Дисертації з теми "Alkyl-Alkyl couplings"

Ce travail de thèse vise à réaliser la formation de liaisons C(sp³)-C(sp²) et C(sp³)-C(sp³) par couplages croisés de Suzuki-Miyaura (S-M) et de Kumada à l'aide de catalyseurs de fer, nouvellement développés, et en mettant l'accent sur l'étude du potentiel applicative de ces catalyseurs en synthèse. Ce travail se concentre aussi sur la mise au point d'une méthode efficace et sélective de 1,2-dicarbofonctionnalisation d'alcènes promue par ces catalyseurs. Le chapitre 1 présente les premières découvertes des couplages croisés médiés par le fer et le développement de catalyseurs de fer pour les couplages croisés de S-M et de Kumada. Les formations de liaisons C(sp²)-C(sp²), C(sp²)-C(sp³) et C(sp³)-C(sp³) seront couvertes. La conception de ligands adaptés et les études mécanistiques ont joués un rôle crucial dans le développement du domaine. La section suivante présente l'état de l'art de la méthode de 1,2-dicarbofonctionnalisation des oléfines catalysées par les métaux abondants, en soulignant les stratégies développées pour surmonter les réactions secondaires indésirables. Le chapitre 2 traite de la réaction de S-M, dont l'utilisation s'est largement répandue en raison de sa large applicabilité, ainsi que de la stabilité, de la disponibilité et de la faible toxicité des réactifs organoborés. Tant en recherche académique qu'en l'industrie, la plupart des couplages de S-M sont dominés par des catalyseurs à base de palladium et de nickel. Récemment, le fer a fait l'objet d'une attention particulière en raison de sa forte abondance et de sa nature respectueuse de l'environnement. Malgré le rôle crucial du fer dans l'offre d'une catalyse plus durable pour le couplage de S-M, ce dernier impliquant des partenaires hybridés sp³ reste rare et se heurte à d'importantes limitations en termes de champ d'applications. Ce chapitre présente le développement d'un catalyseur de fer(II), versatile et de structure bien définie, qui réalise avec succès les couplages alkyle-aryle et alkyle-alkyle de S-M entre des halogénures d'alkyle et des esters boroniques (hétéro)arylés ou des dérivés boranes alkylés. Ces couplages ont été réalisés dans des conditions douces et ont montré une large compatibilité avec diverses fonctionnalités, y compris des N-, O- et S-hétérocycles importants en chimie médicinale. Les halogénures d'alkyle primaires, secondaires (Br, Cl, I) et tertiaires, ainsi que les esters boroniques neutres, riches et pauvres en électrons, de même que les boranes d'alkyle 1° et 2° sont compatibles et ont donné des rendements élevés à excellents. Des solvants plus écologiques ont été utilisés lors de la synthèse d'intermédiaires pharmaceutiques clés et d'un candidat médicament avec des rendements élevés, ce qui démontre un fort potentiel applicatif pour une production industrielle à grande échelle. Le chapitre 3 présente l'application du couplage croisé de S-M dans une méthode de 1,2-alkylarylation d'oléfines à trois composants, promue par un catalyseur de fer(II). Cette méthode facilite la formation de deux liaisons carbone-carbone en une seule étape de synthèse et représente le premier exemple de couplage de S-M combiné à une fonctionnalisation d'alcènes, conduisant sélectivement au produit de fonctionnalisation-1,2 alkyle-aryle. Bien que la méthodologie actuelle soit limitée par la nécessité d'un excès d'oléfines (10 équiv.) et d'esters boroniques donneurs en électrons, l'utilisation de réactifs borés démontre un potentiel pour des applications synthétiques plus larges. Le chapitre 4 étend l'application du catalyseur de fer(II) développé dans les chapitres 2 et 3, en démontrant son efficacité remarquable dans la réaction de couplage croisé de Kumada entre des halogénures d'alkyle hybridés sp³ et des réactifs organomagnésiens hybridés sp² et même sp³ dans des conditions douces. Cela souligne la grande polyvalence de ce catalyseur qui facilite le couplage de divers centres carbonés hybridés sp² et sp³, sans le besoin de conditions drastiques
This PhD research aims to achieve challenging C(sp³)-C(sp²) and C(sp³)-C(sp³) bond formations through Suzuki-Miyaura and Kumada cross-couplings using newly-designed iron-based catalysts, with an emphasis on their potential for synthetic applications. This work also focuses on achieving efficient and selective 1,2-dicarbofunctionalization of unactivated alkenes promoted by these catalysts. Chapter 1 primarily introduces the early discoveries of iron-mediated cross-couplings and the development of iron-based catalysts in Suzuki-Miyaura and Kumada cross-couplings, covering C(sp²)-C(sp²), C(sp²)-C(sp³), and C(sp³)-C(sp³) bond formations. The design of bespoke ligand and mechanistic investigations have played a crucial role in the development of this field. The following section introduces the state-of-the-art in earth-abundant metal-catalyzed 1,2-dicarbofunctionalization of olefins, highlighting strategies developed to overcome undesired side reactions. Chapter 2 covers the Suzuki-Miyaura reaction, which has gained widespread use due to its broad applicability, along with the stability, availability, and low toxicity of organoboron reagents. Most Suzuki-Miyaura couplings (SMC), both in academia and industry, are dominated by palladium and nickel catalysts. Recently, iron has garnered significant attentions due to its earth abundance and environmentally friendly nature. Despite the crucial role of iron in offering more sustainable catalysis for Suzuki-Miyaura coupling, iron-catalyzed SMC involving sp³-hybridized systems remains rare and faces significant scope limitations. This chapter reports on the development of a versatile, well-defined iron(II) catalyst that successfully facilitated C(sp3)-C(sp2) and C(sp3)-C(sp3) SMC of alkyl halide electrophiles with (hetero)aryl boronic esters and alkyl borane nucleophiles, respectively. These couplings were carried out under mild reaction conditions, exhibited broad functional group compatibility - including various medicinally important N-, O-, and S-based heterocycles. Primary, secondary alkyl halides (Br, Cl, I), and tertiary alkyl chlorides, as well as electron-neutral, electron-rich, and electron-poor boronic esters, alongside 1° and 2° alkyl boranes all were tolerated with high to excellent yields. Greener solvents were used in the synthesis of key intermediates relevant to pharmaceuticals and potential drug candidates with high yields, demonstrating significant potential for large-scale industrial production. Chapter 3 introduces the application of Suzuki-Miyaura cross-coupling in the three-component 1,2-alkylarylation of unactivated olefins, using a well-defined iron(II) catalyst. This method facilitates the formation of two carbon-carbon bonds in a single synthetic step and represents the first example of combining Suzuki-Miyaura cross-coupling and 1,2-functionalization of unactivated alkenes, selectively yielding the desired 1,2-alkylarylation product. Although the current methodology is limited by the requirement for an excess of olefins (10 equiv.) and electron-donating boronic esters, the use of boron reagents demonstrates a potential for broader synthetic applications. Chapter 4 extends the application of the iron(II) catalyst developed in Chapters 2 and 3, demonstrating its remarkable efficacy in catalyzing the Kumada cross-coupling reaction between C(sp³)-hybridized alkyl halides and either C(sp²)- or even C(sp³)-hybridized organomagnesium reagents under mild conditions. This achievement underscores the broad versatility of this catalyst in facilitating the coupling of diverse carbon centers, including both sp² and sp³ hybridizations, without requiring harsh conditions

