本文選題：銅催化 + 氮烯基苯并咪唑衍生物�。� 參考：《西南大學(xué)》2017年碩士論文

【摘要】：氮烯基結(jié)構(gòu)存在于許多天然產(chǎn)物和醫(yī)藥分子中,顯示出廣泛的生物活性。在自然界中發(fā)現(xiàn)了許多具有生物活性的氮烯基天然產(chǎn)物的存在,如(±)-ξ-Clausenamide、(+)-SB-204900就是從蕓香料黃皮中提取出來(lái)的天然有機(jī)分子并具有許多藥理作用。由于烯胺衍生物的特殊結(jié)構(gòu),特別是氮烯基苯并咪唑,在有機(jī)反應(yīng)中常用作復(fù)雜化合物的原料和重要的醫(yī)藥中間體。在高分子化學(xué)中,該類化合物也可作為聚合過(guò)程的反應(yīng)單體。其中氮烯基吡咯烷酮(NVP)就用于構(gòu)建具有經(jīng)濟(jì)重要性的聚合物。烯胺衍生物含有雙鍵和氮原子,可與多種過(guò)渡金屬進(jìn)行配位,因此也是許多金屬絡(luò)合物的核心配體。不僅如此,烯胺衍生物可以用于合成傳統(tǒng)方法難以制備的多取代氮雜環(huán)化合物。經(jīng)研究發(fā)現(xiàn),氮烯基唑類化合物已經(jīng)應(yīng)用于金屬的分離、極性化合物的提取、化妝品和染料的提純等。另外,氮烯基咪唑類衍生物在醫(yī)藥和農(nóng)藥領(lǐng)域也被發(fā)現(xiàn)具有較好的抗真菌和抗寄生蟲(chóng)方面作用。尋找到一種簡(jiǎn)便適用的方法合成具有潛在生物活性的新型氮烯基苯并咪唑類衍生物也是科研工作者正在努力的方向。C-H鍵活化被稱為有機(jī)化學(xué)領(lǐng)域中的“圣杯”,而實(shí)現(xiàn)碳?xì)滏I的高選擇性活化也是化學(xué)科研工作者的追求目標(biāo)。特別是過(guò)渡金屬參與C-H鍵活化的體系中,對(duì)反應(yīng)底物具有較好官能團(tuán)容忍性,絕大多數(shù)文獻(xiàn)中報(bào)道的反應(yīng)對(duì)鹵素、酰胺、硝基和酯基等均適用,因而一直是有機(jī)化學(xué)的熱門(mén)領(lǐng)域。隨著對(duì)過(guò)渡金屬催化C-H鍵活化的深入研究,反應(yīng)催化劑由價(jià)格昂貴的Ru、Ir、Rh和Pd等過(guò)渡金屬轉(zhuǎn)變?yōu)槭褂孟鄬?duì)廉價(jià)的Cu催化劑,并且反應(yīng)條件也越來(lái)越溫和。在有機(jī)合成中,較多結(jié)構(gòu)復(fù)雜化合物的合成路線需要多步反應(yīng),而傳統(tǒng)方法則涉及繁雜的純化分離過(guò)程。從綠色化學(xué)和經(jīng)濟(jì)的角度看,減少不必要的后處理,盡可能地避免中間體的分離過(guò)程完全順應(yīng)了時(shí)代要求。而串聯(lián)反應(yīng)即為在一個(gè)反應(yīng)體系中不進(jìn)行任何操作,反應(yīng)原料進(jìn)行了多個(gè)反應(yīng)結(jié)合的過(guò)程。因?yàn)槠渚哂胁僮骱?jiǎn)便、無(wú)需分離中間體、收率好且高效等優(yōu)點(diǎn),相比于傳統(tǒng)方法充分展示出優(yōu)越性而一直活躍于有機(jī)化學(xué)的研究前沿。因此,我們實(shí)現(xiàn)了N-烯基苯并咪唑的C-N鍵通過(guò)苯并咪唑和缺電子烯烴的分子間串聯(lián)氮雜邁克爾加成反應(yīng),及Cu(II)和碘化鋰共同作用下苯并咪唑酯發(fā)生分子內(nèi)α位C-H鍵的碘化和脫鹵化氫的形式α,β-脫氫過(guò)程。該方法對(duì)唑類具有較好的官能團(tuán)容忍性,對(duì)苯環(huán)上含有甲基、酯基、硝基、鹵素及大的共軛環(huán)均適用。這些官能團(tuán)還可以進(jìn)行衍生反應(yīng),便于化合物的結(jié)構(gòu)修飾而得到更多結(jié)構(gòu)新穎且存在潛在生物活性的含唑類化合物。但是,對(duì)于苯并咪唑的2位、丙烯酸酯的α或β位存在的位阻效應(yīng),對(duì)反應(yīng)影響較大,目標(biāo)產(chǎn)物的分離產(chǎn)率顯著降低。該方法首次報(bào)道了在溫和條件下,苯并咪唑衍生物分子間和分子內(nèi)酯α位碳?xì)滏I的選擇性碘化的串聯(lián)反應(yīng)。該過(guò)程并非自由基反應(yīng),包括通過(guò)銅鹽催化sp3 C-H的活化得到α-碘酯中間體,有效地合成了二十多個(gè)新型唑類化合物。我們對(duì)所有化合物的高分辨質(zhì)譜、氫譜、碳譜及紅外光譜進(jìn)行解析,證實(shí)了化合物的分子結(jié)構(gòu)。另外,我們還成功培養(yǎng)出了4a的單晶,經(jīng)過(guò)X-射線單晶衍射進(jìn)一步確認(rèn)了其空間立體構(gòu)型。在反應(yīng)機(jī)理的探討時(shí),我們發(fā)現(xiàn)一個(gè)重要的中間體—α-碘代酯,并進(jìn)一步證實(shí)了該反應(yīng)其中的一個(gè)過(guò)程為苯并咪唑和丙烯酸酯發(fā)生邁克爾加成反應(yīng),然后再進(jìn)行Cu催化的C-H鍵活化生成α-碘代酯中間體,最后發(fā)生脫鹵代氫得到目標(biāo)產(chǎn)物。在控制實(shí)驗(yàn)對(duì)比過(guò)程中,我們發(fā)現(xiàn)Cu鹽雖在酯的α-H活化中起到重要作用,但對(duì)后續(xù)反應(yīng)影響較小,而在脫鹵代氫的過(guò)程中堿的作用是不可忽略的。并且在我們報(bào)道在溫和條件下生成碘酯的方案,亦可以運(yùn)用到許多醫(yī)藥反應(yīng)中得到關(guān)鍵中間體。由于多數(shù)苯并咪唑衍生物具有生物活性,因此,我們也對(duì)合成的氮烯基化苯并咪唑衍生物進(jìn)行了抗菌活性測(cè)試。對(duì)比我們課題組先前做的苯并咪唑邁克爾加成產(chǎn)物的抗微生物活性實(shí)驗(yàn)對(duì)比研究發(fā)現(xiàn),部分化合物脫氫后的抗微生物活性明顯增強(qiáng),甚至個(gè)別化合物對(duì)微生物測(cè)試的MIC值低于參考藥物。與此同時(shí),我們還發(fā)現(xiàn)化合物4i的抗微生物活性普遍較好,具有中等或者強(qiáng)的抑菌活性,有望進(jìn)一步開(kāi)發(fā)和研究作為抑菌藥物合成的備選之一。
