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研究生: 林藝芳
Lin, Yi-Fang
論文名稱: (一.) 經有機鹼催化調控區域選擇性Aza-1,4-/類Aza-1,6-加成之連續反應合成螺環/三取代四氫喹啉衍生物 (二.) 經分子內威悌反應合成螺環吡唑啉酮與1H-㗁呯[2,3-c]吡唑之衍生物
I. Base-controlled Catalytic Regioselective Aza-1,4/Formal Aza-1,6-addition Cascade Reaction for the Synthesis of Tetrahydroquinoline. II. Synthesis of Spiropentadiene Pyrazolones and 1H-Oxepino[2,3-c]pyrazoles from α,β,γ,δ-unsaturated Pyrazolones via Intramolecular Wittig Reaction
指導教授: 林文偉
Lin, Wen-Wei
口試委員: 林文偉
Lin, Wenwei
陳焜銘
Chen, Kwunmin
劉維民
Liu, Wei-Min
口試日期: 2021/06/24
學位類別: 碩士
Master
系所名稱: 化學系
Department of Chemistry
論文出版年: 2021
畢業學年度: 109
語文別: 中文
論文頁數: 294
中文關鍵詞: 有機鹼催化區域選擇性四氫喹啉衍生物化學選擇性分子內威悌反應磷-1,6-加成δ-碳-醯化
英文關鍵詞: Organobase Catalysis, Regioselective, Tetrahydroquinoline Derivatives, Chemoselective, Intramolecular Wittig Reaction, Phospha-1,6-Addition, δ-C-Acylation
DOI URL: http://doi.org/10.6345/NTNU202100782
論文種類: 學術論文
相關次數: 點閱:159下載:0
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  • (一). 本論文第一部分利用了對亞甲基苯醌及1,3-茚二酮衍生物經不同的鹼催化系統良好的控制其區域選擇性,使其合成出有良好產率的兩種具有不同骨架之四氫喹啉衍生物。透過4-二甲氨基吡啶 (DMAP) 可經過aza-1,4-加成/1,6-加成合環後得到具有螺環結構之四氫喹啉衍生物;而當使用四甲基胍 (TMG) 進行反應時,則會先得到1,4-加成後的產物,再經過重排/vinylogous 1,6-加成後得到(4+2)環加成之三取代四氫喹啉衍生物。
    (二). 本論文第二部分利用α, β, γ, δ -不飽和吡唑啉酮 (α, β, γ, δ -Unsaturated Pyrazolones) 作為起始物,在經過取代基之立體效應、反應溶劑及反應條件的優化後,可以經由化學選擇性來得到不同的產物。反應經膦-1.6-加成/氧-醯化反應後生成七元環的betaine中間體,而其中當使用的取代基立體障礙較大時,可直接進行分子內威悌反應得到七元環–1H-㗁呯[2,3-c]吡唑衍生物。但當取代基上的立體障礙較小時,則會進行δ-碳-醯化/環化/分子內威悌反應而得到五元環–螺環吡唑啉酮衍生物,此兩種產物皆可在溫和的條件得到良好的產率及選擇性,並具有良好的官能基耐受性。

    I. We developed a strategy for the regioselective synthesis of two different skeletons of tetrahydroquinoline derivatives by using para-quinone methide and 1,3-indandione derivatives under organobase catalysis. In the reaction condition using dimethylaminopyridine (DMAP) as the catalyst, the reaction underwent smoothly via aza-Michael addition/1,6-addition to obtain spirotetrahydroquinoline products. While 1,1,3,3-Tetramethylguanidine (TMG) was employed as the catalyst, it will generate the 1,4-addition product first, then underwent rearrengment/vinylogous 1,6-addition to obtain trisubstituted tetrahydroquinoline. Both of these two pathways achieved moderate to good yields and good regioselectivities.
    II. We developed an efficient method for the synthesis of spiropentadiene pyrazolones and 1H-oxepino[2,3-c]pyrazoles in good to excellent yield. The methodology attributes O-acylation of phosphorus zwitterions which were formed by a tandem phospha-1,6-addition of PBu3 to α,β,γ,δ-unsaturated pyrazolones, further generating betaine intermediates that preferentially resulted in the aforementioned cyclic products in a diversity-oriented manner. When the highly steric hindered were employed, oxepino pyrazole derivatives were afforded as major products. On the contrary, spiropentadiene pyrazolone derivatives will be selectively provided. Mechanistic investigations revealed that formation of the betaines is the key step to provide the products via an intramolecular Wittig reaction or an unprecedented δ-C-acylation/cyclization/Wittig reaction.

    謝辭 I 摘要 II Abstract IV 目錄 VI 表格列表 IX 圖列表 X 式列表 XIII 縮寫對照表 XVI 第一章、經有機鹼催化調控區域選擇性Aza-1,4-加成/類Aza-1,6-加成之連續反應合成螺環/三取代四氫喹啉衍生物 1 1-1 前言 1 1-1.1 四氫喹啉之生物活性 1 1-1.2 介紹對亞甲基苯醌衍生物 2 1-2 研究動機 9 1-2.1 初步反應物之篩選 9 1-2.2 1,4-或1,6-加成之區域選擇性 10 1-2.3 1,3-茚二酮衍生物之應用 14 1-3 實驗結果與討論 16 1-3.1 反應條件優化 16 1-3.2 取代基效應探討 21 1-3.3 克級反應 23 1-3.4 控制實驗 24 1-3.5 反應機制之探討 28 1-3.6 一鍋化反應 29 1-3.7 對亞甲基苯醌衍生物之不對稱應用 31 1-4 結論與未來展望 37 1-5 光譜解析 39 1-6 實驗數據與操作步驟 47 1-6.1 分析儀器 47 1-6.2 實驗操作步驟 48 1-6.3 光譜數據 51 1-7 參考文獻 78 附件一、NMR光譜數據 81 附件二、X-ray單晶繞射數據 107 附件三、Checklist 111 第二章、經分子內威悌反應合成螺環吡唑啉酮與1H-㗁呯[2,3-c]吡唑之衍生物 113 2-1 前言 113 2-1.1 螺環吡唑啉酮與㗁呯吡唑骨架之生物活性 113 2-1.2 螺環吡唑啉酮骨架分子合成方式 114 2-1.3 㗁呯吡唑骨架分子合成方式 118 2-2 研究動機與實驗設計 119 2-2.1 利用威悌反應建構雜環分子 119 2-2.2 實驗分子設計 120 2-2.3 β-醯化反應與非預期δ-醯化反應 124 2-2.4 化學選擇性合成螺環吡唑及㗁呯吡唑骨架 125 2-3 實驗結果與討論 127 2-3.1 螺環吡唑啉酮之反應條件優化 127 2-3.2 螺環吡唑啉酮之取代基效應探討 131 2-3.3 Betaine中間體之反應位向探討 134 2-3.4 1H-㗁呯[2,3-c]吡唑之反應條件優化 136 2-3.5 1H-㗁呯[2,3-c]吡唑之取代基效應探討 138 2-3.6 克級反應與延伸反應 141 2-3.7 控制實驗與反應機制推論 142 2-3.8 反應機制之探討 146 2-3.9 催化量之有機膦試劑進行威悌反應 148 2-4 結論與未來展望 152 2-5 光譜解析 154 2-6 實驗數據與操作步驟 162 2-6.1 分析儀器 162 2-6.2 實驗操作步驟 163 2-6.3 光譜數據 166 2-7 參考文獻 218 附件四、NMR光譜數據 220 附件五、X-ray單晶繞射數據 285 附件六、Checklist 291

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