Auswahl der wissenschaftlichen Literatur zum Thema „Carbon-hetero bond transformation reactions“

The Pd-catalyzed cross-coupling between N-tosylhydrazones and organic halides is a powerful method for the creation of C–C bonds. This transformation has been included recently in cascade processes in which the same catalyst promotes various independent catalytic steps, a process known as auto-tandem catalysis. This strategy proves to be very useful for the construction of relatively complex carbo- and heterocyclic structures, as well as for the generation of molecular diversity. This short review will cover the different Pd-catalyzed auto-tandem reactions­ involving N-tosylhydrazones organized by the bond-forming sequence: C–C/C–N and C–C/C–C. Some examples of related tandem reactions leading to acyclic compounds are also highlighted.1 Introduction2 Auto-Tandem C–C/C–N Bond-Forming Reactions3 Auto-Tandem C–C/C–C Bond-Forming Reactions4 Tandem Reactions for the Synthesis of Linear Molecules5 Summary and Outlook

The polymeric graphitic carbon nitride (g-C3N4) has been one of the interesting earth abundant elements. Though g-C3N4 finds application as a photocatalyst, its photocatalytic behaviour is limited because of low efficiency, mainly due to rapid charge recombination. To overcome this problem, several strategies have been developed including doping of metal/non-metal in the cavity of g-C3N4. Moreover, the CoFe2O4 NPs have been used in many organic transformations because of its high surface area and easy separation due to its magnetic nature. This review describes the role of cobalt ferrite as magnetic nanoparticles and metal-doped carbon nitride as efficient heterogeneous catalysts for new carbon-carbon and carbon-hetero atom bond formation followed by heterocyclization. Reactions which involved new catalysts for selective activation of readily available substrates has been reported herein. Since nanoparticles enhance the reactivity of catalyst due to higher catalytic area, they have been employed in various reactions such as addition reaction, C-H activation reaction, coupling reaction, cyclo-addition reaction, multi-component reaction, ring-opening reaction, oxidation reaction and reduction reactions etc. The driving force for choosing this topic is based-on huge number of good publications including different types of spinels/metal doped-/graphitic carbon nitride reported in the literature and due to interest of synthetic community in recent years. This review certainly will represent the present status in organic transformation and for exploring further their catalytic efficiency to new organic transformations involving C-H activation reaction through coupling, cyclo-addition, multi-component, ring-opening, oxidation and reduction reactions.

Domino reactions are defined as processes of two or more bond-forming reactions under identical conditions, in which the subsequent transformation takes place at the functionalities obtained in the former transformation. They allow the efficient synthesis of complex molecules from simple substrates in an ecologically and economically favorable way. A very powerful domino process is the domino Knoevenagel–hetero-Diels–Alder reaction, in which an aldehyde or an beta-ketoester is condensed with a 1,3-dicarbonyl compound or a heteroanalog to give a 1-oxa-1,3-butadiene, which can undergo an inter- or intramolecular hetero-Diels–Alder reaction with dienophiles such as enol ethers or alkenes. The products are dihydropyrans, which can be transformed in a variety of ways. Thus, an extension of the process is the synthesis of highly substituted pyrrolidines, piperidines, and azepanes using aminoaldehydes. The process has also been employed for the enantioselective total synthesis of a variety of alkaloids, such as indol- and ipecacuanha alkaloids. In another domino process, erythrina and homoerythrina alkaloids have been prepared from simple phenylethylamines and ketoesters.

Chemical synthesis typically relies on reactions that generate complexity through elaboration of simple starting materials. Less common are deconstructive strategies toward complexity—particularly those involving carbon-carbon bond scission. Here, we introduce one such transformation: the hydrodealkenylative cleavage of C(sp3)–C(sp2) bonds, conducted below room temperature, using ozone, an iron salt, and a hydrogen atom donor. These reactions are performed in nonanhydrous solvents and open to the air; reach completion within 30 minutes; and deliver their products in high yields, even on decagram scales. We have used this broadly functionality tolerant transformation to produce desirable synthetic intermediates, many of which are optically active, from abundantly available terpenes and terpenoid-derived precursors. We have also applied it in the formal total syntheses of complex molecules.

Hydrogenation is one of the most important transformation reactions widely used in a large variety of areas such as Chemical, pharmaceutical and agricultural industries. Granulated carbon supported palladium catalysts have been used here for hydrogenation of carbon-carbon triple bonds. Catalyst composites and granules were produced by using sodium alginate binder under the certain thermal treatment process. After that, metal salt precursors were deposited using impregnation method. The final catalysts obtained through reduction of metal oxides by hydrazine as reducing agent. After that, metal particles loaded catalysts were utilized to perform hydrogenation reaction. Scanning Electron Microscopy (SEM) and Transmission Electron Microscopy (TEM) techniques applied for investigation of catalysts. Reaction products were evaluated by High Performance Liquid Chromatography (HPLC) technique. It has been concluded that MWCNT as support exhibits high conversion in the hydrogenation of 2-butyne-1, 4-diol as a typical triple bond carbon-carbon precursor.

Recently the K₂S₂O₈ mediated cyclization/coupling reactions to construct carbon–carbon/carbon–heteroatom bond via oxidative transformation is became much interesting in organic synthesis.

