Citation: Liu Qingquan, Hu Xiangguo. Application of Benzylic C-H Fluorination for the Formal Synthesis of syn-α, β-Difluoro-γ-amino Acid[J]. Chinese Journal of Organic Chemistry, ;2018, 38(6): 1525-1529. doi: 10.6023/cjoc201712020 shu

Application of Benzylic C-H Fluorination for the Formal Synthesis of syn-α, β-Difluoro-γ-amino Acid

Liu Qingquan ,
Hu Xiangguo ^,

National Engineering Research Center for Carbohydrate Synthesis, Jiangxi Normal University, Nanchang 330022

Corresponding author: Hu Xiangguo, huxiangg@iccas.ac.cn
Received Date: 13 December 2017
Revised Date: 19 January 2018
Available Online: 6 June 2018
Fund Project: the National Natural Science Foundation of China 21502076the Outstanding Young Talents Scheme of Jiangxi Province 20171BCB23039Project supported by the National Natural Science Foundation of China (No. 21502076) and the Outstanding Young Talents Scheme of Jiangxi Province (No. 20171BCB23039)

Figures(3)

Benzylic C-H fluorination has emerged as a valuable tool for the introduction of fluorine. However, the powerfulness of benzylic C-H fluorination has not been tested in any multi-step synthesis. α, β-Difluoro-γ-amino acids are useful entities for biological application owing to the so-called fluorine conformational effect. In this work, benzylic C-H fluorination has been successfully utilized as the key step for the formal synthesis of syn-α, β-difluoro-γ-amino acid 1, a very challenging but useful target. The approach developed in this work could be viewed as more practical compared to the previous one, because:(1) no corrosive and toxic nucleophilic fluorinating reagents are used, (2) the overall yield is 18% (the previous approach is about 5%), and (3) the key benzylic C-H reaction developed by Chen and co-workers was scaled up to one gram without decreasing its original efficiency. A striking fluorine effect was observed:a carbon with one fluorine atom on the adjacent carbon is much less reactive than an ordinary carbon for the benzylic C-H fluorination.
- C-H fluorination,
- organofluorine,
- amino acid
1. [1]
  (a) Champagne, P. A. ; Desroches, J. ; Hamel, J. D. ; Vandamme, M. ; Paquin, J. F. Chem. Rev. 2015, 115, 9073.
  (b) Rong, J. ; Ni, C. ; Wang, Y. ; Kuang, C. ; Gu, Y. ; Hu, J. Acta Chim. Sinica 2017, 75, 105(in Chinese).
  (荣健, 倪传法, 王云泽, 匡翠文, 顾玉诚, 胡金波, 化学学报, 2017, 75, 1, 105. )
  (c) Zhang, P. ; Lu, L. ; Shen, Q. Acta Chim. Sinica 2017, 75, 744(in Chinese).
  (张盼盼, 吕龙, 沈其龙, 化学学报, 2017, 75, 744. )
  (d) He, J. ; Lou, S. ; Xu, D. Chin. J. Org. Chem. 2016, 36, 1218(in Chinese).
  (何将旗, 娄绍杰, 许丹倩, 有机化学, 2016, 36, 1218. )
  (e) Gu, Y. ; Lu, C. ; Gu, Y. ; Shen, Q. Chin. J. Chem. 2018, 36, 55.
2. [2]
  Koperniku, A.; Liu, H.; Hurley, P. B. Eur.J.Org. Chem. 2016, 871.
3. [3]
  Bloom, S.; Pitts, C. R.; Miller, D. C.; Haselton, N.; Holl, M. G.; Urheim, E.; Lectka, T. Angew.Chem., Int.Ed. 2012, 51, 10580. doi: 10.1002/anie.201203642
4. [4]
