Dissertations / Theses on the topic 'Grignard reagents'

The synthesis of cyclopenta[c]thiophenes is sparsely found in literature due to the several difficulties of their synthesis. Our research has shown that we could modify a previously known route to 1,3-disubstituted cyclopenta[c]thiophenes using traditional Grignard chemistry. Along the way we discovered the synthetic route we were using had several omissions. Therefore, we were required to completely fill in missing experimentals in order to obtain each cyclopenta[c]thiophene intermediate, in high purity and good yield. In addition, we were able to fully characterize via NMR, our intermediates which was found in the literature. Finally, we were able to show using 'H 13 and 13C NMR spectroscopy evidence of 5-alkyl-l,3-disubstituted cyclopenta[c]thiophenes by treating l,3-dimethyl-5,6-dihydro-4H-cyclopenta[c]thio-phene-5-one with an alkyl Grignard reagent. 1 A ser1i3e s of cyclopenta[c]thiophene intermediates will be presented along with their H and C NMR spectra. A discussion of cyclopenta[c]thiophene synthesis will be provided along with attempts to improve its experimental conditions. A paper has been submitted to Letters in Organic Chemistry to report our work.

The development of chiral organometallics for asymmetric synthesis is a topic of significant research in the recent past. The most studied in this class are the chiral organolithium reagents with many reported examples. The primary focus of our research is the development of C_α-chiral Grignard reagents, where the metal bearing α-carbon is the sole source of chirality. Examples of such Grignard reagents are rare owing to the problems associated with their synthesis, and their low configurational stability. We have studied these problems in three different modules of this project. Reactions of 1-magnesio-2,2-diphenyl-cyclopropylcarbonitrile with carbon electrophiles are first attempted in order to expand the utility of this configurationally stable C_α-chiral Grignard reagent in asymmetric synthesis. This reagent has been shown to be non-reactive towards carbon electrophiles at low temperatures. Consequently, we attempt to enhance the reactivity of this compound through two different approaches, Lewis-base activation and the "ate-complex" generation. The Magnesium/Halogen (Mg/X) exchange reactions have been shown to be extremely useful in the synthesis of complex Aryl, alkenyl (sp²) and alkynyl (sp) Grignard reagents. Examples of Mg/X exchange reactions of Alkyl (sp³) halides are, however, rare. Even more rare are such examples with secondary and tertiary alkyl halides, justifying the relative paucity of chiral Grignard reagents. In this module of our project, we study the Mg/X exchange reactions on secondary alkyl halides possessing a γ-hydroxyl group, as an internal activator for such Mg/X exchange reactions. Enantiomerization pathways of chiral organolithium compounds have been widely studied. However, few such studies have been performed on chiral Grignard reagents. In this module of the project, we studied the solvent assisted enantiomerization mechanism of the C_α-chiral 1-magnesio-2,2-diphenyl-cyclopropylcarbonitrile. Rate constant for the enantiomerization of this compound was measured in three different ethereal solvents to study the effect of solvent on the configurational stability. Finally, the order of the enantiomerization process with respect to [Et₂O] was studied in order to predict the mechanism of this process in Et₂O solvent. Our kinetic studies on the enantiomerization process provided us with a definitive picture for the enantiomerization of the C_α-chiral 1-magnesio-2,2-diphenyl-cyclopropylcarbonitrile, where solvation of the Grignard reagent preceded an ion-pair separation step which eventually lead to enantiomerization of the Grignard species. However, the precise structure of all the involved solvated intermediates could not be determined as kinetics was not able to distinguish between these intermediates. We next performed computational calculations to study the effect of solvation on the analogous 1-magnesio-cyclopropylcarbonitrile in order to address the unanswered questions from our kinetic studies.
Ph. D.

Single electron transfer (SET) mechanisms are becoming ubiquitous in modern organic chemistry. However, it is often difficult to distinguish SET mechanisms from polar mechanisms. Kinetics, products and product distributions, and response to perturbation in solvent and substituents are often identical between the two mechanisms. Detection techniques such as EPR, CIDNP, and UV absorption can often detect "blind" pathways and thus cannot provide unambiguous evidence regarding the true mechanism of interest. In recent years mechanistic probes have been developed which can test for single electron transfer in the mechanism of interest in a more unambiguous manner, although a given probe is often applicable to a narrower range of reactions.

In this work 1,1-dimethyl-5,7-di-t-butylspiro[2.5]octa-4,7-dien-6-one (6) is presented as a new "hypersensitive" probe for single electron transfer to conjugated carbonyl compounds. This new probe functions in a rather unique fashion, allowing interpretation of the mechanism at work on the basis of the regiochemistry of spirocyclic ring opening. This "regiodifferentiation" based probe was studied with a variety of nucleophiles (particularly Grignard reagents) and has been found to be effective in differentiating SET from polar processes, although surprising results indicative of polar pathways in the case of reaction of 6 with Grignard reagents other than methyl Grignard were found. Additional insight into the mechanism of the reaction of Grignard reagents with conjugated ketones is also presented.

Master of Science

Thesis advisor: Amir H. Hoveyda
Chapter One: An overview of Cu-catalyzed enantioselective allylic substitutions with organometallic reagents. Chapter Two: Development of Cu-catalyzed enantioselective allylic alkylations of allylic chlorides with Grignard reagents for the formation of all-carbon quaternary stereogenic centers is disclosed. Chapter Three: Development of Cu-catalyzed enantioselective allylic substitutions of allylic phosphates with alkyl, aryl, and heterocyclic aluminum reagents for the formation of quaternary stereogenic centers is discussed
Thesis (MS) — Boston College, 2010
Submitted to: Boston College. Graduate School of Arts and Sciences
Discipline: Chemistry

