xicheng Wang ^{b, 1} ,
Tao Li ^{b, 1} ,
Linghua Wang ^c ,
Shuai Zhang ^b ,
Yizhao Ouyang ^b ,
Xue Zhao ^d ,
Liang Xu ^{d, *,} ,
Pengfei Li ^{a, b, *,}

a.
School of Chemistry, Xi’an Jiaotong University, Xi’an 710049, China
b.
Frontier Institute of Science and Technology and Interdisciplinary Research Center of Frontier Science and Technology, Xi’an Jiaotong University, Xi’an 710049, China
c.
Institute of Analytical Chemistry and Instrument for Life Science, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi’an Jiaotong University, Xi’an 710049, China
d.
School of Chemistry and Chemical Engineering/State Key Laboratory Incubation Base for Green Processing of Chemical Engineering, Shihezi University, Shihezi 832003, China

saima.364@mail.xjtu.edu.cn

xuliang4423@shzu.edu.cn

lipengfei@xjtu.edu.cn

Received Date: 9 June 2025
Revised Date: 6 August 2025
Accepted Date: 30 August 2025
Available Online: 1 September 2025

Figures(7)

α-Chiral amides are common in pharmaceuticals, agrochemicals, natural products, and peptides, prompting the need for new synthetic methods. Here, we introduce a nickel-catalyzed asymmetric reductive amidation method to synthesize α-chiral amides from benzyl ammonium salts and isocyanates. The key to success is using a chiral 2,2′-bipyridine ligand (-)-Ph-SBpy, enabling high yield (up to 95%) and enantiomeric ratio (up to 98:2 er) under mild conditions. Addition of phenol prevents isocyanate polymerization by reversibly forming a carbamate intermediate, enhancing selectivity and efficiency. The synthetic utility is showcased through transformations of the enantioenriched amides, and the mechanism and enantioselectivity are supported by experimental and computational studies.
- α-Chiral amide,
- Amidation,
- Asymmetric synthesis,
- Bipyridine ligand,
- Nickel catalysis
1. [1]
  D.G. Brown, J. Boström, J. Med. Chem. 59 (2015) 4443–4458.
2. [2]
  M.T. Sabatini, L.T. Boulton, H.F. Sneddon, T.D. Sheppard, Nat. Catal. 2 (2019) 10–17. doi: 10.1038/s41929-018-0211-5
3. [3]
  J. Pitzer, K. Steiner, J. Biotechnol. 235 (2016) 32–46. doi: 10.1016/j.jbiotec.2016.03.023
4. [4]
  S. Sun, Q. Jia, Z. Zhang, Bioorg. Med. Chem. Lett. 29 (2019) 2535–2550. doi: 10.1016/j.bmcl.2019.07.033
5. [5]
  X. Wang, Nat. Catal. 2 (2019) 98–102. doi: 10.1038/s41929-018-0215-1
6. [6]
  A. Greenberg, C.M. Breneman, J.F. Liebman, Biochem. Mater. Sci, Wiley-Interscience, New York, 2000.
7. [7]
  S. Ponra, B. Boudet, P. Phansavath, V.R. Vidal, Synthesis 53 (2020) 193–214.
8. [8]
  X. Fu, Y. Zhang, J. Liao, et al., Chin. Chem. Lett. 35 (2024) 109688. doi: 10.1016/j.cclet.2024.109688
9. [9]
  C.D. Zhao, H. Yao, S.Y. Li, et al., Chin. Chem. Lett. 35 (2024) 108879. doi: 10.1016/j.cclet.2023.108879