[Abstract]:The nitrogeny structure exists in many natural products and pharmaceutical molecules, showing a wide range of biological activities. In nature, many natural products of biologically active nitrogeny are found, such as (+) - -Clausenamide, (+) -SB-204900 is a natural organic molecule extracted from the yellow skin of Brassica and has many pharmacological effects. Due to the special structure of alkene derivatives, especially nitrogenyl benzimidazole, they are used as raw materials and important pharmaceutical intermediates for complex compounds in organic reactions. In polymer chemistry, this kind of compounds can also be used as reaction monomers in the polymerization process. Among them, nitrogenyl pyrrolidone (NVP) is used for the construction of economic importance. Enamine derivatives contain double bonds and nitrogen atoms, which can be coordinated with a variety of transition metals and are therefore the core ligands of many metal complexes. Not only that, the alkene derivatives can be used to synthesize the multi substituted heterocyclic compounds that are difficult to be prepared by traditional methods. Separation, extraction of polar compounds, the purification of cosmetics and dyes. In addition, nitrogenyl imidazole derivatives have also been found in the fields of medicine and pesticides with good antifungal and antiparasitic effects. A simple and convenient method for synthesis of new nitrogenyl benzimidazole derivatives with potential bioactivity is also found. .C-H key activation is known as the "Holy Grail" in the field of organic chemistry, and the high selective activation of hydrocarbon bonds is also the goal of the chemical researchers. Especially, in the system of C-H bond activation, the transition metal has a good functional group tolerance to the reaction substrate. Most of the documents are reported in the literature. The reaction of the channel is suitable for halogens, amides, nitro and ester groups, and has been a hot field in organic chemistry. With the in-depth study of the activation of C-H bonds catalyzed by transition metals, the reaction catalysts are converted from expensive Ru, Ir, Rh and Pd to the relatively cheap Cu catalysts, and the reaction conditions are becoming more and more mild. In organic synthesis, the synthetic route of more complex compounds requires a multistep reaction, while the traditional method involves a complex process of purification and separation. From a green chemical and economic point of view, the reduction of unnecessary post-processing and as much as possible to avoid the separation process of intermediates are fully aligned with the requirements of the times. There are no operations in the system, and the reaction materials are combined with multiple reactions. Because they have the advantages of simple operation, no separation of intermediates, good yield and high efficiency, we have been active in the research frontier of organic chemistry compared with the traditional methods. Therefore, we have realized the C- of N- alkyl benzimidazole. N bonds through the intermolecular tandem azo Michael addition reaction of benzimidazole and the absence of electronic olefin, and Cu (II) and lithium iodide in the form of intramolecular