In recent years, despite the large amount of novel and clinically validated targets identified from the human genome project, the number of new drug launched on the market is decreasing and the overall costs for the development of a drug are rising significantly. Pharmaceutical and biotechnology companies are under a strong pressure to produce a steady stream of innovative, well-differentiated drugs with a reduced cost both for discovery and development. Currently it takes an estimated 10-14 years to develop and market a drug at a cost that exceeds 1 billion dollars. With the aim at increasing the productivity of original and highly pure molecules as potential modulators of therapeutic targets, different and novel technologies, related to synthesis, work-up and isolation, were developed. In particular the so called “Enabling Techniques” have emerged and were studied in a large extent in Academia. Among these new technologies continuous flow organic synthesis is now being investigated widely in fine chemistry and, with the advent of commercially available microreactors, also in pharmaceutical industry. In the framework of my PhD thesis exploring the application of the so called “Enabling Techniques” in a medicinal chemistry laboratory, my efforts were devoted to the evaluation of the benefits that continuous flow chemistry could provide in Drug Discovery programs and in the synthesis of natural products in comparison with traditional synthetic techniques. Flow technologies have recently received a great deal of attention and a fair number of scientific publications have demonstrated their potential for improving productivity in organic synthesis. Established continuous flow chemistry advantages include precise control of temperature, pressure, concentration, residence time and heat transfer. All these aspects significantly affect the reaction outcome improving yield and selectivity. Within my thesis, continuous flow chemistry was firstly applied to the synthesis of hydroxamic acids, a class of well known inhibitors of important biological targets such as metalloproteinases and histone deacetylases. As a part of a medicinal chemistry project, a simple conversion of ester into hydroxamic acids (Scheme 1) was envisaged as a suitable and convenient synthetic method for the preparation of a collection of compounds featuring such privileged substructure. The effects of flow rate, reactor volume and temperature were examined and the optimized reaction conditions were then successfully applied for the preparation of a small collection of ten hydroxamic acids featuring a range of functional groups. Good yields, purity and high reproducibility were observed using this simple protocol. R = Aryl, Alkyl, Heteroaryl, Aminoalkyl; R' = Me, Et Scheme 1. Synthesis of Hydroxamic Acids No racemisation occurred when the reaction was performed on protected amino acids. The yields were comparable and, in some cases, even better than what reported in literature where the same transformation was performed by MW irradiation. Even if the reaction time is relatively longer than with MW, no limitation in scale-up is present using flow chemistry. Based on the good results obtained in the development of the continuous flow synthesis of hydroxamic acids this new methodology was applied to the synthesis of SAHA (suberoylanilide hydroxamic acid). Our two-step sequence entails the conversion of the commercially available methyl suberoyl chloride into methyl suberanilate under Schotten-Baumann conditions, followed by the transformation of ester by aqueous hydroxylamine in presence of sodium methoxide (Scheme 2). Scheme 2. Synthesis of SAHA (suberoylanilide hydroxamic acid) To avoid a time consuming work-up procedure and extensive manual purification of the final compound, an integrated sequential flow synthetic pathway was set-up employing immobilized scavenger. The reaction stream was directly passed through a short packed column containing silica supported quaternary amine for the selective removal of the carboxylic acid by-product. The solution containing the product and traces of the starting material was collected and, after solvent evaporation, crystallization from MeOH afforded SAHA in 84% yield and 99% purity (80% yield over two steps). With the aim at studying the applicability of flow technique also to the synthesis of a natural compound, the continuous flow multi-step synthesis of Dumetorine was undertaken. (+)-Dumetorine, isolated in 1985 from the tubers of Dioscorea dumetorum Pax, shows a notable use in folk medicine and arrow poisons. Its total batch-synthesis was recently published by our group (Scheme 3). Scheme 3. Batch-Total synthesis of Dumetorine The planned synthetic route envisaged a flow process where the synthetic steps were combined into only one continuous sequence minimizing work up and purifications. The reaction crudes had to be processed through packed columns containing immobilized reagents, catalysts, scavengers or catch and release agents. In this way the improvements gained through the precise control of reaction conditions and the reduction in manual handling could be easily evaluated. To synthesize this natural alkaloid, new protocols had to be developed for performing classical reactions under continuous flow conditions. With this aim the flow addition of Grignard reagent to carbonyl compounds was the first reaction that we broadly investigated. In fact, despite many classes of reaction was successfully transferred to continuous flow approach, the addition of Grignard reagents to aldehydes and ketones under flow conditions is up-to-date poorly exemplified in the literature. The optimization of the experimental parameters was investigated by varying the temperature of the stored solution, the residence time and the number of Grignard equivalents. A short column containing polymer supported benzaldehyde was used for the scavenging of the excess of Grignard reagent. The optimized conditions (room teperature; 1.2 Grignard eq; residence time 33 minutes) were successfully applied on different aldehydes and ketones (arylic, heteroarylic, alkylic etc.) for the preparation of a small collection of alcohols (Scheme 5). Good yields (ranging from 88% to 96%), purity and high reproducibility were observed. Scheme4. Flow Grignard addition to carbonyl compounds The protocol was applied to the synthesis of Tramadol, a well known centrally active analgesic used for treating moderate to severe pain (Yield 96%). The developed conditions also allowed the selective addition of Grignard reagents to aldehydes and ketones in the presence of a nitrile function (Scheme 5). Scheme5. Flow Grignard addition to carbonyl compounds in presence of nitriles. In the light of the interesting results concerning the flow addition of Grignard reagent to carbonyl compounds, we started to perform the five-step continuous flow synthesis of (+) Dumetorine reported below (Scheme 6). Scheme 6. Flow-Total synthesis of (+)Dumetorine This synthesis entailed IBX oxidation of primary alcohol, Grignard addition on carbonyl compounds, acylation, ring closing metathesis and Eschweiler-Clarke reductive amination. In the second step the flow addition of suitable Grignard reagent to aldehyde (2) was performed under the previously optimized conditions. The yield of the isolated compound was 90% with a remarkable improvement respect to the batch process. This result is a direct consequence of the efficient mixing and heat dispersion due to the high surface area-to-volume ratios in the PTFE tubing that keeps the temperature constant minimizing the occurrence of side reactions. Compound (5) presents the structural features for ring-closing metathesis and this type of reaction was performed in batch using 2nd generation Grubbs catalyst in good yield. The same result was obtained flowing for short time (less than 20 min) the starting material in presence of dissolved catalyst (both 1st and 2nd generation catalysts were tested) but, in this way, the problem of the final purification by flash chromatography was still present. After a few failing attempts using not commercially available supported Grubbs catalysts of 1st (a) and 2nd (b) generation (Figure 1) , we evaluated the application to flow chemistry of a homogeneous PEG supported Grubbs catalyst in order to increase the performance in RCM maintaining the possibility of a simple catalyst recovery. Figure 1. Supported Grubbs Catalysts prepared A newly synthesized PEG- Supported Hoveyda catalyst (8) was prepared (Scheme 5) in collaboration with Prof. M. Benaglia and Dr. A. Caselli (Università degli Studi di Milano). Using this PEG-supported catalyst, the flow RCM was successfully and we observed the total conversion of (5) in (6). The pure compound (6) was simply obtained by evaporation of the solvent after the precipitation of the catalyst in presence of Et2O. The catalyst easily recovered can be recycled for RCM reactions. Scheme 5. Synthesis of PEG-supported Hoveyda catalyst The Dumetorine batch synthesis was affected by a low yielding acid catalyzed cleavage of Boc protecting group due to a Michael side reaction of the secondary amine on the α-β unsaturated lactone ring. As a consequence, the reductive amination resulted not an easy task to be managed. In order to overcome these problems, we performed the unprecedented flow Eschweiler-Clarke reaction, a particular amination reduction. Under optimized continuous flow conditions, we assessed the concomitant BOC deprotection and N-methylation. The solutions of starting materials and reagents were pumped in the PTFE tubing reactor and then through a column containing SCX cartridge (catch and release purification) obtaining (+)-Dumetorine in high purity and good yield (Overall yield: 29% (65% diastereoisomeric mixture); obtained (+)-Dumetorine amount: 227 mg). So, a flow-based synthesis of (+)-Dumetorine was accomplished; remarkable results were obtained in the Grignard reaction, performed in an efficient and safe manner at room temperature avoiding cryogenic temperature; in the RCM reaction, carried out with a newly synthesised PEG-supported Hoveyda catalyst and finally in the unprecedented flow Eschweiler-Clarke reaction with concomitant BOC deprotection and N-methylation in high yield. This flow total synthesis represents a significant improvement over the existing protocol characterized by lower yield and more steps and the synthetic route was also tested for the preparation of additional analogue derivatives. In fact on the basis of the results that we obtained in the synthesis of (+)-Dumetorine, we applied flow technology to the preparation of its simplified natural congeners (+)-Sedridine (9) and (-)-Sedamine (10). The synthesis of the two natural alkaloids was assessed with good results using protocols (Grignard addition, Eschweiler Clarke reaction) optimized for the preparation of (+)-Dumetorine. Figure 2. (+)-Sedridine (9) and (-)-Sedamine (10) All the results that were assessed in this PhD thesis clearly demonstrate how flow chemistry shows great potentiality in the Medicinal Chemistry field and how that this technique is of great advantage in the assembly of challenging molecules, as natural products, in terms of overall yield reaction time and limitation of handling and purification.

