Dissertations / Theses on the topic 'Electrophilic reaction'

The epoxide-olefin [3+2] cycloaddition reaction is an important tool in synthesizing heterocyclic five member rings. Such cyclic compounds are well known for the formation of biologically active compounds. In this experiment, we developed a method for a [3+2] cycloaddition reaction between gem-dicyano phenyl epoxide and diethyl (E)-2-fluoromaleate to synthesize 2, 2-dicyano-3, 4-diethoxycarbonyl-4-fluoro-5-phenylfuran. The yield of the product was 55.56 %.

Fluorine is small in size and is the most electronegative element. These properties of fluorine make its incorporation into drugs easy and also increase the efficacy and selectivity of the drugs. Atropic acid has wide applications as an antagonist. The non-fluorinated atropic acid derivative binds to glycine binding sites, which help in the treatment of a number of disease states. Moreover, its derivatives are used in the preservation of beverages, pests control agents and fungicides. Considering the above facts, fluorination of ethyl atropate using XeF₂ via an electrophilic addition reaction in the presence of compounds like I₂, Se₂Ph ₂ and S2Ph₂ was performed. The percentage yield of addition products were fairly high, ranging from 63 % to 67 %.

The terpene and terpenoid family of compounds is considered to be the largest group of natural products. These compounds not only display great diversity in their structural features but are also known to have a multitude of biological activities including but not limited to anti-bacterial, anti-cancer, anti-inflammatory, and anti-HIV properties. Remarkably, all the terpenoids formed in nature come from two molecules viz. isopentenyl pyrophosphate and its isomer, dimethylallyl pyrophosphate both consisting of just five carbons but assembled in many ways. Nature utilizes highly efficient, enzyme-mediated cascade reactions to transform simple linear molecules to more complex cyclic scaffolds. Cascade or domino reactions are organic chemistry’s most powerful tools that, if executed correctly, mimic the extreme complexity of reactions occurring in nature. Our group has successfully utilized cationic cascade cyclization reactions, to prepare a large library of natural products along with their analogues. It was during the synthesis of one such natural product that it was discovered that a methoxymethyl (MOM) “protecting group” had been transferred within the same molecule. The optimization of this process not only allowed the synthesis of the desired tricyclic framework but also resulted in the liberated MOM group doing an EAS reaction which gave a new C-C bond. This transferred MOM group was further elaborated to different functional groups. Use of the tandem reaction sequence in an attempt to prepare radulanin E has been described. Total syntheses of two chalcone-based analogous meroterpenoids have been successfully completed using the aforementioned sequence. An advanced intermediate for an entire new class of acridine-based schweinfurthins has been elaborated. The results will be discussed in detail.

The work presented in this thesis is an investigation into the halogen bond using both experimental and theoretical techniques. These studies have contributed toward the understanding of the interaction during a period when the definition of this interaction was being debated.1 The interactions investigated have a range of strengths; varying from the very weak interactions with rare gas atoms to the strong interactions with halonium ions acting as halogen-bond donors. The competition and cooperation between halogen and hydrogen bonds have been investigated including a situation where halogen bonding can be favoured over hydrogen bonding. Small-molecule analogues of orthogonal halogen and hydrogen bonding observed in biological systems have also been produced. The similarity between the two interactions has been highlighted by the fact that the Steiner-Limbach equation can model the bonding in both cases. New halogen-bonded liquid crystals between dihalogens and alkoxystilbazoles and alkoxyphenylpyridines have been synthesised and the complexes between elemental iodine and alkoxystilbazoles unexpectedly showed SmC phases with high stability. Attempts to synthesise equivalent liquid crystals with elemental bromine were unsuccessful, an electrophilic bromination reaction followed by elimination of HBr taking place instead. In order to understand this reaction further, the intermediates of the electrophilic bromination reaction for different substituted stilbenes was investigated computationally and the results showed that a carbocation intermediate is favoured if an electron-donating substituent is present. In contrast, stilbenes with two electron-withdrawing substituents favoured symmetric bromonium ion intermediates. Such halonium ion intermediates feature a halogen atom that carries a positive charge, which can interact with Lewis bases in a novel category of halogen bonding, which has properties similar to halogen bonding with traditional halogen-bond donors.

Thesis (Ph. D.)--University of North Carolina at Chapel Hill, 2007.
Title from electronic title page (viewed Mar. 27, 2008). "... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Chemistry." Discipline: Chemistry; Department/School: Chemistry.

Thesis (Ph. D.)--University of North Carolina at Chapel Hill, 2009.
Title from electronic title page (viewed Jun. 26, 2009). "... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Chemistry. " Discipline: Chemistry; Department/School: Chemistry.

Reaction de l'organozinicique allylique prepare, avec divers electrophiles conduisant a des methylene-3 perhydrofurannones-2 et -pyrrolidones-2. Etude de l'activite de ces composes sur la leucamie p388

During my PhD I was involved in many studies concerning the nucleophilic (SNAr) and electrophilic (SEAr) aromatic substitution reactions. My research activity was focused on the study of different electrophile/nucleophile combinations between strongly activated species, with the purpose to investigate on their reactivity, to detect new intermediates of the aromatic substitution reaction and to obtain new higly conjugated structures bearing contemporaneously electron donor and acceptor moieties on the same unit for application in different fields. Different reactions between both neutral or charged electrophilic and nucleophilic species were performed and from their combinations new products for applications in different fields (e.g. medicine, biology and materials) were obtained and new intermediates of the aromatic substitution reactions [e.g. Wheland (W), Meisenheimer (M), and even Wheland-Meisenheimer (WM)], were detected and characterized, mainly using NMR spectroscopic techniques. In particular the involved nucleophilic species were: tri- and diaminobenzene derivatives, trihydroxybenzene, trimethoxybenzene, anisole derivatives and aminothiazole derivatives; whereas the selected electrophilic species were: aryldiazonium ions, benzofuroxan and benzofurazan derivatives, thiophene derivatives and benzhydrylium ions. Furthermore, the last year of my PhD course, I spent a period in the Department of Chemistry, Ludwig-Maximilians-University of Munich, in collaboration with Prof. Herbert Mayr’s group, with the aim to investigate on the nucleophilic reactivities of di- and triaminobenzene derivatives performing their combination with different reference electrophiles, selected from the Mayr’s reactivity scales.

Thesis (M.S.)--Dept. of Chemistry. University of Missouri--Kansas City, 2007.
"A thesis in chemistry." Typescript. Advisor: Keith R. Buszek. Vita. Title from "catalog record" of the print edition Description based on contents viewed Dec. 18, 2007 Includes bibliographical references (leaves 46-51). Online version of the print edition.

Thesis (Ph. D.)--University of North Carolina at Chapel Hill, 2007.
Title from electronic title page (viewed Mar. 27, 2008). " ... in partial fulfillment of the requirements of the degree of Doctor of Philosophy in the Department of Chemistry." Discipline: Chemistry; Department/School: Chemistry.

Activated esters, e.g. triflates, sulfonates, nonaflates and phosphates are excellent electrophiles for a variety of cross-coupling reactions. However, other phosphorus-based esters have received little attention in these protocols. This thesis discusses the synthesis and cross-coupling chemistry of vinyl phosphinates, a new class of electrophilic species. A simple model vinyl phosphinate, N-(tert-butyloxycarbonyl)-4,5,6,7-tetrahydro-1H-azepin-2-yl-diphenylphosphinate, was prepared in excellent yield from commercially available caprolactam. A screening study identified Suzuki cross-coupling conditions under which this phosphinate smoothly coupled with a variety of electron-rich, electron-poor and sterically-hindered boronic acids. The scope and limitations of this chemistry were investigated and a variety of electron-withdrawing nitrogen protecting groups, e.g. Boc, CO(_2)Ph, C0(_2)Bn and Ts could be used without problem. However, electron-donating protecting groups, e.g. Me and Bn proved unsuccessful. Additionally, where seven and eight-membered ring lactam phosphinates coupled efficiently, five and six-membered ring derivatives proved largely unsuccessful. Relative reactivity studies were carried out with N-phenyloxycarbonyl-2- (diphenylphosphinoyloxy)-3,4-dihydro-6-bromoquinolone and indicated that the reactivity of vinyl phosphinates lies between that of aryl chlorides and aryl bromides in the Suzuki reaction. Attempts to improve the efficiency of the cross-coupling of this substrate using DoE and PCA modelling was attempted, but was largely unsuccessful. Studies towards the total synthesis of Lennoxamine via a cross-coupling reaction between a benzazepine-derived vinyl phosphinate and 2,3-dimethoxy-N-(2'-phenylpropan-2-yl)-6-(tributylstannyl) benzamide were commenced. Synthesis of the stannane was achieved in high yield via a directed metallation strategy. Unfortunately, preliminary attempts to cross-couple this stannane with N-(benzyloxycarbonyl)-4,5,6,7- tetrahydro-1 H-azepin-2-yl diphenylphosphinate in a model reaction were unsuccessful. Synthesis of the desired benzazepine phosphinate fragment proved more difficult and although progress has been made, this work remains unfinished. Additionally, treatment of N-([4'-methylphenyl]sulfonyl)-2-oxo-azepane with LDA/TMEDA in the presence of diphenylphosphoryl chloride afforded the sultam 1,2,3,4-tetrahydro-7-methylazepino[1,2-b][1,2]benzothiazole-10,10-dioxide in moderate yield. A range of aryl sulfonamides could be used affording the corresponding sultams in moderate yields.

