【作者】 尚睿；

【导师】 傅尧； 中村栄一；

【作者基本信息】 中国科学技术大学 ， 有机化学， 2014， 博士

【摘要】 本论文包含两大部分内容,第一部分是基于过渡金属催化脱羧的新型碳-碳键构筑反应,该部分内容为2008年底至2012年期间在中国科学技术大学所完成。该论文的第二部分内容是基于铁催化的碳-氢键活化的若干新型碳-碳成键反应。该部分内容为2012年底至2014年期间,在日本国东京大学中村研究室进行联合培养期间所完成的工作。第一部分：基于脱羧的新型碳-碳键构筑方法金属催化的交叉偶联反应的出现极大的改变了人类创造复杂化学品的能力,传统的金属催化交叉偶联反应(Kumada Coupling, Stille Coupling, Suzuki Coupling等)依赖于金属有机试剂的使用。从2006年左右开始,使用羧酸或羧酸盐来代替金属有机试剂作为负合成子等价物而应用与交叉偶联合成方法学的思想成为热点而引起了关注。该论文的第一部分第一章综述了过渡金属催化脱羧偶联反应的历史发展与研究现状,按反应类型对金属催化的脱羧偶联反应进行了分类描述,并探讨了脱羧偶联反应研究中的挑战和机遇。该部分的第二章,我们发展出了一种基于钯催化脱羧的新型芳香羧酸酯合成方法,首次将廉价的草酸单酯酸钾发展成为酯基合成子的等价物而应用在金属催化的交叉偶联中。通过对反应条件的研究以及40例含有不同取代基的底物的拓展,我们证实了该脱羧芳香酸酯合成法对于芳基溴化物,芳基氯化物以及芳基碘化物具有普适性,并且具有优秀的官能团兼容性。该方法也可以应用到烯基羧酸酯的合成中。该方法被证实成为一种操作简单,安全高效的新型芳香酸酯合成法。该论文的机理研究指明了二价钯中间体催化的脱羧是该反应的决速步。该部分的第三章,我们发现并研究了一例新颖的铜催化的脱羧多氟联苯合成反应。该反应将多氟芳香羧酸钾作为芳基负合成子等价物运用在铜催化的偶联反应中。通过64例底物,该方法被证实是一种从芳基碘化物和溴化物出发的高效多氟联芳基化合物构筑方法,该方法具有优秀的官能团兼容性。在此课题中我们发现该铜催化反应对于一些特定结构的烯基卤化物和烷基卤化物同样适用。该研究中我们首次发现二缩乙二醇二甲醚可以作为脱羧偶联反应体系中的有效溶剂。机理研究指出了铜催化实现脱羧偶联反应的可能性,指出了先脱羧后氧化加成,Cu(Ⅰ)-Cu(Ⅲ)变价循环、Cu(Ⅰ)上催化脱羧的反应历程。该部分的第四章,我们针对上述铜催化反应中存在的芳基亲电试剂局限于芳基溴化物和芳基碘化物的问题,希望开发一种钯催化的体系来实现使用廉价芳基亲电试剂(芳基氯化物,芳基磺酸酯)的多氟联芳基化合物合成法。我们成功的发现使用简单的醋酸钯加三环己基膦配体的催化剂体系,在二缩乙二醇二甲醚体系中,可以实现高产率、高效率、高官能团兼容性的多氟联芳基化合物合成法。通过40例样本,我们证实了该方法的实用价值。在该研究中我们发现了钯催化体系中卤化物氧化加成和脱羧速率匹配对于反应的影响,并成功通过对配体的调节,实现了不同芳基卤化物的高效转化。机理研究中我们通过理论计算的辅助指出先氧化加成后脱羧、Pd(0)-Pd(II)变价循环、Pd(Ⅱ)上催化脱羧的反应历程。该部分的第五章,我的研究关注从脱羧的Csp2-Csp2化学键构筑方法转移到了使用烷基羧酸的脱羧Csp3-Csp2键构筑方法。通过稳定金属-碳键中间体的烷基羧酸脱羧偶联反应缺乏相关报道,绝大多数对于脱羧偶联反应的研究集中在芳香羧酸上。在第五章中,我们成功的实现了一例钯催化的Csp3-COOH键断裂的脱羧芳基化反应。该反应实现了一种新型的2-苄基取代氮杂环衍生物的合成方法。通过40例反应,该方法被证实可以高效和高选择性的合成一系列2-苄基吡啶、2-苄基吡嗪、2-苄基喹啉、2-苄基苯并噻唑和2-苄基苯并噁唑。该反应成为生理活性杂环衍生物的一个新型合成方法。我们通过理论计算以及分离中间体实验的支持,讨论了该反应的机理,指出了Pd(0)-Pd(II)变价循环、Pd(Ⅱ)催化剂与杂环氮原子配位催化脱羧的反应历程。该机理阐明了底物受限的原因并为烷基羧酸脱羧偶联的发展提供了指导。该部分的第六章,我们继续着钯催化烷基羧酸脱偶联的目标。沿着这样的目标思路,在该章节中我们成功的实现了钯催化氰乙酸盐以及丙二酸单酯羧酸盐的脱羧α-芳基化反应。开发出了2-芳基腈类和2-芳基乙酸酯的新型合成方法。该反应成为可代替Hartwig-Buchwald a-芳基化反应的互补方法。通过96例样本的研究,我们证实了该反应极其广阔的底物适用面、优秀的官能团兼容性和优秀的单芳基化选择性。针对一些碱性敏感底物的尝试,我们证实该方法具有相比传统方法更优越的特性。在该工作中我们成功的将该方法运用在了布洛芬家族药物的合成中,并且利用该方法成功开发了阿斯利康公司的抗乳腺癌药物-阿那曲唑中间体的新型合成方法,并申请了自主知识产权的方法专利,该中间体合成专利已经被应用于该中间体公斤级别的工业生产。该部分第七章中我们报道了钯催化下硝基取代苯乙酸盐与芳基氯化物、芳基溴化物的脱羧偶联反应。通过50例样本的研究,证明该反应可以用于高效合成硝基取代的二芳基甲烷类衍生物。在该工作中我们成功实现了三级和四级硝基取代苯乙酸盐衍生物的脱羧芳基化反应。在该工作中我们从脱羧偶联产物出发,开发出了合成4-芳基喹啉和4-芳基喹啉酮的新路线。通过硝基官能团的转化,我们指出该方法可以进一步合成多种取代的1,1-二芳基烷烃衍生物。该部分第八章,我的研究重点从烷基羧酸的脱羧芳基化反应转移到了烷基羧酸的脱羧苄基化反应。我们开发出了一类新颖的钯催化α-氰基烷基羧酸盐与苄基亲电试剂的脱羧苄基化反应。该反应避开了金属有机试剂和强碱的使用,在较为温和的反应条件下进行,并且具有良好的官能团兼容性。通过50例底物,我们证明利用该脱羧苄基化反应可以以中等到高的收率来合成多种含有p-芳基骨架结构的四级,三级和二级腈类化合物。在这些腈类产物中,一些化合物是难以通过传统的强碱参与的烯醇阴离子亲核取代反应来合成的。该反应展示了第一例饱和羧酸盐参与的分子间脱羧苄基化反应。第二部分：基于铁催化碳-氢键活化的新型碳-碳键构筑方法通过选择性碳-氢键活化的手段来构筑碳-碳键是理想的成键方法,这是由于碳-氢键是广泛存在于有机化合物分子中的。通过高选择性的碳-氢键活化手段可以发展出高选择性的碳-碳成键方法。近二十年来,通过贵金属催化(钯、钌、铑、铱)转化的碳-氢键活化反应受到了广泛的研究。这些贵金属资源具有不可再生性和毒性。铁是无毒的并且是地球内部含量最为丰富的过渡金属元素。开发出基于铁催化剂的新型碳-氢键转化反应来代替贵金属催化,以及探究出铁元素未知的催化活性,通过铁催化来实现贵金属催化中所不能实现的化学转化,我们相信这是化学家所应该致力研究的问题。该论文的第二部分第一章综述了铁催化的碳-氢键活化、碳-碳键构筑反应的发展与研究现状,按碳-碳键成键类型对该类反应进行了分类描述,并探讨了该领域发展中需要解决的问题。该部分的第二章,该章节中我们研究和报道了一例罕见的铁催化的高选择性饱和碳-氢键芳基化反应。已被报道的铁催化的饱和碳-氢键官能团化反应主要通过铁参与的自由基过程发生。通过形成铁碳环中间体来选择性活化饱和碳-氢键的反应只局限于针对特定底物的当量金属有机反应。该工作中我们揭示了使用铁盐和特定双齿膦配体催化剂的体系可以实现烷基羧酸酰胺与芳基锌试剂的氧化型交叉偶联。该反应可以在温和的条件下得到较高的收率。我们揭示了双齿膦配体结构和导向基对于该反应的发生有着决定性的作用。通过28例底物的研究我们证明该反应只在一级饱和碳-氢键处发生,在二级和苄基碳-氢键处完全不反应；偶联底物上的立体效应和电子效应也被研究。同位素实验证明了该反应中碳氢键活化步骤是反应的决速步。该工作揭示了铁的一种新型催化活性,并且提供了一种新型的p-芳基酰胺的制备方法。该部分的第三章,在通过有机铁化合物中间体的催化碳-碳键生成反应中,格氏试剂和有机锌试剂是目前被成功使用的主要碳亲核试剂,实现使用其他稳定碳亲核试剂的偶联反应一直是铁催化领域的难题。该工作中我们实现了使用大储量,廉价无毒铁催化剂催化的芳基或者烯基碳-氢键与各种芳基、烯基以及烷基硼酸酯试剂的高选择性交叉碳-碳偶联反应。该反应中我们揭示了一种有趣的铁-锌共催化体系。通过50例底物的研究,我们证明该反应具有广阔的底物适用面以及官能团兼容性,底物研究同时证明,除了联芳基和苯乙烯骨架,该铁催化反应可以同时高效、高立体选择性的构筑1,3-共轭二烯和1,3,5-共轭三烯骨架结构。该工作中的机理研究证明了该铁催化碳-氢键活化反应中铁元素的变价是Fe(III)/Fe(I)的变价循环。碳氢键活化步骤通过类似6-键复分解的机理发生在Fe(Ⅲ)有机中间体上。研究中同时解释了铁催化中的配体效应,指出了阴离子型Fe(Ⅰ)中间体上存在铁原子和配体之间的电荷迁移,解释了含有共轭骨架的双齿膦配体(Z)-1,2-二(二苯基膦基)乙烯是最佳配体的原因。更多还原