  Pitts, C. R.; Bloom, S.; Woltornist, R.; Auvenshine, D. J.; Ryzhkov, L. R.; Siegler, M. A.; Lectka, T. J.Am.Chem.Soc. 2014, 136, 9780. doi: 10.1021/ja505136j
5. [5]
  Bloom, S.; Pitts, C. R.; Woltornist, R.; Griswold, A.; Holl, M. G.; Lectka, T. Org.Lett. 2013, 15, 1722. doi: 10.1021/ol400424s
6. [6]
  Bloom, S.; Sharber, S. A.; Holl, M. G.; Knippel, J. L.; Lectka, T. J. Org.Chem. 2013, 78, 11082. doi: 10.1021/jo401796g
7. [7]
  Liu, W.; Groves, J. T. Angew.Chem., Int.Ed. 2013, 52, 6024. doi: 10.1002/anie.201301097
8. [8]
  Amaoka, Y.; Nagatomo, M.; Inoue, M. Org.Lett. 2013, 15, 2160. doi: 10.1021/ol4006757
9. [9]
  Xu, P.; Guo, S.; Wang, L.; Tang, P. Angew.Chem., Int. Ed. 2014, 53, 5955. doi: 10.1002/anie.201400225
10. [10]
  Nodwell, M. B.; Bagai, A.; Halperin, S. D.; Martin, R. E.; Knust, H.; Britton, R. Chem.Commun. 2015, 51, 11783. doi: 10.1039/C5CC04058B
11. [11]
  Xia, J.-B.; Zhu, C.; Chen, C. J.Am. Chem.Soc. 2013, 135, 17494. doi: 10.1021/ja410815u
12. [12]
  Bloom, S.; Knippel, J. L.; Lectka, T. Chem. Sci. 2014, 5, 1175. doi: 10.1039/C3SC53261E
13. [13]
  Bloom, S.; McCann, M.; Lectka, T. Org.Lett. 2014, 16, 6338. doi: 10.1021/ol503094m
14. [14]
  Cantillo, D.; de Frutos, O.; Rincon, J. A.; Mateos, C.; Kappe, C. O. J.Org.Chem. 2014, 79, 8486. doi: 10.1021/jo5016757
15. [15]
  Ma, J.-J.; Yi, W.-B.; Lu, G.-P.; Cai, C. Org. Biomol.Chem. 2015, 13, 2890. doi: 10.1039/C4OB02418D
16. [16]
  Huang, X.; Liu, W.; Ren, H.; Neelamegam, R.; Hooker, J. M.; Groves, J. T. J.Am.Chem.Soc. 2014, 136, 6842. doi: 10.1021/ja5039819
17. [17]
  Carroll, L.; Evans, H. L.; Spivey, A. C.; Aboagye, E. O. Chem.Commun. 2015, 51, 8439. doi: 10.1039/C4CC05762G
18. [18]
  Zimmer, L. E.; Sparr, C.; Gilmour, R. Angew. Chem., Int.Ed. 2011, 50, 11860. doi: 10.1002/anie.v50.50
19. [19]
  Hunter, L. Beilstein J.Org.Chem. 2010, 6.
20. [20]
  O'Hagan, D. Chem.Soc.Rev. 2008, 37, 308. doi: 10.1039/B711844A
21. [21]
  (a) Hunter, L. ; Jolliffe, K. A. ; Jordan, M. J. T. ; Jensen, P. ; Macquart, R. B. Chem. -Eur. J. 2011, 17, 2340.
  (b) Yamamoto, I. ; Jordan, M. J. T. ; Gavande, N. ; Doddareddy, M. R. ; Chebib, M. ; Hunter, L. Chem. Commun. 2012, 48, 829.
22. [22]
  Hu, X. G.; Thomas, D. S.; Griffith, R.; Hunter, L. Angew.Chem.Int.Ed. 2014, 53, 6176. doi: 10.1002/anie.201403071
23. [23]
  Hunter, L.; Butler, S.; Ludbrook, S. B. Org. Biomol.Chem. 2012, 10, 8911. doi: 10.1039/c2ob26596f
24. [24]
  Patel, A. R.; Hu, X. G.; Lawer, A.; Ahmed, M. I.; Au, C.; Jwad, R.; Trinh, J.; Gonzalez, C.; Hannah, E.; Bhadbhade, M. M.; Hunter, L. Tetrahedron 2016, 72, 3305. doi: 10.1016/j.tet.2016.04.070
25. [25]
  Beeson, T. D.; MacMillan, D. W. C. J.Am. Chem.Soc. 2005, 127, 8826. doi: 10.1021/ja051805f
26. [26]
  Steiner, D. D.; Mase, N.; Barbas, C. F. Angew. Chem., Int.Ed. 2005, 44, 3706. doi: 10.1002/(ISSN)1521-3773
27. [27]
  Marigo, M.; Fielenbach, D. I.; Braunton, A.; Kjoersgaard, A.; Jorgensen, K. A. Angew.Chem., Int.Ed. 2005, 44, 3703. doi: 10.1002/(ISSN)1521-3773
28. [28]
  Fadeyi, O. O.; Lindsley, C. W. Org.Lett. 2009, 11, 943. doi: 10.1021/ol802930q