Chapter 1 highlights the many advantages of heterogeneous inorganic solids as catalysts, and summarises the various microporous and mesoporous solids that have been employed as catalysts. The synthesis and characterisation of the mesoporous materials that were used in the study are described. Chapter 2 focuses on the nitration of naphthalene. An introduction to nitration is given, and the results of nitration over a range of solids are presented. Unusual dinitronaphthalene product ratios were achieved over Al-MCM-41. Reactions catalysed by heteropoly acid immobilised within the pores of mesoporous materials are also described. Chapters 3 to 6 focus upon the alkylation of naphthalene. Emphasis is placed upon the importance of 2,6-dialkylnaphthalenes (2,6-DAN) as intermediates for the production of high performance engineering plastics, and why there is still significant room for improvement in both 2,6-DAN yield and selectivity. A molecular modelling study of 2,6- and 2,7- di-tert-butylnaphthalene (DTBN) highlighted the potential for achieving selectivity for the 2,6-over the 2,7-isomer. Zeolite H-Mordenite (HM) was the most selective catalyst for 2,6-DTBN, but showed poor activity. Efforts to increase both the 2,6-DTBN yield and selectivity over HM focused upon varying the reaction time; temperature; pressure; solvent; amount of alkylating agent, solvent, and catalyst; Si/Al ratio of the catalyst; and mode of addition. Optimisation resulted in a 60% yield of 2,6-DTBN with a 2,6/2,7 ratio of over 50. tert-Butylation reactions were achieved using mainly tert-butanol as the alkylating agent. The identification of by-products in the tert-butylation reaction has been attempted. Alkylation with other alkylating agents has been attempted, but selectivity for 2,6-DAN was inferior to that achieved in the tert-butylation reaction using tert-butanol.

Thesis (Ph. D.)--University of California, San Diego and San Diego State University, 2006.
Title from first page of PDF file (viewed June 7, 2006). Available via ProQuest Digital Dissertations. Vita. Includes bibliographical references (p. 280-290).

A fair amount of research has been carried out on the reactions of nitrous acid with aryl hydrazines, with marked differences in mechanism between the reaction of nitrous acid with 2,4-dinitrophenylhydrazine, and the reaction of nitrous acid with alkyl and halogen substituted aryl hydrazines. It was hoped that study of the electrophilic nitrosation of 2-nitrophenylhydrazine would serve as a link between the two sets of results. A large range of electrophilic nitrosating agents are known, and the spectra of two of these; dinitrogen trioxide (N₂O₃) and nitrosyl thiocyanate (ONSCN), have been studied using stopped flow spectrophotometry. Earlier studies of the nitrosation of hydrazine using sodium acetate/acetic acid buffers, produced discrepancies between observed rates compared to a rate calculated from measurements made in much more acidic conditions in HC1O₄. Consequently the original study has been re-investigated and extended. There is considerable current interest in the electrophilic nitrosation of sulfur compounds, which leads to the formation of sulfur-nitroso intermediates, and in the subsequent decomposition reactions of these intermediates. Preliminary work on the reaction of nitrous acid with tetramethylthiourea (NMe)₂CS, showed some unexpected ¹H NMR spectra for the products. A likely product of the decomposition of the S-nitrosothiouronium ion intermediate (NMe₂)₂CSNO⁺ is [(NMe₂)₂CSSC(NMe₂)₂]²⁺ and this species should also be formed in the oxidation of tetramethylthiourea by bromine. This led to an investigation of the reaction of (NMe₂)₂CS with bromine in aqueous solution, with a comparison made between the products gained by bromination and nitrosation, using ¹H NMR.

Reactions of highly hindered phosphorus (III) esters derived from 2,2,2-triphenylethanol, 2,2-diethylbutan-1-o1, and norbornan -1-o1 with electrophilic reagents, in particular, α-haloketones were studied by P and pH spectroscopy.

The thesis gives an account of work directed towards developing new reagent systems and methodology, with particular reference to the Friedel–Crafts and Vilsmeier–Haack reactions of aromatic and heteroaromatlc compounds. Ways of improving regioselectivity and developing a stereoselective Friedel–Crafts reaction have been investigated for a range of hetero-atom stabilised carbocations. This work is divided into two main areas: (1) the synthesis and use of pyrophosphoryl chloride in the Vilsmeier–Haack reaction, the results of this has shed new light on the mechanism of this classical reaction; (2) the control of the Friedel–Crafts reactions of bi-functional derivatives of glyoxylic acid and the use of chiral relays to induce diastereoselectivity.

First popularized in the 1970s, transition metal-catalyzed cross-couplings now constitute staple reactions for the formation of carbon-carbon and carbon-heteroatom bonds. Recent endeavours in the field have been invested towards expanding the range of compatible coupling partners, with the aim of accessing complex molecules from simple, widely available starting materials. Notably, esters represent an attractive class of alternative coupling partners compared to traditional aryl halides, due to their ubiquity and robustness. Moreover, different cleavage modes can be accessed with esters. Which bond cleavage occurs is highly dependent on which catalyst is used, providing an opportunity to quickly access diverse products from a common precursor. Chapter 1 of this thesis provides a literature overview of cross-couplings with carboxylic acid derivatives to contextualize our contributions described in Chapter 2 and 3. Chapter 2 describes the Pd-catalyzed cross-coupling of phenyl esters with alkyl boranes. Two reaction modes are enabled, namely C(acyl)–O bond activation with carbonyl-retention and C(acyl)–O bond activation with decarbonylation. As such, both alkyl ketones and alkylated arenes are accessed selectively by simple changes in the catalytic system. The disclosed reaction is applied to the diversification of bioactive molecules and discussed in light of recent mechanistic studies of related transformations. In Chapter 3, the first additive-free Ni-catalyzed amidation and transesterification of methyl esters are disclosed. In both transformations, a simple Ni catalyst enables widely available methyl or ethyl esters to be converted into value-added products, producing methanol as the only stoichiometric waste by-product. The Ni-catalyzed amidation protocol strongly contrasts wasteful yet common methods used to convert methyl esters into amides, involving wasteful hydrolysis and coupling with stoichiometric activating agents.

