化学学报 ›› 2018, Vol. 76 ›› Issue (12): 962-966.DOI: 10.6023/A18070307 上一篇    下一篇

所属专题: 有机氟化学

研究通讯

2-氨基吡嗪衍生物在水相中的选择性氟化反应研究

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
  • 收稿日期:2018-07-30 出版日期:2018-12-15 发布日期:2018-10-08
  • 通讯作者: 赵晓明,E-mail:xmzhao08@mail.tongji.edu.cn E-mail:xmzhao08@mail.tongji.edu.cn
  • 基金资助:

    项目受国家自然科学基金(No.21272175)和同济大学中央高校基础研究基金资助.

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 Online:2018-12-15 Published:2018-10-08
  • Contact: 10.6023/A18070307 E-mail:xmzhao08@mail.tongji.edu.cn
  • Supported by:

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

2-氨基吡嗪衍生物广泛存在于天然产物、医药以及具有生物活性分子的结构中.目前含氟的氨基吡嗪化合物已在医药、农药等领域获得了应用.在活性分子中引入氟原子常常导致其化学、物理以及生物活性方面的变化,所以氨基吡嗪的氟化新方法的研究备受关注.事实上,吡嗪的氟化方法报道很少.常利用Balz-Schiemann反应将氟引入芳环,但该方法不适用吡嗪,因为Balz-Schiemann反应使用强酸,而吡嗪很容易在强酸中分解.报道了2-氨基吡嗪衍生物的氟化新方法,该方法具有反应条件温和、选择性好、收率较高等特点,并应用于B-Raf酶抑制剂类似物的合成.

关键词: 2-氨基吡嗪, selectfluor, 氟化, 化学选择性, 区域选择性

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