During the last decade, gold-catalyzed reactions have become a tour de force in organic synthesis. Recently, the gold-, Brønsted acid- or Lewis acid-catalyzed oxygen transfer from carbonyl to carbon–carbon triple bond, the so-called alkyne–carbonyl metathesis, has attracted much attention because this atom economical transformation generates α,β-unsaturated carbonyl derivatives which are of great interest in synthetic organic chemistry. This mini-review focuses on the most recent achievements on gold-catalyzed oxygen transfer reactions of tethered alkynones, diynes or alkynyl epoxides to cyclic enones. The corresponding mechanisms for the transformations are also discussed.

A major challenge in carbon‒hydrogen (C‒H) bond functionalization is to have the catalyst control precisely where a reaction takes place. In this study, we report engineered cytochrome P450 enzymes that perform unprecedented enantioselective C‒H amidation reactions and control the site selectivity to divergently construct β-, γ-, and δ-lactams, completely overruling the inherent reactivities of the C‒H bonds. The enzymes, expressed in Escherichia coli cells, accomplish this abiological carbon‒nitrogen bond formation via reactive iron-bound carbonyl nitrenes generated from nature-inspired acyl-protected hydroxamate precursors. This transformation is exceptionally efficient (up to 1,020,000 total turnovers) and selective (up to 25:1 regioselectivity and 97%, please refer to compound 2v enantiomeric excess), and can be performed easily on preparative scale.

Dihetaryl disulfides were used as electrophiles in a palladium-catalyzed carbon–carbon cross-coupling reaction with arylsilanes to ­realize a Hiyama-type reaction. This unique transformation shows high reactivity, excellent functional-group tolerance, and mild reaction conditions, making it an attractive alternative to conventional cross-coupling approaches for carbon−carbon bond construction.

The carbon-carbon bond formation has always been one of the most important reactions in C1 resource utilization. Compared to traditional organic synthesis methods, biocatalytic C-C bond formation offers a green and potent alternative for C1 transformation. In recent years, with the development of synthetic biology, more and more carboxylases and C-C ligases have been mined and designed for the C1 transformation in vitro and C1 assimilation in vivo. This article presents an overview of C-C bond formation in biocatalytic C1 resource utilization is first provided. Sets of newly mined and designed carboxylases and ligases capable of catalyzing C-C bond formation for the transformation of CO2, formaldehyde, CO, and formate are then reviewed, and their catalytic mechanisms are discussed. Finally, the current advances and the future perspectives for the development of catalysts for C1 resource utilization are provided.

Thesis (Ph. D. in Organic Chemistry)--Massachusetts Institute of Technology, Dept. of Chemistry, 2013.
Cataloged from PDF version of thesis.
Includes bibliographical references.
Chapter 1 Nucleophilic trifluoromethyl sources were systematically examined in stoichiometric palladium experiments to determine the most efficient class of reagents for transmetallation. In conjunction with reductive elimination studies, this led to the development of the first system for the trifluoromethylation of aryl chlorides. Chapter 2 A method for the oxidative trifluoromethylation of (hetero)aryl boronic acids is reported. Bench top setup and visual reaction monitoring makes this process particularly well suited to medicinal and academic chemists. Fast reaction times allow for the trifluoromethylation of heterocyclic boronic acids that are prone to facile protodeboronation. Chapter 3 A trifluoromethylation of potassium vinyl trifluoroborates via iron catalysis has been developed. Excellent E:Z ratios are observed for styryl trifluoroborates. Initial investigations suggest a mechanistic pathway that diverges from our previous (hetero)aryl trifluoromethylation systems. Chapter 4 A highly efficient system for the palladium-catalyzed cyanation of (hetero)aryl halides is disclosed. By employing palladacycle precatalysts, cyanide binding during catalyst formation is minimized, allowing for low catalyst loadings even with unactivated aryl chlorides. The method utilizes a non-toxic cyanide source and exhibits excellent functional group tolerance, particularly of free N-H groups and typically challenging five membered heterocycles.
by Todd D. Senecal.
Ph.D.in Organic Chemistry