Stereochemistry is important aspect of chemistry that customarily includes the study of the relative spatial arrangement of atoms within molecules (static stereochemistry), and the study of the stereochemical requirements and outcomes of chemical reactions (dynamic stereochemistry). These two branches complement each other in modern stereochemistry. Chiral organometallics feature prominently in organic synthesis as reactive intermediates. The possibility of exploring their stereochemistry in synthesis is associated with the configurational stability of the metal-bearing stereogenic center. We were interested in the configurational stability of lithiated and magnesiated nitriles. We developed a new series of lithio-cyclopropylnitriles bearing chelating groups for intramolecular coordination, as a possible strategy to impart configurational stability. Although this strategy has not yet been successful, using density functional theory (DFT) method, we addressed the effect of chelating groups on racemization via the â conducted tourâ mechanism. We then explored metal-bromine exchange on enantiopure bromonitrile as alternative route to metalated nitriles. In this way, we demonstrated that magnesiated 2,2-diphenyl cyclopropylnitrile is configurationally stable on the macroscopic timescale. No other metallated nitrile has ever demonstrated configurational stability on this timescale. In contrast, bromine-lithium exchange of 1-bromo-2,2-diphenyl-cyclopropylnitrile demonstrated fast racemization under the same conditions. Another major project focused on conformational control of acyclic molecules. Using X-ray crystallography and NMR spectroscopy, we found that the 2,6-disubstituted aryl group eclipses its geminal hydrogen, and induces an antiperiplanar relationship of the geminal and vicinal hydrogens. Interestingly, anti-nitrile aldols or syn-ketone aldols bearing 2,6-disubstituted aryl groups demonstrate unanticipated remote effects on acyclic conformation: the 2,6-disubstituted aryl group prefers to be in a gauche position to the largest vicinal group. The minimization of allylic 1,3-strain and syn-pentane-like interaction works together in establishing this conformational preference.
Ph. D.

This thesis deals with the development and application of new synthetic methodology in organic chemistry. The first part describes the development of a new protocol for the synthesis of 3-pyrrolines by means of a microwave-assisted ring-expansion reaction of 2-vinylaziridines. In addition, this methodology is implemented as a key-step in a formal total synthesis of the antibiotic (-)-anisomycin. In the second part, a new methodology for the synthesis of arylglycines from Weinreb amides is described. In this procedure, a Grignard reagent is added to the iminium ion formed from the Weinreb amide upon treatment with a base. When a chiral amide is used, the nucleophilic addition proceeds with high diastereoselectivity. Finally, an easy and straightforward synthesis of α-amino amides via a base-mediated rearrangement of modified Weinreb amides into N,O-acetals is presented. Subsequent arylation, alkylation, alkenylation or alkynylation of this intermediate affords the corresponding α-amino amides in excellent yields. Furthermore, a more generalized protocol for the α-arylation of Weinreb amides lacking an α-amino moiety is also discussed.
QC 20100719

A brief introduction explaining phosphine ligand properties, Pd catalysed cross-coupling reactions; the importance of the steps involved in the catalytic cycle (oxidative addition, transmetalation & reductive elimination), mechanistic studies and a comparison of various reactions will give an overview of important cross-coupling reactions and their limitations. The development of a “super-concentrated” (5M) Pd catalysed Kumada type coupling reaction has been developed for coupling a range of aryl bromide and chloride substrates with the Grignard reagents ((p-CF₃-C₆H₄)MgBr)) and PhMgBr in methyl-tetrahydrofuran (Me-THF). Using a range of bidentate ligands such as bis-phosphinoferrocenyl ligands, good conversions were achieved using small amounts of solvent; up to 10 times less than typical procedures in THF. The unsymmetrical Pt complexes of the form [Pt(P-P)Br₂], [Pt(P-P)(Ph)Br] and [Pt(P-P)Ph₂] have been synthesised and characterised. The variations of substituents on the ligand system and the steric bulk have been shown to have a dramatic effect on the rate of transmetalation. The results provide one explanation why 1,1’-bis(di tert-butylphosphino)ferrocene (dtbpf), an excellent ligand for certain Suzuki reactions, is quite poor in reactions where transmetalation is more difficult. Palladium dichloride complexes of the ferrocenylphosphine based ligands 1,1’-bis- (diphenylphosphino)ferrocene (dppf), 1,1’-bis-(diisopropylphosphino)ferrocene (dippf) and 1,1’-bis-(di-tert-butylphosphino)ferrocene (dtbpf) have been shown to be active in the Hiyama cross-coupling of p-bromoacetophenone and vinyltrimethoxysilane (CHCH₂Si(OMe₃)) in the presence of TBAF under thermal heating and microwave conditions. Ligands with the optimum balance for promoting the transmetalation, oxidative addition and reductive elimination steps along the reaction pathway have been identified. Competition experiments are consistent with slow transmetalation being an issue with the Hiyama reaction relative to the Suzuki coupling. A novel protocol has been developed for the synthesis of aryl-alkyl ethers via C-O bond activation under Pd catalysed conditions. Utilising the unsymmetrical 1-bis-(ditertbutyl-1’- bis-diphenylphosphino)ferrocene (dtbdppf) under optimised conditions with silicon based nucleophiles and NaOH or TBAF as an activator, the formation of methyl, ethyl, n-propyl and n-butyl ethers with a range of aryl halides was achieved in good yield.

