Transition Metal-Catalyzed Carboxylic Acid And Nitrogen-Containing Group Directed C-H Bond Functionalization

Transition-metal catalyzed coordination-directed C-H bond functionalization has been emerged as an important synthetic strategy in the past few decades.It is one of the green and efficient ways to selectively construct C-C bonds and C-heteroatom bonds.The C-H bond functionalization strategy exhibits the advantages of strong regional selectivity,high atomic economy and wide substrate universality.The directing group（DG）in the substrate is coordinated with the transition metal to guide it to a specific position near the C-H bond,and then the regional selective functionalization of C-H bond is achieved.Functional groups containing O and N are the two most widely used directing groups in C-H bond activation.Therefore,the C-H functionalization involving O-containing or N-containing directing groups is one of the most important research contents in organic synthesis.At the same time,heterocyclic compounds are extremely important organic compounds and they are the basic structural units of numerous natural products,drug active compounds and functional materials.Therefore,in the dissertation,carboxylic acids,enamides and oxime esters were selected as the directing groups.Through the C-H bond functionalization assisted by transition metal catalysts including rhodium（Rh）,palladium（Pd）and cobalt（Co）,a series of heterocyclic skeletons with potential application value such asα-pyrones,isocoumarins,furans,isoquinolines and pyridines were successively constructed.The main research contents are as follows:1.Rh-Catalyzed Cyclization of Carboxylic acids withα-Diazoesters toα-Pyrones/IsocoumarinsCarboxylic acids are cheap,easy to obtain and ubiquitous in nature,which have been widely used to construct structural units such as bioactive molecules.The transition-metal catalyzed carboxyl-directed C-H bond activation strategy can achieve the selective functionalization of carboxylic acids at specific positions,thereby constructing a series of important heterocyclic molecular skeletons.At the same time,as a metal carbene precursor with easy preparation and high reactivity,diazo carbonyl compounds are one of the most commonly used coupling synthons in organic synthesis.Therefore,it is particularly necessary to develop a method for C-H bond functionalization directly using carboxyl groups with diazo carbonyl compounds.In this chapter,α-pyrones and isocoumarins were obtained smoothly by using acrylic acids or aromatic carboxylic acids withα-diazocarbonyl compounds,under the catalysis of Rh（III）,via the carboxyl directed coupling cyclization reaction.These products are the basic skeleton of some important natural products.α-Pyrones can be further used as organic synthesis reagents;Isocoumarins have some biological activity.The mechanism study proved that the addition of Zn（OAc）₂ could effectively inhibit the side reaction of carboxyl O-H bond on the nucleophilic insertion of metal carbene.2.Rhodium-Catalyzed Annulation of Acrylic Acids withα?Diazocarbonyl Compounds to FuransPolysubstituted furans are not only the basic structural units of many natural products and drug molecules,but also important intermediates in organic synthesis.The methods for synthesizing furan rings mainly include various transition metal-catalyzed coupling reactions,as well as intramolecular cyclization reactions of chain compounds containing multifunctional groups.In addition,it is a green and efficient way for the synthesis of furans by using transition metal catalyzed C-H bond activation strategy.In this chapter,we continue to use acrylic acids andα-diazocarbonyl compounds as substrates.Based on the previous work,furan compounds can be selectively obtained by adjusting the solvent and additive conditions of the reaction system.Mechanistic studies showed that the reaction underwent some main steps including alkenyl C-H bond alkylation,cyclization and decarbonylation under Rh（III）catalysis.Unlike many transformations,this reaction does not need any oxidants,thereby increasing the practicality of this method.3.Rhodium-Catalyzed Cyclization of Enamides with Sulfoxonium Ylides to IsoquinolinesIsoquinolines are ubiquitous in natural products,drugs,chiral ligands and organic materials,and the synthetic strategies for isoquinolines have always been the focus of chemists.The traditional methods for the synthesis of isoquinolines mainly include Bischler-Napieralski,Pictet-Spengler and Pictet-Gams name reactions.Most of these methods have the disadvantages of difficult to obtain starting materials,harsh reaction conditions,cumbersome post-processing steps and low yields.In recent years,the construction of isoquinoline skeleton by C-H bond activation catalyzed by transition metal has become a focus of research.As an important organic functional group in organic synthesis,enamides have adjustable reactivity and they have been widely used in various transition-metal catalyzed coupling reactions.In this chapter,we developed a Rh（III）-catalyzed tandem cyclization strategy for enamides and sulfoxonium ylides to obtain isoquinolines in one pot.Among them,sulfoxonium ylide is a new type of carbene precursor which is easy to prepare,stable and safe to operate.The reaction conditions are mild and have high substrate universality.Unlike most C-H bond activation,this transformation does not require any oxidants or acid/base additives,and hexafluoroisopropanol has a specific promoting effect on the initiation and transformation of the reaction.4.Palladium Catalyzed C-H Arylation of Acrylic Acids with Aryl IodidesCarboxylic acid is a particularly ideal directing group,which is widely existed in natural products and organic synthetic blocks.Transition-metal catalyzed aromatic carboxylic acid directed C-H bond arylation has made great progress.In contrast,there are a few reports on ortho-arylation of acrylic acid.There are two main reasons.Firstly,acrylic acid substrates are so active that they can occur addition or polymerization and other side reactions easily.Furthermore,they are easy to decarboxylate at high temperature.Secondly,the rigidity of the vinyl double bond of the acrylic acid substrate is relatively poor,which makes it difficult to activate the C-H bond by the transition metal coordinated with the directing group.Therefore,it is of great significance to realize the activation of the ortho C-H bond of acrylic acid.In this chapter,we adopted（DPPF）Pd Cl₂ as a catalyst to realize the ortho-arylation of acrylic acid with aryl iodine in one step.The 1,2-diarylethylene products can be obtained by decarboxylation of theβ-arylated acrylic acids.Substrate expansions and mechanism studies showed that the reaction was mainly carried out in the form of C-H bond activation,and the products had good regioselectivity.Most of the products were mainly Z-configuration.5.Cobalt-catalyzed synthesis of polysubstituted pyridines fromα,β-unsaturated ketoxime esters via self-coupling cyclizationPyridine and its derivatives have important application prospects in the fields of medicine,pesticide,metallurgy,auxiliaries and organic synthesis.The synthesis of polysubstituted pyridines has always been the focus of chemists.Usually,pyridine skeletons can be constructed by carbonyl condensation or cycloaddition between nitriles and alkynes.However,both methods have many disadvantages.α,β-Unsaturated ketone oxime esters are easy to prepare and possess good reactivity.Many research achievements have been obtained by using them to construct structurally diverse pyridine skeletons.In this chapter,using Cp*Co（CO）I₂/Ag Sb F₆ as a catalytic system,we developed a new method for the synthesis of polysubstituted pyridines by self-coupling ofα,β-unsaturated ketoxime esters.The reaction conditions are mild and a series of 2,4,6-trisubstituted pyridine derivatives can be obtained in moderate to good yields.In addition,some polysubstituted pyridine derivatives containing furan,thiophene or pyridine could be obtained through the rational design of the substrates.These compounds can be used as multidentate ligands and are expected to be applied in the fields of medicine,catalysis and bioactive drug research.