烯键上的氨溴加成反应及其应用研究

【作者】 陈战国；

【导师】 魏俊发；

【作者基本信息】 陕西师范大学 ， 有机化学， 2012， 博士

【摘要】 本文建立了一系列高度区域选择和立体选择性的烯键上氨溴加成反应新体系,从大量的实验结果中总结了该类反应的普遍性机理,提出反应按照何种机理进行,依赖于底物结构的新见解。对于烯键氨溴加成反应的应用研究进行了深入探索,建立了由氨溴加成产物定量合成相应氮丙啶和由氮丙啶高收率合成脱氢氨类化合物的新方法,提出了相应的反应机理。全文共分9章。第1章为研究背景及选题依据；第2章-第8章为烯键上的氨溴加成反应新体系及其应用研究；第9章为全文总结。主要工作包括以下7章：1铜粉催化α,β-不饱和酮的氨溴加成反应研究(第2章)基于一价铜盐和二价铜盐及其络合物能催化烯键上的氨卤加成反应的研究结果,也基于单质铜粉能被N-溴代丁二酰亚胺(NBS)氧化成较高价铜这一原理,我们提出了单质铜粉有可能被原位氧化生成路易斯酸而对烯键上的氨溴加成反应有催化作用这一研究设想。本章以对甲苯磺酰胺(TsNH2)和N-溴代丁二酰亚胺(NBS)为氮源和卤素源,以铜粉为催化剂,成功的建立了铜粉催化的α，β-不饱和酮氨溴加成反应新方法。该方法具有高度的立体选择性和区域选择性,在温和的反应条件下,无需氮气保护,大多数α,β-不饱和酮几乎能定量的转化成相应的加成产物,且催化剂的用量仅为底物的1mol%,为合成邻位氨溴衍生物提供了一个有效的途径。实验结果证明,α，β-不饱和酮中与双键直接相连苯环上强的供电子基能活化C=C双键的反应活性,而吸电子基却有顿化C=C双键反应活性的趋势。区域选择性也受控于苯环上的取代基的性质,供电子基能选择性的给出α-溴-β-氨基加成产物,而吸电子基能选择性的生成α-氨基-β-溴加成产物。该体系共研究了26个例子,证明新方法有广泛的适应性。2铝粉催化烯键上的氨溴加成反应研究(第3章)基于铜粉具有很好的催化作用这一实验事实,本章对常见的17种过渡金属和主族金属进行了筛选,发现多种金属单质均有较好的催化作用,其中铝粉的催化效果最好,于是建立了铝粉催化烯键上的氨溴加成反应新方法。该方法以TsNH2/NBS为氮源和卤素源,以二氯甲烷为溶剂,以低毒、经济、稳定的单质铝粉为催化剂,在室温无氮气保护条件下,能够以高度的立体选择性和区域选择性,高收率的使α,β-不饱和羰基化合物(包括α,β-不饱和酮、α、β-不饱和酯)和普通烯烃(包括链烯和环烯)转变成相应的邻位氨溴加成产物。在大量实验的基础上,提出了在该反应条件下的两类可能的反应机理(溴鎓离子过程和氮鎓离子过程)两类反应机理很好地解释了产物的立体选择性和区域选择性。(±)-trans-3-溴-4-(3,4,5-三甲氧基苯基)-4-(对甲苯磺酰氨基)-2-丁酮16c单晶结构证实了以上推理的可靠性。对于富电子烯烃,反应按溴鎓离子过程进行。对于缺电子烯烃,反应按氮鎓离子过程进行。本章共考察了24个例子,证明有广泛的适应性。在所考察的多种金属单质催化烯烃的氨溴加成反应中,虽然铝粉是一种最有效的单质催化剂,实验中发现,Cr、Mn、Zn、Mg、Sn、Sb和Pb单质粉末在相同条件下也有较好的催化作用。3硅粉催化烯键上的氨溴加成反应研究(第4章)继发现金属单质有很好的催化作用后,我们在思考一个问题,非金属单质能否也具有良好的催化作用呢?为此,我们对常见的11种非金属单质进行了筛选,发现单质硅粉也可有效的催化碳碳双键上的氨溴加成反应。所建立的硅粉催化新体系不仅适应于α,β-不饱和羰基化合物,而且也适应于普通烯烃,具有广泛的适应性(30个例子)。当用TsNH2和NBS组合体系作为氮源和卤素源时,产物具有高度的区域选择性和立体选择性。在非常温和的反应条件下,对于富电子烯烃能够几乎给出定量的反应收率,而缺电子烯烃也能顺利进行。单质硅粉作为催化剂的另一优点在于使产物避免残留金属离子,这在药物合成中是非常重要的。硅粉作为催化剂具有毒性低、价格低廉、可以重复使用以及易与产物分离等优点,因此是制备邻位氨基卤素合成子的有效催化剂。特别重要的是,硅粉作为催化剂使用于有机反应中,本文可能成为首例。除了单质硅粉能有效催化碳碳双键上的氨溴加成反应外,实验证明,单质硼粉也有很好的催化作用。这一结果有望对有机硼化学的深入研究有一定的推动作用。4酒石酸催化烯键上的氨溴加成反应研究(第5章)文献报道,不仅路易斯酸是烯键上氨卤加成反应的有效催化剂,而且Br(?)nsted酸(如硫酸)也是该反应的良好催化剂。考虑到硫酸的腐蚀性,我们对22种有机酸的催化性能进行了考察,发现(+)-酒石酸也能有效催化烯键上的氨卤加成反应。于是我们建立了(+)-酒石酸催化的高度区域选择和立体选择性氨溴加成反应新方法。该反应提供了一个由有机小分子催化的,以TsNH2/NBS为氮源和卤源、在室温下无需惰性气体保护的烯烃氨溴加成反应新范例。该方法具有适应范围广(21个例子)、操作方便、产品易于纯化等特点。酒石酸作为催化剂的显著特点是无毒、副作用,在药物合成中具有较高的安全性。对于α,β-不饱和羰基化合物来说,当与双键相连苯环对位有强供电子基时,其产物为α-溴-β-氨基结构,当与双键相连苯环对位有吸电子基时,其产物为α-氨基-β-溴结构。5磷酸钾催化氮溴代乙酰胺(NBA)与β-硝基苯乙烯衍生物区域专一性氨溴加成反应研究(第6章)为了扩大氨卤加成反应的研究范围,本章建立了一个简单有效的β-硝基苯乙烯衍生物的氨溴加成反应新方法。在室温下,以N-溴代乙酰胺(NBA)为氮源/卤素源,在二氯甲烷中,以K3PO4为催化剂,无需惰气保护,β-硝基苯乙烯衍生物能被方便而有效的转化成具有邻位氨溴双官能团的有机合成子。在所考察的21个例子中,其收率在78-99%,所有产物的溴原子均选择性加在了与硝基相连的碳原子上,而氨基氮原子均选择性加在了与苯环相连的碳原子上,呈现出区域专一性。磷酸钾作为催化剂具有成本低、无毒、使用方便和储存稳定等特点。实验结果表明,底物双键的电子密度越低,反应的活性越高,这一趋势证明该反应具有共轭亲核加成的特点。本章提出的共轭亲核加成的机理,很好的说明了底物反应活性大小的规律性和产物应具有的立体化学特征。6无溶剂研磨法快速定量合成氮丙啶的研究(第7章)氮丙啶类化合物是一种重要的有机合成子,很多具有生物活性的物质,如氨基酸、β-内酰胺抗生素、生物碱均可由氮丙啶衍生而来。目前虽然合成氮丙啶的方法较多,但都是在有机溶剂中进行,收率不高,并且要用到金属催化剂。作为氨卤加成反应的应用研究,为了探索更有效的合成氮丙啶方法,我们由烯烃的氨溴加成产物出发,开展了无溶剂研磨法快速定量合成氮丙啶的研究。研究结果表明,K2CO3/尿素组合体系能高效催化具有1,2-邻位氨溴结构化合物的氮丙啶化反应,并且发展了一个反应容易、环境友好的将各种烯烃的氨溴加成产物100%地转化成相应氮丙啶的新方法。该方法在无溶剂条件下,在室温和空气环境中通过研磨可实现快速定量合成氮丙啶。尤其是后处理非常方便,仅需要用有机溶剂把产物从反应混合物中萃取后,蒸掉有机溶剂就能得到几乎纯净的产物。该方法具有广泛的适应性,不仅适合于各种具有1,2-邻位氨溴结构的酮、烷烃,还能适应于各种具有1,2-邻位氨溴结构的酯。该方法与已报道的方法相比,具有很多潜在的优势,如定量反应、反应条件温和、快速(反应最长不超过60min)、后处理简单和避免了使用金属催化剂对产物的污染等。7硫脲催化的α,β-脱氢氨类化合物的合成研究(第8章)具有功能化的烯胺是药物化学合成中的重要合成单元,它们不仅可应用于亲电加成和亲核加成反应中,同时也是光化学与电化学中有关化合物合成的重要合成子,尤其是在杂环化合物的合成中有着非常重要的作用。作为氮丙啶重要用途之一,如何把氮丙啶高收率地转化成相应的α，β-脱氢氨类化合物(烯胺),是目前有机合成的热点之一。为此,本章开展了将各种氮丙啶转化成相应α，β-脱氢氨类化合物新方法的研究,并建立了由氮丙啶转化成α,β-脱氢氨类化合物的新方法。在无水K2CO3/NH2CSNH2催化下,在CH2Cl2:DMF=1:1(v/v)的混合溶剂中,各种不同结构的氮丙啶均能几乎定量的转化成α,β-脱氢氨类化合物(16个例子,收率97-99%)。该方法操作简单,催化剂易得、稳定,价格低廉,为合成α,β-脱氢氨类化合物提供了一个有效的途径。本章对反应机理进行了探讨。更多还原