【Abstract】 This thesis contains two parts. The first part is about new carbon-carbon bond formation methodology based on transition-metal-catalyzed decarboxylation. The work involved in this part was done in the University of Science and Technology of China during the end of2008to2012. The second part of this thesis is about several new carbon-carbon bond formation methodologies based on iron-catalyzed C-H activation. The work in the second part was done during my joint-training period in the University of Tokyo, from October2012to April2014, in the Nakamura Laboratory.The FIRST PART:New Method of carbon-canbon bond formation based on transition-metal-catalyzed decarboxylationThe development of transition-metal-catalysis in organic synthesis significantly changed the way and improved the capability that of humanbeing creating complex chemicals. Traditional transition-metal-catalyzed cross-coupling reactions (Kumada Coupling, Negishi Coupling, Stille Coupling, Suzuki Coupling, etc.) rely on the use of organometallic reagents. Since2006, instead of organometallic reagent, the ideal of using carboxylic acid as nucleophilic synthon via decarboxylation in transition-metal-catalyzed cross-coupling reactions was proved to be viable and got extensive attentions in the synthetic community. The chapter I of the first part in this thesis reviews the historic development and current situation of transition-metal-catalyzed decarboxylative couplings. The reactions were sorted and discussed according to different reaction types. We also discussed the challenges and opportunities of decarboxyative coupling in this chapter.In chapter II of this part, we develpoted a new method for aromatic ester synthesis based on palladium-catalyzed decarboxylation of oxalate monoester. We developed oxalate monoester into ester synthon equivalent in transition-metal-catalyzed cross-coupling for the first time. By optimization study and scope investigation of40examples containing various substituents, we proved that this method is suitable for not only aryl bromides and iodides but also aryl chlorides with good functional group compatibility. This method is also feasible for synthetizing cinnamate esters. This methodology shows advantages of easy operation, safety and high yields. The mechanistic study in this paper indicates that decarboxylation on Pd(II) intermediate is the rate determine step in this transformation.In Chapter III of this part, we found and developed a new copper-catalyzed decarboxylative coupling reaction for polyfluorobiaryl synthesis. In this reaction, we developed potassium polyfluorobenzoate into nucleophilic polyfluorophenyl synthon in copper-catalyzed cross-coupling reactions. By scope study of64examples, this method was proved to be an efficient method for polyfluorobiary preparation from aryl iodides and aryl bromides with excellent functional group compatibility. In this work, we also revealed that this copper-catalyzed method is suitable for some vinylbromide and tertiary alkyl bromide. We first time discovered diglyme is a suitable solvent for some decarboxylative cross-couplings. Mechanistic study of this work revealed the possibility of decarboxylative coupling under sole copper catalysis, and point out