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Fonctionnalisation de liaisons C(sp3)-H non activées catalysées par le palladium / Palladium catalyzed functionalization of nonactivated C(sp3)-H bondsRenaudat, Alice 04 October 2010 (has links)
La fonctionnalisation de liaisons C-H réputées peu réactives ouvre de nouvelles perspectives en synthèse organique. Une stratégie efficace consiste en l’utilisation d’un métal de transition. Les travaux de thèse présentés dans ce mémoire s’inscrivent dans ce contexte. Dans un premier temps, la réaction étudiée, catalysée par le palladium, vise à étendre une méthodologie mise au point au laboratoire, permettant la synthèse de benzocyclobutènes par activation intramoléculaire de liaisons C(sp3)-H de groupements méthyles benzyliques, à des composés non aromatiques. Plusieurs substrats ont été synthétisés pour être ensuite placés dans les conditions de la réaction d’activation C(sp3)-H, dans le but d’induire la formation du cyclobutène ou du cyclobutane désiré. Le processus n’est pas sélectif et de nombreux produits secondaires sont obtenus par des réactions péricyliques ou par des réarrangements suite à l’ouverture du palladacycle intermédiaire. Dans un deuxième temps, nos travaux ont permis de mettre à jour une nouvelle réaction de fonctionnalisation C(sp3)-H, catalysée par le palladium permettant l’arylation d’esters en position β par un mécanisme original. Les investigations portent sur l’optimisation complète de cette réaction, la compréhension du mécanisme et le développement d’une version énantiosélective prometteuse. Le mécanisme de cette réaction, confirmé par des calculs DFT réalisés en collaboration avec C. Kefalidis et E. Clot, se rapproche formellement de celui observé en α-arylation, puisqu’il repose sur la formation d’un énolate de palladium. La stratégie mise au point permet le couplage, dans des conditions douces, d’esters simples et commerciaux avec des halogénures d’aryles contenant un groupement électronégatif en position ortho, donnant ainsi accès à des intermédiaires de synthèse intéressants tels qu’un analogue de la phénylalanine ou des composés fluorés. / The direct functionalization of C-H bonds represents an atom- and step-economical alternative to more traditional synthetic methods based on functional group transformation, which often require multi-step sequences. In particular, transition-metal catalysis has recently emerged as a powerful tool to functionalize otherwise unreactive C-H bonds. In this context, we first investigated the extension of a methodology that has been developed in our laboratory for the synthesis of benzocyclobutenes via C(sp3)-H activation, to non aromatic compounds. Substrates have been synthesized in order to be evaluated in the reaction to form cyclobutenes or cyclobutanes. The process was not selective and several by-products were formed via pericylic reactions or rearrangements of the intermediate palladacycle. Our research has also focused on a conceptually new palladium catalyzed β-C-H arylation of carboxylic esters method. The investigations consisted of a complete optimization of the reaction conditions, an evaluation of the scope and elucidation of the mechanism. It was found that this type of [bêta]-arylation is mechanistically related to α-arylation because it involves the formation of a palladium-enolate. Computational studies (DFT calculations, C. Kefalidis et E. Clot) confirmed the proposed mechanism. Our strategy allowed a mild and efficient intermolecular arylation reaction from aryl halides bearing an ortho electronegative group, giving rise to a range of synthetically useful functionalized carboxylic esters such as phenylalanine analogues and new fluorinated building blocks.
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Part 1: Transition Metal Catalyzed Functionalization of Aromatic C-H Bonds / Part 2: New Methods in Enantioselective SynthesisSchipper, Derek 25 July 2011 (has links)
Part 1:
Transition-metal-catalyzed direct transformations of aromatic C-H bonds are emerging as valuable tools in organic synthesis. These reactions are attractive because of they allow for inherently efficient construction of organic building blocks by minimizing the pre-activation of substrates. Of these processes, direct arylation has recently received much attention due to the importance of the biaryl core in medicinal and materials chemistry. Also, alkyne hydroarylation has garnered interest because it allows for the atom-economical synthesis of functionalized alkenes directly from simple arenes and alkynes. Described in this thesis are number of advancements in these areas.
