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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'.

  • 1.   引言

    吡嗪(pyrazine)是1、4位含两个氮杂原子的六元芳杂环化合物, 分子式为C4H4N2, 与嘧啶和哒嗪互为同分异构体, 其气味和芳香性与吡啶类似, 它是一个很弱的碱.吡嗪环不易发生亲电取代反应, 易和亲核试剂反应[1].吡嗪片段广泛存在于天然产物[2]、生物活性分子[3]以及药物分子[4]中.譬如, 吡嗪存在于叶酸结构中, 是叶酸中蝶呤的组成部分, 叶酸参与氨基酸代谢, 并与维生素B12(riboflavin)共同促进红细胞的生成和成熟[2a].特拉普韦[4a]是治疗C型丙肝的药物, 通过阻断丙肝病毒的复制来起作用.硼替佐米[4b]临床用于治疗多发性骨髓瘤.值得注意的是, 特拉普韦和硼替佐米两种药物都含有“吡嗪片段”(图 1).一般来说, 吡嗪骨架上引入氟原子可以导致其药物活性的显著提高.代表性例子, 如:法匹拉韦, 其分子结构中存在“氟代吡嗪片段”[4c].法匹拉韦是RNA聚合酶抑制剂, 用于治疗H1N9和乙型流感等, 临床二期试验表明, 它也可用于治疗埃博拉病毒(图 1).鉴于此, 发展吡嗪衍生物的氟化新方法不仅具有理论意义, 而且更具有实际意义.

    图 1

    图 1.  一些含有吡嗪骨架的生物活性分子
    Figure 1.  Some bioactive molecules containing pyrazine motif
    下载: 全尺寸图片 幻灯片

    迄今为止, 氟代吡嗪衍生物的合成方法报道很少, 仅有通过芳香亲核取代的反应合成氟代吡嗪的报道[5].通常, 芳香化合物经硝化、硝基还原、然后进行Balz- Schiemann反应是在芳环上引入氟原子的传统方法, 但该方法很难用于氟代吡嗪衍生物的合成, 因为吡嗪衍生物在强酸性条件下易于分解.在吡嗪环上导入一个氨基是解决其不易发生氟化反应的有效策略.一方面氨基能够活化吡嗪环, 增加吡嗪环的电子云密度; 另一方面氨基可以进行多种官能团之间的相互转换, 提高氟代吡嗪的应用价值.代表性的氨基吡嗪化合物, 如: 2-氨基吡嗪化合物, 其是重要的中间体, 广泛应用于医药制造工业[4].值得注意的是, 2-氨基吡嗪衍生物的氟化新方法尚未有文献报道.这里报道了6-取代2-氨基吡嗪衍生物与1-氯甲基-4-氟-1, 4-重氮化二环2, 2, 2-辛烷双(四氟硼酸)盐(Selectfluor)的氟化反应, 该反应可生成5-氟-6-芳基-2-氨基吡嗪衍生物.