Au cours de ce travail, nous avons etudie les reactions de cyclisation radicalaire et electrophile, ainsi que leur application a la synthese de derives heterocycliques azotes du type alcaloides. Dans un premier temps, nous avons realise la synthese du ()--lycorane, qui est un des alcaloides present chez les amaryllidacees et appartenant a la sous-famille de la lycorine. Ainsi, le squelette pentacyclique du ()--lycorane a ete construit en utilisant comme etapes-cles, deux reactions de cyclisation radicalaire intramoleculaire. D'autre part, nous avons egalement synthetise de facon enantioselective l'aldehyde, intermediaire cle de la synthese menant au (+)--lycorane. Celui-ci a ete obtenu grace a une reaction de cyclisation radicalaire diastereoselective appliquee a un iodure vinylique. Nous avons ainsi une synthese formelle du (+)--lycorane. Dans le but de synthetiser la clivonine, un alcaloide des amarillydacees de la sous-famille de la lycorenine, nous avons obtenu intermediaire avance de la synthese. Une reaction de cyclisation radicalaire tandem appliquee a un azide pourrait permettre d'acceder a la clivonine. Nous avons egalement etudie des reactions d'ouverture de lactames n-tosyles, derives de l'acide (l)-pyroglutamique par differents types de nucleophiles. Ces reactions d'ouverture ont ensuite ete transposees sur support solide en greffant le substrat sur une resine possedant un linker dhp. D'autre part, une alkylation en position du lactame realisee avant d'effectuer les reactions d'ouverture du cycle pyrrolidinique nous a permis d'obtenir des n-tosylamines insaturees. Suivant les conditions operatoires et les substrats utilises lors des reactions d'iodocyclisation appliquees a ces composes, nous avons alors obtenu differents types de derives heterocycliques tels que des piperidines et des tetrahydrofuranes.

Zur Bestimmung der toxizitätsrelevanten Thiolreaktivität wurde ein Chemoassay mit dem Modellnukleophil 4-Nitrothiophenol (NBT) entwickelt. Es wurden die Reaktionsgeschwindigkeitskonstanten kNBT für insgesamt 145 Verbindungen aus verschiedenen Stoffklassen bestimmt. Ein Modell zur Berücksichtigung der Flüchtigkeit der Elektrophile bei der Berechnung von kNBT wurde entwickelt. Außerdem wurde der Einfluss des pH-Werts auf die Thiolreaktivität unter reaktionsmechanistischen Gesichtspunkten diskutiert. Die NBT-Reaktivität wurde mit der Reaktivität gegenüber anderen toxizitätsrelevanten Nukleophilen verglichen. Zur Einordnung der Thiolreaktivität in den toxikologischen Zusammenhang wurden die Korrelationen zwischen kNBT und ausgewählten toxikologischen Endpunkten betrachtet. Am Beispiel der aquatischen Toxizität im Bioassay mit Tetrahymena pyriformis konnten stoffklassenspezifische Modelle zur Beschreibung der absoluten Toxizität log EC50 und der Toxizitätserhöhung log Te mit guter bis sehr guter Vorhersagekraft abgeleitet werden.

Cross-coupling reactions, where a transition metal catalyst facilitates the formation of a new carbon-carbon or carbon-heteroatom bond between two coupling partners, has become one of the most widely used, reliable, and robust family of transformations for the construction of molecules. The Nobel Prize was awarded to pioneers in this field who primarily used aryl iodides, bromides, and triflates as electrophilic coupling partners. The expansion of the reaction scope to non-traditional electrophiles is an ongoing challenge to enable an even greater number of useful products to be made from simple starting materials. The major goal of this thesis research is to improve and expand upon this field by using esters as electrophiles via the activation of the strong C(acyl)−O bond. Esters are particularly robust in comparison to other carboxylic acid derivatives used in cross-coupling reactions. Success on the activation of such inert functional group using catalysis has both fundamental and practical value. By discovering new reaction modes of this abundant functional group, synthetic routes to access novel or industrially important molecules can be improved. Chapter 1 of this thesis describes a literature overview of what has been accomplished in the field of cross coupling reactions using carboxylic acid derivatives as electrophilic coupling partners. Chapter 2 discloses the first palladium Suzuki-Miyaura couplings of phenyl esters to produce ketones. The method is efficient and robust, giving good yields of useful products. The reaction is proposed to proceed via an oxidative addition to the strong C(acyl)−O bond of the ester. In contrast to previous efforts in this field that use traditional catalysts such as Pd(PPh3)4, the developed reaction requires use of an electron-rich, bulky N-heterocyclic carbene ligand, which facilitates the strong bond activation. Furthermore, a palladium-catalyzed cross-coupling between aryl esters and anilines is reported, enabling access to diverse amides. The reaction takes place via a similar activation of the C−O bond by oxidative addition with a Pd−NHC complex, which enables the use of relatively non-nucleophilic anilines that otherwise require stoichiometric activation with strong bases to react. Chapter 3 discloses a nickel-catalyzed amide bond formation using unactivated and abundant esters. In this transformation, an accessible nickel catalyst can facilitate the activation of diverse aliphatic and aromatic esters to enable direct amide bond formation with amines as nucleophiles. No stoichiometric base, acid, or other activating agent is needed, providing exceptional functional group tolerance and producing only methanol as a by-product. This reaction is of both fundamental and practical importance because it is the first to demonstrate that simple conditions can enable Ni to cleave the C–O bond of an ester to make an oxidative addition product, which can be subsequently coupled with amines. This discovery contrasts industrially-common and wasteful methods that still require stoichiometric activating agents or multistep synthesis. Chapter 4 describes the evaluation of different types of cross-coupling reactions using methyl esters as electrophilic coupling partner. A high-throughput screening technique has been applied to this project. A combination between specific ligands, known by their efficiency to activate strong C−O bonds, and literature-based conditions has been designed for the chosen transformations. Using this strategy, two promising hits have been obtained using the same NHC ligand: a decarbonylative Suzuki-Miyaura and a decarbonylative borylation reaction.

The experimental results of the current work has three parts. First, the cycloaddition and copolymerization of methyl tricyanoethylenecarboxylate 2 with electron-rich olefins, such as p-methoxystyene, trans-anethole, isobutyl vinyl ether and ethyl cis-propenyl ether are discussed. The nature of the cycloadduct is determined by the orientation of the electrophilic olefins. Copolymerization of 2 with p-methoxystyrene under free-radical initiation gave an alternating copolymer. Second, trimethylsilyl methanesulfonate and trimethylsilyl diphenylphosphate were used as initiators for cationic polymerization. In the presence or absence of hindered pyridine, trimethylsilyl diphenylphosphate and trimethylsilyl methanesulfonate did not initiate the polymerization of p-methoxystyrene, anethole, 4-isopropenylanisole, 1,3-dioxolane or trioxane. Only trimethylsilyl methanesulfonate was able to initiate the cationic polymerization of 1,3-dioxepane in the presence of a hindered base. A model study demonstrates fast desilylation of a carbocation β to a silicon by an oxygen-containing counterion. Finally, block copolydioxepane-polydimethylsiloxane has been synthesized by the "silyl sulfonate approach." In this approach, the nucleophilic macromer, lithium polydimethylsiloxanate, was reacted with chlorodimethylsilane or allylchlorodimethylsilane to produce the corresponding macromers with silylated end groups. They contained a labile substituent, an allyl or a proton, on silicon. These macromers were then converted to electrophilic macropolydimethylsiloxane arylsulfonate by reaction with an aryl or alkyl sulfonic acid. The sulfonate polydisiloxanes can initiate the cationic polymerization of 1,3-dioxepane to yield block polydimethylsiloxane-polydioxepane. This cationic polymerization did proceed in the presence of 2,6-di-t-butylpyridine, which would trap any acid impurities.
The experimental results of the current work has three parts. First, the cycloaddition and copolymerization of methyl tricyanoethylenecarboxylate 2 with electron-rich olefins, such as p-methoxystyene, trans-anethole, isobutyl vinyl ether and ethyl cis-propenyl ether are discussed. The nature of the cycloadduct is determined by the orientation of the electrophilic olefins. Copolymerization of 2 with p-methoxystyrene under free-radical initiation gave an alternating copolymer. Second, trimethylsilyl methanesulfonate and trimethylsilyl diphenylphosphate were used as initiators for cationic polymerization. In the presence or absence of hindered pyridine, trimethylsilyl diphenylphosphate and trimethylsilyl methanesulfonate did not initiate the polymerization of p-methoxystyrene, anethole, 4-isopropenylanisole, 1,3-dioxolane or trioxane. Only trimethylsilyl methanesulfonate was able to initiate the cationic polymerization of 1,3-dioxepane in the presence of a hindered base. A model study demonstrates fast desilylation of a carbocation β to a silicon by an oxygen-containing counterion. Finally, block copolydioxepane-polydimethylsiloxane has been synthesized by the "silyl sulfonate approach." In this approach, the nucleophilic macromer, lithium polydimethylsiloxanate, was reacted with chlorodimethylsilane or allylchlorodimethylsilane to produce the corresponding macromers with silylated end groups. They contained a labile substituent, an allyl or a proton, on silicon. These macromers were then converted to electrophilic macropolydimethylsiloxane arylsulfonate by reaction with an aryl or alkyl sulfonic acid. The sulfonate polydisiloxanes can initiate the cationic polymerization of 1,3-dioxepane to yield block polydimethylsiloxane-polydioxepane. This cationic polymerization did proceed in the presence of 2,6-di-t-butylpyridine, which would trap any acid impurities.
The experimental results of the current work has three parts. First, the cycloaddition and copolymerization of methyl tricyanoethylenecarboxylate 2 with electron-rich olefins, such as p-methoxystyene, trans-anethole, isobutyl vinyl ether and ethyl cis-propenyl ether are discussed. The nature of the cycloadduct is determined by the orientation of the electrophilic olefins. Copolymerization of 2 with p-methoxystyrene under free-radical initiation gave an alternating copolymer. Second, trimethylsilyl methanesulfonate and trimethylsilyl diphenylphosphate were used as initiators for cationic polymerization. In the presence or absence of hindered pyridine, trimethylsilyl diphenylphosphate and trimethylsilyl methanesulfonate did not initiate the polymerization of p-methoxystyrene, anethole, 4-isopropenylanisole, 1,3-dioxolane or trioxane. Only trimethylsilyl methanesulfonate was able to initiate the cationic polymerization of 1,3-dioxepane in the presence of a hindered base. A model study demonstrates fast desilylation of a carbocation β to a silicon by an oxygen-containing counterion. Finally, block copolydioxepane-polydimethylsiloxane has been synthesized by the "silyl sulfonate approach." In this approach, the nucleophilic macromer, lithium polydimethylsiloxanate, was reacted with chlorodimethylsilane or allylchlorodimethylsilane to produce the corresponding macromers with silylated end groups. They contained a labile substituent, an allyl or a proton, on silicon. These macromers were then converted to electrophilic macropolydimethylsiloxane arylsulfonate by reaction with an aryl or alkyl sulfonic acid. The sulfonate polydisiloxanes can initiate the cationic polymerization of 1,3-dioxepane to yield block polydimethylsiloxane-polydioxepane. This cationic polymerization did proceed in the presence of 2,6-di-t-butylpyridine, which would trap any acid impurities.