Thesis (S.M.)--Massachusetts Institute of Technology, Dept. of Chemistry, September 2007.
"August 2007."
Includes bibliographical references.
A method for the palladium-catalyzed intramolecular Heck coupling of unactivated alkyl bromides and chlorides is described. The optimal catalyst system was composed of Pd2(MeO-dba)3 as the metal source and N-heterocyclic carbene SIMes as the ligand, and the influence of both parameters is discussed. Reaction of a diastereomerically pure, deuterium-labeled substrate gave only one diastereomer of product, suggesting that the reaction does not proceed through radical pathway, in contrast to processes currently described in the literature. Mechanistic studies involved the synthesis of novel complex Pd(SIMes)2 and a number of its oxidative addition adducts, which were thought to resemble intermediates along a postulated catalytic cycle. However, the alkylpalladium species thus obtained, which were characterized by X-ray crystallography and which bear freely accessible 3 hydrogen atoms, are air and moisture-stable compounds that display no tendency for P-hydride elimination, even upon heating. These complexes are therefore not thought to be part of the catalytic cycle. It was further demonstrated that while Pd(SIMes)2 is not itself catalytically competent in the reaction, it may serve as a catalyst precursor. Evidence is provided to suggest that the true active catalyst is composed of a mixed ligand complex involving both SIMes and dba ...
by Luke Firmansjah.
S.M.

Thesis: Ph. D., Massachusetts Institute of Technology, Department of Chemistry, 2014.
Cataloged from PDF version of thesis. Vita.
Includes bibliographical references.
Chapter 1 describes the development of three nickel-catalyzed asymmetric Negishi cross-couplings of secondary alkyl electrophiles via a stereoconvergent process. In Section 1.1, asymmetric Negishi arylations and alkenylations of [alpha]-bromonitriles with arylzinc and alkenylzinc reagents are achieved using a nickel/bis(oxazoline) catalyst. Section 1.2 describes stereoconvergent cross-couplings of secondary unactivated alkyl electrophiles, specifically, Negishi arylations and alkenylations of [alpha]-bromosulfonamides and abromosulfones with arylzinc reagents and alkenylzirconium reagents, respectively. Section 1.3 details progress toward asymmetric cross-couplings between [alpha]-haloboronate esters and alkylzinc reagents using a nickel/diamine catalyst. Chapter 2 describes the development of photoinduced, copper-catalyzed C-N couplings between N-heterocycles and aryl halides. In particular, a variety of N-heterocycles, such as indoles, benzimidazoles, imidazoles, and carbazoles, undergo Ullmann couplings under mild conditions (room temperature) with an inexpensive catalyst (Cul, without an added ligand).
by Junwon Choi.
Ph. D.

