Citation: Wang Lin, Wang Nan, Qi Yue, Sun Shutao, Liu Xigong, Li Wei, Liu Lei. Synthesis of Sterically Hindered α-Aminonitriles through 1, 6-Aza-conjugate Addition of Anilines to δ-Cyano Substituted para-Quinone Methides[J]. Chinese Journal of Organic Chemistry, ;2020, 40(11): 3934-3943. doi: 10.6023/cjoc202004027 shu

Synthesis of Sterically Hindered α-Aminonitriles through 1, 6-Aza-conjugate Addition of Anilines to δ-Cyano Substituted para-Quinone Methides

Wang Lin ^a,† ,
Wang Nan ^c,† ,
Qi Yue ^a ,
Sun Shutao ^b ,
Liu Xigong ^b,, ,
Li Wei ^a,, ,
Liu Lei ^b,,

a.
Department of Pharmaceutical Analysis, School of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250355
b.
School of Chemistry and Chemical Engineering, Shandong University, Jinan 250100
c.
The First Ward of Intervention Department, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan 250117

Corresponding author: Liu Xigong, 201990000024@sdu.edu.cn Li Wei, liwei6911@163.com Liu Lei, leiliu@sdu.edu.cn

^†

Received Date: 17 April 2020
Revised Date: 14 May 2020
Available Online: 19 May 2020
Fund Project: Project supported by the National Natural Science Foundation of China (Nos. 21722204, 21971148)the National Natural Science Foundation of China 21971148the National Natural Science Foundation of China 21722204

Figures(4)

