Dissertations / Theses on the topic 'C-c bond formation reactions'

Esta tesis doctoral se centró en la síntesis y la caracterización de nanopartículas metálicas (Pd, Ni, Pt) estabilizadas por varios tipos de ligandos y el uso de estas nanopartículas en reacciones de formación de nuevos C-C o C-heteroatomo: a) Reacción de substitución alílica catalizadas por Pd; b) Reacción de acoplamiento asimétrico de Suzuki-Miyaura; c) Reacción de acoplamiento de Suzuki-Miyaura; d) reacción de adición 1,4 de ácidos borónicos a cetonas. En cada una de estas reacciones se llevó a cabo la síntesis y caracterización de nanoparticulas metálica y complejos moleculares usando muchos tipos de ligandos en los sistemas moleculares y los sistemas análogos cataliazados por nanopartículas. Excelentes actividades y enatioselectividades fueron obtenidas en la reacción de alquilación y aminación alílica. Además, estos sistemas fueron reciclados usando líquidos iónicos. También, nuevos y selectivas nanoparticulas fueron sintetizadas y caracterizadas. Estas nanopartículas fueron usadas exitosamente en varias reacciones de formación de nuevos enlaces C-C.
This doctoral thesis focuses on the synthesis and characterization of metal nanoparticles (Pd, Ni, Pt) stabilized by several types of ligands and the used of these nanoparticles in new C-C or C-heteroatom bond formation reactions: a) Pd-catalysed asymmetric allylic substitution reactions; b) Pd-catalysed asymmetric Suzuki-Miyaura coupling reactions; c) Ni-catalysed Suzuki-Miyaura coupling reactions; d) Pt-catalysed 1,4-addition of phenylboronic acid to 2-cyclohexen-1-one reaction. For each reaction, the synthesis and characterization of metal nanoparticles and molecular complexes using several types of ligands were performed and both types of catalytic systems were tested in the appropriate reactions. Remarkably, excellent enantioselectivities using Pd/phosphite ligand were obtained in allylic substitution reaction. An efficient recovery of the catalytic system was carried out using ionic liquids as reaction medium. New active and selective nanoparticles were synthesized and characterized. These nanoparticles were applied successfully in various C-C bond formation reactions.

La gran quantitat de fluorocarbons a la natura i la seva estabilitat a animat a la comunitat científica a trobar noves metodologies per trencar l'enllaç C-F d'aquest compostos. D'aquesta manera, aquest flurorocarbons poden ser utilitzats com a reactius a la síntesi orgànica. L'estabilitat dels fluorurs d'aril es dona per la força de l'enllaç C-F, que és l'enllaç simple més fort de la natura. Aquesta és la seva principal característica i la raó de la seva poca reactivitat. Per aquest motiu, es desafiant per la comunitat científica trobar la manera per trencar l'enllaç C-F. De la mateixa manera l'enllaç C-O te característiques molt similars a les del C-F i per això, s'ha utilitzat com a alternativa per evitar residus fluorats. Aquesta Tesi tracta de l'estudi computacional del trencament d'enllaços C-F y C-O mitjançat borilacions i catalitzades per un catalitzador de níquel. Concretament, s'ha estudiat tres reaccions diferents, les hem comparades i trobat els punts en comú de les tres reaccions.
La gran cantidad de fluorocarbonos en la naturaleza y su estabilidad a animado a la comunidad científica a buscar nuevas metodologías para la rotura del enlace C-F de estos compuestos. De esta manera, estos fluorocarbonos pueden ser utilizados como reactivos en la síntesis orgánica. La estabilidad de los fluoruros de arilo se da por la fuerza del enlace C-F, que es el enlace simple más fuerte de la naturaleza. Ésta es su principal característica y la razón de su poca reactividad. Por este motivo, es desafiante para la comunidad científica encontrar la manera de romper el enlace C-F. De la misma forma el enlace C-O tiene características muy similares a las del C-F y por esto, se ha utilizado como alternativa para evitar residuos fluorados. Esta Tesis trata del estudio computacional de la ruptura de los enlaces C-F y C-O mediante borilaciones y catalizadas por un catalizador de níquel. Concretamente, se ha estudiado tres reacciones diferentes y las hemos comparado y buscado sus puntos en común.
The large presence of fluorocarbons in nature and its great stability encourage science community to found new methods to break the C-F bond of this compounds, because it could be used as a starting reactant in organic synthesis. The stability of aryl fluorides is given because its C-F bond is the strongest single bond in the nature. That is its principal characteristic and the reason of it lack of reactivity. For this reason, it is challenging for scientists found the manner for C-F cleavage. As the same wise, C-O becomes an alternative of C-F to avoid the fluoride waste. This Thesis is about the computational study of the C-F and C-O cleavage through the borylation catalysed by nickel catalyst. Concretely, we have studied three borylation of C-F and C-O bonds and we compared it and show what have in common the three reactions.

