Acta Chim. Sinica ›› 2018, Vol. 76 ›› Issue (12): 962-966.DOI: 10.6023/A18070307 Previous Articles     Next Articles

Special Issue: 有机氟化学



田亚伟, 周刚, 赵晓明, 淡文彦   

  1. 同济大学化学科学与工程学院 上海 200092
  • 投稿日期:2018-07-30 发布日期:2018-10-08
  • 通讯作者: 赵晓明,
  • 基金资助:


Selective Fluorination of 2-Aminopyrazine Derivatives in Aqueous Phase

Tian Yawei, Zhou Gang, Zhao Xiaoming, Dan Wenyan   

  1. Tongji University, School of Chemical Science & Engineering, Shanghai 200092
  • Received:2018-07-30 Published:2018-10-08
  • Contact: 10.6023/A18070307
  • Supported by:

    Project supported by the National Natural Science Foundation of China (No. 21272175) and the Fundamental Research Funds for the Central Universities.

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'.

Key words: 2-aminopyrazine, selectfluor, fluorination, chemoselectivity, regioselectivity