alpha C-H bond iodization and dehalogenated hydrogen in the form of alpha, beta dehydrogenation process. This method has good functional group tolerance to the azoles and contains methyl and ester groups on the benzene ring. Nitro, halogens and large conjugated rings are all applicable. These functional groups can also be derivatized to facilitate the structural modification of the compounds to obtain more novel and potentially bioactive compounds. However, the 2 position of benzimidazole, the presence of the alpha or beta of acrylate, has a larger effect on the reaction. The separation yield of the products is significantly reduced. This method is the first time to report a series reaction of selective iodization of the alpha hydrogen bond between the benzimidazole derivatives and the benzimidazole derivatives under mild conditions. This process is not a free radical reaction, including the activation of SP3 C-H through copper salts as an intermediate of alpha iodide, which effectively syntheses more than 20 new compounds. The high resolution mass spectra, hydrogen, carbon and infrared spectra of all the compounds have been analyzed to confirm the molecular structure of the compound. In addition, we have also successfully cultured the single crystal of 4A, and further confirmed its spatial stereotactic by X- ray single crystal diffraction. The essential intermediate, alpha iodate, further confirmed that one of the processes was the Michael addition reaction of benzimidazole and acrylate, and then activated by the C-H bond catalyzed by Cu to generate the intermediate of alpha iodate and finally dehalogenation of hydrogen to obtain the target product. In the control experiment, we found the Cu salt. Although it plays an important role in the activation of the ester's alpha -H, it has little effect on the subsequent reaction, and the effect of alkali is not negligible in the process of dehalogenation of hydrogen. And in our report, the scheme of producing iodine ester under mild conditions can also be used in many pharmaceutical reactions to obtain key intermediates. As a result, we also tested the antibacterial activity of the synthetic benzimidazole derivatives. Comparison of the anti microbial activity experiments of the benzimidazole Michael addition products previously done by our group found that the anti microbiological activity of some compounds was obviously enhanced after dehydrogenation, even to a few compounds. The MIC value of biological tests is lower than that of the reference drugs. At the same time, we also found that the anti microbial activity of the compound 4I is generally good, with moderate or strong antibacterial activity. It is expected to further develop and study as one of the alternatives for the synthesis of antibacterial drugs.

【學(xué)位授予單位】：西南大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：O626.23

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相關(guān)期刊論文 前2條

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本文編號(hào)：1890922