En els últims anys, la creixent demanda de compostos enantiomèricament purs (fàrmacs, agroquímics...) ha impulsat el desenvolupament de la catàlisi asimètrica, sobretot emprant compostos organometàl·lics quirals com a catalitzadors. En aquest context, la síntesi de nous lligands quirals és essencial per descobrir bons sistemes catalítics en catàlisis asimètrica. Els sucres són una font important de lligands per l'elevada disponibilitat i baix preu. A més, són compostos altament funcionalitzats amb centres esterogènics. Això permet la síntesi de sèries sistemàtiques de lligands amb l'objectiu d'obtenir altes activitats i selectivitats per cada reacció en particular.
Aquesta tesi s'ha centrat en la síntesi de compostos derivats de la D-(+)-glucosa, de la D-(+)-fructosa i la D-(+)-galactosa i l'aplicació com a lligands de catalitzadors homogenis quirals en quatre reaccions asimètriques: substitució al·lílica, Heck, addició 1,2 i addició conjugada 1,4. Per assolir aquest objectiu, s'ha plantejat la síntesi de tres famílies de compostos: fosfit-oxazolina (L1-L5), fosfit-fosforoamidit (L6) i monofosfit (L7-L11) (Figura 1).
Després de la introducció (Capítol 1) i els objectius (Capítol 2), al capítol 3 es discuteix la síntesi i caracterització de les tres llibreries de compostos (L1-L11) i s'estudia l'aplicació de les tres llibreries a la reacció de substitució al·lílica asimètrica catalitzades per pal·ladi.
La primera llibreria de compostos fosfit-oxazolina (L1-L5) ha mostrat altes enantioselectivitats (fins a un 99%) i bones activitats en un ampli ventall de substrats amb diferents propietats electròniques i estèriques. S'han observat importants efectes al variar els substituents de l'anell oxazolina, de la quiralitat axial i dels diferents substituents del biaril. L'estudi de diferents intermedis de reacció pal·ladi al·lil mitjançant espectroscòpia de ressonància magnètica nuclear ha permès entendre el comportament catalític d'aquests compostos. L'estudi també ha indicat que l'atac nuclèofil té lloc preferentment al carboni al·lílic terminal localitzat trans al fosfit.


Figura 1. Fosfit-oxazolina (L1-L5), fosfit-fosforamidit (L6) i monofosfit (L7-L11).

