Citation: Tian Yawei, Zhou Gang, Zhao Xiaoming, Dan Wenyan. Selective Fluorination of 2-Aminopyrazine Derivatives in Aqueous Phase[J]. Acta Chimica Sinica, ;2018, 76(12): 962-966. doi: 10.6023/A18070307 shu

Selective Fluorination of 2-Aminopyrazine Derivatives in Aqueous Phase

Tongji University, School of Chemical Science & Engineering, Shanghai 200092

Corresponding author: Zhao Xiaoming, xmzhao08@mail.tongji.edu.cn
Received Date: 30 July 2018
Available Online: 8 December 2018
Fund Project: Project supported by the National Natural Science Foundation of China (No. 21272175) and the Fundamental Research Funds for the Central Universitiesthe Fundamental Research Funds for the Central Universities the National Natural Science Foundation of China 21272175

Figures(4)

2-Aminopyrazines are widely found in naturally occurring compounds, drugs and biologically active ingredients. Especially, the compounds containing a fluorinated aminopyrazine have been applied in the pharmaceutical industry. The introduction of a fluorine atom into organic compounds generally leads to a significant change in the chemical, physical and biological properties. Therefore, new method for introducing a fluorine atom into the aminopyrazine ring is highly desirable. Traditional Balz-Schiemann reaction is difficult to employ in the preparation of fluorinated aminopyrazines because of the decomposition of pyrazine derivatives under strong acidic conditions. In general, pyrazines can take place nucleophilic fluorination; aminopyrazines, which is activated by an amino group, can occur electronphilic halogenation; the radical fluorination of pyrazine derivatives has not reported yet. We envisage a direct fluorination of 2-aminopyrazines with Selectfluor may proceed under mild conditions. In this paper, the fluorination of 2-aminopyrazine derivatives with Selectfluor in aqueous phase was studied, and a transition-metal free fluorination of 2-aminopyrazine derivatives was developed. The method affords 5-fluoro-2-aminopyrazines in good yield with excellent chemoselectivity and high regioselectivity. The results suggested that the fluorination may undergo a radical process. Using this method, an enzyme inhibitor having a certain inhibitory effect on analog of B-Raf enzyme was synthesized. The synthesis was as follows: 6-phenyl-2-aminopyrazine (1a, 0.2 mmol), selectfluor (2a, 0.1 mmol), toluene:water [V(toluene):V(water)＝1:1, 2 mL] in a reaction tube. The reaction was carried out at room temperature, monitoring by ¹⁹F NMR. After the completion of the reaction, the reaction mixture was cooled, diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated and purified by silica gel column chromatography (petroleum ether/ethyl acetate) to give 5-fluoro-2-aminopyrazines 3 and 3-fluoro-2-aminopyrazines 3'.
- 2-aminopyrazine,
- selectfluor,
- fluorination,
- chemoselectivity,
- regioselectivity
1. [1]
  (a) Vollhardt, P.; Schore, N. Organic Chemistry, Freeman Palgrave Macmillan, New York, 2011. (b) Wang, M.; Zhang, Y.; Wang, T.; Wang, C.; Xue, D.; Xiao, J. Org. Lett. 2016, 18, 1976. (c) Jean, B.; Marc, L.; Guy, Q. J. Heterocycl. Chem. 1980, 17, 257. (d) Gainer, H.; Kokorudz, M.; Langdon, W. K. J. Org. Chem. 1961, 26, 2360. (e) Bourguignon, J.; Lemarchand, M.; Quéquiner, G. J. Heterocycl. Chem. 1980, 17, 257.
2. [2]
  (a) Hart, B. P.; Haile, W. H.; Licato, N. J.; Bolanowska, W. E.; Mcguire, J. J.; Coward, J. K. J. Med. Chem. 1996, 27, 56. (b) Jhulki, I.; Chanani, P. K.; Abdelwahed, S. H.; Begley, T. P. J. Am. Chem. Soc. 2016, 138, 8324.
3. [3]
  (a) Zou, Y.; Zhao, D.; Yan, C.; Ji, Y.; Liu, J.; Xu, J.; Lai, Y.; Tian, J.; Zhang, Y.; Huang, Z. J. Med. Chem. 2018, 61, 1821. (b) Cheng, X. C.; Liu, X. Y.; Xu, W. F.; Guo, X. L.; Ou, Y. Bioorg. Med. Chem. 2007, 15, 3315. (c) Zhao, Y.; Qian, G.; Ye, Y.; Wright, S.; Chen, H.; Shen, Y.; Liu, F.; Du, L. Org. Lett. 2016, 18, 2495. (d) W chter, G. A.; Davis, M. C.; Martin, A. R.; Franzblau, S. G. J. Med. Chem. 1998, 41, 2436. (e) Kalinowski, D. S.; Sharpe, P. C.; Bernhardt, P. V.; Richardson, D. R. J. Med. Chem. 2008, 51, 331.