The thesis entitled “Copper-Catalyzed Novel Oxidative Transformations: Construction of Carbon-Hetero Bonds” is divided into two main sections. Section A deals with the utility of azide as a nitrogen source for C-N bond formation, which is further divided into 4 chapters, and section B presents decarboxylative radical coupling reaction for C-heteroatom bond formation which is further divided in to two chapters. Section A Chapter 1 describes an approach for the direct synthesis of nitrile from the corresponding alcohols using azide as a nitrogen source. Nitrile functionality is a versatile and ubiquitous which occurs in a variety of natural products. Nitrile functionality can be easily transformed into a variety of functional groups and products such as aldehydes, ketones, acids, amines, amides and nitrogen-containing heterocycles, such as tetrazoles and oxazoles. In this chapter a successful attempt for developing a novel methodology to oxidize benzylic and cinnamyl alcohols to their corresponding nitriles in excellent yields has been described. This strategy uses DDQ as an oxidant and TMSN3 as a source of nitrogen in the presence of a catalytic amount of Cu(ClO4)2·6H2O. A few representative examples are highlighted in Scheme 1.1 Scheme 1. Oxidative conversion of alcohols to nitriles Second chapter represents a protocol for the synthesis of 1,5-disubstituted tetrazoles from the corresponding secondary alcohols. Among heterocyles, tetrazole and its derivatives are important class of nitrogen containing molecules. Due to their well-known biological activities as well as vast applications in pharmaceuticals and material science, they are potential targets for synthetic organic chemists. Therefore, a simple and user-friendly method for the synthesis of tetrazole is desirable. In this chapter, a mild and convenient method to synthesize 1,5-disubstituted tetrazoles using easily accessible secondary alcohols by employing TMSN3 as a nitrogen source is developed. This reaction is performed in the presence of a catalytic amount of Cu(ClO4)2·6H2O using DDQ as an oxidant under ambient conditions (Scheme 2).2 Scheme 2. Oxidative conversion of secondary alcohols to tetrazoles Third chapter presents a method for synthesizing amides from their corresponding secondary alcohols. Amide functionality is a crucial backbone in peptide chemistry, it also serve as an important precursor or intermediate for variety of organic transformations. In this contention, a mild and convenient method to synthesize amides using easily accessible secondary alcohols by employing TMSN3 as a nitrogen source is developed. This reaction is performed in the presence of a catalytic amount of Cu(ClO4)2·6H2O using DDQ as an oxidant under ambient conditions (Scheme 3).3 Scheme 3. Oxidative conversion of secondary alcohols to amides Additionally, the application of this methodology has also been revealed for the synthesis azides directly from their alcohols. Some of the representative examples are shown in the Scheme 4.3 Scheme 4. Direct conversion of alcohols to their azides. Fourth chapter describes highly chemoselective Schmidt reaction. The classical Schmidt reaction involves the formation of new carbon-nitrogen bonds in a reaction of a carbon-centred electrophile with hydrazoic acid followed by loss of nitrogen, which usually occurs via a rearrangement. It is well known that under the Schmidt reaction conditions, ketones and carboxylic acids are converted into their corresponding amides and amines respectively, whereas aldehydes furnish a mixture of formanilides and nitriles. In this chapter, Schmidt reaction of aldehydes to obtain their nitriles without formation of the corresponding formanilide is presented (Scheme 5).4 It was also observed that aromatic ketones and acids functionalities were intact under the reaction condition, unlike the conventional Schmidt reaction. Scheme 5. Highly chemoselective Schmidt reaction Section B It is divided into two chapters, describes a copper catalyzed decarboxylative radical coupling for the synthesis of vinyl sulfones and nitroolefins (Scheme 6). Scheme 6. General strategy for the second part First chapter narrates a strategy for synthesizing nitroolefins from the α,β-unsaturated carboxylic acids. Nitroolefins represent a unique class of nitro compounds, which have multifaceted utility in organic synthesis. They possess antibacterial, rodent-repelling, and antitumor activities. They serve as important intermediates in organic synthesis. Nitroolefins also react with a variety of nucleophiles, and their electron-deficient character renders them as a powerful dienophiles in Diels-Alder reactions. In our attempt to use the decarboxylative strategy, this chapter describes a method for the nitrodecarboxylation of substituted cinnamic acid derivatives to their corresponding nitroolefins. This nitrodecarboxylation reaction is performed using catalytic amount of CuCl in the presence of air using TBN as a nitrating source (Scheme 7).5 Besides, the reaction provides a useful method for the synthesis of β,β-disubstituted nitroolefin derivatives which are generally difficult to access from other conventional methods. Scheme 7. Decarboxylative nitration Second chapter presents a new protocol for the synthesis of vinyl sulfones from the α,β-unsaturated carboxylic acid. Vinyl sulfones are versatile building blocks, which find their utility as Michael acceptors and used in cycloaddition reactions. This functional group has also been shown to potently inhibit a variety of enzymatic processes, and thus provides unique properties for drug design and medicinal chemistry. Vinyl sulfones are prominent in medicinal chemistry owing to their wide presence in pharmaceutically active molecules, such as enzyme inhibitors and biological activity. In this chapter, we report a method for the construction of C-S bonds via ligand promoted decarboxylative radical sulfonylation of ,-unsaturated carboxylic acids to synthesize vinyl sulfones using Cu catalysis (Scheme 8).6 This is the first report for this particular conversion. Scheme 8. Decarboxylative sulfonation