the mechanistic pathway of oxidative addition of aryl halide after decarboxylation, Cu(I)-Cu(III) valent change and decarboxylation is catalyzed by Cu(Ⅰ).In Chapter IV of this part, with the limitation of the copper-version of part III in mind, such as the aryl electrophile is limited to aryl bromides and expensive aryl iodides. We aimed at achieving a palladium-version of this reaction that can utilize inexpensive aryl chlorides and phenol derivatives for polyfluorobiaryl synthesis. In this part we successfully found by using a simple catalyst system of combination of Pd(OAc)2/P(Cy)3, a broad scope of polyfluorobiaryl can be synthesized in diglyme solvent with good yield and high functional group compatibility. Using diglyme as solvent was crucial for the success of this reaction.The synthetic value of this method was further proved by scope study of40examples. In this study, we discovered that in this palladium system, matching of the rate of oxidative addition and palladium catalyzed decarboxylation is crucial for the good performance of this reaction. By adjusting the ligand on palladium, we achieved high efficient reaction by using not only aryl bromides but also aryl chlorides, and by using this discovery, we achieved orthogonal incorporation of two different polyfluorophenyl into dihalide compound in a sequential manner. Mechanistic study suggests a mechanism involving decarboxylation follows by oxidative addition, Pd(0)-Pd(Ⅱ) valent change and decarboxylation on Pd(II) intermediate.In Chapter V of this part, my research interest changed from decarboxylative formation of Csp2-Csp2bond to decarboxylative formation of Csp3-Csp2bond using aliphatic carboxylic acid. At this time, transition-metal-catalyzed decarboxylative cross-coupling of aliphatic carboxylic acids via well defined organometallic intermediates was lack of investigation, most of the studies on decarboxylative coupling at that time were focused on aryl carboxylic acids.In Chapter V, we successfully achieved a novel type of palladium-catalyzed decarboxylative arylation reaction by breaking Csp3-COOH bond. This reaction offers a new pathway for the synthesis of2-arylmethyl substituted azaarenes and its derivatives. By scope investigation of40examples, we proved this method is a useful method for highly efficient and selective synthesis of a series of2-benzyl pyridines,2-benzyl pyrazines,2-benzyl qionolines,2-benzyl benzothiazoles and2-benzyl benzoxazoles with good functional group tolerance. This method can be utilized for the preparation of various aza-heterocycle compounds which have potential bioactivity. With the supporting of DFT analysis and the isolation of intermediate, we discussed the detailed reaction mechanism which may involve Pd(0)-Pd(II) valent change. The coordination of N-atom on the heteroaromatic ring with Pd(II) intermediate was proved to be crucial for decarboxylation. Mechanistic discussion is also supported by the scope limitation and gives guidance for the development of new decarboxylative coupling reactions.In Chapter VI of this part, we went on our goal of exploring new synthetically useful reactions utilizing palladium-catalyzed decarboxylation of aliphatic carboxylic acids. In this chapter, we discovered palladium-catalyzed decarboxylative a-arylation reactions of2-cyanoacatate, its derivatives and malonate monoesters. This reaction was demonstrated to be a complementary method of the famous Hartwig-Buchwald a-arylation reactions. By scope