4. [4]
  (a) Liu, L. W.; Wang, F. Y.; Tian, F.; Peng, L.; Wang, L. X. Org. Process Res. Dev. 2016, 20, 320. (b) Ashley, J. D.; Stefanick, J. F.; Schroeder, V. A.; Suckow, M. A.; Kiziltepe, T.; Bilgicer, B. J. Med. Chem. 2014, 57, 5282. (c) Wang, G.; Wan, J.; Hu, Y.; Wu, X.; Prhavc, M.; Dyatkina, N.; Rajwanshi, V. K.; Smith, D. B.; Jekle, A.; Kinkade, A. J. Med. Chem. 2016, 59, 4611. (d) Asaki, T.; Kuwano, K.; Morrison, K.; Gatfield, J.; Hamamoto, T.; Clozel, M. J. Med. Chem. 2015, 58, 7128. (e) Guillotin, D.; Austin, P.; Begum, R.; Freitas, M. O.; Merve, A.; Brend, T.; Short, S. C.; Marino, S.; Martin, S. A. Clin. Cancer Res. 2016, 23, 2880. (f) Wang, G.; Wan, J.; Hu, Y.; Wu, X.; Prhavc, M.; Dyatkina, N.; Rajwanshi, V. K.; Smith, D. B.; Jekle, A.; Kinkade, A. J. Med. Chem. 2016, 59, 4611.
5. [5]
  (a) Ryan, S. J.; Schimler, S. D.; Bland, D. C.; Sanford, M. S. Org. Lett. 2015, 46, 1866. (b) Schimler, S. D.; Ryan, S. J.; Bland, D. C.; Anderson, J. E.; Sanford, M. S. J. Org. Chem. 2015, 80, 12137. (c) Sun, H.; DiMagno, S. G. Angew. Chem., Int. Ed. 2006, 45, 2720. (d) Kindon, N.; Andrews, G.; Baxter, A.; Cheshire, D.; Hemsley, P.; Johnson, T.; Liu, Y.; McGinnity, D.; McHale, M.; Mete, A.; Reuberson, J.; Roberts, B.; Steele, J.; Teobald, B.; Unitt, J.; Vaughan, D.; Walters, I.; Stocks, M. J. ACS Med. Chem. Lett. 2017, 8, 981.
6. [6]
  Fier, P. S.; Hartwig, J. F. Science 2013, 342, 956. doi: 10.1126/science.1243759
7. [7]
  Selectfluor made from F₂ and 1, 4-diazabicyclo[2.2.2] octane in the presence of CH₂Cl₂ and BF₃ was reported, see: (a) Banks, R. E.; Mohialdin-Khaffaf, S. N.; Lal, G. S.; Sharif, I.; Syvret, R. G. J. Chem. Soc., Chem. Commun. 1992, 23, 595. (b) Review: Nyffeler, P. T.; Durón, S. G.; Burkart, M. D.; Vincent, S. P.; Wong, C. H. Angew. Chem., Int. Ed. 2004, 36, 192. (c) Account: Singh, R. P.; Shreeve, J. M. Acc. Chem. Res. 2004, 37, 31.
8. [8]
  CCDC 1826147 for 3a contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Center.
9. [9]
  CCDC 1847836 for 3a' contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Center.
10. [10]
  (a) Gahman, T. C.; Lang, H.; Davis, R. L.; Scranton, S. A. WO 2006124874, 2006[Chem. Abstr. 2006, 146, 13164]. (b) Yin, J.; Zhao, M. M.; And, M. A. H.; Mcnamara, J. M. Org. Lett. 2002, 4, 3481.
1. [1]
  Shihui Shi , Haoyu Li , Shaojie Han , Yifan Yao , Siqi Liu . Regioselectively Synthesis of Halogenated Arenes via Self-Assembly and Synergistic Catalysis Strategy. University Chemistry, 2024, 39(5): 336-344. doi: 10.3866/PKU.DXHX202312002
2. [2]
  Danqing Wu , Jiajun Liu , Tianyu Li , Dazhen Xu , Zhiwei Miao . Research Progress on the Simultaneous Construction of C—O and C—X Bonds via 1,2-Difunctionalization of Olefins through Radical Pathways. University Chemistry, 2024, 39(11): 146-157. doi: 10.12461/PKU.DXHX202403087
3. [3]
  Yaqin Zheng , Lian Zhuo , Meng Li , Chunying Rong . Enhancing Understanding of the Electronic Effect of Substituents on Benzene Rings Using Quantum Chemistry Calculations. University Chemistry, 2025, 40(3): 193-198. doi: 10.12461/PKU.DXHX202406119
4. [4]
  Jun LUO , Baoshu LIU , Yunchang ZHANG , Bingkai WANG , Beibei GUO , Lan SHE , Tianheng CHEN . Europium(Ⅲ) metal-organic framework as a fluorescent probe for selectively and sensitively sensing Pb²⁺ in aqueous solution. Chinese Journal of Inorganic Chemistry, 2024, 40(12): 2438-2444. doi: 10.11862/CJIC.20240240
5. [5]
  Peng YUE , Liyao SHI , Jinglei CUI , Huirong ZHANG , Yanxia GUO . Effects of Ce and Mn promoters on the selective oxidation of ammonia over V₂O₅/TiO₂ catalyst. Chinese Journal of Inorganic Chemistry, 2025, 41(2): 293-307. doi: 10.11862/CJIC.20240210