The thesis entitled “Copper-Catalyzed Novel Oxidative Transformations: Construction of Carbon-Hetero Bonds” is divided into two main sections. Section A deals with the utility of azide as a nitrogen source for C-N bond formation, which is further divided into 4 chapters, and section B presents decarboxylative radical coupling reaction for C-heteroatom bond formation which is further divided in to two chapters. Section A Chapter 1 describes an approach for the direct synthesis of nitrile from the corresponding alcohols using azide as a nitrogen source. Nitrile functionality is a versatile and ubiquitous which occurs in a variety of natural products. Nitrile functionality can be easily transformed into a variety of functional groups and products such as aldehydes, ketones, acids, amines, amides and nitrogen-containing heterocycles, such as tetrazoles and oxazoles. In this chapter a successful attempt for developing a novel methodology to oxidize benzylic and cinnamyl alcohols to their corresponding nitriles in excellent yields has been described. This strategy uses DDQ as an oxidant and TMSN3 as a source of nitrogen in the presence of a catalytic amount of Cu(ClO4)2·6H2O. A few representative examples are highlighted in Scheme 1.1 Scheme 1. Oxidative conversion of alcohols to nitriles Second chapter represents a protocol for the synthesis of 1,5-disubstituted tetrazoles from the corresponding secondary alcohols. Among heterocyles, tetrazole and its derivatives are important class of nitrogen containing molecules. Due to their well-known biological activities as well as vast applications in pharmaceuticals and material science, they are potential targets for synthetic organic chemists. Therefore, a simple and user-friendly method for the synthesis of tetrazole is desirable. In this chapter, a mild and convenient method to synthesize 1,5-disubstituted tetrazoles using easily accessible secondary alcohols by employing TMSN3 as a nitrogen source is developed. This reaction is performed in the presence of a catalytic amount of Cu(ClO4)2·6H2O using DDQ as an oxidant under ambient conditions (Scheme 2).2 Scheme 2. Oxidative conversion of secondary alcohols to tetrazoles Third chapter presents a method for synthesizing amides from their corresponding secondary alcohols. Amide functionality is a crucial backbone in peptide chemistry, it also serve as an important precursor or intermediate for variety of organic transformations. In this contention, a mild and convenient method to synthesize amides using easily accessible secondary alcohols by employing TMSN3 as a nitrogen source is developed. This reaction is performed in the presence of a catalytic amount of Cu(ClO4)2·6H2O using DDQ as an oxidant under ambient conditions (Scheme 3).3 Scheme 3. Oxidative conversion of secondary alcohols to amides Additionally, the application of this methodology has also been revealed for the synthesis azides directly from their alcohols. Some of the representative examples are shown in the Scheme 4.3 Scheme 4. Direct conversion of alcohols to their azides. Fourth chapter describes highly chemoselective Schmidt reaction. The classical Schmidt reaction involves the formation of new carbon-nitrogen bonds in a reaction of a carbon-centred electrophile with hydrazoic acid followed by loss of nitrogen, which usually occurs via a rearrangement. It is well known that under the Schmidt reaction conditions, ketones and carboxylic acids are converted into their corresponding amides and amines respectively, whereas aldehydes furnish a mixture of formanilides and nitriles. In this chapter, Schmidt reaction of aldehydes to obtain their nitriles without formation of the corresponding formanilide is presented (Scheme 5).4 It was also observed that aromatic ketones and acids functionalities were intact under the reaction condition, unlike the conventional Schmidt reaction. Scheme 5. Highly chemoselective Schmidt reaction Section B It is divided into two chapters, describes a copper catalyzed decarboxylative radical coupling for the synthesis of vinyl sulfones and nitroolefins (Scheme 6). Scheme 6. General strategy for the second part First chapter narrates a strategy for synthesizing nitroolefins from the α,β-unsaturated carboxylic acids. Nitroolefins represent a unique class of nitro compounds, which have multifaceted utility in organic synthesis. They possess antibacterial, rodent-repelling, and antitumor activities. They serve as important intermediates in organic synthesis. Nitroolefins also react with a variety of nucleophiles, and their electron-deficient character renders them as a powerful dienophiles in Diels-Alder reactions. In our attempt to use the decarboxylative strategy, this chapter describes a method for the nitrodecarboxylation of substituted cinnamic acid derivatives to their corresponding nitroolefins. This nitrodecarboxylation reaction is performed using catalytic amount of CuCl in the presence of air using TBN as a nitrating source (Scheme 7).5 Besides, the reaction provides a useful method for the synthesis of β,β-disubstituted nitroolefin derivatives which are generally difficult to access from other conventional methods. Scheme 7. Decarboxylative nitration Second chapter presents a new protocol for the synthesis of vinyl sulfones from the α,β-unsaturated carboxylic acid. Vinyl sulfones are versatile building blocks, which find their utility as Michael acceptors and used in cycloaddition reactions. This functional group has also been shown to potently inhibit a variety of enzymatic processes, and thus provides unique properties for drug design and medicinal chemistry. Vinyl sulfones are prominent in medicinal chemistry owing to their wide presence in pharmaceutically active molecules, such as enzyme inhibitors and biological activity. In this chapter, we report a method for the construction of C-S bonds via ligand promoted decarboxylative radical sulfonylation of ,-unsaturated carboxylic acids to synthesize vinyl sulfones using Cu catalysis (Scheme 8).6 This is the first report for this particular conversion. Scheme 8. Decarboxylative sulfonation