First, palladium catalyzed direct arylation of azine N-oxides using synthetically important aryl triflates is described. Interesting reactivity of aryl triflates compared to aryl bromides was uncovered and exploited in the synthesis of a compound that exhibits antimalarial and antimicrobial activity. Also reported is the efficient, direct arylation enabled (formal) synthesis of six thiophene based organic electronic materials in high yields using simple starting materials. Additionally, the site-selective direct arylation of both sp2 and sp3 sites on azine N-oxide substrates is described. The arylation reactions are carried out in either a divergent manner or a sequential manner and is applied to the synthesis of the natural products, Papaverine and Crykonisine. Mechanistic investigations point towards the intimate involvement of the base in the mechanism of these reactions.
Next, the rhodium(III)-catalyzed hydroarylation of internal alkynes is described. Good yields are obtained for a variety of alkynes and arenes with excellent regioselectivity for unsymmetrically substituted alkynes. Mechanistic investigations suggest that this reaction proceeds through arene metalation with the cationic rhodium catalyst, which enables challenging intermolecular reactivity.
Part 2:
Access to single enantiomer compounds is a fundamental goal in organic chemistry and despite remarkable advances in enantioselective synthesis, their preparation remains a challenge. Kinetic resolution of racemic products is an important method to access enantioenriched compounds, especially when alternative methods are scarce. Described in this thesis is the resolution of tertiary and secondary alcohols, which arise from ketone and aldehyde aldol additions. The method is technically simple, easily scalable, and provides tertiary and secondary alcohols in high enantiomeric ratios. A rationale for the unique reactivity/selectivity associated with (1S,2R)-N-methylephedrine in the resolution is proposed.
Organocatalysis is a rapidly developing, powerful field for the construction of enantioenriched organic molecules. Described here is a complimentary class of organocatalysis using simple aldehydes as temporary tethers to perform challenging formally intermolecular reactions at room temperature. This strategy allows for the enantioselective, intermolecular cope-type hydroamination of allylic amines with hydroxyl amines. Also, interesting catalytic reactivity for dichloromethane is revealed.
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Palladium-Catalyzed C(sp2)-C(sp3) Bond FormationRousseaux, Sophie 16 July 2012 (has links)
Palladium-catalyzed reactions for carbon-carbon bond formation have had a significant impact on the field of organic chemistry in recent decades. Illustrative is the 2010 Nobel Prize, awarded for “palladium-catalyzed cross couplings in organic synthesis”, and the numerous applications of these transformations in industrial settings. This thesis describes recent developments in C(sp2)-C(sp3) bond formation, focusing on alkane arylation reactions and arylative dearomatization transformations. In the first part, our contributions to the development of intramolecular C(sp3)-H arylation reactions from aryl chlorides are described (Chapter 2). The use of catalytic quantities of pivalic acid was found to be crucial to observe the desired reactivity. The reactions are highly chemoselective for arylation at primary aliphatic C-H bonds. Theoretical calculations revealed that C-H bond cleavage is facilitated by the formation of an agostic interaction between the palladium centre and a geminal C-H bond. In the following section, the development of an alkane arylation reaction adjacent to amides and sulfonamides is presented (Chapter 3). The mechanism of C(sp3)-H bond cleavage in alkane arylation reactions is also addressed through an in-depth experimental and theoretical mechanistic study. The isolation and characterization of an intermediate in the catalytic cycle, the evaluation of the roles of both carbonate and pivalate bases in reaction mechanism as well as kinetic studies are reported. Our serendipitous discovery of an arylation reaction at cyclopropane methylene C-H bonds is discussed in Chapter 4. Reaction conditions for the conversion of cyclopropylanilines to quinolines/tetrahydroquinolines via one-pot palladium(0)-catalyzed C(sp3)-H arylation with subsequent oxidation/reduction are described. Initial studies are also presented, which suggest that this transformation is mechanistically unique from other Pd catalyzed cyclopropane ring-opening reactions. Preliminary investigations towards the development of an asymmetric alkane arylation reaction are highlighted in Chapter 5. Both chiral carboxylic acid additives and phosphine ligands have been examined in this context. While high yields and enantiomeric excesses were never observed, encouraging results have been obtained and are supported by recent reports from other research groups. Finally, in part two, the use of Pd(0)-catalysis for the intramolecular arylative dearomatization of phenols is presented (Chapter 7). These reactions generate spirocyclohexadienones bearing all-carbon quaternary centres in good to excellent yields. The nature of the base, although not well understood, appears to be crucial for this transformation. Preliminary results in the development of an enantioselective variant of this transformation demonstrate the influence of catalyst activation on levels of enantiomeric excess.