10. [10]
  N.A. Magnus, T.M. Braden, J.Y.B. DeBaillie, et al., Org. Process Res. Dev. 16 (2012) 830–835. doi: 10.1021/op300053a
11. [11]
  E.A. Iardi, A. Zakarian, Chem. Asian J. 6 (2011) 2260–2263. doi: 10.1002/asia.201100338
12. [12]
  S. Feng, Y. Dong, S.L. Buchwald, Angew. Chem. Int. Ed. 61 (2022) e202206692. doi: 10.1002/anie.202206692
13. [13]
  B. Li, T. Li, M.A. Aliyu, Z.H. Li, W. Tang, Angew. Chem. Int. Ed. 58 (2019) 11355–11359. doi: 10.1002/anie.201905174
14. [14]
  C.L. Allen, J.M.J. Williams, Chem. Soc. Rev. 40 (2011) 3405–3415. doi: 10.1039/c0cs00196a
15. [15]
  J. Wang, Y. Chen, S. Miao, C. Yao, K. Zhang, New J. Chem. 48 (2024) 15287–15291. doi: 10.1039/d4nj03410d
16. [16]
  X.G. Zhang, Z.C. Yang, J.B. Pan, X.H. Liu, Q.L. Zhou, Nat. Commun. 15 (2024) 4793. doi: 10.1007/s11071-024-09285-5
17. [17]
  J.B. Pan, Z.C. Yang, X.G. Zhang, M.L. Li, Q.L. Zhou, Angew. Chem. Int. Ed. 62 (2023) e202308122. doi: 10.1002/anie.202308122
18. [18]
  C. Pei, S. Han, H. Wu, B. Li, B. Wang, Chin. J. Chem. 43 (2025) 1255–1262. doi: 10.1002/cjoc.202401208
19. [19]
  M. Feng, A.J. Fernandes, R. Meyrelles, N. Maulide, Chem 9 (2023) 1538–1548. doi: 10.1016/j.chempr.2023.03.002
20. [20]
  G. Schäfer, C. Matthey, J.W. Bode, Angew. Chem. Int. Ed. 51 (2012) 9173–9175. doi: 10.1002/anie.201204481
21. [21]
  V. Pace, L. Castoldi, W. Holzer, Chem. Commun. 49 (2013) 8383–8385. doi: 10.1039/c3cc44255a
22. [22]
  H. Zhou, P. Lu, X. Gu, P. Li, Org. Lett. 15 (2013) 5646–5649. doi: 10.1021/ol402573j
23. [23]
  D. Fiorito, Y. Liu, C. Besnard, C. Mazet, J. Am. Chem. Soc. 142 (2019) 623–632.
24. [24]
  S.C. Galisteo, J. Schörgenhumer, C. Hervieu, C. Nevado, Angew. Chem. Int. Ed. 63 (2024) e202313717. doi: 10.1002/anie.202313717
25. [25]
  X. Wang, Y. Dai, H. Gong, Topp. Curr. Chem. 374 (2016) 43. doi: 10.1007/s41061-016-0042-2
26. [26]
  C. Tran, A. Abdallah, V. Duchemann, G. Lefèvre, A. Hamze, Chin. Chem. Lett. 34 (2023) 107758. doi: 10.1016/j.cclet.2022.107758
27. [27]
  Y.Z. Yang, G.F. Lv, M. Hu, Y.L. Li, J.H. Li, Chin. Chem. Lett. 34 (2023) 108590. doi: 10.1016/j.cclet.2023.108590
28. [28]
  J. Liu, X. Tao, Z. Zou, et al., Chin. Chem. Lett. 36 (2025) 110461. doi: 10.1016/j.cclet.2024.110461
29. [29]
  J. Li, C. Chen, Y. Dong, et al., Chin. Chem. Lett. 35 (2024) 109732. doi: 10.1016/j.cclet.2024.109732
30. [30]
  C.E.I. Knappke, S. Grupe, D. Gärtner, et al., Chem. Eur. J. 20 (2014) 1–16. doi: 10.1002/chem.201390210
31. [31]
  X.B. Liu, R.M. Liu, X.D. Bao, et al., Chin. Chem. Lett. 35 (2024) 109783. doi: 10.1016/j.cclet.2024.109783
32. [32]
  S. Perveen, G. Zhang, P. Li, Org. Biomol. Chem. 23 (2025) 4006–4023. doi: 10.1039/d5ob00392j