    2.   结果与讨论

    2.1   反应条件的优化

    以6-苯基-2-氨基吡嗪(1a)为底物, 开展氟化反应的研究. Hartwing报道了两例吡嗪化合物与二氟化银(AgF2)的氟化反应[6], 据此我们尝试了吡嗪底物1a与AgF2的氟化反应, 即: 1.0 equiv.的1a与3.0 equiv.的AgF2于乙腈(acetonitrile)溶剂中室温下反应.遗憾的是, 并没有观察到氟化产物(表 1, Entry 1).令人惊喜的是, 用Selectfluor[7] (2a)代替AgF2进行氟化反应时, 观察到了痕量的5-氟-6-苯-2-氨基吡嗪(3a); 未见3-氟-6-苯-2-氨基吡嗪(3a'); 也未见苯环氟化产物(Entry 2).受此结果的鼓舞, 我们还考察了溶剂对该氟化反应的影响.尝试了一系列不同的溶剂, 包括:二氯甲烷(DCM)、甲苯(toluene)、四氢呋喃(THF)和乙腈(acetonitrile); 其中, 于二氯甲烷(DCM)和甲苯(toluene)中, 该反应均能得到近7%收率的氟化产物(3a)和痕量的(3a'); 在四氢呋喃(THF)和乙腈(acetonitrile)中, 仅得到痕量的氟化产物(3a) (Entries 2~5).意料之外的是, 这种对位选择性与文献报道的结果[1b~1e]不一致.吡嗪环的电子结构具有缺电性, 易进行亲核反应; 当吡嗪环被供电基团(烷基和氨基等)活化后, 也能进行亲电卤化反应; 但反应通常发生在活化基团的邻位[1b~1e].除此之外, 6-苯基-2-氨基吡嗪(1a)的3-位位阻也比5-位的位阻效应小, 所以应该得到更多3-位的氟化产物.另外, 考虑水有利于Selectfluor (2a)的溶解, 尝试使用混合溶剂.有趣的是, 当使用甲苯(toluene)：水(H2O) (V：V＝1：1)为溶剂时, 以26%的收率和较好的区域选择性(3a：3a', 4：1)得到了氟代吡嗪产物(Entry 7). Selectfluor具有氧化性, 我们也确实观察到了吡嗪化合物在过量Selectfluor存在下分解现象; 由此, 尝试通过改变吡嗪底物(1a)与Selectfluor (2a)之间的比例来避免发生分解现象.当1a与Selectfluor (2a)的比例为2：1时, 该氟化反应能达到63%的总收率和好的区域选择性(3a：3a', 5：1) (Entry 8).深入考察温度对该氟化反应的影响.实验数据表明:当温度降低至15 ℃时会导致收率降低; 温度升高至35 ℃时, 该反应的总收率没有明显的提升, 两种氟化产物的选择性略有降低(Entries 9~10).另外, 在该反应体中额外添加自由基阻聚剂2, 2, 6, 6-四甲基哌啶氧化物(2, 2, 6, 6-tetramethylpiperidine-1-oxyl, TEMPO)时, 未观察到氟化的吡嗪产物.这些结果表明:该反应可能经历了自由基过程(Entry 11).最后, 考察了不同的氟源, 如: N-氟代双苯磺酰胺(N-Fluorobenzenesulfonimide, NFSI)和氟化银(AgF), 发现并没有氟化产物生成(Entries 12~13).通过条件的筛选, 确定了该氟化反应的最佳条件, 即:甲苯和水为混合溶剂, 室温下反应.再有, 5-氟-6-苯基-2-氨基吡嗪(3a)和3-氟-6-苯基-2-氨基吡嗪(3a')分别在乙酸乙酯和正己烷混合溶剂中培养出了单晶, 通过四圆X光单晶衍射分析确定了它们的结构(图 2和3)[8, 9].

    表 1

    表 1  6-苯基-2-氨基吡嗪(1a)氟化反应的条件筛选a
    Table 1.  Optimizing the reaction conditions for the fluorination of 6-phenyl-2-aminopyrazine 1a
    下载: 导出CSV
    Entry F source 2 Additive Solvent Temp./℃ 3ab/% 3a'b/%
    1 AgF2 — MeCN 25 — —
    2 selectfluor — MeCN 25 trace —
    3 selectfluor — DCM 25 6 trace
    4 selectfluor — toluene 25 7 trace
    5 Selectfluor THF 25 trace —
    6 selectfluor — DCM：H2Oc 25 20 6
    7 selectfluor — Toluene：H2Oc 25 26 7
    8d selectfluor — Toluene：H2Oc 25 63 11
    9d selectfluor — Toluene：H2Oc 15 38 8
    10d selectfluor — Toluene：H2Oc 35 41 10
    11d selectfluor TEMPO Toluene：H2Oc 25 trace trace
    12d NFSI — Toluene：H2Oc 25 trace trace
    13d AgF — Toluene：H2Oc 25 — —
    a Reaction conditions: 1a (0.10 mmol, 1.0 equiv.), 2 (0.12 mmol, 1.2 equiv.) in solvent (2.0 mL) at appropriate temperature in a sealed tube for 8 h. b Determined by 19F NMR using 1-fluoronaphthalene (1.0 equiv.) as an internal standard. c solvent：H2O is 1：1 (V：V). d 1a：2 (2：1).