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Part 1: Transition Metal Catalyzed Functionalization of Aromatic C-H Bonds / Part 2: New Methods in Enantioselective SynthesisSchipper, Derek 25 July 2011 (has links)
Part 1:
Transition-metal-catalyzed direct transformations of aromatic C-H bonds are emerging as valuable tools in organic synthesis. These reactions are attractive because of they allow for inherently efficient construction of organic building blocks by minimizing the pre-activation of substrates. Of these processes, direct arylation has recently received much attention due to the importance of the biaryl core in medicinal and materials chemistry. Also, alkyne hydroarylation has garnered interest because it allows for the atom-economical synthesis of functionalized alkenes directly from simple arenes and alkynes. Described in this thesis are number of advancements in these areas.
First, palladium catalyzed direct arylation of azine N-oxides using synthetically important aryl triflates is described. Interesting reactivity of aryl triflates compared to aryl bromides was uncovered and exploited in the synthesis of a compound that exhibits antimalarial and antimicrobial activity. Also reported is the efficient, direct arylation enabled (formal) synthesis of six thiophene based organic electronic materials in high yields using simple starting materials. Additionally, the site-selective direct arylation of both sp2 and sp3 sites on azine N-oxide substrates is described. The arylation reactions are carried out in either a divergent manner or a sequential manner and is applied to the synthesis of the natural products, Papaverine and Crykonisine. Mechanistic investigations point towards the intimate involvement of the base in the mechanism of these reactions.
Next, the rhodium(III)-catalyzed hydroarylation of internal alkynes is described. Good yields are obtained for a variety of alkynes and arenes with excellent regioselectivity for unsymmetrically substituted alkynes. Mechanistic investigations suggest that this reaction proceeds through arene metalation with the cationic rhodium catalyst, which enables challenging intermolecular reactivity.
Part 2:
Access to single enantiomer compounds is a fundamental goal in organic chemistry and despite remarkable advances in enantioselective synthesis, their preparation remains a challenge. Kinetic resolution of racemic products is an important method to access enantioenriched compounds, especially when alternative methods are scarce. Described in this thesis is the resolution of tertiary and secondary alcohols, which arise from ketone and aldehyde aldol additions. The method is technically simple, easily scalable, and provides tertiary and secondary alcohols in high enantiomeric ratios. A rationale for the unique reactivity/selectivity associated with (1S,2R)-N-methylephedrine in the resolution is proposed.
Organocatalysis is a rapidly developing, powerful field for the construction of enantioenriched organic molecules. Described here is a complimentary class of organocatalysis using simple aldehydes as temporary tethers to perform challenging formally intermolecular reactions at room temperature. This strategy allows for the enantioselective, intermolecular cope-type hydroamination of allylic amines with hydroxyl amines. Also, interesting catalytic reactivity for dichloromethane is revealed.
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Computational study of c-h bond cleavage and c-c bond formation processes catalyzed by transition metal complexesLocati, Abel Jean Serge 09 March 2012 (has links)
La primera parte de la tesis se dedica al estudio del mecanismo de una reacción de activación C-H por un complejo de niobio. Se racionalizó el mecanismo de activación de enlaces C-H del benceno por el complejo TpMe2NbCH3(c-C3H5)(MeCCMe). El intermedio clave es un complejo inusual de 2-ciclopropeno. Conseguimos también racionalizar las selectividades obtenidas para la activación de varios alquilaromáticos por el complejo de niobio 2-ciclopropeno. También se investigó el papel del ligando alquino en estos complejos y su posible papel en procesos de migración de ligandos.