Les reaccions de substitució asimètrica utilitzant els compostos fosfit-fosforoamidit (L6) han mostrat que l'excés enantiomèric depèn preferentment dels substituents de les posicions en para dels bifenils. Aquests efectes han estat diferents segons el tipus de substrat. S'han obtingut excessos enantiomèrics fins a un 89% i altes activitats utilitzant el substrat rac-1,3-difenil-acetoxipropè, rac-(E)-etil-2,5-dimetil-3-hex-4-enilcarbonat i el rac-3-acetoxicicloheptè. Pel substrat lineal 1-(1-naftil)al·lil acetat, aquests lligands han mostrat no ser útils en termes de regioselectivitat però s'han obtingut bons excessos enantiomèrics de fins a un 72%.
Si comparem aquests resultats amb els obtinguts amb els compostos fosfit-oxazolina (L1-L5) s'observa que el canvi de la funció oxazolina per la funció fosforoamidit té un efecte negatiu en la reacció de substitució al·lílica i en general decreixen les enantioselectivitats i la versalitat d'aquests compostos.
L'aplicació de la llibreria de compostos monofosfit (L7-L11) en la reacció de substitució al·lílica asimètrica ha mostrat moderades enantioselectivitats (fins a un 46%). Els resultats en la catàlisi es veuen afectats en gran mesura per la diferència en la mida de l'anell carbohidrat, de les configuracions del carboni-3 i del carboni-4 de l'esquelet del lligand i pel tipus de substituents de l'anell biaril.
El capítol 4 descriu l'aplicació dels compostos fosfit-oxazolina (L1-L5) com a lligands en la reacció de Heck asimètrica intermolecular. Una selecció correcta dels substituents en la funció oxazolina i del fosfit han permès obtenir excel·lents activitats (fins un 100% de conversió en 10 minuts), regioselectivitats i enantioselectivitats (fins un 99%) en un ampli rang de substrats utilitzant diferents fonts de triflat.
El capítol 5 descriu l'aplicació de les tres llibreries de compostos (L1-L11) a les reaccions d'addició 1,2 a aldehids catalitzades per níquel. En primer lloc, s'ha estudiat l'aplicació dels compostos L1-L6. S'ha observat que la selectivitat del procés depèn principalment del grup funcional unit a l'esquelet del lligand, de les propietats estèriques del substituent en la funció oxazolina i de l'estructura del substrat. S'ha obtingut fins a un 59% d'excés enantiomèric utilitzant el precursor de catalitzador que conté el lligand L3a. En canvi, la utilització de la llibreria de compostos monofosfit (L7-L11) ha mostrat elevades enantioselectivitats (fins a 94%) i activitats en diferents tipus de substrat utilitzant baixes concentracions de catalitzador i sense excés de lligand.
El capítol 6 descriu l'aplicació de les tres famílies de compostos (L1-L11) com a lligands en la reacció d'addició 1,4 catalitzada per coure de compostos organometàl·lics a diferents enones amb diferents propietats estèriques.
L'ús de les llibreries de compostos fosfit-oxazolina (L1-L5) i fosfit-fosforamidit (L6) han proporcionat bones enantioselectivitats (fins a 78%) en l'addició de reactius de trialquilalumini a diferents enones. En canvi, la llibreria de compostos monofosfit (L7-L11) ha mostrat bones activitats però enantioselectivitats fins a 57%.
The growing demand for enantiomerically pure compounds for the development of pharmaceuticals, agrochemicals and flavors has captured the interest of the chemist in the last few decades. Of the various methods for producing enantiopure compounds, enantioselective homogeneous metal catalysis is an attractive one. In this context, carbohydrates have many advantages: they are readily available, are highly functionalized and have several stereogenic centers. This enables series of chiral ligands to be synthesized and screened in the search for high activities and selectivities for each particular reaction.
In this context, this thesis focuses on the development of new chiral ligand libraries derived from carbohydrates, the synthesis of new catalyst precursors and their application in the Pd-catalyzed asymmetric allylic substitution, Pd-catalyzed asymmetric Heck reactions, Ni-catalyzed asymmetric addition of trialkylaluminium to aldehydes, and Cu-catalyzed asymmetric 1,4-conjugated addition of trialkylaluminium reagents to enones.
For this porpose, we have designed and syntezied 3 new sugar based ligand libraries: phosphite-oxazoline (L1-L5), phosphite-phosphoroamidite (L6) i monophosphite (L7-L11) (Figure 1).
After introduction (Chapter 1) and objectives (Chapter 2), in chapter 3 is discussed the synthesis and characterization of the ligand libraries (L1-L11) and and their application in the asymetric Pd-catalyzed allylic substituion reactions.
Using phosphite-oxazoline ligands (L1-L5) we observed important effects of the oxazoline substituents and the axial chirality and the substituents of the biaryl moieties. However, the effects of these parameters depended on each substrate. High enantioselectivities (up to 99%) and good activities have been achieved in a wide range of substrates with different steric and electronic properties.
The study of the Pd-1,3-diphenyl, 1,3-dimethyl and 1,3-cyclohexenyl allyl intermediates by NMR spectroscopy made it possible to understand the catalytic behaviour observed. This study also indicated that the nucleophilic attack takes place predominantly at the allylic terminal carbon atom located trans to the phosphite moiety.