【Abstract】 This thesis developed a serious of new systems of high regio-and stereoselective aminobromination of olefins. The general mechanism of aminobromination was proposed based on a large number of experiment results in this work. A new viewpoint was recommended in which the reaction how to work in aminobromination is according to substrate’s structure strongly. For the applications of aminomromination to the olefins, the two new methods were developed. The first method is to synthesize aziridines via intramolecular cyclization of vicinal haloamine products. The corresponding aziridines were quantitative obtained catalyzed by urea. The second method is to synthesize N-protected α,β-dehydroamino derivatives via opening ring reaction of aziridines. The corresponding α,β-dehydroamino derivatives were obtained in excellent yield catalyzed by thiourea. The mechanism of the reaction was proposed. Nine chapters are included in this thesis. The first part (chapter one) includes a review of the aminohalogenation research progress and the determination of the subject for this thesis. The second part (chapter two to chapter eight) are the development of new systems of aminobromination reaction of olefins and their applications including to synthesize aziridines from vicinal haloamine products as well as synthesizing α,β-dehydroamino derivatives from aziridines. The third part (chapter nine) is a summary. The main contribution of this thesis is included in chapter two to chapter eight below:1Copper-Powder Catalyzed Aminobromination of α,β-Unsaturated Ketones (chapter2)Considering copper powder (Cu0) can be oxidized by NBS into Cu+or Cu2+, the idea of a Lewis acid produced in-situ from above oxidation to catalyze amonobromination of olefins was generated. Thus, a new method of aminobromination of α,β-unsaturated ketones has been developed in which the NBS and p-toluenesulfonamide (4-TsNH2) are as halogen and nitrogen sources and the copper powder is employed as catalyst to displace Cu(Ⅰ)-or Cu(Ⅱ)-containing compounds. The results showed that the reaction was carried out smoothly at room temperature to afford the desired aminobrominated products. The nearly quantitative products were obtained in most reactions under mild conditions without the protection of inert gaseous atmosphere. This method provides an easy process for preparation of vicinal aminohalo derivatives. The strong electron-donating substituents bearing benzene ring activate the double bond of α,β-unsaturated ketones remarkably to the addition reactions, whereas the strong electron-withdrawing substituents deactivate them, revealing that the addition reaction has an electrophilic feature. Regioselective of the reaction have been controlled in this method. The strong electron-donating substituents bearing4-position of benzene ring selectively afforded the a-bromo-β-amino adductive products and the strong electron-withdrawing substituents selectively afforded the a-amino-β-bromo adductive products.26Cases were