Thesis (Ph. D. in Organic Chemistry)--Massachusetts Institute of Technology, Dept. of Chemistry, 2013.
Cataloged from PDF version of thesis. Vita.
Includes bibliographical references.
Chapter 1 describes the development of two nickel-catalyzed Suzuki cross-coupling methodologies that employ alkyl halides as electrophiles. In Section 1.1, asymmetric [gamma]-alkylation relative to a carbonyl group is achieved via the stereoconvergent cross-coupling of racemic secondary [gamma]-chloroamides with primary alkylboranes. Section 1.2 describes the first Suzuki carbon-carbon bond-forming reaction using tertiary alkyl halides as electrophiles; specifically, unactivated tertiary alkyl bromides are cross-coupled with arylboranes. Chapter 2 describes the establishment of photoinduced asymmetric copper-mediated C-N Ullmann-type coupling processes between racemic secondary alkyl halides and N-heterocycles. Preliminary yields and enantioselectivities for a reaction between secondary benzylic halides and carbazoles, with the use of a monodentate chiral phosphine ligand, are presented. The methodology is then extended to secondary [alpha]-haloamides, including [alpha]-halolactams, which are found to afford very promising yields and enantioselectivities.
by Susan L. Zultanski.
Ph.D.in Organic Chemistry

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemistry, 2005.
Vita.
Includes bibliographical references.
My graduate research at MIT has been focused on the development of palladium- or nickel-catalyzed cross-coupling reactions using unactivated alkyl electrophiles (e.g., halides and sulfonates). Although aryl and alkenyl electrophiles have been commonly used in such processes, the utility of alkyl substrates has been underdeveloped, and merits further exploration. We have developed the first palladium-based catalyst that is effective for Negishi couplings of primary alkyl electrophiles. A single protocol (2%Pd₂(dba)₃/8%P(Cyp)₃/NMI in THF/NMP at 80⁰C) can be applied to a broad spectrum of electrophiles, including chlorides, bromides, iodides, and tosylates. Concerning the scope of the nucleophilic components, an array of alkyl-, alkenyl-, and arylzinc halides can be coupled. The process is tolerant of a variety of functional groups, including esters, amides, imides, nitriles, and heterocycles. Furthermore, geometrically- defined alkenylzinc species, generated from titanium-mediated hydrozincation of internal alkynes, can be directly used in the process. Despite the progress in nickel- and palladium-catalyzed C(sp³)-C(sp³) bond formation, the methods had been limited to primary alkyl electrophiles.
(cont.) No doubt, the ability to use more challenging, secondary ones will further augment the usefulness of these metal- catalyzed processes. To this end, we have determined that Ni(cod)₂/s-Bu-Pybox can catalyze room-temperature Negishi couplings of an array of functionalized alkyl bromides and iodides. To the best of our knowledge, this is the first nickel- or palladium- catalyzed cross-coupling procedure for unactivated, [beta]-hydrogen-containing secondary alkyl halides. In addition, preliminary studies using substrate-based probes suggest that the oxidative addition proceeds through a radical pathway. This may explain the unparalleled reactivity of the nickel catalyst. As an extension of the nickel catalysis, we have established that the combination of Ni(cod)₂ and bathophenanthroline can effect Suzuki reactions of secondary halides and organoboronic acids. These organoboron reagents are particularly widely used in the cross-coupling chemistry, owing to their chemical stability, biological non-toxicity, and commercial availability. Again, mechanistic evidence has been collected to support the involvement of organic radicals during the oxidative addition step.
by Jianrong (Steve) Zhou.
Ph.D.

The use of cyclic sulfamidates as pseudo-alkyl halides in Sp3 -based cross-coupling chemistry has been studied and two approaches were explored. The first approach involved a transition metal-mediated cross-coupling of cyclic sulfamidates, including studies into the oxidative addition step of the catalytic cycle. Various transition metal catalysts (palladium, nickel and iron) and nucleophiles (zinc, boron, magnesium and tin reagents) were investigated. After extensive screening, the desired cross-coupling was achieved under palladium-catalysed Suzuki-Miyaura conditions, albeit in a low yield (20%) and with poor mass recovery. The second approach, via enantiomerically pure f3- and y-aminoalkyl boronic esters, required development of efficient conditions for borylation of cyclic sulfamidates. A range of known and novel 1,2- and 1,3-cyclic sulfamidates was synthesised and subjected to the optimised borylation conditions to determine the scope of this transformation. Mechanism of the copper-catalysed borylation process was also explored, together with the utility of boronic esters in sp3 _Sp2 and Sp3 _sp3 cross-coupling reactions. Aminoalkyl boronic esters (from borylation of cyclic sulfamidates) were also assessed as possible substrates for Matteson homologation. After extensive screening, it was found that f3-aminoalkyl boronic esters (from 1,2-cyclic sulfamidates) can be homologated in a 50% yield, while y-aminoalkyl boronic esters are completely unreactive to a range of homologation conditions.