Figura 1. Fosfit-oxazolina (L1-L5), fosfit-fosforamidit (L6) i monofosfit (L7-L11).

Asymmetric substitution reactions with catalyst precursors containing the phosphite-phosphoroamidite ligands showed that enantiomeric excesses depend strongly on the substituents at the para positions of the biphenyl moieties. However, these effects were different depending on the substrate in study. Enantiomeric excesses of up to 89% with high activities were obtained for rac-1,3-diphenyl-3-acetoxyprop-1-ene, rac-(E)-ethyl-2,5-dimethyl-3-hex-4-enylcarbonate and rac-3-acetoxycycloheptene. For the monosubstituted linear substrate 1-(1-naphthyl)allyl acetate, these ligands proved to be inadequate in terms of regioselectivities. However, we obtained good enantioselectivity by carefully selecting the substituents on the para position of the biphenyl moieties (ee's up to 72%).
If we compare these results with those from the catalyst precursors containing the previous phosphite-oxazoline ligands (L1-L5), we found that the replacement of the oxazoline moiety by a phosphoroamidite group decreased enantioselectivities and versatibility.
Asymmetric allylic alkylation with catalyst precursors containing the sugar-based monophosphite ligand library showed that the catalytic performance is highly affected by the size of the sugar backbone, the configurations at C-3 and C-4 of the ligand backbone and the type of substituents/configurations in the biaryl phosphite moiety. Low-to-moderate enantioselectivities (up to 46%) were obtained.
In the asymmetric Pd-catalyzed Heck reactions (Chapter 4) with catalysts precursors based on phosphite-oxazoline ligands, we obtained excellent activities (up to 100% conversion in 10 minutes), regio- (up to >99%) and enantioselectivities (up to 99%) were obtained in a wide range of substrates and triflate sources.
In the asymmetric Ni-catalyzed 1,2-addition of trialkylaluminium to aldehydes (Chpater 5) with catalysts precursors based on phosphite-oxazoline and phosphite-phosphoroamidite ligands, we found that the selectivity depends strongly on the type of functional group attached to the carbohydrate backbone, on the steric properties of the oxazoline substituents and on the substrate structure. Enantioselectivities up to 59% were obtained using the catalyst precursor containing the phosphite-oxazoline ligand L3a. In contrast to what we observed with the previous two ligand libraries, using sugar-based monophosphite ligands (L7-L11) provides high enantioselectivities (up to 94% ee) and activities in different substrate types, with low catalysts loadings and without excess of ligand.
In Chapter 6, we described the phosphite-oxazoline and phosphite-phosphoroamidite ligands as chiral auxiliaries in the asymmetric Cu-catalyzed 1,4-conjugated addition of trialkylaluminium reagents to several enones provides good enantioselectivities (up to 80% ee).
In the asymmetric Cu-catalyzed asymmetric 1,4-conjugated addition of trialkylaluminium reagents to several enones with catalysts precursors based on sugar monophosphite ligands, we found good activites and enantioselectivities up to 57% ee.

