流體化學高效率合成生物活性分子和炔烴衍生物

我在博士班求學期間，研究的課題專注在利用流體化學以新的化學方法快速且有效的合成有機小分子。流體化學是近幾十年來在有機合成的化學領域中蓬勃的發展，與批次的方法相比有明顯更好的產率，簡易的操作步驟，且能夠多步驟的大量合成出各種藥物前驅物。炔酮在是構建各種雜環化合物和生物活性化合物的重要元件。根據文獻報導，使用過渡金屬、路易斯酸和特殊的酰化試劑能夠合成炔酮。此外，使用乙炔基陰離子與醛反應生成炔丙醇，接著再進行金屬催化的氧化反應，是一個常見的炔酮製備方法。乙炔基陰離子是一種高反應活性的中間體，因為反應性高，在傳統的批次反應中很難控制。使用連續流體的方法，我們成功克服了不穩定的有機鋰內乙炔基中間體進而合成炔酮。最後該混合物在70 oC.下與肼混合，成功應用於合成吡唑。同時，該反應具有容易控制、反應時間短、環境反應溫度低且不需要過渡金屬催化等特性。使用連續流體方法應用於sp-sp2 Negishi 交叉偶聯已經成功被開發，在室溫下，以流體的方式，透過乙炔基鋰的生成即時的製備Negishi 試劑，接著馬上與芳基碘化物反應以合成出內炔。此方法能在溫和的反應條件和極短的反應時間（73 s）下，成功的合成各種炔烴和烯炔烴衍生物。在最後一章中，我們開發了一種由具有各種芳香族的N-芳基琥珀酰亞胺與和脂肪硫醇合成硫酯的方法。這個方法的的優勢是不需要使用金屬催化、操作容易、底物範圍廣、不錯的產率以及極短的反應時間（40 s）。

關鍵字

流動化學；非過渡金屬；鋰化反應；交叉耦合反應；炔酮；有機鋰乙炔基；烯炔硫酯

並列摘要

My graduate research work is focused on rapid and efficient synthesis of organic small molecules using flow chemistry as a platform, which is a very important in drug synthesis, heterocyclic, natural product and bio-active compounds. On-demand of drug molecules day by day increase and need large productivity. Flow chemistry has been developed in the field of synthetic organic chemistry in the past decades and shows better results over the batch method various drugs are synthesized successfully on multi-step process by this method. So I decided to focus on flow chemistry. Ynones are important building blocks to construct various heterocycles compounds and bio-active compounds. According to the literature, synthesis of ynones requires transition-metal, Lewis acid, and special acylating reagents. The classical way to synthesis of ynones was prepared by acetylide anion (ylide) react with the aldehyde to give propargyl alcohol, and followed by metal catalyzed oxidation. Ylide is a highly reactive intermediate which is very difficult to control in the traditional batch reaction due to high nucleophilicity. Here we demonstrated in continuous flow method for ynones synthesis via unstable organolithium ylide intermediate. Application for this method was demonstrated to pyrazole synthesis an integrating the final mixer with hydrazine at 70 oC. This method is highly controllable, short reaction time, ambient temperature and transition-metal free. The development of new sp-sp2 Negishi cross-coupling in a continuous flow method was successfully developed. In situ preparation of Negishi reagent in flow method at room temperature starts from the generation of lithium acetylide and subsequently reacted with aryl iodides to synthesize internal alkynes. A wide range of alkynes and enynes derivatives were demonstrated with mild reaction conditions and short reaction time (73 s). In the final chapter, we have developed a protocol for the synthesis of thioesters from N- arylsuccinimide with various aromatic and aliphatic thiols. The key features of this protocol are metal free, operational friendly, broad substrate scope with good to excellent yields and short reaction time (40 s).