Ultrahigh vacuum (UHV) surface science experiments were designed to study reaction kinetics and mechanisms of gas-phase NO3 radicals with well-organized, highly characterized, organic thin films. The surface reactions were monitored in situ with reflection-absorption infrared spectroscopy (RAIRS). The oxidation states of surface-bound molecules were identified with X-ray photoelectron spectroscopy (XPS). Consumption of vinyl groups was observed concurrently with formation of organic nitrates in RAIRS. XPS spectra showed little oxidation of sulfur head groups. The observed rate constant was determined based on the consumption of carbon-carbon double bonds and the formation of organic nitrates. Using this rate constant, the initial reaction probability was determined to be (3 ± 1) X 10-3. This reaction probability is approximately two orders of magnitude higher than that for the reactions between the same surface and pure O3, which is due to the higher electron affinity of NO3 relative to O3. These results led to the development of a proposed mechanism that involves electrophilic addition of NO3 to the double bonds. Reactions between NO3 and a methyl-terminated SAM were also monitored in situ with RAIRS. In the CH3-SAM studies, hydrogen abstraction was observed during NO3 exposure. The results presented in this thesis should help develop an understanding of the fundamental interfacial reaction dynamics of NO3 radicals with organic surfaces.
Master of Science

he thesis entitled "Theoretical Studies of pie-Facial Selectivity in Organic Reactions" involve a computational examination of a suitable reactivity problem in organic chemistry. Systematic and efficient -procedures have been developed and tested for rationalizing observed face selectivities in numerous substrates. In a number of cases precise transition state structures have also been computed in a rigorous manner. The molecules examined are by and large sterically unbiased. Considerable emphasis has been placed on obtaining general interpretations, In particular, the relative contributions of various sterio electronic and electrostatic effect have been considered in detail.Predictions of a-face selectivities haw also been made in a few cases. In recent years many mildly perturbed substrates have been shown to undergo pie-face selective reactions. Chapter 1 provides a brief review of the available experimental result involving nucleophilic, electrophilic, radical and Diels- Alder reactions.The current status of theoretical understanding of theae rasults is also summarized.The discussion includes qualitative proposal as well as quantitative calculations on selected substrates. The principal goals of the present work and general features of the MO methods used are briefly discussed.

Ce travail consiste en l'étude de la réaction de métallation en série diazinique. Dans une première partie, nous avons pu mettre en évidence pour la première fois en série diazinique, un mécanisme d'halogen-dance avec migration de l'iode. De plus, nous avons pu observer pour la première fois dans cette série, un exceptionnel échange iode-métal avec les alkylamidures de lithium. Cette réaction a été appliquée à la synthèse de leshmaniacides. Dans une seconde partie, nous avons mis au point l'amination électrophile par métallation en série diazinique. Cette réaction d'amination a été appliquée à la synthèse de molécules biologiquement actives et nous a permis d'accéder à un azaanalogue de la Névirapine ainsi qu'à des précurseurs de sulfamides connus. Dans une troisième partie, nous avons tenté d'élargir la gamme des groupes ortho-directeurs en série pyrimidinique (NHCOtBu, CONHtBu). Dans la dernière partie, une nouvelle fonctionnalisation directe des diazines sans groupe ortho-directeur a été réalisée avec succès

Pyrazoles constitute one of the most important classes of heterocyclic compounds due to their interesting chemical and biochemical features. Researchers have studied many pyrazole containing structures for almost over a century in order to investigate the various biological activities possessed by these molecules. A new and important trend in these studies is to produce ferrocenyl substituted pyrazoles since ferrocene attracts considerable interest in the research field of organometallic and bioorganometallic chemistry because of its valuable chemical characteristics like high stability, low toxicity and enhanced redox properties. Moreover, the results of the studies focusing on ferrocenyl compounds have been quite promising. Therefore, the scope of this project involves the combination of the essential structural features of pyrazoles with a ferrocene moiety, which could provide new derivatives with enhanced biological activities. In the course of the project the synthesis of new pyrazole derivatives was performed through Sonogashira and Suzuki-Miyaura cross-coupling reactions of 5-ferrocenyl-4-iodo-1-phenyl-1H-pyrazole with terminal alkynes and boronic acids respectively in the presence of a catalytic amount of PdCl2(PPh3)2. Although Sonogashira and Suzuki-Miyaura coupling reactions are well known in literature, they were not studied in much detail with multi-substituted pyrazoles. This also revealed the requirement of the reinvestigation of the reactions and improvement of the yields of pyrazoles by optimizing the reaction conditions.

Thesis advisor: Marc L. Snapper
Chapter 1: Over the past 100 years, ring expansion chemistry with non-stabilized diazoalkanes has grown slowly. While the intrinsic hazards and stigma associated with the use of diazoalkanes has been a serious impediment to more widespread development, a number of groups have made significant advances over the years. This chapter aims to provide a brief historical account of the most significant developments related to diazoalkane- based ring expansion methods. Chapter 2: The construction of stereogenic centers adjacent to ketones remains a challenging synthetic problem for chemists. Deficiencies with regard to reaction scope, efficiency, and generality remain. In contrast to the majority of other methods in the literature, stereoselective insertion of diazoalkanes provides a pathway to directly access enantiomerically enriched α-substituted cycloalkanones. In this chapter, an account of how we developed the first catalytic asymmetric diazoalkane-based ring expansion reactions is presented. Ring expansion of unfunctionalized cycloalkanones with diazoalkanes efficiently affords α-aryl substituted cycloalkanones with high enantiopurity. Additionally, this work led to the synthesis of new chiral bis(oxazoline) ligands and the discovery of a rapid method to assay the concentration of diazoalkane solutions. Chapter 3: Single-carbon ring expansion is a powerful synthetic disconnection, allowing chemists to construct or purchase the lower homologue of a ring system before expanding to the target ring size. Starting from a smaller ring size can often allow access to a broader array of transformations that proceed with greater stereoselection. In our approach to a class of natural products bearing a cis-decalin core, we successfully implemented a catalytic regioselective single-carbon ring expansion reaction in the context of an advanced synthetic intermediate. This chapter describes the experimental details behind the first catalytic single carbon cyclopentanone homologations and how we extended the method to more complex substrates. Chapter 4: Catalytic activation of sp2 hybridized electrophiles by nucleophilic catalysts has been studied extensively and proceeds through a well-defined mechanistic pathway. In constrast, activation of sp3 hybridized electrophiles in a similar fashion with small-molecule organocatalysts remains an elusive endeavor for chemists. This chapter describes prelimi- nary studies towards this lofty goal and how we discovered a new class of imidazole-based catalysts. Thorough mechanistic studies with the newly discovered catalysts ultimately proved that the reactions proceeded through a pathway that does not involve electrophile activation. However, inexpensive and commercially available imidazolium salts were found to catalyze Williamson etherification reactions under mild conditions through a mechanism that involves an unusual imidazolium alkoxide ion-pair
Thesis (PhD) — Boston College, 2013
Submitted to: Boston College. Graduate School of Arts and Sciences
Discipline: Chemistry

