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研究生： 薛筱瑾
Hsueh, Hsiao-Chin
論文名稱： 一、利用新穎三氮烯結構對胺類官能基的保護及去保護方法之研究 二、探討官能基的修飾對氮轉移試劑的穩定性及化學反應性之影響
1.Development of Novel Triazenes for Amine Protection and Deprotection 2.Investigation into the Stability and Reactivity of Functionalized N-Transfer Reagents
指導教授： 周鶴軒
Chou, Ho-Hsuan
學位類別： 碩士
Master
系所名稱： 理學院 - 化學系
Department of Chemistry
論文出版年： 2020
畢業學年度： 108
語文別： 中文
論文頁數： 204
中文關鍵詞： 氮轉移試劑 、重氮鹽 、重氮化合物 、三氮烯 、胺類保護基
外文關鍵詞： N-transfer reagent, Diazonium Salt, Diazo compound, Triazene, Amine protecting group
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    • 本實驗室已設計出一種新穎的第一代氮轉移試劑(N-transfer reagent)，可藉由此試劑的親電性下，與-胺基酯、-胺基醯胺等各樣的伯胺(primary amine)形成三氮烯中間體(triazene intermediate)，再進一步於溫和的弱鹼環境下扣六環的驅動力降解成其所相對應的重氮化合物與內醯胺環化合物，同時表現出相當穩定的產率。
    在結果與討論的第一部份，是針對氮轉移試劑形成的三氮烯中間體去做探討，因三氮烯化合物也能作為胺類保護基存在並可由三氟醋酸或氫氧化鉀搭配鎳鋁合金的方式去保護。因此，我們以此氮轉移反應的分子內環化作為驅動力，預期氮轉移試劑所生成的三氮烯中間體也能試著作為胺類保護基使用，並在無金屬的情況下由酸/鹼溶液或氟離子等簡易的試劑活化三氮烯並在original form下進行反向的分子內環化去保護基的反應機制。為此首先我們需要將重氮鹽試劑側鏈上的4-氟苯酚基團改為陰離子基團，在形成三氮烯時透過此陰離子使反應機制走逆闔環路徑，而此陰離子基團則是透過矽-氟鍵以及水解反應生成。在合成中，我們嘗試了關五環以及關六環的結構、不同的保護基，還有嘗試不一樣的重氮化條件來得到三氮烯保護基，試著找到合適的三氮烯結構。雖然於某些例子中順利得到了三氮烯保護基，可惜最後仍因為三氮烯的互變異構化使結構傾向azo-transfer form，而無法達成目的。
    在結果與討論的第二部份，主要是為了改善第一代氮轉移試劑本身穩定性的不足，同時降低還原副產物的生成並維持或提升該試劑原有的反應性為目標。因此，我們在第一代氮轉移試劑的苯環上引入不同的推/拉電子官能基，並以第一代氮轉移試劑的結構作為模板，奠定了第二代氮轉移試劑的製造方式；在我們得到了一系列第二代氮轉移試劑後，再透過實驗以及儀器(核磁共振儀、熱重分析儀等)追蹤並觀察，以數據結果直接比較引入官能基以後的差異性。最後，在新一代的氮轉移試劑中，其不只物性上有大幅改善，在化性方面也有出色的表現，整體來說是一個不錯的結果。

    In our laboratory, we have designed a novel N-transfer reagent, and it would reacts with α-amino ester and amide to form triazene intermediate then further degrades to its corresponding diazo and lactam via the intra-molecular lactamization.
    In the first part, we focused on the triazene. We expected the triazene generated from N-transfer reagent would be a protecting group of amine and undergo deprotection by simple reagent. To achieve this goal, we changed the 4-fluorophenol on diazonium salt into a functional group that could generate an anion group at first, and this anion was generated by cleavage of the Si-F bond or hydrolysis reaction. In order to afford this anion, we adjusted from the structure of diazonium salt, the functional groups on the side chain and the reaction conditions one by one. Try to activate the anion group through the basic solution or F- reagent and make the triazene have the driving force to conduct the de-protection.
    In the second part, improving the drawbacks of instability and side product of N-transfer reagent were our goals. Therefore, we introduced a variety of electron-donating/withdrawing functional groups on the benzene ring of N-transfer reagent to obtain a series of the second-generation N-transfer reagents. Then, we examined the improvement of the properties via experiments and instruments and compared the differences after the introduction of the functional groups. Finally, not only the stability have great improvement, but also the reactivity have excellent performance in the second-generation N-transfer reagents. Overall, it presented a good result for us.

    摘要 ................................ I 致謝 ........................................ .... VII 目錄 ............ ................................ .. VIII 圖目錄 ............................................. .. X 表目錄 ..................................... . XI 流程目錄 ......................................... XII 1. 前言 ................................................. 1 1.1 重氮鹽化合物 ............................ ... 1 重氮化合物的反應....... 1 1.2 三氮烯化合物 .............................. ... 4 1.2.1 三氮烯化合物的藥應用 ............................. 4 1.2.2 保護或生成胺類化合物 ......................... 5 1.2.3 三氮烯化合物可用於衍生其他官能基團 ............. 6 1.2.4 三氮烯用 於以苯乙炔為基礎的巨分子 .................. 7 1.3 重氮化合物 ................................ ....... 8 1.3.1 α-羰基重氮化合物 .................................. 10 1.3.2 α-重氮化合物的成 ................................ 11 1.4 研究動機 ................................ ......... 12 2. 結果與討論 .................................... 15 2.1 第一部份 ................................ ............ 15 2.1.1 實驗設計與原理 .................................. 15 2.1.2 矽酯三氮烯保護基 -形成 γ-內酯環以及胺類化合物 酯環以及胺類化合物 ........................ 16 2.1.3 矽酯三氮烯保護基 -形成 δ-內酯環以及胺類化合物 ........... 18 2.1.4 矽醚三氮烯保護基 -形成環醚化合物 以及胺類............. 21 2.1.5 乙醯氧三氮烯保護基 -形成環醚化合物 以及胺類............. 25 2.2 第二部分 ................................ ........... 27 2.2.1 實驗設計與原理 ............................... 27 2.2.2 第二代氮轉移試劑的合成 ........................ . 28 2.2.3 第二代氮轉移試劑的物性 ..................... . 39 2.2.4 第二代氮 轉移試劑的轉移反應 ................ 47 2.2.5 第二代氮轉移試劑之反應的速度追蹤 ............. . 54 3. 結論 ................................ ........ 67 4. 實驗部份 ................................... 68 4.1 General Information..................... ..... 68 4.1.1 Materials .......................... ..... 68 4.1.2 Methods ..................... ...... 68 4.1.3 Machines ............................ ..... 68 4.2 Synthesis of Result and Discussion Part I ........... 69 4.3 Synthesis of Result and Discussion Part II .......... 76 4.3.1 Start Materials of Diazonium Salt ............ 78 4.3.2 Diazonium Salt .............................. 99 4.3.3 Triazene Compound.......................... 105 4.3.4 Lactam Derivatives ........................ 111 5. 參考文獻 ........................................ 114 6. 核磁共振光譜 ....................................... 120 6.1 表 七 核磁共振光譜 ................................... 189 6.2 表 八 核磁共振光譜 ................................... 192 6.3 表 九 核磁共振光譜 ................................... 194

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