Current 1, 6-conjugate addition typically focused on pre-synthesized para-quinone methides bearing a δ-mono substituent for tertiary stereocenter formation. Here, an efficient 1, 6-aza-conjugate addition of primary anilines to pre-prepared δ-CN-δ-aryl disubstituted para-quinone methides for facile access to sterically hindered amines with a fully substituted α-car-bon center has been described. The mild and expeditious method exhibited broad scopes of both aniline and para-quinone methide components. The generality of the method in modular preparation of medicinally valuable, sterically hindered amines was further demonstrated by using cyclic secondary amines like morpholine and imidazole as nucleophilic components.
- para-quinone methide,
- δ-CN-δ-aryl disubstitution,
- sterically hindered amine,
- aza-quaternary carbon,
- 1, 6-aza-conjugate addition
1. [1]
  (a) Turner, A. B. Q. Rev., Chem. Soc. 1964, 18, 347.
  (b) Peter, M. G. Angew. Chem. Int. Ed. 1989, 28, 555.
  (c) Itoh, T. Prog. Polym. Sci. 2001, 26, 1019.
  (d) Parra, A.; Tortosa, M. ChemCatChem 2015, 7, 1524.
  (e) Li, W.; Xu, X.; Zhang, P.; Li, P. Chem. Asian J. 2018, 13, 2350.
2. [2]
  (a) Angle, S. R.; Turnbull, K. D. J. Am. Chem. Soc. 1989, 111, 1136.
  (b) Angle, S. R.; Arnaiz, D. O. J. Org. Chem. 1990, 55, 3708.
  (c) Baik, W.; Lee, H. J.; Jang, J. M.; Koo, S.; Kim, B. H. J. Org. Chem. 2000, 65, 108.
  (d) Reddy, V.; Anand, R. V. Org. Lett. 2015, 17, 3390.
  (e) Ramanjaneyulu, B. T.; Mahesh, S.; Anand, R. V. Org. Lett. 2015, 17, 3952.
  (f) Shen, Y.; Qi, J.; Mao, Z.; Cui, S. Org. Lett. 2016, 18, 2722.
  (g) Huang, X. Y.; Ding, R.; Mo, Z. Y.; Xu, Y. L.; Tang, H. T.; Wang, H. S.; Chen, Y. Y.; Pan, Y. M. Org. Lett. 2018, 20, 4819.
  (h) Wu, Q. Y.; Ao, G. Z.; Liu, F. Org. Chem. Front. 2018, 5, 2061.
  (i) Ke, M.; Song, Q. Adv. Synth. Catal. 2017, 359, 384.
3. [3]
  (a) Chu, W. D.; Zhang, L. F.; Bao, X.; Zhao, X. H.; Zeng, C.; Du, J. Y.; Zhang, G. B.; Wang, F. X.; Ma, X. Y.; Fan, C. A. Angew. Chem. Int. Ed. 2013, 52, 9229.
  (b) Caruana, L.; Kniep, F.; Johansen, T. K.; Poulsen, P. H.; Jørgensen, K. A. J. Am. Chem. Soc. 2014, 136, 15929.
  (c) Lou, Y.; Cao, P.; Jia, T.; Zhang, Y.; Wang, M.; Liao, J. Angew. Chem. Int. Ed. 2015, 54, 12134.
  (d) Dong, N.; Zhang, Z. P.; Xue, X. S.; Li, X.; Cheng, J. P. Angew. Chem. Int. Ed. 2016, 55, 1460.
  (e) Li, X.; Xu, X.; Wei, W.; Lin, A.; Yao, H. Org. Lett. 2016, 18, 428.
  (f) Ge, L.; Lu, X.; Cheng, C.; Chen, J.; Cao, W.; Wu, X.; Zhao, G. J. Org. Chem. 2016, 81, 9315.
  (g) Ma, C.; Huang, Y.; Zhao, Y. ACS Catal. 2016, 6, 6408.
  (h) He, F. S.; Jin, J. H.; Yang, Z. T.; Yu, X.; Fossey, J. S.; Deng, W. P. ACS Catal. 2016, 6, 652.
  (i) Jarava-Barrera, C.; Parra, A.; López, A.; Cruz-Acosta, F.; Collado-Sanz, D.; Cárdenas, D. J.; Tortosa, M. ACS Catal. 2016, 6, 442.
  (j) Li, S.; Liu, Y.; Huang, B.; Zhou, T.; Tao, H.; Xiao, Y.; Liu, L.; Zhang, J. ACS Catal. 2017, 7, 2805.
  (k) Huang, G. B.; Huang, W. H.; Guo, J.; Xu, D. L.; Qu, X. C.; Zhai, P. H.; Zheng, X. H.; Weng, J.; Lu, G. Adv. Synth. Catal. 2019, 361, 1241.
4. [4]
  Errede, L. A.; Szwarc, M. Q. Rev., Chem. Soc. 1958, 12, 301.
5. [5]
  (a) Wang, Z.; Wong, Y. F.; Sun, J. Angew. Chem. Int. Ed. 2015, 54, 13711.
  (b) Chen, M.; Sun, J. Angew. Chem. Int. Ed. 2017, 56, 11966.
6. [6]
  (a) Wang, Z.; Zhu, Y.; Pan, X.; Wang, G.; Liu, L. Angew. Chem. Int. Ed. 2020, 59, 3053.
  (b) Pan, X.; Wang, Z.; Kan, L.; Mao, Y.; Zhu, Y.; Liu, L. Chem. Sci. 2020, 11, 2414.
7. [7]
  Qi, Y.; Zhang, F.; Wang, L.; Feng, A.; Zhu, R.; Sun, S.; Li, W.; Liu, L. Org. Biomol. Chem. 2020, 18, 3522.
8. [8]
  (a) Beatty, J. W.; Stephenson, C. R. J. Acc. Chem. Res. 2015, 48, 1474.
  (b) Enders, D.; Reinhold, U. Tetrahedron: Asymmetry 1997, 8, 1895.
  (c) Lu, Z.; Ma, S. Angew. Chem. Int. Ed. 2008, 47, 258.
  (d) Legnani, L.; Bhawal, B. N.; Morandi, B. Synthesis 2017, 49, 776.
  (e) Ellman, J. A. Pure Appl. Chem. 2003, 75, 39.
9. [9]
  (a) Jadhav, A. S.; Pankhade, Y. A.; Anand, R. V. J. Org. Chem. 2018, 83, 8596.
  (b) Jiang, F.; Yuan, F. R.; Jin, L. W.; Mei, G. J.; Shi, F. ACS Catal. 2018, 8, 10234.
  (c) Feng, Z.; Yuan, Z.; Zhao, X.; Huang, Y.; Yao, H. Org. Chem. Front. 2019, 6, 3535.
  (d) Roy, D.; Panda, G. Synthesis 2019, 51, 4434.
  (e) Torán, R.; Vila, C.; Sanz-Marco, A.; Muñoz, M.; Pedro, J.; Blay, G. Eur. J. Org. Chem. 2020, 5, 627.
  (f) Zhang, J.-R.; Jin, H.-S.; Wang, R.-B.; Zhao, L.-M. Adv. Synth. Catal. 2019, 361, 4811.
10. [10]
  (a) Otto, N.; Opatz, T. Chem. Eur. J. 2014, 20, 13064.
  (b) Huang, P. Q. Acta Chim. Sinica 2018, 76, 357(in Chinese).
  (黄培强, 化学学报, 2018, 76, 357.)
  (c) Gao, Y. J.; Xiao, Z. H.; Liu, L. X.; Huang, P. Q. Chin. J. Org. Chem. 2017, 37, 1189.
11. [11]
  Singh, M.; Schott, J. T.; Leon, M. A.; Granata, R. T.; Dhaha, H. K.; Welles, J. A.; Boyce, M. A.; Oseni-Olalemi, H. S.; Mordaunt, C. E.; Vargas, A. J.; Patel, N. V.; Maitra, S. Bioorg. Med. Chem. Lett. 2012, 22, 6252.
12. [12]
  (a) Tiffert, T.; Ginsburg, H.; Krugliak, M.; Elford, B. C.; Lew, V. L. Proc. Natl. Acad. Sci. U. S. A. 2000, 97, 331.
  (b) Saliba, K. J.; Kirk, K. Trans. R. Soc. Trop. Med. Hyg. 1998, 92, 666.
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