Abstract Thirty three aryl and aryl alkyl phosphane ligands were prepared and characterized for catalytic purposes. The aryl groups in both types of ligands were modified with alkyl substituents (methyl, ethyl, isopropyl, cyclohexyl, phenyl) or hetero substituents (methoxy, N,N-dimethylaniline, thiomethyl). The alkyl groups directly attached to the phosphorous atom were ethyl, isopropyl or cyclohexyl. Mono- and in some cases also dinuclear palladium (II) complexes of the ligands were prepared and characterized. The syntheses of the palladium complexes are solvent-dependent and afford either mono- or dinuclear complexes depending on the choice of the solvent. Additionally, two 2-mercaptobenzothiazole palladium complexes were synthesized and characterized. A rare distorted lantern-type structure was presented for the first time. The ligands were characterized by 1H, 13C, 31P NMR spectroscopy and mass spectrometry. The palladium complexes were characterized by 31P NMR spectroscopy, X-ray crystallography and elemental analysis. Links between the NMR data of the palladium complexes and ligands and their catalytic activity was screened and correlation found. The crystal structures of the palladium complexes were studied for possible attractive interactions between two ligands. Such interactions were found from two examples. There is an attractive interaction between the phenyl and quinolinyl moieties of 2-quinolinyldiphenyl phosphane. A similar interaction was found between the methyl substitute and phenyl ring of o-tolylphosphane. The ligands and palladium complexes presented in this thesis were prepared in hope of finding suitable catalysts for Suzuki coupling reactions of various bulky aryl halides and phenyl boronic acids to prepare sterically hindered bi- and triaryls under microwave irradiation. A selection of aryl alkyl phosphane ligands catalyzed the couplings of bulky aryl bromides and even unactivated aryl chlorides efficiently and produced high yields. The reaction conditions of a new catalyst system were optimized, and it was noticed that the addition of a small amount of water enhanced the purity and yield of the coupling products further.

L'objectif de ces travaux était d'utiliser certains aspects de l'activité chimique et photochimique de télomères fluorés porteurs de fonctions azides, dans le but de promouvoir les synthèses de polymères thermostables et de nouveaux matériaux photoréticulés. En premier lieu, nous avons développé et caractérisé une nouvelle classe de poly(alkyl-aryl) éthers par une promotion de la compétition de la réaction de « Click » et de couplage de Hay. Par la suite, l'activité photochimique de ces composés fluorés a été étudiée et utilisée pour élaborer des matériaux photoréticulés. Les énergies libres des surfaces des films obtenus ont été calculées en utilisant le modèle d'Owens et Wendt. Les rugosités et les compositions de ces surfaces présentant des mouillabilités singulières ont été investiguées par le biais d'analyses par profilométrie, AFM et EDX. En dernier lieu, les synthèses et caractérisations de réseaux photoréticulés sont abordées. La post sulfonation de ces matériaux a conduit à la préparation de nouveaux électrolytes pour l'application pile à combustible dont les microstructures et propriétés physico-chimiques ont été étudiées
This work aims at using both chemical and photochemical activities of fluorinated telomers bearing azido end groups, to promote the synthesis of thermostable macromolecules and original photocrosslinked networks. In a first part, we have prepared and characterized a novel class of linear poly(alkyl aryl) ethers by the promotion of competitive “Click” reaction and Hay coupling. Then, the photolysis under UV irradiation of these fluorinated polymers was studied and used to generate photocrosslinked materials. The surface free energies of the resulting films were established using the Owens-Wendt model. The roughness and composition of the surfaces were investigated by profilometry, AFM and EDX analysis. Finally, the preparation under UV irradiation of original polymer networks was performed. The post-sulfonation of these materials allowed to prepare new proton exchange membranes for fuel cells application. The microstructures, physical and chemical properties of these electrolytes were investigated

Transition-metal catalysis has enabled the development of an unprecedented number of mild and selective C-C bond-forming reactions. We sought to access the reactivity of palladium and nickel catalysts for two types of transformations: conjugate allylations and sp³-sp ³ cross-coupling reactions.

Conjugate allylation of malononitriles was evaluated with N-heterocyclic carbene-ligated palladium complexes. The allylation was found to yield a variety of mono-allylated products. These results are in contrast to the bis-allylation of malononitriles using other palladium-based catalysts. Additionally, conjugate addition of α,β-unsaturated N-acylpyrroles was found to be accelerated in the presence of sulfoxide substitution on the pyrrole ring. These substrates are lead compounds for the development of an enantioselective allylation reaction.

Transition metal-catalyzed cross-coupling reactions have become standard practice in organic synthesis. Recent advances in alkyl-alkyl couplings have been transformative in the way organic chemists approach the construction of target molecules. This dissertation focuses on the development of stereospecific sp³-sp³ cross-coupling reactions. We discovered that in the presence of nickel catalysts, secondary benzylic ethers were found to undergo stereospecific substitution reactions with Grignard reagents. Reactions proceeded with inversion of configuration and high stereochemical fidelity. This reaction allows for facile enantioselective synthesis of biologically active diarylethanes from readily available optically enriched carbinols.

Subsequently, this reaction was expanded to dialkylzinc reagents and the first stereospecific Negishi cross-coupling reaction of secondary benzylic esters was developed. A series of traceless directing groups were evaluated for their ability to promote cross-coupling with dimethylzinc. Esters with a chelating thioether derived from commercially-available 2-(methylthio)acetic acid were found to be the most effective. The products were formed in high yield and with excellent stereospecificity. A variety of functional groups were tolerated in the reaction including alkenes, alkynes, esters, amines, imides, and O-, S-, and N-heterocycles. The utility of this transformation was highlighted in the enantioselective synthesis of a retinoic acid receptor (RAR) agonist.