investigated in this reaction which indicates that the new system is suitable for a wide scope.2Aluminium-Powder Catalyzed Aminobromination of α,β-Unsaturated Carbonyl Compounds and Simple Olefins(chapter3)Based on the copper powder can catalyze the aminobromination of α, β-unsaturated ketones, and in order to seek more efficient, low poisonous and less loaded catalysts for the regio-and stereoselective aminobromination of α,β-unsaturated carbonyl compounds and simple olefins, a systematic study was carried out via screening various elementary metals. Some elementary metal powders were also found to be suitable catalyst toward the aminobromination. Considering the lower toxicity and effectiveness of aluminium-powder, the new system of the aluminium powder-catalyzed high regio-and stereoselective aminobromination of α,β-unsaturated carbonyl compounds and simple olefins with the combination of TsNH2and NBS as halogen and nitrogen sources has been developed. The electron-rich and-deficient olefins shown significant differences in activity to the aminobromination reaction and gave the converse regioselectivity product. Based on a large number of experiment results, the possible mechanisms of aluminium-catlyzed aminobromination reaction for electron-deficient olefins including α,β-unsaturated carbonyl compounds and simple olefins were proposed. The proposed mechanisms involving process of bromonium and aziridinium intermediates not only could explains the anti-stereochemistry and the regioselectivity of the adductive products, but also explains well the remarkable difference in reactivity between the electron-rich olefin and electron-deficient olefin. The X-ray crystallographic study of3-bromo-4-(3.4.5-trimethoxyphenyl)-4-(p-toluenesulfonamido)butan-2-one showed clearly that the nitrogen atom was added to the β-carbon and the bromine atom was added to the a-carbon of the α,β-unsaturated ketones in trans relative stereochemistry.24Cases were investigated in this system which indicates that the new system has a wide scope suitable for the aminobromination of α,β-unsaturated ketones.Beside aluminium powder, the Cr、Mn、Zn、Mg、Sn、Sb and Pb et al elementary powders were also found to be good catalysts for the aminobromination of olefins.3Silicon Powder-Catalyzed Aminobromination of α,β-Unsaturated Carbonyl Compounds and Simple Olefins (chapter4)After the study of aminobromination reaction of olefins catalyzed by some metals powder successfully, a very important question was engraved on my mind:could or not nonmetal powders catalyze this reaction? Thereupon, our attention focused on the investigating the catalytic activity of11nonmetal elements powders in the aminobromination of olefins. Herein, the chalcone (1,3-diphenyl-propen-l-one) is as the model substrate, the reaction was carried out by stirring a mixture of catalyst, chalcone, NBS， and TsNH2in CH2Cl2at room temperature under the common conditions described above. The experiment result showed that the elemental silicon powder can be used as an efficient catalyst to the aminobromination reaction. This protocol has the advantages of applicability for a large scope of olefins (30cases) and high regio-and stereoselectivity with the NBS/TsNH2combination at ambient