Design and Development of Carbon-Carbon and Carbon-Heteroatom Bond Forming Reactions” is divided into two sections. Section-A, contains two chapters, describes the catalytic ability of iodine for cross coupling reactions. Section-B, divided into three chapters, presents the azidation of organic scaffolds under oxidative conditions. Section A Chapter 1 presents a C-H functionalization of tetrahydroisoquinolines using iodine as a catalyst under aerobic conditions.1 This methodology employs Cross Dehydrogenative Coupling (CDC) strategy as a key step, which is highly atom economical as it doesn’t require pre-functionalized starting materials.2 Owing to the importance of tetrahydroisoquinoline moiety which is present in the umpteen natural products, considerable attention has been put up to functionalize tetrahydroisoquinoline scaffold.3 Iodine a non-metal which is non-toxic was found to catalyze the C-H functionalization of tetrahydroisoquinolines with a variety of nucleophiles such as coumarin, alkyl phosphite, phenols, indoles, acetone and dialkyl malonoates were coupled to it. Significant mechanistic study has been carried out to find the possible intermediate and support the mechanistic proposal. A few representative examples are highlighted in Scheme 1.1 Synopsis Scheme 1: A CDC coupling of tetrahydroisoquinoline with variety of nucleophiles Chapter 2 describes the Cross Hetero Dehydrogenative Coupling (CHDC) reactions of amines, alcohols and sulfoximines with various phosphites.4 Phosphoramidates and phosphate esters are structural scaffolds that are present in a variety of biologically active molecules.5 The conventional methods for synthesizing phosphoramidates/phosphate esters largely involve treating alcohol/amine with appropriate phosphorus halides which generates stoichiometric amount of halogen waste.6 Due to the usage of stoichiometric reagents and difficulties associated with the reported methods, there is a need for developing a protocol which is catalytic and mild. Therefore, we developed a method which employs catalytic amount of iodine and aq. H2O2 as a sole oxidant under milder conditions. Using this methodology, variety of phosphoramidates, phosphorous triesters and sulfoximine derived Synopsis Scheme 2: Phosphorylation of amines, alcohols and sulfoximines phosphoramidates have been synthesized with great efficiency and environmentally benign conditions. A few representative examples are highlighted in Scheme 2.4 Section B Chapter 1 of Section B demonstrates a mild way of synthesizing quaternary azides from α-substituted active methylene compounds which will serve as surrogates for several unnatural amino acid derivatives.7 Azidation has emerged as one of the efficient methods to introduce nitrogen atom in to the organic molecules.8 Azides are versatile functional groups which can be converted to amine, amide, and nitro compounds by simple modification. Moreover, azides are potential handle for “click” chemistry and provide late stage modifications in drug candidates, biomolecules and polymers, etc.9 Azidation of 1,3-dicarbonyl compounds is challenging, as both azides and 1,3-dicarbonyl compounds are nucleophilic in nature. In this section of the thesis, azidation of 1,3-dicarbonyl compounds has been carried out using tetrabutyl ammonium iodide (TBAI) as a catalyst, aq. TBHP as an oxidant and TMSN3 as a azide source. This method uses water as a solvent under mild reaction conditions to generate Synopsis quaternary azides in good to excellent yields. This operationally simple, practical, mild and green method provides an opportunity for synthesizing a variety of azidated β-keto esters, amides and ketones in good yields, Scheme 3.7 The application of this methodology has been demonstrated by synthesising a few triazole and pyrazolone derivatives. Scheme 3: Azidation of 1,3-dicarbonyl compounds Chapter 2 of Section B comprises the azidation and peroxidation of β-napthol derivatives using dearomatization strategy. Azidation and peroxidation are efficient ways to introduce nitrogen and oxygen into organic molecules, which serve as surrogates for amines and alcohol functional groups. In the present study, the azidative or peroxidative dearomatization of naphthol derivatives have been described. The azidation of β-napthol derivatives has been achieved by using CuBr (5 mol %) as a catalyst, TMSN3 as an azide source and aq. TBHP as an oxidant. Whereas, the peroxidation β-napthol derivatives has been accomplished using CuBr (5 mol %) in the presence of aq. TBHP at ambient reaction conditions.10 The products obtained are naphthalenone derivatives, which serve as valuable Synopsis synthetic intermediates and has potential handle for further functionalization.11 Several α-amino or α-peroxy naphthalenones are synthesized using this method in good yields. The usefulness of the methodology has been illustrated by synthesizing a few chiral azides and peroxides in good yields and with moderate enantioselectivity Scheme 4.10 Scheme 4: Dearomatizative azidation and peroxidation of 2-naphthols Chapter 3 reveals the azidation of indole at C-2 position by employing CuBr (10 mol %) as a catalyst and aq. TBHP as an oxidant in acetonitrile under reflux conditions (Scheme 5).12 The C-H functionalization of indole at C-2 position is one of pivotal methods, since it paves a way for synthesizing a variety of indolo-alkaloids.13 Azide is a versatile functionality which can be converted to several other nitrogen containing functional groups such as Synopsis Scheme 5: Azidation of indoles amine, amide, triazole, etc.9 A variety of functional groups were tolerated under the reaction conditions, and furnished the azidated product in good to excellent yields. Through radical inhibition study, we presume that the reaction may be proceeding through radical mechanism. In Scheme 5, a few representative examples are depicted.