study of96examples, we showed the quite broad scope, excellent functional group compatibility and good mono-arylation selectivity of this methodology. By attempts of some base-sensitive substrates, we further demonstrated the advantages of this method over existing ones. In this work, we also successfully utilized this method in the synthesis of Ibuprofen(?) and their derivatives. Moreover, we demonstrate this method can be used for the synthesis of an important anti-breast cancer drug-Anastrazole(?). We got a granted patent of preparing the key intermediate of this drug molecular using our method, and it is worth a mention that this patent method had already been used in companies for kilogram-scale preparation of this drug intermediate.In Chapter VII of this part, we reported palladium-catalyzed decarboxylative arylation of nitrophenyl acetates and derivatives with aryl bromides and aryl chlorides. By scope investigation of50examples, we proved this reaction is useful for the convenient preparation of nitro substituted1,1-diarylalkane derivatives. In this work, we achieved decarboxylative arylation on tertiary and quaternary carbon center of nitrophenyl acetate derivatives. We also demonstrated in our work that from our decarboxylative arylation products, we can get easy access into4-aryl quinoline and4-aryl dihydroquinolinone via our newly developed pathway. We point out by using the transformation of nitro functional group, this method can be used for further preparation of other substituted1,1-diarylalkane derivatives.In Chapter VIII of this part, our research interest changed from decarboxylative arylation of aliphatic carboxylate salts to decarboxylative benzylation of aliphatic carboxylate salts. In this chapter, an efficient and practical palladium-catalyzed decarboxylative benzylation reaction of a-cyano aliphatic carboxylate salts with benzyl electrophiles has been established. This reaction proceeds under relatively mild conditions, avoids the use of organometallic reagents, and possesses good functional group compatibility. By50examples, we demonstrates that a diverse range of quaternary, tertiary and secondary β-aryl nitriles can be conveniently prepared via this methodology. Many of these nitriles are difficult to be synthesized via traditional base mediated nucleophilic substitution reactions. This is the first example of intermolecular decarboxylative benzylation of activated aliphatic carboxylate salts.The SECOND PART:New Method of Carbon-Canbon Bond Formation based on Iron-Catalyzed C-H Bond ActivationCarbon-carbon bond formation through transition-metal-catalyzed selective direct carbon-hydrogen bond activation is an ideal reaction pathway, since carbon-hydrogen bond is ubiquitous in various organic molecules. Highly selective carbon-hydrogen activation methodology may lead to carbon-carbon formation method with high selectivity and step economy. In the last20years, direct carbon-hydrogen functionalization reactions using noble metals had drawn intensive attentions of the catalysis community. However, almost all these transformations were investigated using noble metals, such as palladium, rhodium, ruthenium and iridium etc. Direct C-H transformation methodology flourishes on the basis of reactivities of these noble transition-metals. However these metals are toxic and most importantly, on the time scale of centuries, these rare metal resources are nonrenewable and even now the price and distribution are often affected