conditions. Additionally, silicon powder as catalyst has the advantage of avoiding any hazardous metals retained in the products. The relative nontoxicity, low cost, recyclability, and simpleness of silicon separation from reaction mixture make the methodology to be a useful tool for preparation of the vicinal aminobromo products, especially considering that the trace transition metal residues are highly regulated. More importantly. this may be the first example of using elemental silicon powder as catalyst in organic reactions.Beside silicon powder. the boron powder was found to be another efficient catalyst for the aminobromination of olefins. This result may be a promotion for the research of boron-organic chemistry.4(+)-Tartaric Acid-Catalyzed Aminobromination of α,β-Unsaturated Carbonyl Compounds and Simple Olefins(chapter5)Lewis acids were as efficient catalysts toward the aminohalogenation of olefins have been reported previously. Br(?)nsted acid (sulphuric acid) was also as catalyst has been reported recently. Considering the sulphuric acid has strong corrosivity,22kinds of organic acids have been screed for catalyzing aminobromination reaction of olefins. It was found that the tartaric acid was an efficient catalyst to this reaction. Thus, the new method of (+)-tartaric acid-catalyzed regio-and stereoselective aminobromination of olefins in CH2Cl2with p-toluenesulfonamido (TSNH2) and NBS as the nitrogen/bromine sources has been developed. This protocol offered an example of the small molecular organic acid-catalyzed methodology to synthesize civinal haloamino derivatives at the ambient temperature. The method is successfully applied to a wide range of α, β-unsaturated ketones. α,β-unsaturated esters and simple olefins (21cases). Among α, β-unsaturated carbonly compounds, higher regioselective isomers of a-bromo-β-amino products have been obtained when4-position of benzene ring bearing OCH3group. The other α,β-unsaturated carbonly compounds afforded correspouding converse isomers of a-amino-/?-bromo products. To the best of our knowledge.(+)-tartaric acid is a most convenient and practical organic small molecular catalyst to aminohalogenation so far.5K3PO4-Catalyzed Regiospecific Aminobromination of β-Nitrostyrene Derivatives with N-Bromoacetamide as Aminobrominating Reagent (chapter6)To expand the research scope of substrate for the aminobromination of olefins, an easy and efficient new method for the aminobromination reaction of β-nitrostyrene derivatives has been established. The method can conveniently and efficiently convert β-nitrostyrenes into vicinal haloamines at room temperature with N-bromoacetamide (NBA) in excellent yields (78-99%) and full regiospecificity products were obtained in CH2Cl2catalyzed by K3PO4. This methodology has advantages of low cost, nontoxicity, and elimination of the toxic issue associated with metal. The tendency indicates that the reaction is worked as a nucleophilic fashion due to the more electron-deficient is in the double bond of substrate, the more reactivity behave in the reaction. A possible mechanism involving conjugate addition was proposed and it explains well the reactivity of substrates and the regiochemistry of products.6Solvent-Free Grind:a Rapid