En la segunda parte de la tesis, se investigaron las reacciones de acoplamiento cruzado con reactivos basados en silicio. Los resultados sugieren que la transmetalación es más fácil después de la disociación de la fosfina, o cuando un ligando bromuro está coordinado al paladio. El efecto beneficioso de la dibencilidenoacetona en el acoplamiento también fue aclarado. / The first part of the thesis is mainly devoted to the mechanism of a C-H activation reaction by a niobium complex. The mechanism of C-H bond activation of benzene by the TpMe2NbCH3-(c-C3H5)-(MeCCMe) complex was rationalized. The key intermediate is an unusual 2-cyclopropene complex. We rationalized the selectivities obtained for the activation of several alkylaromatics by the 2-cyclopropene niobium complex. The intriguing role of the alkyne ligand of the same complex, and its possible role in the migration processes, was investigated.
In the second part of the thesis, we focused on the silicon based cross-coupling. The results suggest than the transmetalation is easier after phosphine dissociation, and in presence of the bromide ligand on the palladium. The beneficial effect of dibenzylideneacetone on the coupling was clarified.
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Developing Dirhodium-Complexes for Protein Inhibition and Modification & Copper-Catalyzed Remote Chlorination of Alkyl-HydroperoxidesKundu, Rituparna 16 September 2013 (has links)
The work describes the development of a new class of protein-inhibitors for protein-protein interactions, based on metallopeptides comprised of a dirhodium metal center. The metal incorporation in the peptide sequence leads to high increase in binding affinity of the inhibitors. The source of this strong affinity is the interaction of histidine on the protein surface with the rhodium center. In addition to this work, rhodium-based small molecule inhibitors for FK-506 binding proteins are investigated. Also, methodology for rhodium-catalyzed modification of proteins containing surface cysteine has been developed where a simple rhodium(II) complex catalyzes cysteine modification with diazo reagents. The reaction is marked by clean cysteine selectivity and mild reaction conditions. The resulting linkage is significantly more stable in human plasma serum, when compared to common maleimide reagents.
Apart from this body of work in chemical-biology, the thesis contains the discussion of development of copper-catalyzed remote chlorination of alkyl hydroperoxides. The atom transfer chlorination utilizes simple ammonium chloride salts as the chlorine source and the internal redox process requires no external redox reagents.
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Synthesis of N-(2-pyridinyl)-carbazoles and Their Iridium (III) ComplexesShen, Wei-ting 30 July 2010 (has links)
N-phenylpyridin-2-amine , treated with stochiometric amount of palladium(II) acetate in dichloromethane at 65-70¢J for 4 h, to give high yield palladacycle 53. The reaction of palladacycle 53 with potassium aryltrifluoroborates in 1,4-dioxane at 140¢J for 24 h, could give a variety of N-(2-pyridinyl)carbazoles 55a-55m
via sequential C-H bond activation. Carbazole derivative 55a reacted with irdium chloride gave iridium dimer, which followed by addition of picolinic acid via ligand exchange will form iridium complexes, which can further be utilized as OLEDs materials.
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Reactivity Study of Diarylamido-phosphino Zirconium, Hafnium and Nickel ComplexesHsiao, Yi-Chen 18 August 2010 (has links)
A series of tetravalent zirconium and hafnium complexes were developed in their
abundant chemistry and photophysical properties, where those complexes were supported by
diarylamido-phosphino [iPr-PNP]- (bis(o-diisopropylphosphinophenyl)amide) ligand.
[iPr-PNP]MCl3 (M = Zr, Hf) were prepared by sequentially reacting [iPr-PNP]H with
n-butyllithium and following MCl4(THF)2 in toluene solution under ambient temperature.
UV-Vis absorption, emission, excitation spectrum, cyclic voltammetry experiments, and
density functionalization theory (DFT) calculations are applied to approach their unique
photophysical phosphorescence properties. Alkyls which are lack of £]-hydrogen have been
used to achieve in synthesis of degenerate ([iPr-PNP]MR3, R = Me, CH2SiMe3) or
non-degenerate ([iPr-PNP]M(E)(R)2, R = CH2SiMe3, E = Cl, Me) derivatives since we could
control the desired product from steric effect. Strong fluxional exchange was found in those
complexes. By variable temperature NMR monitoring and X-ray diffraction, their
fluxionality seems interesting not only in mechanism, but it does affect our reaction. By
heating [iPr-PNP]Zr(Cl)(CH2SiMe3)2 in solution, we can afford new alkylidene complexes
[iPr-PNP]M(Cl)(=CHSiMe3) via self £\-abstraction. Through variable temperature analysis,
the activation energy of £\-abstraction have £GH‡ = 18.5 kcal/mol and £GS‡ = -19.8 cal/mol¡PK.