6. [6]
  Jie ZHAO , Sen LIU , Qikang YIN , Xiaoqing LU , Zhaojie WANG . Theoretical calculation of selective adsorption and separation of CO₂ by alkali metal modified naphthalene/naphthalenediyne. Chinese Journal of Inorganic Chemistry, 2024, 40(3): 515-522. doi: 10.11862/CJIC.20230385
7. [7]
  Yunhao Zhang , Yinuo Wang , Siran Wang , Dazhen Xu . Progress in Selective Construction of Functional Aromatics from Nitrogenous Cycloalkanes. University Chemistry, 2024, 39(11): 136-145. doi: 10.3866/PKU.DXHX202401083
8. [8]
  Peiran ZHAO , Yuqian LIU , Cheng HE , Chunying DUAN . A functionalized Eu³⁺ metal-organic framework for selective fluorescent detection of pyrene. Chinese Journal of Inorganic Chemistry, 2024, 40(4): 713-724. doi: 10.11862/CJIC.20230355
9. [9]
  Xilin Zhao , Xingyu Tu , Zongxuan Li , Rui Dong , Bo Jiang , Zhiwei Miao . Research Progress in Enantioselective Synthesis of Axial Chiral Compounds. University Chemistry, 2024, 39(11): 158-173. doi: 10.12461/PKU.DXHX202403106
10. [10]
  Jiakun BAI , Ting XU , Lu ZHANG , Jiang PENG , Yuqiang LI , Junhui JIA . A red-emitting fluorescent probe with a large Stokes shift for selective detection of hypochlorous acid. Chinese Journal of Inorganic Chemistry, 2024, 40(6): 1095-1104. doi: 10.11862/CJIC.20240002
11. [11]
  .
  CCS Chemistry | 超分子活化底物为自由基促进高效选择性光催化氧化
  . CCS Chemistry, 2025, 7(10.31635/ccschem.025.202405229): -.
12. [12]
  Yinuo Wang , Siran Wang , Yilong Zhao , Dazhen Xu . Selective Synthesis of Diarylmethyl Anilines and Triarylmethanes via Multicomponent Reactions: Introduce a Comprehensive Experiment of Organic Chemistry. University Chemistry, 2024, 39(8): 324-330. doi: 10.3866/PKU.DXHX202401063
13. [13]
  Junjie Zhang , Yue Wang , Qiuhan Wu , Ruquan Shen , Han Liu , Xinhua Duan . Preparation and Selective Separation of Lightweight Magnetic Molecularly Imprinted Polymers for Trace Tetracycline Detection in Milk. University Chemistry, 2024, 39(5): 251-257. doi: 10.3866/PKU.DXHX202311084
14. [14]
  Baitong Wei , Jinxin Guo , Xigong Liu , Rongxiu Zhu , Lei Liu . Theoretical Study on the Structure, Stability of Hydrocarbon Free Radicals and Selectivity of Alkane Chlorination Reaction. University Chemistry, 2025, 40(3): 402-407. doi: 10.12461/PKU.DXHX202406003
15. [15]
  Xiufang Wang , Donglin Zhao , Kehua Zhang , Xiaojie Song . “Preparation of Carbon Nanotube/SnS₂ Photoanode Materials”: A Comprehensive University Chemistry Experiment. University Chemistry, 2024, 39(4): 157-162. doi: 10.3866/PKU.DXHX202308025
16. [16]
  Wenliang Wang , Weina Wang , Lixia Feng , Nan Wei , Sufan Wang , Tian Sheng , Tao Zhou . Proof and Interpretation of Severe Spectroscopic Selection Rules. University Chemistry, 2025, 40(3): 415-424. doi: 10.12461/PKU.DXHX202408063
17. [17]
  Yonghui Wang , Weilin Chen , Yangguang Li . Knowledge Construction of “Solubility of Inorganic Substances” in Elemental Chemistry Teaching. University Chemistry, 2024, 39(4): 261-267. doi: 10.3866/PKU.DXHX202312102
18. [18]
  Lei Shi . Nucleophilicity and Electrophilicity of Radicals. University Chemistry, 2024, 39(11): 131-135. doi: 10.3866/PKU.DXHX202402018
19. [19]
  Kai Yang , Gehua Bi , Yong Zhang , Delin Jin , Ziwei Xu , Qian Wang , Lingbao Xing . Comprehensive Polymer Chemistry Experiment Design: Preparation and Characterization of Rigid Polyurethane Foam Materials. University Chemistry, 2024, 39(4): 206-212. doi: 10.3866/PKU.DXHX202308045
20. [20]
  Wenkai Chen , Yunjia Shen , Xiangmeng Kong , Yanli Zeng . Quantum Chemistry Calculation of Key Physical Quantity in Circularly Polarized Luminescence: Introducing an Exploratory Computational Chemistry Experiment. University Chemistry, 2025, 40(3): 83-91. doi: 10.12461/PKU.DXHX202405018

Get Citation

PDF

XML

Metrics

PDF Downloads(16)
Abstract views(996)
HTML views(67)

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