Dans ce travail, il est montré que les alkyl/vinyl/aryl lithiens et magnésiens réagissentavec les acides C-1(F/OMe) naphtoïques en l'absence de catalyseur métallique. Cette nouvelleréaction de substitution nucléophile aromatique permet potentiellement de préparer n'importequel biaryle tout en s'affranchissant des étapes de protection et de déprotection de la fonctionacide (CO2H). Les alkyllithiens linéaires et ramifiés réagissent avec la même efficacité que lesalkylmagnésiens même à basse température (-78 °C). Le déplacement d'un fluor ou d'unméthoxy s'effectue avec la même facilité. L'absence d'ortho-lithiation est confirmée par lepiégeage du milieu réactionnel en fin de réaction par l'iodométhane (après addition de n-BuLi,s-BuLi et t-BuLi). Le bromure de vinylmagnésium requiert un chauffage au reflux du THF.La méthode étudiée permet de préparer extrêmement facilement des 1- et 2-phénylnaphtalènes, 1,1'-binaphtalènes et 2,2'-binaphtalènes. Dans les exemples où lesaryllithiens donnent des rendements moyens-faibles en produits de couplage, les réactifs deGrignard sont beaucoup plus efficaces. Le o-tolyllithium, le bromure de o-tolylmagnésium, lebromure de (4-méthoxyphényl)magnésium, le bromure de (2,5-diméthylphényl)magnésium etle bromure de benzo[d][1,3]dioxol-5-ylmagnésium déplacent facilement le groupefluoro/méthoxy en ortho du groupe CO2M pour donner les produits de substitutioncorrespondants alors que la réaction du bromure de (2,6-diméthoxyphényl)magnésium estmoins efficace sans doute en raison de l'encombrement stérique causé par les deux groupesortho-méthoxy. L'acide 1-(2-méthoxyphényl)-2-naphtoïque est un produit particulièrementintéressant. La déprotection du groupe méthoxy suivie d'une cyclisation est réalisée par BBr3pour donner la 6H-naphtho[2,1-c]chromén-6-one qui est isolée avec un rendement de 97 %.Cette lactone est utile pour la préparation de composés atropoisomères optiquement actifsaprès ouverture énantiosélective du cycle lactone selon la technique mise au point parBringmann.

Les cyclopropanes sont des motifs structuraux importants en chimie médicinale. Parmi les synthèses existantes du fragment aminocyclopropane, les réactions dérivées de la réaction de Kulinkovich, appliquées aux amides et aux nitriles, sont des méthodes simples d'accès. Cependant, il n'existe pas de version asymétrique efficace. Dans une première partie, l'étude de l'utilisation de complexes de titane optiquement actifs pour la préparation de spirolactames chiraux à partir de cyanoesters a été réalisée. Ce travail a permis de mettre au point une méthode d'évaluation rapide de ligands chiraux dont leur criblage a montré que les composés de la famille du Taddol fournissent les meilleurs excès énantiomériques. L'énantiosélectivité demeure cependant actuellement trop faible pour présenter un intérêt en synthèse. Dans une seconde partie, la synthèses de carbinamines tertiaires, un autre motif important, a été étudié à partir d'acylcyanhydrines et d'organométalliques. En particulier, la synthèse d'une bibliothèque d'acides aminés quaternaires a été entreprise à partir d'hydroxyamides. L'incorporation de deux organométalliques différents sur des acylcyanhydrines a été également effectuée conduisant à l'obtention d'hydroxyamides chiraux sous forme racémique. Enfin, l'emploi de réactifs organozinciques allyliques nous a permis d'accéder à de très bons rendements en produits de double addition. Ces hydroxyamides ont été ensuite valorisés comme précurseurs de plateformes multifonctionnelles pour la ligation chimique
Cyclopropylamines are important scaffolds in medicinal chemistry. Among the syntheses of the aminocyclopropane moiety, the Kulinkovich-related reactions applied to amides and nitriles furnish straightforward access. However, no efficient asymmetric version has been published to date. In a first part, the study of optically active titanium complexes for the preparation of chiral spirolactams from cyanoesters has been undertaken. This work allowed us to setup a quick evaluation method for chiral ligands whose screening revealed that Taddol and its derivatives lead to the best enantiomeric excesses. However, the enantioselectivity remains too low for synthetic purposes. In a second part, the synthesis of tertiary carbinamines, another important scaffold, has been studied from acylcyanohydrins and organometallics. Notably, the synthesis of a quaternary aminoacids library was achieved. The incorporation of two different organometallics on acylcyanohydrins was also undertaken, leading to the preparation of chiral hydroxyamides in a racemic fashion. Lastly, very good yields in double addition products were obtained by using allylic organozinc reagents. The obtained hydroxyamides were used as precursors of polyfunctional linkers for the chemical ligation

L’addition nucléophile des réactifs de Grignard sur les nitriles conduit généralement aux cétones après hydrolyse acide. La double addition, menant à des carbinamines tertiaires après traitement, est beaucoup plus difficile et ne s’effectue habituellement qu’avec les organomagnésiens allyliques. Dans ce contexte, nous avons découvert que les organomagnésiens peuvent effectuer une double addition sur la fonction nitrile des acylcyanhydrines, pour fournir des hydroxyamides. Cette réaction est originale par le fait qu’une large gamme d’organomagnésiens peut être utilisée, dans des conditions particulièrement douces. Cette réaction a été appliquée à la synthèse de différents acides α-aminés α,α-disubstitués, par oxydation de la fonction alcool et hydrolyse du motif amide. La divinylglycine a notamment pu être préparée avec un bon rendement. L’addition successive de deux organomagnésiens différents a aussi pu être réalisée, après optimisation des conditions de réaction, pour accéder à des hydroxyamides disymétriques, précurseurs d’acides aminés quaternaires chiraux. Enfin, l’addition des réactifs de Grignard sur les 3-cyano iminocoumarines N-éthoxycarbonylées a été étudiée. Malgré la présence de nombreux sites électrophiles, la réaction est très chimiosélective, et des chromènes originaux substitués en position 4 ont été obtenus. Les propriétés antifongiques et antibactériennes de ces derniers ont été évaluées
The nucleophilic addition of Grignard reagents on nitriles generally leads to ketones after acidic hydrolysis. The double addition, providing tertiary carbinamines after work-up, is more difficult and usually occurs only with allylic Grignard reagents. In this context, we discovered that Grignard reagents can perform a double addition on the nitrile function of acyl cyanohydrins, to provide hydroxyamides. This reaction is original by the fact that a wide range of Grignard reagents can be used, in particularly mild conditions. This reaction has been applied to the synthesis of different α,α-disubstituted α-aminoacids, by oxidation of the alcohol functionality and hydrolysis of the amide moiety. Especially, divinylglycine has been prepared in good yield. The successive addition of two different Grignard reagents was also carried out, after optimization of reaction conditions, to access unsymmetrical hydroxyamides, which are precursors of chiral quaternary aminoacids. Finally, the addition of the Grignard reagents on N-ethoxycarbonyl 3-cyano-iminocoumarines was studied. Despite the presence of several electrophilic centers, the reaction is highly chemoselective, and novel chromenes displaying substituent on position 4 were obtained. The antifungal and antibacterial properties of these compounds have been evaluated