Nesta tese foram desenvolvidas metodologias sintéticas para a preparação de compostos orgânicos de telúrio empregando reagentes organometálicos. Primeiramente, foi estudada a abertura tipo SN2 de lactonas, por organoiltelurolatos de lítio ou magnésio para obtenção dos respectivos ácidos telurocarboxílicos. Os organoiltelurolatos foram preparados a partir da reação do telúrio elementar com o organometálico desejado, evitando a manipulação de diteluretos alquílicos que apresentam odores desagradáveis. As reações de abertura de lactonas são de fácil execução e levam aos produtos em bons rendimentos (60 - 88 %). Além disso, há a possibilidade de transformação funcional dos produtos para alcoóis, a partir de uma redução in situ, ou para acil derivados, por meio da esterificação de Steglich. Os alcoóis obtidos são precursores sintéticos das respectivas espécies dilitiadas. Adicionalmente, foram preparados teluretos de alquil arila funcionalizados a partir da reação entre alquiltelurolatos de lítio com iodetos de arila catalisada por CuI (5 mol %). Também foi explorada a influência de ligantes, o que levou a um aumento do rendimento das reações testadas. Também foi estudada a reatividade de n-butilteluretos vinílicos e arílicos com reagentes organometálicos. Ou seja, foi estudada a reação de troca telúrio/metal com compostos organoilzinco e organoilmanganês. As reações com compostos de organoilzinco apresentaram resultados insatisfatórios, devido à baixa seletividade de transferência de grupos ligados ao zinco. As reações com compostos de manganês apresentaram bons resultados, com seletividade na transferência de ligantes e bons rendimentos dos produtos de captura dos compostos de organoilmanganês com eletrófilos. Foi estudada também a reação de acoplamento cruzado entre compostos de aril Grignard e teluretos de butil-vinila na presença de cloreto de manganês e iodeto de cobre (MnCl2/CuI). A reação ocorreu com elevada estereosseletividade e com rendimentos de moderados a bons.
In this PhD thesis synthetic methodologies for the preparation of organic compounds of tellurium employing organometallic reagents were developed. Initially, the SN2 type opening reaction of lactones by means of lithium or magnesium organotellurolates leading to the corresponding carboxylic acids was studied. The metal organotellurolates were prepared by reacting elemental tellurium with organolithium or Grignard reagents, avoiding the manipulation of bad smelling dialkylditellurides. The opening reactions occured easily, leading to the products in good yields (60 - 88 %). The tellurocarboxylic acids were transformed into alcohols by in situ reduction or into acyl derivatives, by a Steglich esterification. The obtained alcohols are precursors of the corresponding dilithium species by reaction with n-butyllithium. Additionally, functionalized arylbutyltellurides were prepared by reacting lithium alkyltellurolates with functionalized aryl iodides in the presence of CuI (5 mol %). The influence of ligands was also explored, leading to improved yields. It was also investigated the reactivity of vinyl butyltellurides with organometallic reagents. The tellurium/metal exchange reaction with organozinc and organomanganese compounds was studied. The reactions with organozinc compounds presented unsatisfactory results, in view of the low selectivity transfer of the groups linked to zinc. The reaction with organomanganese compounds presented better results in view of the fast Te/Mn exchange reaction, selectivity in the ligand transfer and good yields of the organomanganese capture products with electrophiles. It was also studied the cross-coupling reaction between aryl Grignard reagents and vinyl butyl tellurides in the presence of manganese chloride and copper iodide (MnCl2/CuI). The reaction occuried with high stereosselectivity and in moderate to good yields.

Le 21e siècle est le berceau d’une conscientisation grandissante sur les impacts environnementaux des processus utilisés pour synthétiser des molécules cibles. Parmi les avancées qui ont marqué ces dernières décennies, il est également question de réduction de déchets, de conservation de l’énergie et de durabilité des innovations. Ces aspects constituent les lignes directrices de la chimie verte. De ce fait, il est impératif de développer des stratégies de synthèse dont les impacts environnementaux sont bénins. Dans ce mémoire nous présentons la synthèse, la caractérisation et l’étude des propriétés catalytiques en milieu aqueux d’un ligand composé d’une unité -cyclodextrine native, d’une unité imidazolium et d’une chaine alkyle à 12 carbones. Ce ligand hybride s’auto-assemble dans l’eau sous forme de micelles, permettant ainsi d’effectuer en sa présence des couplages de Suzuki-Miyaura dans l’eau, avec de bons rendements. La fonctionnalisation de la face primaire de la -cyclodextrine par un noyau alkyl-imidazolium, précurseur de ligand de type carbène N-hétérocyclique, a permis le développement d’un système catalytique vert et hautement recyclable. Dans un deuxième temps, nous présentons l’utilisation du même ligand hybride dans des couplages de Heck dans l’eau, démontrant ainsi la versatilité du ligand.
Chemistry keeps evolving in new directions. Research has provided improved methodologies for the design and synthesis of targeted molecules. At the same time, the 21st century is witnessing increasing concern about the environmental impacts of chemical wastes. A new philosophy of chemical research and engineering has emerged, known as «Green chemistry». This concept encourages the design of products, processes and technologies that minimize the use and generation of hazardous substances. Therefore, there is an urge to develop environmentally friendly process to convert molecules into product of interest. In the present thesis, we describe the synthesis, characterization and catalytic properties of a novel alkylimidazolium-modified β-cyclodextrin (-CD). Our strategy was to construct a single amphiphilic bimodal ligand by the combination of a mass transfer unit (-CD), covalently bound to a ligand moiety (alkylimidazolium, an N-heterocyclic carbene (NHC) precursor) for aqueous catalysis. First, we demonstrated that the introduction of a dodecyl chain on the imidazolium moiety attached to the primary face of a native β-CD allows the formation of a highly active micellar self-assembled catalytic system in neat water with remarkable recyclable properties for the Suzuki–Miyaura coupling. In addition, we studied the versatility of this self-assembled bimodal system by performing Heck coupling in neat water.