and Simple Method for Quantitative Synthesis Aziridine from Aminobrominated Derivatives of Various Olefins (chapter7)Aziridination is an important synthetic transformation. Aziridines are found broad in the Pharmaceuticals and agrochemicals as electrophiles and as synthetic intermediates. Although the formation of aziridines from the addition of thermally or photochemically generated nitrenes to olefins is a well-known reaction, its utility is limited due to low yields and competing hydrogen abstraction and insertion reactions. In the preparation of aziridines, the metal catalyst is necessary in previously aziridination methods. In this chapter, a new method of urea-catalyzed aziridination of vicinal haloamino compounds with unexpectedly high efficiency has been developed. This protocol is a very easy and eco-friendly procedure for the aziridination of aminohalogenated derivatives of olefins by simply grinding the solid mixture of the substrate, K2CO3and catalytic amount of urea at room temperature in air. The reaction proceeded completely and cleanly to give aziridines in quantitative yields, and thus this method provides a "real" green protocol for preparation of aziridines from a large scope of aminohalogenated derivatives of simple and electron-deficient conjugated olefins. Compared with the standard procedures, this method offers many essential advantages such as quantitative yields, mild conditions, short reaction times, easy work-up and elimination of the toxicity issues related to metal catalysts.7Thiourea-Catalyzed Synthesis of α,β-Dehydroamino Derivatives from Aziridines (chapter8)The functionalized enamines have long served as the useful building blocks in the synthesis of a variety of importance different structure compounds in the biological chemisty and the pharmaceutical chemistry. As a member of this family, a-ketoenamines (also referred to as α,β-dehydroamino derivatives) occur frequently as a unit in natural products and biologically active compounds. This unit also plays an important role in organic synthesis. Not only this is the application of organic synthesis in the electrophilic and the nucleophilic chemistry, but also is the application in the photochemistry and the electrocyclic reactions, especially for the synthesis of the heterocyclic compounds. As one of an important application of aziridines, how to transform aziridines into corresponding α,β-dehydroamino derivatives in high yields is a topic of the organic synthesis so far. Thus, aziridine was converted into corresponding α,β-dehydroamino derivatives has been studied in this work and an easy and efficient new method has been established. The experiment result indicated that various aziridines can be transformed into corresponding α,β-dehydroamino derivatives in nearly quantitative yield catalyzed by K2CO3/NH2CSNH2in a mixing solvent (CH2Cl2:DMF=1:1(v/v)) at room temperature(16cases,97%-99%yield). This protocol has many advantages such as handling easily, high selectivity, high yield. And, the reaction can be catalyzed by an available, stable and economical thiourea. This method affords an efficient process for preparing various α,β-dehydroamino derivatives. The reaction mechanism has been discussed in this thesis.更多还原