Organometallic reactions, including allylation, alkylation, aldol and Reformatsky type reactions of carbonyl compounds in aqueous media mediated by Sn, Zn, Mn, and In were studied. The possible mechanism and stereochemistry of these reactions were investigated. The methodology has successfully been applied to the syntheses of 1,3-butadienes, vinyloxiranes, and methylenetetrahydrofurans; and the syntheses of natural product (+)-muscarine, (+)-epimuscarine, (+)-KDN and (+)-KDO.
A novel tellurium reagent, bis(triphenylstannyl)telluride, for organic synthesis was developed. Its application in the preparation of organotellurium compounds, reduction of vic-dihalides and $ alpha$-halo ketones, desulfurization of organic trisulfides and cleavage of organic disulfides was studied. All the reactions with this reagent proceeded under very mild conditions.

Mixed matrix membranes offer an attractive route to the development of high performance and efficiency membranes required for demanding gas separations. Such membranes combine the advantageous processing characteristics of polymers with the excellent separation productivity and efficiency of molecular sieving materials. This research explores the development of mixed matrix membranes, namely in the form of asymmetric hollow fiber membranes using zeolites as the molecular sieving phase and commercially available high performance polymers as the continuous matrix. Lack of adhesion between the typically hydrophobic polymer and the hydrophilic native zeolite surface is a major hurdle impeding the development of mixed matrix membranes. Silane coupling agents have been used successfully to graft polymer chains to the surface of the zeolite to increase compatibility with the bulk polymer in dense films. However, transitioning from a dense film to an asymmetric structure typically involves significant processing changes, the most important among them being the use of phase separation to form the asymmetric porous structure. During the phase separation, it is believed that hydrophilic sieves can act as nucleating agents for the hydrophilic polymer lean phase. Such nucleation tendencies are believed to lead to the formation of gaps between the polymer and sieve resulting in poor mixed matrix performance. This research focuses on defining procedures and parameters to form successful mixed matrix hollow fiber membranes. The first part of this dissertation describes dope mixing procedures and unsuccessful results obtained using a silane coupling agent to enhance polymer-zeolite adhesion. The next section follows the development of a highly successful surface modification technique, discovered by the author, employing the use of a Grignard reagent. As a test case, two zeolites of different silicon-to-aluminum ratios are successfully modified and used to develop mixed matrix membranes with greatly increased gas separation efficiencies. The broad applicability of the surface treatment is also demonstrated by the successful incorporation of the modified zeolites in a second polymer matrix. The final section of the work describes the novel occurrence of large defects (macrovoids) caused by the presence of large zeolite particles proposing a particle size effect in the formation of such defects.

En chimie organique, le développement de méthodes de synthèse robustes et respectueuses de l’environnement a toujours été un défi. De plus, en chimie médicinale, la mise au point de méthodes de synthèse de synthons fluorés de haute valeur ajoutée sont importantes pour avoir accès à des composés bioactifs. Dans ce manuscrit, nous présentons des méthodes efficaces et faciles à mettre en œuvre pour la formation de liaisons carbone-carbone catalysée par le nickel et la formation de liaisons carbone hétéroatome par un réarrangement de β aminoalcools α-trifluorométhylés.Nous avons montré que le couplage croisé entre un éther d’énol méthylique et un réactif de Grignard pouvait être catalysé par un système simple à base de Ni(OAc)2/(O)PPh3 dans des conditions douces (40°C) via l’insertion du nickel dans la liaison C-OMe. Cette méthode a été appliquée à la synthèse d’un composé antitumoral, le DMU-212.La synthèse d’amines α-trifluorométhylées linéaires énantioenrichies a été réalisée selon une réaction de réarrangement régiosélectif de β-aminoalcools α-trifluorométhylés en se basant sur une stratégie établie dans le laboratoire via un intermédiaire aziridinium. Nous avons montré que les produits obtenus pouvaient être engagés dans des réactions de post-fonctionnalisation
In organic chemistry, the development of robust and sustainable synthetic methods has always been a challenge. Moreover, in medicinal chemistry, the development of fluorinated building blocks synthetic methods with high value is important to access bioactive compounds. In this manuscript, we report efficient and easy to carry methods for the formation of carbon-carbon bonds catalyzed by nickel and the formation of carbon-heteroatom bonds by a rearrangement of α-trifluoromethyl-β aminoalcools.We demonstrated that it is possible to perform a cross-coupling reaction of an alkenyl methy ether with a Grignard reagent using a simple catalytic system based on Ni(OAc)2/(O)PPh3 under mild conditions (40°C) via the insertion of nickel into C-OMe bond. This method has been applied to the synthesis of an antitumoral agent, DMU-212.The synthesis of enantioenriched linear α-trifluoromethylamine derivatives is reported consisting in a rearrangement of α-trifluoromethyl-β aminoalcool based on an established strategy in our group via an aziridinium intermediate. We have shown that the synthesized compounds can be involved in post-functionalization reactions

La recherche d'une méthode de synthèse de phénylséléno phosphate d'alkyle (RO)::(2)P(O)CH::(2)SePh a permis de trouver un nouveau réactif de Grignard (ETO)::(2)P(O)CH::(2)MGCL. Les propriétés de ce nouveau réactif ont été étudiées et comparées à celles des autres organométalliques correspondants connus lithiens et cuivreux. Ce réactif de Grignard conduit à une synthèse originale de sélénophosphonates. Utilisation des phosphates d'alkyle comme agents d'alkylation pour la synthèse de dithioesters. Des énephosphoramides fonctionnels ont été obtenus pour la première fois et la réactivité carbonique de l'un d'entre eux a été étudiée