碩士
國立暨南國際大學
應用化學系
99
In this thesis, we are interested in converting endo formyl [2.2.1]bicyclic carbinols into a bicyclic [3.2.1]α-amino ketone. The consecutive condensation and ring expansion reactions of carbinols 47 and 71 are the most important steps. Compound 47 and compound 71 reacted with various kinds of primary amine which are N-nucleophiles, via intramolecular rearrangement to give ring expansion reaction products. The reaction had proved to be highly chemoselective、regioselective and stereoselective. The bicyclic [3.2.1]α-amino ketone is the final product. The alkyl or aryl group of primary amines might be methyl、ethyl、other alkyl, para-substituted electron donating or electron withdrawing aryl group. The mechanisms for the reactions of carbinols 47 and 71 with various primary amine are also discussed.

碩士
國立中興大學
化學系所
99
Abstract The acetylenic compounds are important building block in the fields of pharmaceutical chemistry and organic synthesis. The transition metal catalyzed coupling reaction of terminal alkynes with aryl halides has become one of the most important methods for preparing functionalized alkynes. Palladium and copper co-catalyzed system is well known as Sonogashira reaction, however, palladium is not only expensive but also highly toxic. Thus, develop the system by using copper as the sole metal source has gain much attention in recent years. The first part of this thesis, we report a highly efficient catalytic system employs the combination of Cu2O (1 mol %) with bisphosphine ligand, giving the products in good to excellent yields. Recently, aryl vinyl sulfides have been reported as drug candidates against drugresistant strains of tuberculosis and anthrax, in addition to many other drug-resistant Gram-positive bacteria. Addition of thiols to alkynes through a radical pathway is a common way to prepare these compounds, however, this method will produce the undesired regioisomers at the same time. Transition metals including palladium, cobalt and copper have been reported for coupling reaction of thiols with vinyl halides. The second part of this thesis, we report the first iron-catalyzed coupling reaction of thiols with vinyl halides in the presence of a bisphosphine ligand, giving the aryl vinyl sulfide in good yields.

Work relating to the transition metal catalyzed cross coupling of sp3 hybridized carbons to sp2 hybridized carbons is reported along with an asymmetric synthetic approach to the fusicoccane diterpenoids. A novel cross-coupling reaction between alkyl bromides (such as 2.40) with vinylzinc and vinylmagnesium reagents was developed. A catalytic system (5 mol % Pd(OAc)2, 5 mol % PCy3) and reaction conditions (NMP, 66 °C) were found which provided slightly over 50 % yield with a minimum amount of side product formation. The use of this reaction was explored in a tandem carboalumination/macrocyclization protocol. The formation of unsaturated macrocycles by way of intramolecular Negishi cross-coupling reaction was investigated. Neopentyl iodides were found to cross-couple with vinyl iodides in the intermolecular stereospecific formation of trisubstituted alkenes, although extending this to the complementary intramolecular reaction was challenging. Reaction conditions were found which allowed for the selective zinc activation of an alkyl iodide in the presence of a vinyl iodide contained within the substrate. The synthesis of the advanced intermediate towards fusicoccadiene, 4.2 was achieved in twenty-one steps (longest linear sequence) from the known (S)-(+)-4-(tertbutyldimethylsilyl) oxymethyl-Y-butyrolactone (4.15). Model studies revealed that fusicoccadiene may be obtained from 4.2 in additional four steps through the use of an acid catalyzed cyclodehydration reaction to form the C-ring. The formation of the 8-membered B-ring was achieved through the use of ring closing enyne metathesis. Other key features of the synthesis include the preparation of the functionalized cyclopentane A-ring through the use of a stereoselective Pauson-Khand [2+2+1] cycloaddition to establish the C-10 and C-14 stereocentres followed by the Norrish Type I reaction and an asymmetric cyclopropanation reaction to establish the remote C-7 stereocentre. Significantly, all stereocentres but one are established by stereochemical relay of the stereochemistry present in 4.15.
Science, Faculty of
Chemistry, Department of
Graduate