The rate of reaction for the copper-catalysed coupling reactions to form C–N bonds between aryl halides and amines can be significantly improved in the presence of various bidentate ligands. This improved reaction is often referred as the modified Ullmann amination reaction. However the intermediates and steps involved in the mechanism and the role of the ligand are not fully understood. In this work, mechanistic studies have been carried out in order to improve the current understanding of this reaction. The role of copper(I) alkylamide complexes as potential intermediates in the modified Ullmann reaction between aryl halides and alkylamines is discussed in Chapter 2. A series of copper(I) alkylamide complexes have been synthesised and shown using single crystal X-ray crystallography to exist as tetramers in the solid state. The structures of these complexes in benzene-d6 were determined by 1H DOSY NMR spectroscopy which revealed equilibrating aggregates, where the equilibrium rate could be faster or slower than the NMR time scale, with average aggregation numbers between the dimeric and tetrameric forms. The complexes have been shown to react stoichiometrically with iodobenzene to give arylamine products, both in the absence and presence of 1,10-phenanthroline as an ancillary ligand. The influence of 1,10-phenanthroline on the solution structures in benzene-d6 and DMSO-d6 is also discussed and can be related to the stoichiometric and catalytic reactivity. Overall these results highlight the role of copper(I) alkylamide complexes as potential intermediates and show the significance of 1,10-phenanthroline in modulating the reactivity of the system. Chapter 3 describes the improvement in product yield from utilising O,O- and N,O-chelating ligands over N,N-chelating ligands in the copper-catalysed C–N cross-coupling reaction between piperidine and iodobenzene. A kinetic study of this reaction using 2-acetylcyclohexanone as the added ligand demonstrated that the poorly soluble potassium phosphate base caused the reaction rate to be limited by mass transfer effects. The results provide insights into the qualitative rate dependences in the reactants and also the role of the ligand in the catalyst deactivation pathway by disproportionation. A mechanistic study of the copper-catalysed C–N cross-coupling reaction between piperidine and iodobenzene using bis(tetra(n-butyl)phosphonium) malonate as a soluble base is presented in Chapter 4. A detailed kinetic study using reaction calorimetry and the reaction progress kinetic analysis (RPKA) methodology reveals first order rate dependences in the substrates and copper catalyst concentration, and negative first order kinetics in the base concentration. NMR spectroscopic evidence suggests the malonate base simultaneously functions as an ancillary ligand and coordinates to give an off-cycle unstable species. Catalyst deactivation by disproportionation was found to be an important consequence of malonate ligand coordination, with the piperidine substrate playing a key role in mitigating the rate of catalyst deactivation. The absence of aryl radical formation suggests that the aryl halide activation mechanism occurs by an oxidative addition process. The experimental data has been successfully modelled to the proposed mechanism to give approximate equilibrium and rate constants for each step.

This thesis describes the development of a new microwave-mediated methodology for C–S bond formation and the issues regarding scaling up heterocyclic transformations. Chapter 1 provides an overview on the current understanding of microwave-mediated synthesis and on the use of microwave technology in copper- and palladium-mediated synthesis. A separate part is dedicated to the current advancements in the use of flow reactors within the chemical community. Chapter 2 describes the application of the current batch and continuous flow technology for the scale-up of selected heterocyclic transformations, starting with the well known Bohlmann- Rahtz pyridine synthesis and moving to other reactions, including pyrimidine and Hantzsch dihydropyridine synthesis. Chapter 3 describes the development of a new methodology for the microwave-mediated C–S bond formation, starting from an investigation on the current available methods and moving to the application of new methodology to the synthesis of a library of compounds. Further application was found in the synthesis of a drug candidate with anti-ageing properties and in the synthesis of a new class of anti-HIV compounds.

The importance of fluorinated organic molecules has grown over the last 50 years, particularly in the pharmaceutical and agrochemical industries. Therefore the development of new methods for fluorination is a very attractive research area. In Chapter 1, the properties and impact of the fluorine atom on organic molecules are overviewed. Existing electrophilic and nucleophilic fluorination methods are reviewed, and new developments in asymmetric fluorination are discussed. The emergence of the Prins fluorination reaction as a side product in BF₃.OEt₂ catalysed processes has been investigated as a synthesis method in Chapter 2. Indeed, it is possible to form 4-fluorotetrahydropyrans with some diastereoselectivity from an allylic alcohol and an aldehyde with a stoichiometric amount of BF₃.OEt₂. During this study, formation of 4-fluoropiperidines from N-tosyl-4-butenylamine was achieved. Optimisation of reaction conditions was investigated such as the solvent, the reaction temperature and the influence of substituents on the alcohol and the aldehyde reagents. A ring-opening reaction of 4-fluoro-2-phenyltetrahydropyran was successfully performed. Both oxa-Prins and aza-Prins fluorination reactions were investigated under microwave conditions, allowing reduced reaction times, a process that had a minimum impact on the diastereoselectivity. Attempt to form γ-hydroxy-α-vinylfluorides by the reduction-fluorination of propargylic alcohols with aluminium hydride, or by Horner-Emmons reaction with diethyl (fluoromethyl)phosphonate are reported in Chapter 3. Unfortunately these approaches were unsuccessful in the preparation of γ-hydroxy-α-vinylfluorides. Attempts to fluorinate epoxides by α-lithiation and then treatment with electrophilic fluorination reagents gave encouraging results, but the products could not be purified and characterised due to an apparent instability.