33. [33]
  T.Z. Wang, L.Y. Tang, Y.Q. Guan, et al., Chin. Chem. Lett. 36 (2025) 111050. doi: 10.1016/j.cclet.2025.111050
34. [34]
  R. Wang, J. Xu, J.X. Li, et al., Chin. Chem. Lett. 34 (2023) 108490. doi: 10.1016/j.cclet.2023.108490
35. [35]
  L. Wan, Y. Tong, X. Lu, Y. Fu, Chin. Chem. Lett. 35 (2024) 109283. doi: 10.1016/j.cclet.2023.109283
36. [36]
  X.W. Chen, J.P. Yue, K. Wang, et al., Angew. Chem. Int. Ed. 60 (2021) 14068–14075. doi: 10.1002/anie.202102769
37. [37]
  C. Li, X.W. Chen, L.L. Liao, et al., Angew. Chem. Int. Ed. 64 (2025) e202413305. doi: 10.1002/anie.202413305
38. [38]
  X. Hu, Chem. Sci. 2 (2011) 1867–1886. doi: 10.1039/c1sc00368b
39. [39]
  E. Serrano, R. Martin, Angew. Chem. Int. Ed. 55 (2016) 11207–11211. doi: 10.1002/anie.201605162
40. [40]
  T. Michiyuki, I. Osaka, K. Komeyama, Chem. Commun. 56 (2020) 1247–1250. doi: 10.1039/c9cc09377j
41. [41]
  S. Zheng, D.N. Primer, G.A. Molander, ACS Catal. 7 (2017) 7957–7961. doi: 10.1021/acscatal.7b02795
42. [42]
  A. Correa, R. Martin, J. Am. Chem. Soc. 136 (2014) 7253–7256. doi: 10.1021/ja5029793
43. [43]
  J.C. Hsieh, C.H. Cheng, Chem. Commun. (2005) 4554–4556. doi: 10.1039/b506903c
44. [44]
  S. Zhang, S. Perveen, Y. Ouyang, et al., Angew. Chem. Int. Ed. 61 (2022) e202117843. doi: 10.1002/anie.202117843
45. [45]
  S. Perveen, S. Zhang, L. Wang, et al., Angew. Chem. Int. Ed. 61 (2022) e202212108. doi: 10.1002/anie.202212108
46. [46]
  L. Wang, T. Li, S. Perveen, et al., Angew. Chem. Int. Ed. 61 (2022) e202213943. doi: 10.1002/anie.202213943
47. [47]
  S. Zhang, Y. Ouyang, Y. Gao, P. Li, Acc. Chem. Res. 57 (2024) 957–970. doi: 10.1021/acs.accounts.3c00808
48. [48]
  M.M. Xu, Q. Chen, L.H. Xie, J.R. Li, Coord. Chem. Rev. 213421 (2020) 1–27.
49. [49]
  Z. Li, G. Zhang, Y. Song, et al., Org. Lett. 25 (2023) 3023–3028. doi: 10.1021/acs.orglett.3c00816
50. [50]
  M. Kalek, G.C. Fu, J. Am. Chem. Soc. 139 (2017) 4225–4229. doi: 10.1021/jacs.7b01826
51. [51]
  W. Guo, L. Zuo, M. Cui, B. Yan, S. Ni, J. Am. Chem. Soc. 143 (2021) 7629–7634. doi: 10.1021/jacs.1c03182
52. [52]
  P. Maity, D.M.S. McAtee, G.P.A. Yap, E.R. Sirianni, M.P. Watson, J. Am. Chem. Soc. 135 (2013) 280–285. doi: 10.1021/ja3089422
53. [53]
  R. Yuan, Z. Lin, Organometallics 33 (2014) 7147–7156. doi: 10.1021/om500962a
54. [54]
  N.W.M. Michel, A.D.M. Jeanneret, H. Kim, S.A.L. Rousseaux, J. Org. Chem. 83 (2018) 11860–11872. doi: 10.1021/acs.joc.8b01763
55. [55]
  R.D. He, C.L. Li, Q.Q. Pan, et al., J. Am. Chem. Soc. 141 (2019) 12481–12486. doi: 10.1021/jacs.9b05224
56. [56]
  H. Chen, L. Huang, H. Chen, J. Li, Mol. Catal. 559 (2024) 114088.
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