Here we also can identified multiple alkylidene derivatives of [iPr-PNP]Zr(Me)(=CHSiMe3)2.
The computational studies of [MeNPiPr]Ni(R)(L) ([MeNPiPr]- = o-diisopropylphosphinoII
phenyl-2,6-dimethylanilite, R = Me, CH2SiMe3; L = 2,4-Lutidine, Py, PMe3) in C-H
activation has been fully established. Start on dissociation mechanism, we considered three
major pathways to explain the activation mechanisms including isomerisation, direct
intermolecular benzene activation, and intramolecular sp3 C-H acitvaition. Here we also
account H-D exchange as experimental observation. Important intermediates and transition
states are found to locate the energy maps to assist our experiments.
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Palladium(II)-Catalyzed Synthesis of 2-(Biphenyl-2-yloxy)pyridines and N-Pyridylcarbazoles via Carbon-Hydrogen Bond ActivationLin, Pi-shan 06 July 2011 (has links)
This thesis is composed of two parts. The palladium-catalysted synthesis of 2-arylphenols and carbazoles via carbon-hydrogen (C-H) bond activation is described. Treatment of 2-phenoxypyridines with two and a half equivalents of potassium aryltrifluoroborate and 10 mol % of Pd(OAc)2 in the presence of two equivalents of Ag2CO3, one equivalent of p-benzoquinone (BQ), and four equivalents of DMSO with (or without) H2O at 130-140 oC for 48 h in dried CH2Cl2 gave the ortho-arylated 2-phenoxypyridines in modest to excellent yields. The investigation of kinetic isotope effect (kH/kD) is determined to be 5.25, which indicates that C-H bond cleavage occurs in the rate-determining step. 2-(Biphenyl-2-yloxy)pyridines was treated with methyl trifluoromethanesulfonate and subsequently sodium methoxide to give the 2-arylphenols to demonstrate the pyridine is a removable directing group. On the other hand, a novel one-pot synthesis for N-pyridylcarbazoles by the reaction of N-phenylpyridin-2-amines with potassium aryltrifluoroborates using Pd(OAc)2 as the catalyst is presented. For instance, reaction of N-phenylpyridin-2-amines with four equivalents of potassium aryltrifluoroborate under the optimal reaction condition gave N-pyridylcarbazoles in 67% yield along with N-(biphenyl-2-yl)pyridin-2-amine in 13% yield. The investigation of kinetic isotope effect (kH/kD) for first C-H bond activation/C-C bond formation step is determined to be 2.14, and that of the second C-H bond activation/C-N bond formation steps is 1.18. On the basis of KIE analysis, it might indicate that first C-H activation undergo direct C-H bond cleacage, and second step should be via electrophilic aromatic substitution.
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Au(I)-Catalyzed Cyclization of Methyl 2-(2-Alkynylphenylethynyl) Benzoates to 6H-Dibenzo[c,h]chromen-6-ones and Synthesis of Arnottin IHsu, Chia-Ling 02 July 2012 (has links)
Gold catalysts have the characteristic of promoting nucleophilic reaction. The cyclization reaction of enediynes catalyzed by gold activated by silver in toluene at 100oC to give 6H-dibenzo[c,h]chromen-6-ones (63), 6H-benzo[c]chromen-6-one (66) and Arnottin I (10) is described.
Treatment of enediynes (61¡B65) with 5 mol% of Ph3PAuCl and 10 mol% of AgSbF6 in toluene at 100oC gave 6H-dibenzo[c,h]chromen-6-ones (63) and 6H-benzo[c]chromen-6-one (66) in good yield. In addition to using gold catalyst, electrophilic reagents employed in the reaction caused one cyclization instead of two cyclization. Furthemore, a mechanistic study and GC-MS data showed that the toluene could participate in the reaction.
Enediynes (73) can be synthesized by a series of organic synthesis with few steps. Treatment of enediynes (73) with 5 mol% of Ph3PAuCl and 10 mol% of AgSbF6 in toluene at 100oC gave natural product-Arnottin I (10).
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