La grande variété de propriétés biologiques associées au noyau purine en fait une structure privilégiée pour la conception et la synthèse de nouvelles molécules à visée thérapeutique. Cette spécificité est étroitement liée à la grande diversité de substituants pouvant être introduits sur les différentes positions du noyau purine et en particulier sur C2, C6, C8 et N9. Par conséquent, le développement de méthodes de fonctionnalisation rapides de cette famille de composés est d'un grand intérêt synthétique. Nous nous sommes focalisés sur la formation de liaisons C-C et C-N sur les positions 6 et 8 du noyau purine pour pouvoir présenter de nouveaux outils de synthèse permettant d'introduire une plus grande diversité fonctionnelle. D'une part, nous avons étudié la fonctionnalisation directe de liaisons C-H de purines, sujet encore peu exploré. En effet, de nos jours, le traditionnel couplage croisé (Negishi, Suzuki-Miyaura), utilisé pour la création de liaisons C-C, se voit de plus en plus concurrencé par ces réactions puisqu'elles ne nécessitent pas la préparation d'un partenaire organométallique. Ce sont des réactions dites à économie d'atomes. En nous basant sur l'expérience du laboratoire dans le domaine de la fonctionnalisation directe de liaisons C-H, nous avons envisagé l'alcénylation et l'alcynylation directes en position 8 de la purine, les motifs alcényle et alcynyle étant présents dans certaines purines d'intérêt biologique. D'autre part, nous nous sommes intéressés à deux méthodes de couplage croisé pallado-catalysé permettant la formation de liaisons C-N et C-C : le couplage de Buchwald - Hartwig entre une 8-iodopurine et des amides ou des amines aromatiques, et le couplage de Liebeskind - Srogl entre une 6-thioétherpurine et divers acides boroniques.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemistry, 2004.
Includes bibliographical references.
In Part I the development of a new method for the construction of oxindoles and benzofuranones bearing quaternary stereocenters is discussed. A planar-chiral PPY derivative catalyzes the O-to-C acyl group migration (Black rearrangement) in a highly efficient and enantioselective manner. The utility of this method is further demonstrated by the formal total synthesis of the natural product aplysin. In Part II reactivity of bisphosphine palladium-complexes is discussed. It is shown that the oxidative addition of bisphosphine palladium-complexes bearing P(t-Bu₂)Me occurs through an SN2-type mechanism. This discovery allows us rationalize the difference in catalytic activity between Pd(P(t-Bu₂)Me)₂ and Pd(P(t-Bu₂)Et)₂ for the cross-coupling of alkyl electrophiles. The reductive elimination of H-X from bisphosphine palladium-hydride complexes is also discussed. The discovery that (P(t-Bu)₃)₂PdHCl undergoes facile reductive elimination in the presence of Cy₂NMe, while (PCy₃)₂PdHCl does not, is explained using X-ray crystal structures. These reactivity patterns may help to explain why Pd(P(t-Bu)₃)₂ is a much better catalyst than Pd(PCy₃)₂ for the Heck coupling of aryl chlorides. Finally, Part III describes preliminary work on a palladium-hydride catalyzed isomerization of allylic alcohols as well as initial attempts to study the mechanism of nickel-catalyzed cross-couplings of secondary alkyl-electrophiles.
by Ivory Derrick Hills.
Ph.D.