The main topic of my Ph.D. thesis is the study of nucleophilic and electrophilic aromatic substitution reaction, in particular from a mechanistic point of view. The research was mainly focused on the reactivity of superactivated aromatic systems. In spite of their high reactivity (hence the high reaction’s rate), we were able to identify and in some case to isolate -complexes until now only hypothesized. For example, interesting results comes from the study of the protonation of the supernucleophiles tris(dialkylamino)benzenes. However, the best result obtained in this field was the isolation and structural characterization of the first stables zwitterionic Wheland-Meisenheimer complexes by using 2,4-dipyrrolidine-1,3-thiazole as supernucleophile and 4,6-dinitrobenzofuroxan or 4,6-dinitrotetrazolepyridine as superelectrophile. These reactions were also studied by means of computational chemistry, which allowed us to better investigate on the energetic and properties of the reactions and reactants studied. We also discovered, in some case fortuitously, some relevant properties and application of the compounds we synthesized, such as fluorescence in solid state and nanoparticles, or textile dyeing. We decided to investigate all these findings also by collaborating with other research groups. During a period in the “Laboratoire de Structure et Réactivité des Systèmes Moléculaires Complexes-SRSMC, Université de Lorraine et CNRS, France, I carried out computational studies on new iron complexes for the use as dyes in Dye Sensitized Solar Cells (DSSC). Furthermore, thanks to this new expertise, I was involved in a collaboration for the study of the ligands’ interaction in biological systems. A collaboration with University of Urbino allowed us to investigate on the reactivity of 1,2-diaza-1,3-dienes toward nucleophiles such as amino and phosphine derivatives, which led to the synthesis of new products some of which are 6 or 7 member heterocycles containing both phosphorus and nitrogen atoms.

Dans le cadre de l'etude de l'amination electrophile, de nouveaux reactifs d'amination ont ete developpes. Ces reactifs derivant de l'hydroxylamine permettent l'introduction d'une fonction amine n-protegee, a partir d'organolithiens et cuivreux facilement accessibles. Nous avons d'abord elargi l'utilisation du n-tosyloxycarbamate de tertiobutyle metalle developpe au laboratoire, en l'appliquant a l'amination de divers organometalliques: alkyllithiens, alkylcuivreux, boranes et organocuivreux aromatiques obtenus par echange halogene-metal. Nous avons egalement mis au point de nouveaux reactifs d'amination, en modifiant le groupe partant et le groupe protecteur portes par l'azote. Il est ressorti de cette etude que la o-mesitylenesulfonyl-n-allyloxycarbonylhydroxylamine ou msah est un agent d'amination particulierement stable et efficace, permettant pour la premiere fois le transfert du groupe nhalloc sur un organometallique et sur la n-methyl-aniline. Dans une deuxieme partie de ce travail, nous avons synthetise des alpha-hydrazino-beta-hydroxyesters optiquement purs par amination electrophile. Nous avons pu, par l'utilisation d'enolates de dioxanones et de dianions zinciques, ameliorer considerablement la diastereoselectivite de la reaction. De plus, nous avons prepare une serie de beta-hydroxyesters par hydrogenation asymetrique en presence de catalyseurs chiraux au ruthenium. Les exces enantiomeriques obtenus sont de 30 a 99%. Ainsi, la sequence hydrogenation asymetrique amination electrophile diastereoselective nous a permis de synthetiser une large gamme d'alpha-hydrazino-beta-hydroxyesters anti optiquement purs. Nous avons illustre cette methodologie par la synthese des deux enantiomeres anti de la (3)-carboxy-(4)-hydroxy-2,3,4,5-tetrahydropyridazine, un constituant de la luzopeptine a, antibiotique antitumoral. Cette synthese a ete realisee en 7 etapes avec un rendement global de 19% a partir de l'acide 3-(e)-hexenoique commercial. D'autre part, dans des travaux figurant en annexe, des essais d'hydroxylation electrophile de beta-hydroxyesters et de dioxanones ont ete realises, mais les resultats obtenus sont mediocres

Thesis advisor: Eranthie Weerapana
Functional amino acids that play critical roles in catalysis and regulation are known to display elevated nucleophilicity and can be selectively targeted for covalent modification by reactive electrophiles. Chemical-proteomic platforms, such as activity-based protein profiling (ABPP), exploit this reactivity by utilizing chemical probes to covalently modify active-site residues to inform on the functional state of enzymes within complex proteomes. These and other applications rely on the availability of a diverse array of electrophiles and detailed knowledge of the reactivity and amino-acid specificity of these groups. The sulfonyl fluoride activity-based probe (ABP) DAS1 was discovered to label and inhibit both serine proteases and glutathione S-transferases (GSTs). In the case of GSTs, DAS1 covalently bound to a tyrosine residue, despite predicted serine reactivity. Investigation of potential aryl halide electrophiles for ABPP found that chloronitrobenzene RB2 and dichlorotriazine RB7 covalently modify cysteine and lysine residues in target proteins. Applying an existing ABP, iodoacetamide alkyne (IA-alkyne), demonstrated the ability of ABPP to discover novel reactive residues in short open reading frame (sORF)-encoded peptides, as well as previously unannotated cysteine residues on glycolysis enzymes. These studies illustrate the development and characterization of novel electrophiles and demonstrate the application of ABPs to interrogate biological systems. Looking further ahead, the novel electrophiles also provide new tools for the development of covalent inhibitors for treatment of disease
Thesis (PhD) — Boston College, 2015
Submitted to: Boston College. Graduate School of Arts and Sciences
Discipline: Chemistry

La reaction de l'enethiolate lithie du dithioacetate de methyle avec des accepteurs de michael est regioselective. Elle conduit a: - une addition-1,4 pour les esters, cetones ethyleniques et un vinylphosphonate. Avec les esters ethyleniques un bon rendement est obtenu lorsque l'accepteur ou l'enolate resultant est stabilise. Avec une cetone diethylenique, un resultat interessant de double addition-1,4 avec cyclisation, a ete observe. Enfin un premier exemple de phosphonate comportant un groupement thiocarbonyle en 4 a ete obtenu de facon quantitative avec le vinylphosphonate ; ces resultats confirment que les enethiolates de dithioesters sont des nucleophiles mous. - une addition-1,2 pour les aldehydes ethyleniques avec la formation d'aldols, souvent instables qui, en se deshydratant, conduisent a des thiopyranes par cyclisation, originalite par comparaison a la serie oxygenee. L'action d'enethiolates lithies de composes thiocarbonyles varies (dithioesters, thiocetones, thionesters) sur les oxiranes donne lieu a une s-addition. L'oxirane doit etre peu encombre. Certains dithioacetals de cetenes obtenus se cyclisent en oxathiolanes en milieu acide. L'etude de la reactivite des dithioacides vis-a-vis des cetones et aldehydes ethyleniques, en milieu basique, montre que les dithioacides sont de bons donneurs pour la reaction de michael. Une s-addition-1,4 selective est observee. Le caractere tres mou des nucleophiles sulfures se trouve ainsi confirme

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.