by politics. Taken these points into consideration, iron is an ideal catalyst since iron is non-toxic and is the most abundant transition-metal on the earth. Exploring new iron-catalyzed direct carbon-hydrogen functionalization to replace noble metal catalysis, exploring the new reactivity of iron and achieving new transformations that could not be achieved by precious metals. We believe these directions are worth to be explored by chemists in the next several decades. In the first chapter of the second part of this thesis, we reviewed the development and typical examples of carbon-carbon bond formation by iron-catalyzed carbon-hydrogen bond activation. The discussion and classification are according to different reaction types. We also discussed the challenges and chances of iron-catalyzed carbon-hydrogen transformation which we considered to be in this chapter.In chapter II of the second part, we reported a novel type of iron-catalyzed selective direct C(sp3)-H arylation reaction. Almost all the reported reaction of iron-catalyzed direct C(sp3)-H functionalizations involve a radical intermediate. Selective C(sp3)-H bond activation via the formation of iron-involved metallocycle was limited to stoichiometric reaction on specific substrates. In this work, we revealed an iron/biphosphine-catalyzed directed arylation of a C(sp3)-H bond in an aliphatic carboxamide with an organozinc reagent in high yield under mild oxidative conditions. The choice of the directing group and of the biphosphine ligand was crucial for the success of this reaction. By scope study of28examples, we found the reaction is selective for primary alkyl over secondary alkyl or benzyl, and is sensitive to the steric factors on both of the amide and the Grignard reagent. Isotope labeling experiments revealed carbon-hydrogen activation is the rate-determine step of this reaction. This work reveals a new type of catalytic activity of iron. Various β-arylated carboxylate amides can be readily prepared via this method.Due to the difficulity of effective formation of an active organoiron species, in catalytic carbon-carbon bond formation reactions catalyzed through organoiron species, Grignard reagent and zinc reagent prepared from Grignard reagent are the most successful carbon nucleophiles, especially in iron-catalyzed direct carbon-hydrogen bond functionalizations. However, the inherent disadvantages of Grignard reagent and zinc reagent limit the utility of this process. Achieving efficient iron-catalyzed carbon-carbon bond formation reaction using other stable carbon nucleophiles is quite important but challenge. In chapter III of the second part, we report here that an abundant, inexpensive, and non-toxic iron salt can catalyze the chelation-assisted reaction of an aromatic or olefinic C-H substrate with a variety of aryl-, alkenyl-, or alkylboronate reagents in the presence of a Zn(II) additive at70℃. The variety of substrates that can be utilized and the unprecedented stereoretentive introduction of a variety of simple or functionalized alkenyl groups into a sp2C-H bond to produce styrene derivatives, conjugated dienes and even1,3,5-triyne highlight the versatility of the present iron catalytic system. Several lines of evidence suggest that an iron(III) reactive intermediate is responsible for the C-H bond activation process. An electron transfer process from iron to ligand is discovered and suggested to be crucial for the operation of a unique Fe(Ⅲ)-Fe(I) mechanism.更多还原