基于导向策略的钯催化惰性sp~3碳氢键官能团化及跨环间位碳氢键芳基化反应研究

发布时间：2018-03-03 00:09

  本文选题：碳氢键活化　切入点：导向基团　出处：《浙江大学》2017年博士论文　论文类型：学位论文

【摘要】：近年来,过渡金属催化的碳氢键官能团化反应为天然产物以及药物分子的合成提供了一种高效且原子经济的方法。由于脂肪族化合物的C(sp~3)-H键键能高、反应活性低,因此实现脂肪族化合物的C(sp~3)-H键活化,特别是惰性亚甲基C(sp~3)-H键活化仍然面临着巨大的挑战。另外,芳香族化合物中含有多个C(sp2)-H键,如何将反应发生在特定的碳氢键上即实现芳烃区域选择性碳氢键活化同样是一个关键而又亟待解决的问题。本论文围绕钯催化惰性C(sp~3)-H键官能团化以及跨环间位选择性碳氢键芳基化两个方面展开,具体包括以下内容：1.钯催化丙氨酸β-C(sp~3)-H键单芳基化／内酰胺化串联反应制备手性α-氨基-β-内酰胺该研究从天然L-丙氨酸底物出发,以5-甲氧基-8-氨基喹啉作为双齿导向基团,实现了钯催化β-C(sp~3)-H键单芳基化／内酰胺化串联反应。该方法的底物普适性广且具有良好的官能团容忍性,导向基团可以在温和的条件下得到脱除,为合成手性α-氨基-β-内酰胺衍生物提供了一种有效的途径。另外,该方法可进一步应用到正交保护手性α,β-二胺的合成。2.钯催化链状脂肪胺γ,-位亚甲基C(sp~3)-H键以及δ-位C-H键芳基化反应该研究以新发展的双齿配位2-嗯唑啉甲酰胺为导向基团,实现了钯催化链状脂肪胺产位惰性亚甲基C(sp~3)-H键芳基化以及远程δ-位C-H键芳基化反应。在嗯唑啉导向基团上引入手性中心,对γ-位亚甲基C(sp~3)-H键不对称芳基化反应进行了初步探究。3.钯催化跨环间位C-H键芳基化反应该研究以降冰片烯作为瞬态介质,实现了钯催化2-氨基联苯衍生物跨环间位选择性C-H键芳基化反应。三氟乙酰基作为氨基保护基在实现区域选择性碳氢键活化过程中起着关键作用。实验中分离得到跨环邻位环钯中间体并通过X-射线单晶衍射进行结构表征,中间体当量以及催化量转化实验表明该中间体是活性环钯中间体。此外,跨环间位芳基化产物可通过氨基原位炔基化反应以及导向同环邻位碳氢键官能团化反应为合成一系列不同官能团化的2-氨基联苯衍生物提供了有效的方法。
[Abstract]:In recent years, transition metal-catalyzed carbon-hydrogen bond functionalization has provided a highly efficient and atomic economical method for the synthesis of natural products and drug molecules. Because of the high bond energy and low reactivity of aliphatic compounds, Therefore, it is still a great challenge to realize the activation of C ~ (sp ~ (3)) -H bond of aliphatic compounds, especially the activation of inert methylene carboxylic acid ~ (3 +) -H bond. In addition, the aromatic compounds contain many Cnsp _ (2) ~ (-H) bonds. It is also a key and urgent problem to realize the activation of aromatics region-selective hydrocarbon bonds on a specific hydrocarbon bond. In this thesis, the functionalization of palladium catalyzed inert CSPN _ 3H bond and the transring separation of aromatics are discussed. Selective arylation of hydrocarbon bonds, The main contents are as follows: 1. Palladium catalyzed single arylation / lactamination of 尾 -Csp-3H bond of alanine to produce chiral 伪 -amino- 尾 -lactam. The study started from the natural L- alanine substrate and used 5-methoxy-8-aminoquinoline as the didentate guiding group. The palladium catalyzed single arylation / lactam reaction of 尾 -Cn SSP 3H bond in series was realized. The substrate of this method is universal and has good functional group tolerance. The guided group can be removed under mild conditions. It provides an effective way for the synthesis of chiral 伪-amino-尾-lactam derivatives. This method can be further applied to the synthesis of chiral 伪, 尾 -diamine. Palladium catalyzed chain fatty amine 纬 -methylene-methylenediamine 3H bond and 未 -site C-H bond arylation reaction. The study is based on the newly developed didentate coordination 2-hmazolinamide as the leading group. The palladium catalyzed arylation of inert methylene methylidene 3H bond at the production site of chain aliphatic amine and the arylation of the long range 未 -site C-H bond have been achieved. Chiral centers have been introduced into the mizoline-guided group. In this paper, the asymmetric arylation of 纬 -methylene-methylene-C ~ (sp) _ (3) -H bond was studied. Palladium catalyzed arylation of C-H bond across rings was studied. Norbornene was used as a transient medium. Palladium catalyzed arylation of transcyclic selective C-H bond of 2-aminobiphenyl derivatives was achieved. Trifluoroacetyl plays a key role in the activation of regioselective hydrocarbon bonds. To the intermediate of trans-ring orthocyclic palladium and characterized by X-ray single crystal diffraction, The intermediate equivalent and catalytic conversion experiments show that the intermediate is an active cyclic palladium intermediate. The transcyclic arylation products can be synthesized by in situ amino-alkynylation reaction and homocyclic ortho-hydrocarbon bond functionalization reaction, which provides an effective method for the synthesis of a series of 2-aminobiphenyl derivatives with different functional groups.
【学位授予单位】：浙江大学
【学位级别】：博士
【学位授予年份】：2017
【分类号】：O621.25
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本文编号：1558687