The modification of proteins by xenobiotic and endogenous electrophilic species produced in cells undergoing oxidative stress contributes to cellular toxicity and disease processes. Many xenobiotics are themselves reactive electrophiles; however non-reactive compounds may become reactive towards proteins and DNA following metabolism. Identifying actual sites of adduction on target proteins is critical for determining the structural and functional consequences associated with the modification. 1,4-benzoquinone (BQ) is a reactive quinone and environmental toxicant, formed from oxidative metabolism of benzene, an aromatic hydrocarbon found in gasoline and other fuels. Although environmental and occupational exposure to benzene is associated with the development of aplastic anemia and leukemia, the mechanism of toxicity remains elusive. Due to the electrophilic nature of BQ, it reacts with glutathione to form quinol-thioether (QT) conjugates that retain the ability to redox cycle between the reduced (HQ) and oxidized (BQ) forms. BQ and its QT metabolites are reactive, and can produce cellular necrosis through oxidative stress and protein modification. One further consequence of oxidative stress is the elevation of cellular membrane lipid peroxidation, resulting in the formation of reactive lipid-aldehydes such as 4-hydroxynonenal (4HNE). Adduction of critical amino acid residues in target bone marrow proteins by 4HNE and QTs following exposure to benzene could contribute to its hematotoxic effects. This dissertation builds upon the foundation of proteins targeted by electrophilic adduction by outlining techniques to pinpoint the specific amino acids targeted and furthermore predict the functional releavance of adduction. For the first time, protein targets of reactive endogenous lipid aldehydes are reported in the bone marrow of chemically treated rats. Furthermore, novel sites of adduction by aldehydes and benzene-glutathione conjugates are reported within functional regions of topoisomerase II. Inhibition of bone marrow DNA topoisomerase II by benzene metabolites is implicated as a potential mechanism of benzene-induced hematotoxicity and acute-myeloid leukemia. The strong inhibitory effect of these compounds on topoisomerase II activity suggests that their presence in the bone marrow may play a role in benzene-induced myelotoxicity.

Dissertation (PhD)--University of Stellenbosch, 2003.
ENGLISH ABSTRACT: This study comprises the preparation and characterisation of various novel organometallic species of gold(I) by employing a range of anionic group 6 metal Fischer-type carbene complexes and group 6 metal-acyl complexes as synthons of the organic moieties introduced to the gold(I) electrophiles. The main objectives of this work are to develop the use of Fischer-type carbene complexes as synthons in the preparation of novel organometallic species along unusual reaction pathways and, in doing so, to expand the organometallic chemistry of gold(I), especially Au-C bond formation reactions. By reacting various β-CH acidic Fischer-type alkoxy/dialkylamino/ alkthio(methyl)carbene complexes, first with a base, and then with a gold(I) electrophile (Ph3PAu+), easy access to vinyl ether/dialkylamine/thioether complexes of gold(I) coordinated to M(CO)5 (M = Cr, Mo, W) fragments, is obtained. When methyl alkoxy- or dialkylaminocarbene complexes are employed, coordination of the novel alkoxyvinyl-gold(I)PPh3 and dialkylaminovinyl-gold(I)PPh3 species to the M(CO)5 fragments occurs in an asymmetrical fashion through the vinyl functionalities of the novel gold(I) species. This usually unstable coordination mode for vinyl ethers is stabilised by delocalisation of partial positive charges from the α-gold vinyl carbon atoms to either the gold(I)PPh3 fragment [for η2-{alkoxyvinyl-gold(I)PPh3}M(CO)5 complexes] or the nitogen atoms of the vinyl amine group [for η2-{dialkylaminovinylgold( I)PPh3}M(CO)5 complexes]. In the latter complexes this delocalisation occurs to such an extent that these complexes are best described as zwitterions. The corresponding negative charges in the bimetallic complexes reside on the M(CO)5 fragments. As a representative example, uncoordinated ethoxyvinyl-gold(I)PPh3 was isolated in high yield via a ligand replacement reaction with PPh3. When Fischer-type alkthio(methyl)carbene complexes are employed in this conversion, novel sulphur coordinated {alkthiovinyl-gold(I)PPh3}Cr(CO)5 complexes are formed.The reaction mechanism involved in these conversions is believed to be the gold(I) analogue of the hydrolysis of Fischer-type carbene complexes. In this mechanism the bimetallic η2-vinyl ether coordinated {alkoxyvinyl-gold(I)PPh3}M(CO)5 complexes represent stabilised gold(I) analogues of postulated transition states in the hydrolytic decomposition of Fischer-type alkoxycarbene complexes. The term aurolysis is conceived to describe the conversion when Ph3PAu+ is employed as electrophile instead of H+. The formation of the bimetallic η2-vinyl ether coordinated complexes in the current conversion, furthermore, strongly supports the existence of similar transition states in the hydrolytic decomposition of Fischer-type alkoxycarbene complexes. This mechanism is also accepted for the formation of analogous η2-{dialkylaminovinyl-gold(I)PPh3}M(CO)5 and {alkthiovinyl-gold(I)PPh3}-S Cr(CO)5 complexes when β-CH deprotonated Fischer-type dialkylamino- and alkthiocarbene complexes are employed in this reaction. The reaction of anionic group 6 metal-acyl complexes and their nitrogen analogues, N-deprotonated Fischer-type aminocarbene complexes, leads to the formation of acylgold(I) and novel imidoylgold(I) complexes coordinated to M(CO)5 (M = Cr, W) fragments. In the previous complexes poor stabilisation of the M(CO)5 fragments allows halide anions to readily form ionic adducts with these groups. This characteristic of these products provides a useful reaction pathway to the first example of a free acylgold(I) complex, benzoyl-AuPPh3. Coordination of the imine nitrogen atom to the M(CO)5 fragments in the analogous bimetallic imidoylgold(I)-M(CO)5 complexes is much stronger. These complexes are remarkably stable and could even be effectively isolated by means of low temperature silica gel chromatography. As a preliminary reaction mechanism for this conversion we propose a mechanism that is closely related to the aurolysis mechanism described above. The only difference is that, instead of formal reductive elimination of vinyl ethers/amine/thioether complexes of gold(I) from the M(CO)5 fragments, acyl and imidoyl complexes of gold(I) are produced in this step. Furthermore, the (Z)- stereoisomers of the bimetallic imidoylgold(I)-M(CO)5 complexes generated in this conversion are exclusively obtained.A second N-deprotonation-auration reaction sequence performed on suitable examples of the bimetallic imidoylgold(I)-M(CO)5 complexes yields, as the only isolable product, a novel triangular Au2Cr cluster complex, cis-{η2-(Ph3PAu)2} PPh3Cr(CO)4. This complex is the isolobal equivalent for the unstable molecular hydrogen complex, (η2-H2)PPh3Cr(CO)4, and exhibits the shortest known Au-Au separation between two gold atoms in cluster complexes of the type Au2M. Finally, two novel and vastly different molecular structures of closely related anionic benzoylpentacarbonyl tungstates, one with Li+ as counterion and another in which exactly half the Li+-cations have been replaced by protons, highlight the importance of hydrogen bonding and ion-dipole interactions in determining the solid state structure of such complexes.
AFRIKAANSE OPSOMMING: Hierdie studie behels die bereiding en karakterisering van verskeie nuwe organometaalkomplekse van goud(I). Hierdie komplekse is berei deur gebruik te maak van n wye reeks anioniese groep 6 metaal Fischer-tipe karbeenkomplekse asook anioniese groep 6 metaal asielkomplekse as sintetiese ekwivalente vir die organiese fragmente wat gedurende die sintese aan die goud atoom gebind word. Die hoofdoel van hierdie studie is om die gebruik van Fischer-tipe karbeenkomplekse as sintetiese voorgangers in die bereiding van nuwe organometaalverbindings te ontwikkel en om sodoende ook die organometaalchemie van goud verder uit te bou. Veral die ontwikkeling van nuwe sintetiese metodologieë vir die bereiding van Au-C bindings is hier van belang. Verskeie Fischer-tipe alkoksie-/dialkielamino-/alktio-(metiel)karbeenkomplekse met suuragtige waterstofatome geleë op die β-metallo-koolstofatoom is eers onomkeerbaar gedeprotoneer. Byvoeging van die goud(I) elektrofiel, Ph3PAu+, lei - volgens n ongewone reaksiemeganisme - tot die vorming van onderskeie vinieleter-, dialkielvinielamien- en vinieltioeterkomplekse van goud(I). Hierdie komplekse is verder ook op verskillende wyses aan M(CO)5 fragmente (M = Cr, Mo, W) gekoördineer. Die vinieleter- en vinielamienkomplekse van goud(I), wat vorm wanneer alkoksie- en dialkielaminokarbeenkomplekse onderskeidelik in hierdie sintese aangewend word, koördineer onsimmetries deur hulle viniel dubbelbindings aan die vrygestelde M(CO)5-groepe. Hierdie normaalweg onstabiele vorm van vinieleterkoördinasie, word gestabiliseer deur delokalisering van positiewe lading vanaf die α-goud viniel koolstofatoom na die AuPPh3-fragment [vir die η2-{alkoksievinielgoud( I)PPh3}M(CO)5 komplekse] óf na die stikstofatoom van die dialkielvinielamien groep [vir die η2-{dialkielaminoviniel-goud(I)PPh3}M(CO)5 komplekse]. Laasgenoemde komplekse kan as zwitterione beskryf word. Die onderskeie negatiewe ladings in hierdie komplekse bevind hulle hoofsaaklik op die M(CO)5 groepe. Sterk koördinerende ligande (bv. PPh3) verplaas die onsimmetriese viniel eter vanaf die M(CO)5-fragment. Só kon, as n voorbeeld, die vrye etoksievinielgoud( I)PPh3-kompleks met n hoë opbrengs berei word. Wanneer β-gedeprotoneerdeFischer-tipe tiokarbeenkomplekse met Ph3PAu+ reageer, vorm swawel gekoördineerde {tioviniel-goud(I)PPh3}Cr(CO)5 bimetalliese komplekse in stede van die π-komplekse. Dit word voorgestel dat in die bogenoemde reaksies die goud(I)elektrofiel dieselfde rol vervul as die proton gedurende die hidrolise van Fischer-tipe alkoksiekarbeenkomplekse. Die bimetalliese, η2-vinieleter-gekoördineerde {alkoksieviniel-goud(I)PPh3}M(CO)5-komplekse hier berei verteenwoordig dus stabiele goud(I) analoë van voorgestelde tusseprodukte in so ’n meganisme. Die term aurolise word voorgestel om die geval waar Ph3PAu+ in stede van H+ as elektrofiel aangewend word te beskryf. Die vorming van bimetalliese, η2-vinieletergeko ördineerde komplekse in die huidige reaksie ondersteun die moontlike vorming van die voorgestelde tussenprodukte tydens die hidrolise van Fischer-tipe alkoksie(metiel)karbeenkomplekse. ’n Soortgelyke meganisme kan ook gebruik word om die vorming van die η2-{dialkiellamienviniel-goud(I)PPh3}M(CO)5- en {alktioviniel-goud(I)PPh3}-S Cr(CO)5-komplekse vanuit β-CH gedeprotoneerde Fischer-tipe dialkielamino- en tiokarbeenkomplekse en Ph3PAuCl te interpreteer. Die reaksie van anioniese groep 6 oorgangsmetaal metaal-asielkomplekse en hulle stikstofanaloë, N-gedeprotoneerde Fischer-tipe aminokarbeenkomplekse, lewer onderskeidelik asiel- en imidoielkomplekse van goud(I) wat aan M(CO)5 fragmente (M = Cr, W) koördineer. Die goud(I)asiel-M(CO)5 koördinasie deur die asielsuurstofatoom is baie swak en die M(CO)5-eenheid in hierdie komplekse word maklik deur haliedanione en sekere oplosmiddel molekules verplaas. Die haliedanione vorm anioniese addukte met the M(CO)5 fragmente. Hierdie eienskap van die bimetalliese komplekse verskaf sodoende n gerieflike sintetiese roete na die eerste voorbeeld van n vrye asielgoud(I)-kompleks, bensoiel-AuPPh3. Koördinasie van die imienstikstofatoom aan M(CO)5-groepe in die bg. imidoielkomplekse is egter veel sterker. Die bimetalliese {imidoielgoud(I)}M(CO)5-komplekse is verbasend stabiel en kan selfs effektief deur middel van lae temperatuur SiO2-kolomkromatografie geïsoleer word. n Soortgelyke reaksie meganisme as wat voorgestel word vir die aurolise van Fischer-tipe karbeenkomplekse word voorgestel vir hierdie reaksie. Die enigste verskil is dat die formele reduktiewe eliminasie van n viniel-eter, -amien of -tioeter vervang word met die vorming van asiel- of imidoielkomplekse van goud(I). Verder word die (Z)-isomere van die bimetalliese {imidoielgoud(I)}M(CO)5-komplekse uitsluitlik in hierdie reaksie verkry. Wanneer geskikte voorbeelde van bimetalliese {imidoielgoud(I)}M(CO)5-komplekse n tweede keer gedeprotoneer word en gereageer word met Ph3PAuCl, is die enigste isoleerbare produk van die reaksie n driehoekige Au2Cr troskompleks, nl. cis-{η2- (Ph3PAu)2}PPh3Cr(CO)4. Hierdie verbinding dien as n isolobale model vir die onstabiele molekulêre waterstof kompleks , (η2-H2)PPh3Cr(CO)4, en besit verder die kortste Au-Au afstand tussen twee goud atome in driehoekige troskomplekse wat nog tot dusvêr gerapporteer is. Laastens is die kristalstrukture van twee nou verwante anioniese {bensoiel}W(CO)5- komplekse bepaal. Die enigste verskil tussen die hierdie twee verbindings is dat die een slegs Li+ as teenioon bevat terwyl presies die helfte van die Li+-teenione in die tweede struktuur deur protone verplaas is. Hierdie klein verskil in samestelling veroorsaak egter drastiese verskille in die kristalstrukture van hierdie verbindings. Die belangrikheid van waterstof bindings en ioon-dipool interaksies in die bepaling van die vastetoestandstrukture van sulke verbindings word hierdeur beklemtoon.