En línia amb la investigació desenvolupada al nostre grup basada en l’elaboració de noves reaccions d’acoblament creuat, hem decidit centrar la tesis doctoral en l’estudi de la formació de nous enllaços Csp3–Csp3, utilitzant reaccions d’acoblament creuat reductores catalitzades per níquel. Al primer capítol, els nostres esforços es centren en la preparació d’una nova metodologia basada en l’alquilació reductiva de a-haloboronats, utilitzant com a matèria prima olefines no activades. Aquest nou protocol, quimio- i regioselectiu, permet l’incorporació d’un fragment alquílic-boronat a olefines no activades, mitjançant condicions de reacció suaus. Per altra banda, l’ús d’olefines internes permet la formació d’enllaços carboni-carboni en posicions C–H sp3 llunyanes, a través del procés anomenat “chain-walking” catalitzat per níquel. Al segon capítol, continuant amb el nostre interès en reaccions catalitzades per níquel, hem estudiat un mètode catalític d’alquilació desaminativa d’olefines no activades. Aquesta nova metodologia opera sota condicions de reacció suaus i es caracteritza per l’ampli espectre de compostos que poden acoblar-se selectivament. Aquesta tècnica pot tenir aplicació en el context de la derivatització de l’etilè i per la funcionalització de molècules d’alt valor afegit.
En línea con la investigación desarrollada en nuestro grupo basada en la elaboración de reacciones de acoplamiento cruzado, hemos decidido centrar la tesis doctoral en el estudio de la formación de enlaces Csp3–Csp3, usando reacciones de acoplamiento cruzado reductoras catalizadas por níquel. En el primer capitulo, nuestros esfuerzos se centran en la preparación de una nueva metodología basada en la alquilación reductiva de a-haloboronatos usando como materia prima olefinas no activadas. Este protocolo, quimio- y regioselectivo, permite la incorporación de un fragmento alquílico-boronato en olefinas no activadas, y presenta unas condiciones de reacción suaves. Por otro lado, el uso de olefinas internas permite la formación de enlaces carbonocarbono en posiciones C-H sp3 lejanas, a través del proceso llamado “chain-walking”, catalizado por níquel. En el segundo capitulo, siguiendo nuestro interés en reacciones catalizadas por níquel, hemos estudiado un método catalítico de alquilación desaminativa de olefinas no activadas. Esta nueva metodología opera bajo condiciones de reacción suaves y se caracteriza por el amplio espectro de compuestos que pueden acoplarse selectivamente. Esta técnica también puede ser aplicada en el contexto de la derivatización del etileno y para la funcionalización de moléculas de alto valor añadido.
In line with our group research interests on cross-coupling-reactions, we decided to focus this doctoral studies on the development of sp3 C–C bond formation by means of nickel catalyzed reductive-cross-coupling. Our first effort was focused on the development of a reductive alkylation of a-haloboronates with unactivated olefin feedstocks. We have developed a mild, chemo- and site-selective catalytic protocol that allows the incorporation of an alkylboron fragment into unactivated olefins. Moreover, the use of internal olefins enables C C bond-formation at remote sp3 C-H sites via nickel catalyzed chain-walking process. Following up our interest on nickel catalyzed chainwalking events, we reported a site-selective catalytic deaminative alkylation of unactivated olefins. This method operates under mild conditions and is characterized by a wide substrate scope and exquisite site-selectivity profile. Particularly noteworthy is that this technique could be employed in the context of ethylene derivatization and for the late-stage functionalization of complex molecules. Our final efforts for the sp3 C–C bond formation was focused on the development of a regio-selective cross-coupling of three electrophiles by means of nickel/photoredox dual catalysis. We developed a modular, chemo- and regio-selective 1,2-difunctionalization of simple vinyl boronates with readily available organic halides.

This thesis has been focused on enzymatic kinetic resolutions and stereoselective oxidative transformations of enallenes catalyzed by PdII. In the first part of the thesis, a detailed discussion on Candida antarctica lipase B (CALB)-catalyzed kinetic resolution (KR) of δ-functionalized alkan-2-acetates is shown. We gained a deeper insight into the mechanism of enzyme-substrate recognition. Changing from an anhydrous solvent to water or a water-containing organic solvent enhanced the enantioselectivity. The effect of –OH was also confirmed by a lipase mutant suggesting that the water molecule mentioned above can be partly mimicked. In the second part of the thesis, we developed an efficient KR for allenic alcohols. On this basis, a novel synthesis of optically pure 2-substituted 2,3-dihydrofurans from allenic alcohols via a Ru-catalyzed cycloisomerization was reported. The developed protocol enabled us to assemble an optically pure precursor for total synthesis with three chiral centers from readily available allenol in 2 days. In the third part, we reported a class of reactions involving C–H cleavage under mild conditions: PdII-catalyzed oxidative transformations of enallenes. These reactions are particularly attractive since a number of meticulous structures have been achieved from readily accessible starting materials. The directing effect of an unsaturated hydrocarbon was found to be key for these transformations. In the final part, we developed the carbonylative insertion reaction discussed in the third part of the thesis into an asymmetric version. By using this methodology, a number of cyclopentenone compounds were obtained in good to excellent enantioselectivity.