Design and Development of Carbon-Carbon and Carbon-Heteroatom Bond Forming Reactions” is divided into two sections. Section-A, contains two chapters, describes the catalytic ability of iodine for cross coupling reactions. Section-B, divided into three chapters, presents the azidation of organic scaffolds under oxidative conditions. Section A Chapter 1 presents a C-H functionalization of tetrahydroisoquinolines using iodine as a catalyst under aerobic conditions.1 This methodology employs Cross Dehydrogenative Coupling (CDC) strategy as a key step, which is highly atom economical as it doesn’t require pre-functionalized starting materials.2 Owing to the importance of tetrahydroisoquinoline moiety which is present in the umpteen natural products, considerable attention has been put up to functionalize tetrahydroisoquinoline scaffold.3 Iodine a non-metal which is non-toxic was found to catalyze the C-H functionalization of tetrahydroisoquinolines with a variety of nucleophiles such as coumarin, alkyl phosphite, phenols, indoles, acetone and dialkyl malonoates were coupled to it. Significant mechanistic study has been carried out to find the possible intermediate and support the mechanistic proposal. A few representative examples are highlighted in Scheme 1.1 Synopsis Scheme 1: A CDC coupling of tetrahydroisoquinoline with variety of nucleophiles Chapter 2 describes the Cross Hetero Dehydrogenative Coupling (CHDC) reactions of amines, alcohols and sulfoximines with various phosphites.4 Phosphoramidates and phosphate esters are structural scaffolds that are present in a variety of biologically active molecules.5 The conventional methods for synthesizing phosphoramidates/phosphate esters largely involve treating alcohol/amine with appropriate phosphorus halides which generates stoichiometric amount of halogen waste.6 Due to the usage of stoichiometric reagents and difficulties associated with the reported methods, there is a need for developing a protocol which is catalytic and mild. Therefore, we developed a method which employs catalytic amount of iodine and aq. H2O2 as a sole oxidant under milder conditions. Using this methodology, variety of phosphoramidates, phosphorous triesters and sulfoximine derived Synopsis Scheme 2: Phosphorylation of amines, alcohols and sulfoximines phosphoramidates have been synthesized with great efficiency and environmentally benign conditions. A few representative examples are highlighted in Scheme 2.4 Section B Chapter 1 of Section B demonstrates a mild way of synthesizing quaternary azides from α-substituted active methylene compounds which will serve as surrogates for several unnatural amino acid derivatives.7 Azidation has emerged as one of the efficient methods to introduce nitrogen atom in to the organic molecules.8 Azides are versatile functional groups which can be converted to amine, amide, and nitro compounds by simple modification. Moreover, azides are potential handle for “click” chemistry and provide late stage modifications in drug candidates, biomolecules and polymers, etc.9 Azidation of 1,3-dicarbonyl compounds is challenging, as both azides and 1,3-dicarbonyl compounds are nucleophilic in nature. In this section of the thesis, azidation of 1,3-dicarbonyl compounds has been carried out using tetrabutyl ammonium iodide (TBAI) as a catalyst, aq. TBHP as an oxidant and TMSN3 as a azide source. This method uses water as a solvent under mild reaction conditions to generate Synopsis quaternary azides in good to excellent yields. This operationally simple, practical, mild and green method provides an opportunity for synthesizing a variety of azidated β-keto esters, amides and ketones in good yields, Scheme 3.7 The application of this methodology has been demonstrated by synthesising a few triazole and pyrazolone derivatives. Scheme 3: Azidation of 1,3-dicarbonyl compounds Chapter 2 of Section B comprises the azidation and peroxidation of β-napthol derivatives using dearomatization strategy. Azidation and peroxidation are efficient ways to introduce nitrogen and oxygen into organic molecules, which serve as surrogates for amines and alcohol functional groups. In the present study, the azidative or peroxidative dearomatization of naphthol derivatives have been described. The azidation of β-napthol derivatives has been achieved by using CuBr (5 mol %) as a catalyst, TMSN3 as an azide source and aq. TBHP as an oxidant. Whereas, the peroxidation β-napthol derivatives has been accomplished using CuBr (5 mol %) in the presence of aq. TBHP at ambient reaction conditions.10 The products obtained are naphthalenone derivatives, which serve as valuable Synopsis synthetic intermediates and has potential handle for further functionalization.11 Several α-amino or α-peroxy naphthalenones are synthesized using this method in good yields. The usefulness of the methodology has been illustrated by synthesizing a few chiral azides and peroxides in good yields and with moderate enantioselectivity Scheme 4.10 Scheme 4: Dearomatizative azidation and peroxidation of 2-naphthols Chapter 3 reveals the azidation of indole at C-2 position by employing CuBr (10 mol %) as a catalyst and aq. TBHP as an oxidant in acetonitrile under reflux conditions (Scheme 5).12 The C-H functionalization of indole at C-2 position is one of pivotal methods, since it paves a way for synthesizing a variety of indolo-alkaloids.13 Azide is a versatile functionality which can be converted to several other nitrogen containing functional groups such as Synopsis Scheme 5: Azidation of indoles amine, amide, triazole, etc.9 A variety of functional groups were tolerated under the reaction conditions, and furnished the azidated product in good to excellent yields. Through radical inhibition study, we presume that the reaction may be proceeding through radical mechanism. In Scheme 5, a few representative examples are depicted.

博士
國立臺灣大學
化學研究所
95
In this thesis, carbon-carbon bond formations are studied through three kinds of reactions: styrene polymerization, cross-couplings and nucleophilic additions. A new series of Ni(II) complexes [(N,N'')NiBr2] bearing bidentate amino-oxazoline ligands have been synthesized and applied for polymerization of styrene. With cocatalyst, MAO, these Ni(II) complexes 4 are highly efficient catalysts for styrene polymerization with activities up to ~107 g / mol [Ni] × h under optimized conditions, which possess the best performance among the catalytic Ni systems now. Effects of the structures of catalysts and the reaction parameters on the activities and characteristic properties for the polymers have been discussed here. From the 13C NMR data, the degree of stereoregularity of the synthesized polystyrene could be moderately controlled by the chiral center in the oxazoline ring although atactic polymers were generally obtained by these Ni(II) catalysts. The neutral Pd(II) complexes [(N,N'')PdCH3Cl] 5 and the cationic complexes [(N,N'')PdCH3L]+ 7 were prepared for studying the mechanism for polymerization. For the neutral Pd complexes, their coordination chemistry, dynamic behavior, geometric isomerization, and reactivity toward alkynes have been studied herein. Furthermore, reactions of cationic Pd complexes with styrene, which led to the η3-π-benzyl Pd(II) complexes, made the possible mechanism of the polymerization of styrene for the Ni(II) system. Neutral Pd(II) complexes were synthesized and involved nitrogen-containing ligands, such as mono-oxazolines, amino-oxazolines and pyridyl-pyrazoles. Among them, the chloromethylpalladium(II) complex with bidentate pyridyl-pyrazole ligands exhibited excellent activities toward Heck coupling reactions with high TONs up to 95,000,000, comparable to the palladacycle systems. In addition, the pyridyl-azolate ligands are good candidates for catalytic Suzuki-Miyaura cross-coupling reactions. In the presence of Pd(OAc)2, KF as base, and such ligands in EtOH, the couplings of aryl bromides with phenylboronic acids could proceed with high conversions at room temperature in the air. Under the same conditions, it could slowly couple aryl chloride with phenylboronic acids, which is rare for Pd catalysts with bidentate nitrogen donor ligands. Finally, we synthesized a series of cationic allylpalladium(II) complexes bearing asymmetric amino-oxazoline ligands. The isomer interconversion is demonstrated by NOESY spectra to show a syn-syn, anti-anti exchange. Nucleophilic attacks to the Pd complexes would result in the linear and branched products. The regioselectivity is strongly dependent on the steric/electronic properties of the nucleophiles and the polarity of the used solvents.