Le travail decrit dans ce memoire porte sur la synthese et la reactivite des cyclobutenes fonctionnalises et sur la reactivite intramoleculaire d'-cetoesters acetyleniques. Nous avons tout d'abord montre qu'une reaction de cycloaddition 2+2 thermique avait lieu entre des acetals trimethylsilyles cycliques de cetenes et des acetyleniques electrophiles conduisant aux cyclobutenes fonctionnalises correspondants a condition d'effectuer la reaction sans catalyseur et sans solvant. L'etude de la reactivite de ces cyclobutenes nous a permis de mettre en evidence de nouvelles voies d'acces a des -methylene lactones substituees, des derives furaniques (qui representent des sous-structures importantes de l'acide trachyspique, un antibitique naturel), des -cetoesters acetyleniques, des derives cyclobutaniques et des lactones fonctionnalisees. Dans la seconde partie de ce travail, nous nous sommes interesses a la reactivite intramoleculaire d'-cetoesters acetyleniques. Nous avons pu montrer que selon les conditions reactionnelles utilisees, il etait possible d'acceder soit a des cyclobutenes polyfonctionnalises par une reaction de cycloaddition 2+2 intramoleculaire, soit a des derives alleniques bicycliques par reaction avec le tbaf ou encore a des oxacycles par reaction avec le tbuok. La methodologie mise en evidence au cours de ce travail a ete utilisee pour effectuer de nouvelles approches vers la synthese de la grasshopper ketone.