    图 2

    图 2.  6-苯基-2-氨基-5-氟吡嗪化合物3a的X射线单晶衍射分子结构图
    Figure 2.  X-ray single crystal diffraction hierarchical structure of 6- phenyl-2- amino-5-fluoropyrazine 3a
    下载: 全尺寸图片 幻灯片

    图 3

    图 3.  6-苯基-2-氨基-3-氟吡嗪化合物3a'的X射线单晶衍射分子结构图
    Figure 3.  X-ray single crystal diffraction hierarchical structure of 6- phenyl-2-amino-3-fluoropyrazine 3a'
    下载: 全尺寸图片 幻灯片

    2.2   底物的普适性

    建立了6-取代的2-氨基吡嗪氟化方法后, 我们对底物的普适性进行了考察.首先, 探索了芳基上官能团的电子效应对氟化反应的影响.对于苯基取代的2-氨基吡嗪底物(1a)和苯环上有甲基(Me)取代的2-氨基吡嗪底物(1b~1h), 无论甲基(Me)在苯环的邻位(o-Me)、间位(m-Me)、对位(p-Me), 以及双甲基取代的2-氨基吡嗪底物(1e~1d)都能以中等到良好的收率得到5-氟-6-取代- 2-氨基吡嗪化合物(表 2, 3a~3f), 反应的区域选择性在3：1至4：1之间.当苯环上连有甲氧基取代基的2-氨基吡嗪底物(1g~1i), 无论甲氧基在苯环的邻位、间位、对位, 都可以得到良好的收率, 且区域选择性都在3：1至5：1区间(表 2, 3g~3i).对于苯环上连有氯取代的2-氨基吡嗪底物(1j~1k), 无论间位取代, 还是对位取代, 均能得到中等收率的氟化产物(3j~3k); 区域选择性在4：1至5：1之间(表 2, 3j~3k).对于苯环上连有其它类型的吸电子取代基, 如:氟(F), 氰基(CN), 反应不能很好的进行.值得关注的是, 该反应体系也适用于杂环取代的2-氨基吡嗪底物的氟化反应, 以65%收率和好的区域选择性得到目标化合物(表 2, 1l).在上述所有反应中, 尚未发现苯环上的氟化产物; 所有生成的氟化产物3和3'都很容易通过硅胶柱层析方法分离.

    表 2

    表 2  6-取代2-氨基吡嗪底物(1)的普适性a, b, c
    Table 2.  Scope of 6-substituted 2-aminopyrazine substrates 1
    下载: 导出CSV

    2.3   氟化方法在合成生物活性分子上的应用

    此氟化方法在生物活性分子的合成上也有应用(图 4).例如, 在Pd2(dba)3, XantPhos和Cs2CO3存在下, 3-氟-6-苯基-2-氨基吡嗪(3a')与溴苯进行偶联反应, 以60%收率生成胺芳基化产物(4a), 4a是一种B-Raf酶抑制剂的类似物[10].

    图 4

    图 4.  氟化产物3a'在合成生物活性分子上的应用
    Figure 4.  The application of the fluorinated 2-aminopyrazine 3a'
    下载: 全尺寸图片 幻灯片

    3.   结论

    本工作研究了2-氨基吡嗪衍生物的直接氟化反应; 发展了无过渡金属催化2-氨基吡嗪衍生物的选择性氟化方法.该方法具有反应条件温和、化学和区域选择性较高、收率较好以及底物普适性好的特点.利用此方法, 合成了对B-Raf酶有一定抑制作用的酶抑制剂类似物.

    4.   实验部分

    所有反应除特别注明外, 都在氩气、氮气惰性气体保护下, 使用双排管严格按照无水无氧标准操作.

