【摘要】：噻唑類化合物是一類重要的含N、S的雜環(huán)化合物,以其獨(dú)特的化學(xué)結(jié)構(gòu)而具有良好的藥理活性和生物活性,廣泛應(yīng)用于醫(yī)藥、農(nóng)藥領(lǐng)域。異腈作為C1合成子,代表了一類重要的反應(yīng)活性物種,廣泛應(yīng)用于含氮雜環(huán)的構(gòu)建。鎳具有多種氧化態(tài)和溫和的氧化加成能力,并且性質(zhì)穩(wěn)定、廉價(jià)經(jīng)濟(jì),近年來(lái)發(fā)展了一系列新型的鎳催化反應(yīng)。在第一章,分別對(duì)噻唑類化合物的傳統(tǒng)合成方法,異腈插入反應(yīng)的進(jìn)展以及鎳催化反應(yīng)進(jìn)行了綜述。在第二章,利用鎳催化的異腈插入反應(yīng)建立了一種簡(jiǎn)單、高效、生態(tài)友好的合成三亞胺噻唑化合物的新方法。以環(huán)己基異腈和1,3-二苯基硫脲為模型底物,分別從鎳催化劑種類、用量,以及溶劑、溫度等方面進(jìn)行了條件探索,并確定最佳條件為:3 mol%的Ni(acac)2為催化劑,丙酮溶劑中,50oC條件下反應(yīng)1h。反應(yīng)結(jié)束后無(wú)需柱層析,抽濾、洗滌即可得到目標(biāo)產(chǎn)物。在此基礎(chǔ)上,利用多樣性的異腈和硫脲進(jìn)行了底物拓展,該方法表現(xiàn)出很好的底物適用性(39 examples;40-93%yields),二芳基、二烷基以及二雜環(huán)取代的硫脲都順利發(fā)生了反應(yīng);并且不對(duì)稱硫脲表現(xiàn)出很高的區(qū)域選擇性。接著進(jìn)行了一系列機(jī)理研究實(shí)驗(yàn):首先,通過單晶衍射分析確定中間體Ni(DPTU)2的結(jié)構(gòu),并驗(yàn)證其催化活性(1 mol%,93%yield);其次,對(duì)照實(shí)驗(yàn)結(jié)果顯示Ni(0)、Ni(II)無(wú)氧條件下均不能催化該反應(yīng),一則證明該催化循環(huán)由Ni(II)啟動(dòng),再者證明反應(yīng)過程中需要氧氣將還原消除得到的Ni(0)氧化成Ni(II)來(lái)完成催化循環(huán);第三,通過XPS對(duì)反應(yīng)過程中鎳的價(jià)態(tài)變化進(jìn)行了分析佐證;在此基礎(chǔ)之上提出了可能的反應(yīng)機(jī)理。最后,對(duì)該方法的克級(jí)規(guī)模反應(yīng)進(jìn)行了初步研究,得到產(chǎn)率85%的目標(biāo)產(chǎn)物。所合成化合物的結(jié)構(gòu)均經(jīng)IR、1H NMR、13C NMR和HRMS分析確定。該方法的最大特點(diǎn)是:催化劑用量小、低毒廉價(jià),原料經(jīng)濟(jì)易得,溶劑綠色,反應(yīng)高效,原子經(jīng)濟(jì)性好,底物范圍廣,操作簡(jiǎn)單,可克級(jí)規(guī)模制備。
[Abstract]:Thiazoles are an important class of heterocyclic compounds containing Nu S, which have good pharmacological and biological activities due to their unique chemical structure, and are widely used in medicine and pesticide fields. Isonitrile, as a C1 synthesizer, represents a class of important reactive species and is widely used in the construction of nitrogen-containing heterocycles. Nickel has a variety of oxidation states and mild oxidation addition ability, and its properties are stable, cheap and economical. In recent years, a series of new nickel catalytic reactions have been developed. In the first chapter, the traditional synthesis methods of thiazole compounds, the progress of isonitrile insertion reaction and nickel catalytic reaction were reviewed. In chapter 2, a simple, efficient and eco-friendly method for the synthesis of triamothiazole compounds was established by nickel catalyzed isonitrile insertion reaction. Using cyclohexylisonitrile and 1-diphenyl thiourea as model substrates, the conditions of nickel catalyst type, dosage, solvent and temperature were studied respectively. The optimum conditions were determined as follows: 3 mol% Ni (acac) _ 2 as catalyst. In acetone solvent, the reaction time was 1 h under 50oC condition. At the end of the reaction, the target product can be obtained without column chromatography, filtration and washing. On this basis, the substrate was expanded by using a variety of isonitrile and thiourea. The method showed good substrate applicability (39 examples;40-93%yields), and the reaction of diaryl, dialkyl and diheterocyclic thiourea was successful. And asymmetric thiourea showed high regioselectivity. Then a series of mechanism experiments were carried out. Firstly, the structure of the intermediate Ni (DPTU) _ 2 was determined by single crystal diffraction analysis, and its catalytic activity (1 mol%,93%yield) was verified. Secondly, the results showed that Ni (0), Ni (II) could not catalyze the reaction. It was proved that the catalytic cycle was initiated by Ni (II). Furthermore, it is proved that oxygen is needed to oxidize Ni (0) to Ni (II) in order to complete the catalytic cycle. Thirdly, the valence state of nickel in the reaction process was analyzed by XPS, and the possible reaction mechanism was put forward. Finally, a preliminary study on the gram scale reaction of this method was carried out, and the target product in 85% yield was obtained. The structures of the synthesized compounds were determined by IR,1H NMR,13C NMR and HRMS. The main characteristics of this method are: small amount of catalyst, low toxicity and low cost, cheap raw material, green solvent, high reaction efficiency, good atomic economy, wide substrate range, simple operation, and can be prepared on a g scale.
【學(xué)位授予單位】：青島科技大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：O621.251

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