Dans le cadre d’un projet général concernant l’étude de la réactivité des acidesbenzoïques non protégés avec les organométalliques, la synthèse totale d’analoguesstructuraux de l’apogossypol mettant en jeu des réactions de métallation aromatique a étéétudiée ainsi que la réaction de substitution nucléophile aromatique des acides benzoïquesortho-fluorés et ortho-méthoxylés.Le gossypol, (1,1’,6,6’,7,7’-hexahydroxy-5,5’-di-iso-propyl-3,3’-diméthyl-2,2’-binaphtalène-8,8’-dicarboxaldéhyde), pigment principal des graines du cotonnier, existe sousla forme de deux atropoisomères et possède de multiples applications pharmaceutiques. Il estnotamment un inhibiteur efficace des protéines anti-apoptotiques de la famille Bcl-2. Legossypol déformylé ou apogossypol présente des propriétés similaires mais est plus stable,plus sélectif et moins toxique. Une méthode permettant de remplacer les groupes iso-propylesdu gossypol par des groupes structurellement proches a été mise au point. La stratégie retenuemet à profit les compétences du laboratoire dans le domaine des réactions de métallation etrepose sur la lithiation latérale de l’acide 4-hydroxy-6,7-diméthoxy-8-méthyl-2-naphtoïquepar le tétraméthylpipéridure de lithium. Divers dérivés 5,5’-didés-iso-propyl-5,5’-dialkylapogossypol racémiques ont été préparés selon cette méthode. La synthèse asymétriqued’analogues de l’apogossypol a également été étudiée et la voie de synthèse sélectionnéerepose sur le « concept lactone ». Un intermédiaire avancé de la synthèse, une lactonefonctionnalisée potentiellement réductible de façon asymétrique, a été préparée.La deuxième partie est consacrée à l’étude de la réaction de substitution nucléophilearomatique des acides benzoïques ortho-fluorés et ortho-méthoxylés (réaction SNArAB). Unerevue de la littérature des réactions de substitution nucléophile aromatique activée par lesesters est présentée. L’influence de substituants méthoxylés et halogénés (F, Cl, Br) sur lasélectivité SNAr/addition 1,2 a été évaluée. Il est montré que les acides 2-fluoro-6-halogénobenzoïques conduisent, par réaction avec les aryllithiens et les arylmagnésiens, auxproduits d’ipso-C2-substitution avec un excellent rendement et la réaction SNArAB permet unaccès efficace aux acides 3-halogéno-[1,1’-biphényl]-2-carboxyliques. Dans le cas de l’acide2,3-diméthoxybenzoïque, il a été découvert que la présence d’un substituant méthoxy enposition 3 permet de limiter la formation de cétone et le produit d’ipso-substitution est isoléavec un rendement correct
As part of a program directed toward the study of the reactivity of unprotected benzoicacids with polar organometallics, the total racemic synthesis of apogossypol analogues bymetalation reactions was studied as well as the aromatic nucleophilic substitution reaction ofortho-fluoro- and ortho-methoxybenzoic acids (SNArAB reaction).Gossypol (1,1’,6,6’,7,7’-hexahydroxy-5,5’-di-iso-propyl-3,3’-diméthyl-2,2’-binaphtalène-8,8’-dicarboxaldéhyde) which is the main pigment of cotton seed, displaysmultiple pharmacological applications. It is a potent anti-apoptotic Bcl-2 protein inhibitor.The racemic route developed herein allows the replacement of the iso-propyl groups byvirtually any alkyl groups, providing a series of 5,5’-dides-iso-propyl-5,5’-dialkylapogossypolderivatives. Lateral metalation of 4-hydroxy-6,7-dimethoxy-8-methyl-2-naphthoic acid withLTMP is the key step of the synthesis. Atroposelective synthesis of apogossypol analoguewas also examined. The strategy relies on the “lactone concept” and involves a functionalizedlactone as a key intermediateThe influence of halogen atoms (F, Cl, Br) and methoxy groups on the 1,2-addition/SNArAB selectivity was examined. Treatment of 2-fluoro-6-halobenzoic acids withorganolithiums or Grignard reagents gives ipso-substituted products in excellent yields. Themethod allows the efficient preparation of 3-halo-[1,1’-biphenyl]-2-carboxylic acids and doesnot require protection of the carboxylate. Interestingly, the presence of an additional methoxyin C3 reduces the nucleophilic addition of the organometallic species to the carboxylate and2,3-dimethoxybenzoic acid affords ipso-substituted products in good yields

碩士
國立臺灣大學
化學學系
81
The nickel catalyzed reactions of 4-substituted-5,6-2H- hiopyran and 2-vinyltetrahydrothiophenes have been investigatedn details. These substrates have two different kinds of C-S bondone is allylic and the other simple aliphatic. The reactions of-substituted-5,6-2H-thiopyrans afforded mainly vinylcyclopropanesThe oxidative addition with the nickel catalyst would occuracily at the allylic C-S bond would undergo further cleavageielding metallocycles followed by reductive elimination toroduce vinylcyclopropane. The reactions of 2-vinyltetrahydrothiophenes behavedifferently, the coupling products being obtained. The allylntermediate may undergo rapidly reductive elimination whichesult in the C-C bond formation. Nevertheless, dibenzyl sulfideas also trapped in small amount from these reactions, whichndicates that the cleavage of aliphatic C-S bonds may alsoccurred competetively.

碩士
國立臺灣師範大學
化學系
84
Reactions of β-nitrostyrene and Grignard Reagents gave 1,4-adducts(nitronates) at -20 ℃.Futher manipulation of the nitronate were demostrated as follows:(1) treatment of the nitronates with 0 ℃ 5% HCl(aq) generated nitroalkanes. (2) tretment of the nitronates with 0 ℃ 85% H2SO4(aq)generated caboxylic acids. (3) tretment of the nitronates with 0℃ conc. HX(aq) generated hydroximoyl halides. Hydroximoyl halides could convert to nitrile oxide in the presence of base such as triethyl amine, followed by 1,3-dipolar cycloaddition with alkenes or alkynes to give 2-isoxazolines or isoxazoles.

博士
國立臺灣大學
化學學系
82
The nickel-catalyzed reactions of allylic dithioketals with excess MeMgI give the geminal dimethylation products in good yields. t-Butylstyrenes and related compounds are synthesized stereoselectively. The formation of a chelation complex results in the enhancement of the reactivity of the nickel-catalyzed cross coupling reaction of aliphatic dithioacetals with Grignard reagents. Various neighboring heteroatom substituents can facilitate the olefination of a dithioacetal group giving the corresponding olefins regioselectively. (2S,3S)-1,4-di-tert- alkoxy-2,3-butanediols are obtained from the reactions of (2S,3 S)-threitol bisketals with Grignard reagents. The size of the alkoxy substituents can be easily tuned. The reactions of benzylic acetals, prepared from (2S,3S)-1,4-di-tert-alkoxy-2,3- butanediols and aromatic aldehyde, with aryl or secondary or sterically hindered Grignard reagents give the corresponding alkylative ring- opening products in high diastereoselectivity (%de=92-99%).

博士
國立臺灣大學
化學學系
81
The relatively unreactive aliphatic C-S bonds can be activated by at least three methods. First, in the presence of a reactive benzylic dithioacetal which is bening generated into an allylic double bond with respect to the aliphatic ditioacetal, renders further coupling possible.Second, the regioselective formation of the double bond via b-heteroatom elimination constitutes another pathway to activate C-S bonds such that a further cross- coupling can occur. Third, the chelation interaction between bisdithioacetal and nickel will also assist the cleavage of the C-S bond leading to the cross coupling reactions.