29. [29]
  (a) Ni, C. F. ; Hu, J. B. Chem. Soc. Rev. 2016, 45, 5441.
  (b) Ni, C. F. ; Hu, M. Y. ; Hu, J. B. Chem. Rev. 2015, 115, 765.
30. [30]
  (a) Ni, C. ; Li, Y. ; Hu, J. J. Org. Chem. 2006, 71, 6829.
  (b) Zhang, W. ; Ni, C. ; Hu, J. Top. Curr. Chem. 2012, 308, 25.
31. [31]
  Ma, H.; Chen, G.; Wang, T.; Li, Q.; Liu, Y. Chem. Biol.Drug Des. 2016, 88, 363. doi: 10.1111/cbdd.2016.88.issue-3
1. [1]
  Xiao Tang , Erik V. Van der Eycken , Liangliang Song . Transition metal-catalyzed C-H activation/annulation for the construction of unnatural amino acids and peptides. Chinese Chemical Letters, 2026, 37(2): 111678-. doi: 10.1016/j.cclet.2025.111678
2. [2]
  Hong CAI , Jiewen WU , Jingyun LI , Lixian CHEN , Siqi XIAO , Dan LI . Synthesis of a zinc-cobalt bimetallic adenine metal-organic framework for the recognition of sulfur-containing amino acids. Chinese Journal of Inorganic Chemistry, 2025, 41(1): 114-122. doi: 10.11862/CJIC.20240382
3. [3]
  Weimei Zeng , Youai Qiu . Electrochemical C-H carboxylation of benzylamines. Chinese Chemical Letters, 2026, 37(1): 111679-. doi: 10.1016/j.cclet.2025.111679
4. [4]
  Dingding Xia , Chundong Huang , Zhimin Hu , Zhiyong Leng , Miaomiao Zhuo , Shoubhik Das , Shaofei Ni , Yu Zhang , Weidong Zhang . Tandem N–H insertion/C–H functionalization-S_N1 reaction to access unnatural amino esters and the concise synthesis of Streptindole and Arsindoline B. Chinese Chemical Letters, 2026, 37(10): 112224-. doi: 10.1016/j.cclet.2025.112224
5. [5]
  Dong-Fang Jiang , Fei Zeng , Rong-Nan Yi , Wei-Min He . Three-component synthesis of β-acyloxyl alkenyl amides for carboxylic acid/amino acid activation toward peptide and carboxylic acid derivatives synthesis. Chinese Chemical Letters, 2026, 37(7): 112488-. doi: 10.1016/j.cclet.2026.112488
6. [6]
  Wei-Bin Li , Xiao-Chao Huang , Pei Liu , Jie Kong , Guo-Ping Yang . Recent advances in directing group assisted transition metal catalyzed para-selective C-H functionalization. Chinese Chemical Letters, 2025, 36(6): 110543-. doi: 10.1016/j.cclet.2024.110543
7. [7]
  Shihaozhi Wang , Jia-Hui Shi , Shan Xu , Xue-Jing Zhang , Ming Yan . Palladium-catalyzed carbene C-H insertion reaction of non-activated arenes. Chinese Chemical Letters, 2026, 37(4): 111225-. doi: 10.1016/j.cclet.2025.111225
8. [8]
  Xin-Juan Wang , Yao-Hang Cheng , Xin-Yan Lv , Li-Ye Liang , Guang-Hui An , Guang-Ming Li . Ruthenium-catalyzed alkylarylation of alkenes via para-selective C-H functionalization of unprotected anilines. Chinese Chemical Letters, 2026, 37(8): 112154-. doi: 10.1016/j.cclet.2025.112154
9. [9]
  Mengyao Yuan , Wansen Xie , Xiaoyu Yang . Enantioselective synthesis of inherently chiral calix[4]arenes via asymmetric C-H bromination of phenols. Chinese Chemical Letters, 2026, 37(9): 112157-. doi: 10.1016/j.cclet.2025.112157
10. [10]
  Yanjie Lv , Xinyu Zhao , Jing Sun , Huiying Sun , Wenxi Zhang , Yuhan Cui , Xiao Li , Zhongmin Su . Atomic-level regulation of POMOF homologous isomer for photocatalytic C-H bond oxidation. Chinese Chemical Letters, 2026, 37(10): 113018-. doi: 10.1016/j.cclet.2026.113018
