New Carbon-Carbon Coupling Reactions Based On Decarboxylation And Iron-Catalyze C-H Activation

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.