博士
國立臺灣師範大學
化學研究所
89
Reaction of β-nitrostyrenes with trialkylboranes under nitrogen to generate alkenes in high yields. The mechanism is proposed to be a free-radical reaction via NO2/ alkyl substitution since the reaction is stimulated by the presence of a trace of oxygen in the nitrogen or tert-butyl peroxide or by photolysis and is retarded or inhibited by the addition of galvinoxyl. Reactions of β-nitrostyrenes and triethylborane or tricyclohexylborane in THF solution at room temperature in the air produce trans-alkenes in high yields. Fair good yields of various (E)-alkenes can also be prepared by treatment of β-nitrostyrenes with radicals, prepared from secondary and tertiary alkyl iodides, in the presence of triethyl- borane and air as radical initiator. The generation of the only product (E)-alkenes can be explained by the formation of the benzylic radical as the intermediate. Both (E)- and (Z)- alkenes are formed when (E)- and (Z)-α-alkyl-β-nitrostyrenes react with adamantyl radical under similar conditions. Only (Z)-alkene was observed when either (E)- or (Z)-α-t-butyl-β-nitrostyrene react with adamantyl radical. The Michael addition reactions of β-nitrostyrenes with 4-pentene-1-magnesium bromide or 3-butene-1-magnesium bromide generated nitronates. At room temperature, fair good yields of isoxazoline derivatives were obtained when nitronates were treated with ethyl chloroformate in the presence of catalytic amount of 4-dimethylaminopyridine (DMAP) in one-pot. The ratios of trans and cis-[4.3.0] isoxazoline were from 1:3.00 to 1:4.06 and the ratios of trans and cis-[3.3.0] isoxazoline were >99:1. The formation of [4.3.0] isoxazoline is proposed to proceed via intramolecular nitrile oxide-olefin cycloaddition (INOC).Compounds,obtained from the trapping of the nitrile oxides by ethyl chloroformate could be isolated. The mechanism of the generation [3.3.0] isoxazoline is proposed to proceed via intramolecular alkoxy-carbonyl nitronate-olefin cycloaddtion (IAOC) to form intermediates N-(ethoxycarbonyl)isoxazolidines and then eliminate EtOH and CO2 (or EtOCO2H) to yield the final products. Finally, a series of ring and side-chain regioisomers of arylethylamines are investigated by GC-MS. Regioisomerization at the aromatic ring and the alkyl side-chain in the arylethylamines produces a variety of compounds that have very similar analytical properties. The specific identification of one of these compounds in forensic drug sample depends on the ability to eliminate other regioisomers as possible interfering substances. The mass spectra for the underivatized amines are very similar and do not provide sufficient information to differentiate among the side-chain or ring regioisomers. Preparation the pentafluoropropionyl- amide of the amines produces derivatives that could show mass spectra fragmentation in identifying the position of methoxy groups attached to the aromatic ring and the number of carbons attached directly to the aromatic ring.

by Lawrence Tin-chi Law.
Thesis (M.Phil.)--Chinese University of Hong Kong, 1993.
Includes bibliographical references (leaves 96).
acknowledgements --- p.iii
ABSTRACT --- p.iv
CONTENTS --- p.v
ABBREVIATION --- p.vii
Chapter CHAPTER I --- METALLATION OF 8-METHYLQUINOLINE
Chapter 1.1 --- INTRODUCTION --- p.1
Chapter 1.1.1 --- A Brief Review of Metal-Alkyl Chemistry --- p.1
Chapter 1.1.2 --- General Considerations --- p.2
Chapter 1.1.3 --- 8-Methylquinoline as Ligand Precursor --- p.8
Chapter 1.1.4 --- Metallations by Organolithium Compounds --- p.9
Chapter 1.1.5 --- Other Methods for Metallations --- p.16
Chapter 1.1.6 --- Aim of the Present Work --- p.21
Chapter 1.2 --- RESULTS AND DISCUSSION --- p.24
Chapter 1.2.1 --- Reactions of 8-Methylquinoline with Organolithium Reagents --- p.26
Chapter 1.2.2 --- Synthesis of Grignard Reagent --- p.35
Chapter 1.2.3 --- Attempted Metal-Halogen Exchange Reaction at Low Temperature --- p.39
Chapter 1.2.4 --- Metallation of 8-methylquinoline by Lithium Diisopropylamide --- p.40
Chapter 1.3 --- EXPERIMENTAL FOR CHAPTER I --- p.43
Chapter 1.4 --- REFERENCES FOR CHAPTER I --- p.53
Chapter CHAPTER II --- SYNTHESIS AND CHARACTERISATION AND STRUCTURE OF SOME MAIN GROUP 14 ALKYLS
Chapter 2.1 --- INTRODUCTION --- p.58
Chapter 2.1.1 --- General Aspects of Group 14 Organometallic Compounds --- p.58
Chapter 2.1.2 --- Group 14 Organometallic Confounds --- p.59
Chapter 2.1.3 --- Subvalent Group 14 Metal Alkyls --- p.63
Chapter 2.2 --- RESULTS AND DISCUSSION --- p.67
Chapter 2.2.1 --- Synthesis of Five Co-ordinated Tin (IV) Compound --- p.67
Chapter 2.2.2 --- Molecular Structure of [Sn{8-(CHSiMe3)C9H6N}Ph2Cl] --- p.70
Chapter 2.2.3 --- Synthesis of Group 14 Subvalent Metal Complexes --- p.74
Chapter 2.3 --- EXPERIMENTAL FOR CHAPTER II --- p.76
Chapter 2.4 --- REFERENCES FOR CHAPTER II --- p.79
Chapter CHAPTER III --- SYNTHESIS AND CHARACTERISATION OF SOME GROUP 12 (ZINC AND CADMIUM) METAL DIALKYLS
Chapter 3.1 --- INTRODUCTION --- p.81
Chapter 3.1.1 --- A General Aspect of Group 12 Organometallics --- p.81
Chapter 3.2 --- RESULTS AND DISCUSSION --- p.88
Chapter 3.2.1 --- Synthesis of Group 12 Organometallic Confounds --- p.88
Chapter 3.2.2 --- Molecular Structure of [Cd{8-(CHSiMe3)C9H6N}(tmeda)Cl] --- p.91
Chapter 3.3 --- EXPERIMENTAL FOR CHAPTER III --- p.93
Chapter 3.4 --- REFERENCES FOR CHAPTER III
APPENDIX I
Chapter 1. --- GENERAL PROCEDURES --- p.97
Chapter 2. --- PHYSICAL AND ANALYTICAL MEASUREMENTS --- p.100
APPENDIX II
LIST OF SELECTED 1H NMR SPECTRA --- p.101

碩士
國立臺灣大學
化學系
85
This thesis contains twe parts: In the first part we discuss the substitution reactions of organomagnesium copper reagents, which were prepaired from Grignard reagents, and the loaner of phosgene, S,S-dimethtldithiocarbonate (DMDTC). We can obtain the disubsti- tuted ketones, even monosubstituted thioesters as products. In the second parts we found that magnesium bromide promoted intramolecular cyclization reactions of Grignard reagents and acetals. By using this method, we can easily get the products which contain 3, 4 or 5 memberd rings.