碩士
國立臺灣大學
化學研究所
88
The first part of this thesis reports the three-component coupling reactions of methyl thiophenecarboxylate with alkyl phenones by the promotion of samarium diiodide. This reaction shows high selectivity, giving two isomers of diol product with four stereocenters. The coupling products undergo dehydration by acid catalysis form the corresponding diene compound. Then the sequential oxidation-electrocyclization-oxidation reaction is effected by using DDQ reagent or by irradiation with UV light, to give the fluorescence compound, 4,7-diphenylbenzo[b]thiophene. Following the similar synthetic procedure, we also synthesize a series of benzo[b]thiophenes. This type of compounds can be modified to have alkyl long chains. For the application to liquid crystals. In second part, we wish to synthesize the chemosensors which can sense biological important peptides. The chemosensor is composed of two recognition units and a sensing unit. The recognition unit is designed as a rigid and macrocyclic molecule which have the characteristics of single comformation, concave binding region, and hydrogen binding aptitude. The sensing unit is anthracene, which is a rigid fluorophore with good resonance.

Boronic acid(esters) have been well recognized as an indispensable coupling partner in the Suzuki-Miyaura cross coupling reactions producing a vast spectrum of molecules, applicable in the diverse field ranging from medicinal to materials sciences.[1] Transition metal catalyzed synthesis of boronic esters from diborons with the assistance of bases is a well-established methodology[2]. In this thesis, the cobalt-N-Heterocyclic carbene complexes catalyzed borylation of organic compounds and interaction of diazabutadienes with diboron compounds will be discussed. (i) In the first section, Co(IMes)2Cl2 catalyzed borylation of aryl halides will be discussed. [3a] The robust protocol, operating under mild condition facilitate the borylation of a diverse range of aryl halides with great efficacy, which includes the challenging aryl chlorides. The preliminary mechanistic studies suggest that base-bis(pinacolato)diboron adduct reduces the Co(IMes)2Cl2 complex to generate Co(IMes)2Cl complex, which acts as an active catalytic species. (ii) The second section deals with catalytic synthesis of primary and secondary alkyl boronic esters using alkyl halides. [3b] The in situ generated Co-NHC complex, in assistance with base and diboron compound, produces the corresponding borylated product from alky halides. The reaction proceeds under very mild conditions and covers a wide range of alkyl halides, including chlorides having different functional groups. (iii) In the third section, development in selective hydroboration of vinyl arenes and aliphatic alkenes will be discussed. [3c] Catalyzed by Co(I)NHC complex, the alkene hydroboration by pinacol borane gives Markovnikov selective product with good selectivity, where the regio-selectivity is controlled by phenyl substituent. In absence of that, complete inversion in the selectivity has been observed. The preliminary mechanistic cycle suggests that the catalytic cycle proceeds via oxidative addition of pinacol borane to [Co] followed by alkene insertion and reduction elimination steps. (iv) The last section discusses the interaction of diazabutadiene molecules with diboron compounds. [3d] The diazabutadiene derivatives have been observed to completely cleave the B-B bond of Bis(catacolato)diboron and Bis(dithiocatacolato)diboron. The preliminary findings hint towards homolytic cleavage of the B-B bond by concerted interaction of the two nitrogen atoms of diazabutadiene with the two boron atoms of the diboron from the same face. References: [1] Boronic Acids-Preparation and Applications in Organic Synthesis, Medicine and Materials, 2nd ed.; Hall, D. G., Ed.; Wiley-VCH: Weinheim, 2011. [2] Neeve, E. C.; Geier, S. J.; Mkhalid, I. A. I.; Westcott, S. A.; Marder, T. B. Diboron(4) Compounds: From Structural Curiosity to Synthetic Workhorse. Chem. Rev. 2016, 116, 9091-9161. [3] (a) Verma, P. K.; Mandal, S.; Geetharani, K. ACS Catal. 2018, 8, 4049-4054. (b) Verma, P. K.; Prasad, K. S.; Varghese, D.; Geetharani, K. Org. Lett. 2020, 22, 4, 1431-1436. (c) Verma, P. K.; Setulekshmi, A. S.; Geetharani, K. Org. Lett. 2018, 20, 7840-7845. (d) Verma, P. K.; Meher, N. K.; Geetharani, K. Accepted for publication in Chem. Commun., Manuscript ID: CC-COM-06-2021-002881.R2.

3,5-Dibromo-2-aminobenzamide was reacted with 1,3-cyclohexanedione derivatives in the presence of iodine as catalyst in toluene under reflux to afford novel 6,8-dibromo-2-[3-(2´-alkyl-1´,2´,3´,4´-tetrahydro-6´,8´-dibromo-4´-oxoquinazoline-2yl)propyl]quinazolin-4(3H)-ones in high yields. Suzuki-Miyaura cross-coupling of the latter with arylboronic acids in the presence of Pd(PPh3)2Cl2–Xphos catalyst complex and K2CO3 as a base in dioxane-water mixture (3:1, v/v) afforded the corresponding polyaryl-substituted bis-heterocycles in a single step operation. The resultant compounds were characterized using a combination of NMR (1H and 13C) and IR spectroscopic techniques, as well as mass spectrometry. The electronic absorption and emission properties of these polyaryl-substituted bis-heterocycles comprising 2,3-dihydroquinazolin-4(1H)-one and quinazolin-4(3H)-one moieties linked by a flexible carbon chain were measured in dimethylsulfoxide (DMSO) and acetic acid by means of UV-Vis and fluorescence spectroscopic techniques. The absorption spectra of the resultant polyaryl-substituted bis-heterocycles showed blue-shift in acetic acid and red-shift in DMSO, while their emission spectra are blue-shifted in DMSO and red-shifted in acetic acid. The 4-methoxy groups on aryl-substituents caused red shift on π‒π* transition of the aryl-substituents. Moreover, it was also observed that as the propyl linkage becomes more substituted, the absorption and emission intensities decrease.
Chemistry
M. Sc. (Chemistry)