Abstract Because selenolate ions are highly reactive, soft nucleophiles, they can be used for the introduction of selenium into a variety of organic molecules. The preparative usefulness of these organoselenium compounds often relies on one of several constructive ways to manipulate the resulting carbon-selenium bond. For example. these can include selenoxide eliminations (see Chapter 2). lithium-selenium exchange to form carbanions (see Chapter 7) or homolytic cleavage to generate carbon-centred radicals (see Chapter 9). Nucleophilic selenium compounds are also useful for a number of functional group manipulations. In these stoichiometric or catalytic processes. the nucleophilic organoselenium species are used as reagents for the one-step transformation of selenium-free starting materials into selenium-free products (see Chapter 6).

This chapter covers enzyme classes that are capable of catalysing reactions to form carbon–carbon bonds, including aldolases, hydroxynitrile lyases, thiamine-dependent lyases, terpene cyclases, carboxylases, Pictet–Spenglerases, P450 monooxygenase variants and methyltransferases. The chapter is divided into separate sections, each detailing the formation of carbon–carbon bonds by a specific enzyme class. Each section begins with a review of chemical methods of carrying out similar transformations, followed by a description of the enzyme class itself. The substrate scope of each enzyme class, including its chemo-, regio- and stereoselectivity, is discussed and a general mechanism for the enzyme-catalysed reaction is presented. This should give the reader a good understanding of when and how to carry out carbon–carbon bond forming reactions using enzymes.

Alkylation is the transfer of an alkyl group (CnH2n+1) from one molecule (alkylating agent) to another where it can attach typically to carbon (C-alkylation), but also to oxygen (O-alkylation), nitrogen (N-alkylation), sulfur (S-alkylation) and phosphorous (P-alkylation) depending on the reaction conditions. This chapter discusses the importance of alkylation reactions, then looks at green improvements made by using solid acid catalysts, ionic liquids in Friedel–Crafts reactions, the atom economic borrowing hydrogen strategy and directed alkylation of C–H bonds using alkenes.

The formation of a carbon–carbon σ-bond via nucleophilic addition of an organometallic reagent to a carbonyl compound constitutes one of the most elementary transformations in organic synthesis. The great value of nucleophilic addition of organometallic reagents is its general applicability for the development of building blocks for an impressive range of different structures. This chapter looks at alternatives to the Grignard reaction, mechanochemical methods and the use of deep eutectic solvents.

AbstractThe generation of carbon-centered radicals via intermolecular hydrogen-atom transfer (HAT) from C—H bonds to an abstracting species (HAT reagent) represents a significant challenge in terms of reactivity, site-selectivity and stereoselectivity. The radical species resulting from such a transfer can then engage in carbon—carbon or carbon—heteroatom bond formation, possibly through the intervention of transition-metal catalysts, leading to a variety of functionalized products. This chapter aims to provide the reader with useful guidelines to understand, predict, and design selective radical transformations based upon initial HAT from a C—H bond coupled to different radical-capture strategies. A selection of examples that illustrate different approaches to implement HAT reactions in synthetically useful procedures are presented.

AbstractOxygen-centered radicals (R1O•) are reactive intermediates in organic synthesis, with versatile synthetic utilities in processes such as hydrogen-atom transfer (HAT), β-fragmentation, radical addition to unsaturated carbon–carbon bonds, and rearrangement reactions. In this review, we focus on recent advances in the generation and transformation of oxygen-centered radicals, including (alkyl-, α-oxo-, aryl-) carboxyl, alkoxyl, aminoxyl, phenoxyl, and vinyloxyl radicals, and compare the reactivity of oxygen-centered radicals under traditional reaction conditions with their reactivity under visible-light-induced reaction conditions.

This chapter studies functional groups, which can be classified according to the number of bonds a given carbon has to elements of greater electronegativity. The functional group level is the number of these bonds. Reactions can be classified according to the change in functional group level. The outcome of a reaction can be rationalized by considering where the highest energy electrons are to be found, and what low energy vacant molecular orbitals are available. Within a particular functional group level, there is often a general order of reactivity for different functional groups. Ultimately, transformations from one functional group to another may take place via different mechanisms depending on the particular reagents and reaction conditions.