11. [11]
  Shaofeng Gong , Zi-Wei Deng , Chao Wu , Wei-Min He . Stabilized carbon radical-mediated three-component functionalization of amino acid/peptide derivatives. Chinese Chemical Letters, 2025, 36(5): 110936-. doi: 10.1016/j.cclet.2025.110936
12. [12]
  Qiang Luo , Jinfeng Sun , Zhibo Li , Bin Liu , Jianxun Ding . Thermo-sensitive poly(amino acid) hydrogel mediates cytoprotection through an antioxidant mechanism. Chinese Chemical Letters, 2025, 36(7): 110433-. doi: 10.1016/j.cclet.2024.110433
13. [13]
  Qi Wei , Hua Xin , Xiaolong Wang , Changjuan Qin , Yuanzhen Su , Di Li , Jianxun Ding . Unimolecular chiral poly(amino acid)s as adjuvants of nanovaccines for augmented cancer immunotherapy. Chinese Chemical Letters, 2025, 36(11): 111477-. doi: 10.1016/j.cclet.2025.111477
14. [14]
  Shulei Hu , Yu Zhang , Xiong Xie , Luhan Li , Kaixian Chen , Hong Liu , Jiang Wang . Rh(Ⅲ)-catalyzed late-stage C-H alkenylation and macrolactamization for the synthesis of cyclic peptides with unique Trp(C7)-alkene crosslinks. Chinese Chemical Letters, 2024, 35(8): 109408-. doi: 10.1016/j.cclet.2023.109408
15. [15]
  Yongli Zhao , Dingsheng Cao , Jie-Ping Wan , Yunyun Liu . Synthesis of 3-phosphinyl chromones via in situ iodination mediated C-H phosphination and the tunable synthesis of 2-phosphoryl chromanones. Chinese Chemical Letters, 2026, 37(1): 111740-. doi: 10.1016/j.cclet.2025.111740
16. [16]
  Yiyue Ding , Qiuxiang Zhang , Lei Zhang , Qilu Yao , Gang Feng , Zhang-Hui Lu . Exceptional activity of amino-modified rGO-immobilized PdAu nanoclusters for visible light-promoted dehydrogenation of formic acid. Chinese Chemical Letters, 2024, 35(7): 109593-. doi: 10.1016/j.cclet.2024.109593
17. [17]
  Shuang Zhao , Fei Jia , Kaibei Zhan , Rui-Xi Wang , Pengfei Tan , Lin Shen , Li-Ming Wu , Ling Chen . Amino substitution strategy achieves significant blue shift while preserving high optical anisotropy: A₂(H₃C₃N₄S₂)₂•H₂O (A =NH₄, K, Rb, Cs). Chinese Chemical Letters, 2026, 37(3): 110625-. doi: 10.1016/j.cclet.2024.110625
18. [18]
  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
19. [19]
  Fengzhi Wang , Ke Hu , Jinquan Chen , Zhubin Hu , Haitao Sun , Tony D. James , Yufang Xu , Xuhong Qian . Meta-amino substituted naphthalimides exhibit large charge transfer and strong N-H vibrations enabling use as ratiometric fluorescent probe. Chinese Chemical Letters, 2026, 37(1): 110971-. doi: 10.1016/j.cclet.2025.110971
20. [20]
  Jing Ren , Feng-Huan Du , Xiaowei Chen , Chi Zhang . Monofluoroiodane(Ⅲ) reagent mediated Wagner−Meerwein rearrangement fluorination: Construction of quaternary C(sp³)−F bond. Chinese Chemical Letters, 2026, 37(5): 111407-. doi: 10.1016/j.cclet.2025.111407

Get Citation

PDF

XML

Metrics

PDF Downloads(38)
Abstract views(2790)
HTML views(247)

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