碩士
國立臺灣師範大學
化學研究所
87
The π-facial selectivity in the reactions of 5-substituted-2-dicyanomethyleneadamantanes and 5-aza-2-dicyanomethyleneadamantane N-oxide with the Grignard reagents, CH3MgCl and/or PhCH2MgCl were examined using semiempirical and ab initio calculation. The substituents investigated include -F, -Cl, -Br, -OH, NH2, -OMgCl, -CH3 and -Si(CH3)3. The reactions for all substituents, except the -Si(CH3)3 group, favor syn attack. The calculated syn/anti product ratio for the substituents of -F, -Cl, -Br groups agree well with available experimental results. The results obtained from the PM3, HF and B3LYP methods show that the HF results agree with the experimental results better than the other two methods. In addition, the results of employed NBO analysis show that the stabilization energy due to the hyperconjugative σCα-Cβ→σ*C-Nu interactions at the transition state correlates well withπ-facial selectivity in the reactions of 5-substituted-2-dicyanomethyleneadamantanes with CH3MgCl. The calculated results for the reaction with PhCH2MgCl appear that the strength of the hyperconjugative σCα-Cβ→π*C-C interactions at the transition state plays a significant role in π-facial selectivity for the substituents of -F, -Cl, -Br groups. Besides the hyperconjugation described above, the electrostatic interactions between the benzyl group of PhCH2MgCl and -OH and/or -NH2 groups in the 5-substituted-2-dicyanomethyleneadamantanes are also a significant factor in the π-facial selectivity. The calculations of 5-aza-2-dicyanomethyleneadamantane N-oxide also gave results that structural effects, as found in previous study, affect the syn/anti product ratio significantly in the π-facial selectivity.

博士
國立臺灣大學
化學系
85
Chelation assisted reactions of acetals,ketals and orthoesters with Grignard reagents afford the corresponding ring-opening products in highly regioselectivity. Contiguous diols can thus be differentiated easily by theses procedures. Reactions of orthoesters of myo-inositol with Grignard reagents yield regio- and stereoselective the corresponding products having a free group at C-1. The regioselectivity is rationalized owning to the presence of 2-methoxy group which will serve as an auxiliary to form a chelation complex with magnesium. Myo-inositol derivatives having two free hydroxy group at C-1,3 position can be achieved from reactions with excess Grignard reagents. The reaction of myo-inositol derivatives with excess LAH/AlCl also yields the corresponding C-1,5 diols. Tunable C-chiral diols are prepared from the reactions of bisketals of L-thretiol with different kinds of Grignard reagent. Chiral ketals obtained from the reactions of such C2-chiral diols and α,β- unsaturated ketones under go Simmons-Smith cyclopropanation in highly diastereoselectivity.

碩士
國立中正大學
化學暨生物化學研究所
106
As the second largest renewable energy source in the world, how lignin can be effectively transformed into higher economic crops is the goal pursued by modern scientists. Among them, the functionalization of carbon and oxygen bonds to convert lignin to other compounds is a common method at present. However, the problem is that compared to common carbon and halogen bonds, the higher bond energy of carbon and oxygen bonds leads to less dissociation, so the use of organometallic catalysis can lower the activation energy of the reaction and thus facilitate the reaction, resulting in a more rapid rate of conversion. A common method is to use a nickel metal complex, which is catalyzed by a strong electron-donor ligand, so that the C–O bond is more easily oxidized and the functionalization reaction is completed. We utilized nickel and Grignard reagent to performed catalytic C–O bond cleavage. The inert C–O bond could be cleaved by a new type of nickel-catalyzed cross-coupling reaction with the assistance of Grignard reagents with an electron-rich carbodicarbene ligand synthesized by our laboratory. The scope of substrates, application and proposed mechanism of this reaction will be reported in this work.

Dans ce mémoire, il sera question de la formation de dérivés pipéridines en utilisant la fragmentation de Grob. Tout d’abord, une introduction sur les alcaloïdes ainsi que sur l’expertise du groupe Charette associée à leur formation démontrera l’importance de ces composés dans le domaine de la chimie organique. Cela sera suivi par un résumé de la fragmentation de Grob incluant les conditions de réactions utilisées, l’importance de la structure de la molécule initiale, les prérequis stéréoélectroniques ainsi que les modifications qui y ont été apportées. Le chapitre 2 sera dédié au développement de la méthodologie c’est-à-dire, à l’optimisation de tous les paramètres jouant un rôle dans la fragmentation de Grob. Par la suite, l’étendue de la réaction ainsi que des explications sur la régiosélectivité et la diastéréosélectivité de la réaction seront fournies. La méthodologie peut être exploitée dans un contexte de synthèse qui sera démontré dans le chapitre 3. De plus, elle servira pour une étude mécanistique qui est encore d’actualité à partir du concept d’effet frangomérique. Finalement, quelques projets futurs, notamment des améliorations possibles de la méthodologie, seront présentés dans le dernier chapitre. Le tout sera suivi d’une conclusion résumant l’ensemble des travaux effectués.
This thesis discusses the formation of piperidine derivatives using the Grob fragmentation. Firstly, an introduction of the important alkaloid family as well as previous work completed by the Charette group towards the synthesis of these compounds will be demonstrated. This will be followed by a summary of the Grob fragmentation including a discussion of the reaction conditions, molecular structures, stereoelectronic requirements and modifications of the Grob fragmentation. Chapter 2 will be dedicated to the development of the methodology and more precisely, to the optimization of all parameters necessary to the reaction. Furthermore, the scope of the reaction and some explanation of the regioselectivity and the diastereoselectivity of the reaction will be discussed. The developed methodology can be used in a total synthesis and will be demonstrated in Chapter 3. Moreover, using the frangomeric effect concept, a mechanistic study on the Grob fragmentation will be discussed. Finally, some future projects, especially possible improvement of the methodology, will be presented in the last chapter. This is followed by a conclusion and a summary of the work completed on this project.

碩士
國立臺灣大學
化學學系
84
Aliphatic substituted dithioacetal cannot react with Grignard reagents under nickel-catalyzed conditions. However, they can couple with Grignard reagents in the presence of the the chel- ation effect of heteroatom in their chains or in the presence of the allylic dithioacetals formation during the reaction. Herein, we describe a new procedure to convert bisdithioacetals to the corresponding homoallylic dithioacetals by reacting with silylmethyl Grignard reagents. Hydoxy Groups will assist the cross-coupling reactions between aliphatic dithioacetals and Grignard reagents to yield olefin- ation products. Because of the coordination of proximal O- and S- atom with nickel, the otherwise unreactive aliphatic C-S bonds can be activated. The competitive chelating ability bet- ween oxygen and sulfur in these reaction is discussed.