Carlo Siciliano and Angelo Liguori of the Università della Calabria showed (J. Org. Chem. 2012, 77, 10575) that an amino acid 1 could be both protected and activated with Fmoc-Cl, so subsequent exposure to diazomethane delivered the Fmoc-protected diazo ketone 2. Pei-Qiang Huang of Xiamen University activated (Angew. Chem. Int. Ed. 2012, 51, 8314) a secondary amide 3 with triflic anhydride, then added an alkyl Grignard reagent with CeCl3 to give an intermediate that was reduced to the amine 4. John C. Walton of the University of St. Andrews found (J. Am. Chem. Soc. 2012, 134, 13580) that under irradiation, titania could effect the decarboxylation of an acid 5 to give the dimer 6. Jin Kun Cha of Wayne State University demonstrated (Angew. Chem. Int. Ed. 2012, 51, 9517) that a zinc homoenolate derived from 7 could be transmetalated, then coupled with an electrophile to give the alkylated product 8. The Ramberg-Bäcklund reaction is an underdeveloped method for the construction of alkenes. Adrian L. Schwan of the University of Guelph showed (J. Org. Chem. 2012, 77, 10978) that 10 is a particularly effective brominating agent for this transformation. Daniel J. Weix of the University of Rochester coupled (J. Org. Chem. 2012, 77, 9989) the bromide 12 with the allylic carbonate 13 to give 14. The Julia-Kocienski coupling, illustrated by the addition of the anion of 16 to the aldehyde 15, has become a workhorse of organic synthesis. In general, this reaction is E selective. Jirí Pospísil of the University Catholique de Louvain demonstrated (J. Org. Chem. 2012, 77, 6358) that inclusion of a K+-sequestering agent switched the selectivity to Z. Yoichiro Kuninobu, now at the University of Tokyo, and Kazuhiko Takai of Okayama University constructed (Org. Lett. 2012, 14, 6116) the tetrasubstituted alkene 20 with high geometric control by the Re-catalyzed addition of 19 to the alkyne 18. André B. Charette of the Université de Montréal converted (Org. Lett. 2012, 14, 5464) the allylic halide 21 to the alkyne 22 by displacement with iodoform followed by elimination. In an elegant extension of his studies with alkyl tosylhydrazones, Jianbo Wang of Peking University added (J. Am. Chem. Soc. 2012, 134, 5742) an alkyne 24 to 23 to give 25.

AbstractDynamic kinetic asymmetric transformations (DYKAT) are an extensively utilized class of reactions to construct carbon–carbon and carbon–heteroatom bonds from racemic starting materials. Much like DYKAT, stereoablative transformations grant access to enantioenriched building blocks from racemic substrates. In contrast to DYKAT, stereoablative transformations function via irreversible destruction of the stereocenter rather than a catalyst-promoted epimerization. While this review is not exhaustive, it focuses on transition-metal-catalyzed processes and outlines the current state-of-the-art of this field.

Leguminous forage crops are high in proteins but deficient in S- amino acids. It has been shown that both wool quality and milk production can be limited by the post-ruminal supply of sulfur-containing amino acids. Efforts to use conventional plant breeding and cell selection techniques to increase the S-amino acid content of alfalfa have met with little success. With the objective to increase the S-amino acid content of forage legumes, the goal of this project was to co- express the methionine rich zein genes from corn along with a gene for a key enzyme in methionine biosynthesis, aspartate kinase(AK). The zeins are seed storage proteins from corn and are groupec into four distinct classes based on their amino acid sequence homologies. The b-zein (15kd) and the 6zein (10kD and 18kD) have proportionately high levels of methionine (10%, 22% and 28%, respectively). Initial studies from our lab had shown that while the 15kD zein accumulated to high levels in vegetative tissues of transgenic tobacco the l0kD zein did not. However, co-expression of the 10kD zein with the 15kD zein genes in tobacco showed stabilization of the 10kD zein and the co-localization of the 10kD and 15kD zein proteins in unique ER derived protein bodies. AK is the key enzyme for producing carbon skeletons for all amino acids of the aspartate family including methionine. It is, however, regulated by end-product feedback inhibition. The specific objectives of this proposal were: i. to co-express the 15kD zein with the 10/18kD zein genes in alfalfa in order to enhance the level of accumulation of the 10/18kD zein; ii. to increase methionine pools by expressing a feedback insensitive AK gene in transformants co-expressing the 15kD and 10/18kD zein genes. The Israeli partners were successful in expressing the AK gene in alfalfa which resulted in an increase in free and bound threonine but not in methionine (Galili et al., 2000). Since our target was to increase methionine pools, we changed our second objective to replace the AK gene with the gene for cystathionine gamma synthase (CGS) in the co-expression studies. The first methionine specific reaction is catalyzed by CGS. An additional objective was to develop a transformation system for Berseem clover, and to introduce the appropriate gene constructs into it with the goal of improving their methionine content. Genes for the 15kD zein along with the genes for either the 10kD or 18kD zein have been introduced into the same alfalfa plant both by sexual crosses and by re-transformation. Analysis of these zein co-expressors have shown that both the IOkD and 18kD zein levels go up 5 to 10 fold when co-expressed with the 15kD zein (Bagga et al., MS in preparation). Incubation of the leaves of transgenic alfalfa co-expressing the 15kD and 10kD zein genes, in the rumen of cows have shown that the zein proteins are stable in the rumen. To increase the level of zein accumulation in transgenic alfalfa different promoters have been used to drive the zein genes in alfalfa and we have concluded that the CaMV 35S promoter is superior to the other strong leaf -specific promoters. By feeding callus tissue of alfalfa plants co-expressing the 15kD and 10kD zein genes with methionine and its precursors, we have shown that the zein levels could be significantly enhanced by increasing the methionine pools. We have now introduced the CGS gene (from Arabidopsis; kindly provided to us by Dr. Leustek), into the 15kD zein transformants and experiments are in progress to check if the expression of the CGS gene indeed increases the level of zein accumulation in alfalfa. We were not successful in developing a transformation protocol for Berseem clover.