Les cyclopropanes sont des unités qui sont très importantes en raison de leur présence dans de nombreux produits naturels, dans certaines molécules synthétiques ayant une activité biologique, ainsi que dans plusieurs intermédiaires synthétiques. Les travaux décrits dans cet ouvrage portent sur l’halogénocyclopropanation stéréosélective d’alcools allyliques en présence d’un ligand chiral stœchiométrique de type dioxaborolane et de carbénoïdes de zinc substitués dérivés de composés organozinciques et d’haloformes. Nous avons ainsi développé des conditions pour l’iodo-, la chloro- et la fluorocyclopropanation stéréosélective. Une étude mécanistique portant sur la nature des carbénoïdes alpha-chlorés et alpha-bromés a révélé qu’il y a un échange des halogènes portés par ces carbénoïdes. Lors de la chlorocyclopropanation, le carbénoïde le plus réactif (alpha-chloré) réagit de façon prédominante en vertu du principe de Curtin-Hammet. Les iodocyclopropanes énantioenrichis ont pu être fonctionnalisés via une réaction d’échange lithium-iode suivie du traitement avec des électrophiles, ou via une réaction de transmétallation au zinc suivie d’un couplage de Negishi. Ainsi, toute une gamme de cyclopropanes 1,2,3-substitués énantioenrichis a pu être synthétisée. Dans l’optique de développer de nouvelles méthodologies de fonctionnalisation des cyclopropanes, nous nous sommes par la suite tournés vers le couplage croisé de type Hiyama-Denmark des cyclopropylsilanols. Dans cette voie synthétique, le groupement silanol a deux fonctions : il sert de groupement proximal basique lors de la cyclopropanation de Simmons-Smith et il subit la transmétallation au cours du couplage croisé. Dans l’étape du couplage croisé, la nature des ligands liés à l’atome de silicium s’est avérée cruciale au bon déroulement de la réaction. Ainsi, l’échange de ligands avec le diéthyl éthérate de trifluoroborane générant le cyclopropyltrifluorosilane in situ est requis pour obtenir de bons rendements. Le dernier volet de cet ouvrage porte sur la cyclisation d’iodures d’alkyle par substitution aromatique par voie homolytique catalysée par le nickel. Une série de composés de type tétrahydronaphtalène et thiochromane ont été préparés selon cette méthode. Une étude mécanistique a confirmé la nature radicalaire de cette réaction et suggère fortement l’action catalytique du nickel. De plus, des études de spectrométrie RMN DOSY ont montré une association entre le complexe de nickel et le substrat ainsi que la base employés dans cette réaction.
Cyclopropanes are important subunits because of their presence in numerous bioactive natural products and synthetic molecules as well as synthetic intermediates. In this work we have investigated the stereoselective halocyclopropanation of allylic alcohols using a dioxaborolane-type stoichiometric chiral ligand and substituted zinc carbenoids derived from organozinc compounds and haloforms. We have thus developed conditions for the stereoselective iodo-, chloro- and fluorocyclopropanation reactions. A mechanistic study on the nature of alpha-chloro and alpha-bromomethylzinc carbenoids has revealed that halogen scrambling is taking place in the case of these carbenoids. During the chlorocyclopropanation reaction, the most reactive carbenoid (alpha-chloromethyl zinc) reacts predominantly, in line with the Curtin-Hammet principle. The enantioenriched iodocyclopropanes have been functionalized through a lithium-iodine exchange followed by treatment with electrophiles or transmetallation to zinc and Negishi cross-coupling. Therefore, a wide array of enantioenriched 1,2,3-substituted cyclopropanes have been synthesized using these methods. In order to develop new methodologies for the functionalization of cyclopropanes, we have studied the Hiyama-Denmark cross-coupling of cyclopropylsilanols. In this approach, the silanol group bears two functions: it serves as a proximal basic group in the Simmons-Smith cyclopropanation and it is involved in the transmetallation event during the cross-coupling reaction. In the cross-coupling step, the nature of the ligands bound to the silicon atom is crucial to the efficiency of the reaction. Hence, the in situ formation of the cyclopropyltrifluorosilane via a ligand exchange with boron trifluoride etherate is required for good yields. The final chapter of this work is on the nickel-catalyzed cyclization of alkyl iodides via a homolytic aromatic substitution mechanism. A series of tetrahydronaphthalene and thiochroman related compounds have been synthesized using this methodology. A mechanistic study has confirmed the radical nature of this reaction and strongly suggests the catalytic role of nickel. DOSY NMR spectrometric investigations have demonstrated an association between substrate, the base employed in this reaction and the nickel complex.