    5-氟-6-苯基-2-氨基吡嗪和3-氟-6-苯基-2-氨基吡嗪的合成方法:将6-苯基-2-氨基吡嗪(1a, 34.2 mg, 0.2 mmol)和selectfluor (2a, 35.4 mg, 0.1 mmol)溶于甲苯和水的混合溶剂中[V(甲苯)：V(水)＝1：1, 2 mL], 在室温下搅拌反应.以1-氟萘为内标使用19F NMR对反应进行跟踪检测分析.反应结束后, 用乙酸乙酯萃取, 饱和食盐水洗涤, 无水硫酸钠干燥, 过滤, 滤液浓缩后硅胶柱层析(石油醚:乙酸乙酯)分离纯化得氟化吡嗪产物(3a).产物的结构表征:黄色固体, m.p. 137~139 ℃, 3a：3a'＝4：1, 63%收率(11.9 mg); 1H NMR (600 MHz, CDCl3) δ: 7.59 (d, J＝1.7 Hz, 2H), 7.45 (d, J＝2.3 Hz, 1H), 7.13~7.07 (m, 1H), 4.55 (s, 2H), 2.39 (d, J＝0.9 Hz, 6H); 13C NMR (151 MHz, CDCl3) δ: 152.32 (d, J＝242.7 Hz), 152.14 (d, J＝2.3 Hz), 138.13, 137.95, 133.63 (d, J＝7.4 Hz), 131.54, 126.36 (d, J＝5.6 Hz), 125.02 (d, J＝9.6 Hz), 21.43; 19F NMR (565 MHz, CDCl3) δ: -92.34; IR (KBr) νmax: 3372, 3319, 3193, 1640, 1547, 1423, 1398, 1373, 1286, 1180 cm-1; HRMS (ESI-TOF) m/z calcd for C12H12FN3Na+ [M+Na]+: 240.0913; found 240.0900.

    B-Raf kinase inhibitor的合成方法:氩气保护下, 将3-氟-6-苯基-2-氨基吡嗪(3a, 26 mg, 0.14 mmol)、溴苯(16 mg, 0.1 mmol)、Pd2(dba)3 (1.83 mg, 0.22 mmol)、4, 5-双(二苯基膦)-9, 9-二甲基氧杂蒽(XantPhos, 2.5 mg, 0.0044 mmol)和Cs2CO3 (46 mg, 0.14 mmol)分别加入2 mL的二氧六环(dioxane)溶剂中, 反应化合物搅拌均匀后, 加热至回流, TLC跟踪反应至结束.将反应液冷却至室温, 用乙酸乙酯稀释, 饱和食盐水洗涤, 无水硫酸钠干燥, 过滤, 滤液浓缩后硅胶柱层析(石油醚：乙酸乙酯)分离得到目标化合物4a.产物的结构表征:黄色固体, m.p. 110~112 ℃, 60%收率(15.9 mg); 1H NMR (600 MHz, Chloroform-d) δ: 7.95 (dd, J＝11.1, 5.1 Hz, 3H), 7.79 (d, J＝8.0 Hz, 2H), 7.53~7.37 (m, 5H), 7.12 (t, J＝7.6 Hz, 1H), 6.85 (s, 1H); 13C NMR (151 MHz, Chloroform-d) δ: 147.62 (d, J＝4.9 Hz), 147.30 (d, J＝251.2 Hz), 140.13 (d, J＝25.0 Hz), 138.66, 136.09, 129.31, 129.20~128.87 (m), 128.92, 126.70, 125.51 (d, J＝7.2 Hz), 123.29, 119.24; 19F NMR (565 MHz, CDCl3) δ: -92.20; IR (KBr) νmax: 3419, 3320, 3058, 1615, 1600, 1521, 1497, 1452, 1400, 1305, 1203, 749, 688 cm-1; HRMS (ESI-TOF) m/z calcd for C16H13FN3+ [M+Na]+ 288.0913, found 288.0907.

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