Electrophilic aromatic substitution (EAS) and directed ortho-metalation (DoM) involve the direct substitution of an arene hydrogen. A major drawback involving EAS is the necessity for harsh forcing conditions for the reaction to proceed. Catalysts such as Lewis acids FeBr3 and AICI3 for the introduction of halogens and acyl groups, respectively, are each highly toxic and corrosive. Textbook preparations of aryl iodides classicaly involved the use of iodine and nitric acid. This approach affords only modest yields and does not provide regiospecific substitution of most substituted aromatics because most contain ortho/para directors which afford mixtures of isomers. The novelty of our procedure for the synthesis of the iodinated aromatics is twofold in that regiospecific para-iodination is observed and hydrocarbon media are utilized. Hydrocarbon media are less hazardous and greener than media used for halogenations reported in literature. This procedure always yields derivatives regiospecifically substituted para to an electron donating substituent. Moreover, this method eliminates the need to use hazardous oxidative catalysts. DoM is a reaction regiospecifically substitute an arene hydrogen at the ortho position. The media used in DoM reactions are less hazardous than those required for a variety of EAS reactions. The only problem for this reaction is use of extremely strong bases, alkyllithium reagents, which are known to be air and water sensitive. However, the DoM reaction does eliminate the need to separate ortho/para isomer mixtures so that only a single product is generated. The metalation yields predominantly products regiospecifically substituted ortho-to the direcing metalating group (DMG). With our deficiency catalysis concept and subsequent purificaion methods, relatively pure ortho-lithiated intermediates have been prepared. The study of catalysts/promoters on the derivatization of these intermediates is anticipated to be extremely insightful. For this study, we have shown that highly selective, efficient ortho-lithiation can be achieved by deficiency catalysis utilizing n-BuLi as the only strong metalating base.

Gas-phase thermolysis is a long-known and well established method for the preparation of reactive species. It is, however, limited to relatively volatile substances, which are easily vaporised. In the present work, the solution-spray technique for preparative scale was developed. With this technique, it is possible to subject low-volatile substances, which hardly vaporise even under high-vacuum conditions, to gas-phase thermolysis. By utilising oil nozzles used in heating and burner systems, it was possible to integrate a stable solution-spray into the existing flash-vacuum-pyrolysis system. The influence of several variables, such as flow-rate, pressure, temperature and solvent was determined. The solution-spray technique was applied in [3,3]-sigmatropic rearrangements of certain propargyl thiocyanates to the corresponding allenyl isothiocyanates. Furthermore, the parent compound propa-1,2-dienyl isothiocyanate was reacted with various sterically demanding primary and secondary amines to form 2-amino-1,3-thiazoles in moderate to excellent yields. Based on this, a catalyst-free four-center three-component reaction was developed. 2-Amino-1,3-thiazoles with complex substituents in 5-position at the heterocyclic ring are formed. Reaction mechanisms are discussed to explain the occurance of a highly substituted 1,3-thiazine structure. The influence of reaction temperature, concentrations and solvent were determined and are also discussed. It was shown that 2-amino-5-methyl-1,3-thiazoles are the apparently first aromatic substance class, that readily undergoes Prins-type 1,3-dioxane ring-formation
Die Gasphasenthermolyse ist eine lang bekannte und etablierte Methodik zur Synthese reaktiver Spezies. Sie ist allerdings auf flüchtige Substanzen mit einer guten Verdampfbarkeit beschränkt. Für schwerflüchtige Verbindungen, welche sich selbst im Hochvakuum nur mäßig oder gar nicht in die Gasphase bringen lassen, wurde in der vorliegenden Arbeit die Solution-Spray-Technik für die Anwendung im präparativen Maßstab entwickelt. Unter Verwendung von Ölzerstäuberdüsen, wie sie in der Heizungs- und Brennertechnik Anwendung finden, wurde die Erzeugung eines stabilen Lösungs-Sprays in die vorhandene Blitzvakuumpyrolyse-Technik integriert. Der Einfluss verschiedener Variablen, wie Flussrate, Druck, Temperatur und Lösungsmittel wurde untersucht. Die Solution-Spray-Technik wurde für die [3,3]-sigmatrope Umlagerung bestimmter Propargylthiocyanate zu Allenyl-isothiocyanaten angewendet. Des Weiteren wurde Propa-1,2-dienylisothiocyanat – das einfachste Allenylisothiocyanat – mit diversen sterisch anspruchsvollen primären und sekundären Aminen in mäßigen bis exzellenten Ausbeuten zu 2-Amino-1,3-thiazolen umgesetzt. Darauf aufbauend konnte eine Vier-Zentren-drei-Komponenten-Reaktion entwickelt werden. Es entstehen in hohen Ausbeuten 2-Amino-1,3-thiazole mit komplexen Substituenten an der 5-Position des Heterocyclus. Reaktionsmechanismen werden diskutiert um die alternative Bildung einer hochsubstituierten 1,3-Thiazinstruktur zu erklären. Der Einfluss von Reaktionstemperatur, Konzentration und Lösungsmittel auf das Produktverhältnis wurde ebenfalls untersucht und wird diskutiert. Es konnte gezeigt werden, dass 2-Amino-5-methyl-1,3-thiazole als offenbar erste aromatische Substanzklasse sehr gute Substrate für die Bildung von 1,3-Dioxanen nach Prins darstellen

A primeira parte desta tese aborda estudos sobre a reatividade de compostos de telúrio eletrofílicos, principalmente tetracloreto de telúrio e tricloretos aromáticos de telúrio. Novos aspectos da reatividade de TeCl4 frente a alcinos e algumas acetofenonas foram observados e, a partir da elucidação estrutural dos compostos obtidos, por cristalografia, uma racionalização mecanística foi proposta para cada caso. As proposições apresentadas encontraram respaldo com a detecção de intermediários transientes por estudos de espectrometria de massas com ionização por electron-spray (ESI-MS/MS). Além de novos aspectos da química do Telúrio, os compostos preparados encontraram aplicação como potentes e seletivos inibidores de cisteíno proteases. Com esta aplicação estabelecida, foram sintetizadas ambos os enantiômeros de uma telurana e a atividade inibitória destas frente a Catepsina B mostrou dependência da estereoquímica devido a dependência estereoquímica da interação entre a enzima e o inibidor. A segunda parte deste trabalho trata do desenvolvimento da reação de abertura de anel de aziridinas por reagentes organometálicos de cobre derivados de teluretos vinílicos e arílicos que resultaram em derivados de aminas homoalílicas ou homobenzílicas. Em seguida, a reatividade de aziridinas alílicas foi estudada frente a uma série de reagentes organometálicos de lítio, magnésio, cobre e zinco que mostraram influenciar a regio- e estereosseletividades das reações de abertura.
The first part of this thesis deals with the study of the reactivity of electrophilic tellurium compounds, mainly tellurium tetrachloride and aromatic tellurium trichlorides. New aspects of the reactivity of TeCl4 towards alkynes and some acetophenones were disclosed. A mechanistic rationale for each of the processes studied was possible by the determination of the stereochemistry for each product by monocrystal X-ray diffraction analysis. The proposition of the formation of cationic intermediates in the addition reaction of TeCl4 to alkynes was corroborated by the detection and characterization of transient intermediates by ESI-MS/MS experiments. Besides the new aspects of the Tellurium chemistry found, the prepared compounds showed a high and selective activity as inhibitors of cysteine proteases. A pair of enantiomers of a tellurane showed different activities against Human Catepsin B due to a stereochemical dependence in the enzyme/inhibitor interaction. The second part of the present work deals with the development of the ring opening reaction of aziridines by organometallic reagents of copper prepared from vinylic and arylic tellurides. These reactions led to homoallylic and homobenzylic amine derivatives. Finally, the reactivity of 2-alkenyl aziridines was studied towards a series of organometallic reagents of lithium, magnesium, copper and zinc which biased the regio- and stereoselectivities of the ring opening reactions.

Nous presentons dans le preambule un apercu des differentes methodes de synthese asymetriques de beta-ceto esters alpha, alpha-disubstitues parues dans la litterature. Dans le premier chapitre nous exposons l'addition de michael des beta-enaminoesters alpha-disubstitues avec divers accepteurs de michael (enones, acrylates, acrylonitrile). Elle conduit, avec de bons exces enantiomeriques et bons rendements chimiques, a des beta-ceto esters alpha, alpha-disubstitues. Ce motif est frequemment rencontre, soit sous sa forme premiere, soit sous des formes derivees dans de nombreux produits biologiquement actifs. Cette reaction a ete catalysee par des acides de lewis et par l'application de hautes pressions. Une etude detaillee de la reactivite de cette addition en fonction de la temperature, du solvant et de la nature de l'acide de lewis a ete realisee. Une interpretation de l'etat de transition, a partir des observations experimentales et des analyses spectrales est proposee. Dans le deuxieme chapitre nous appliquons cette reaction de michael a la synthese enantioselective de lactames spirocycliques, precurseurs directs d'alcaloides: la (+)-isonitramine et la ()-nitramine. Dans le troisieme chapitre nous traitons les differentes approches du pisiferol