The first part of the thesis presents the KMnO4/ carboxylic acid/ organic solvent which is a powerful reagent for C-C bond formation, aryl coupling reactions and enone oxidation. The a¢
-acetoxylation of enones and the a-acetoxylation of aromatic ketones were carried out with potassium permanganate and acetic acid, in which acetoxylation products were obtained in 74-96% yields. The same reaction was carried out with carboxylic acids other than acetic acid, which furnished corresponding acyloxy ketones with the same regioselectivity. For the first time, formyloxylation products were synthesized in a 61-85% yield by using formic acid. The potassium permanganate and acetic acid method was also used for aryl coupling reactions. The reaction of arylboronic acids and aryl hydrazines in benzene with potassium permanganate and acetic acid in turn furnished biaryls in a 85-96% yield. We showed that potassium permanganate/carboxylic acid/organic solvent behaves as manganese(III) acetate. In the second part of the thesis, ipso-nitration of arylboronic acids with AgNO2/ TMSCl was performed. Nitration of aromatic compounds is one of the most extensively studied reactions, and nitroaryl moieties play key roles in the physical and chemical properties of many target molecules in organic synthesis. For electrophilic nitration of aromatic compounds, a wide variety of reagents are available to date. Most of them are very strong nitrating agents and often lead to further nitration and mixture of isomers. Since most nitrating agents are oxidants, oxidation of other functional groups can also occur, giving a mixture of products. Thus, a search for milder and selective nitrating agents is a good research goal. In this work, we aimed to apply AgNO2/ TMSCl system to ipso nitration of arylboronic acids.

Cette thèse est constituée de trois parties : 1) Le contexte bibliographique, 2) le développement de réactions domino cupro-catalysées et 3) une approche vers la synthèse totale des raputindoles.La première partie introduit d’abord le concept de réactions domino ainsi que leurs applications, puis les réactions catalysées par du cuivre permettant de former des liaisons C-N sont passées en revue en incluant les couplages de Ullmann, Goldberg et de Chan-Lam, les séquences d’activation oxydante de liaisons C-H/formation de liaison C-N, l’insertion de nitrènes et l’hydroamination de liaisons C-C multiples. En se basant sur ces réactions élémentaires permettant de former une liaison C-N unique, les développements récents de réactions domino sont ensuite détaillés.La deuxième partie peut être subdivisée en 3 sections : 1) la synthèse de benzimidazoles, 2) la synthèse d’imidazoles and 3) la synthèse de guanidines. Un rappel des méthodes existantes pour la synthèse de ces motifs est proposé dans chaque section. Notre travail, basé sur la formation de liaisons C-N multiples selon une séquence cupro-catalysée domino, est ensuite détaillé. Celui-ci nous a permis d’aboutir au développement de voies d’accès aux benzimidazoles, en utilisant une réaction séquentielle catalysée par du cuivre en présence d’oxygène à partir d’acides boroniques et d’amidines, à la synthèse d’imidazoles par une réaction de di-amination d’alcynes vrai par des amidines et à l’obtention de guanidines et de 2-aminobenzimidines par une réaction à 3 composant. Ces réactions domino montrent une bonne efficacité et permettent d’assembler des hétérocycles à partir de précurseurs aisément accessibles.La dernière partie est consacrée à la synthèse des raputindoles. La structure, les activités et les réactions clé pour la construction de ces alcaloïdes sont discuté d’abord, nous amenant à proposer une rétrosynthèse pour accéder à ces molécules. Les réactions qui ont retenues notre attention pour construire ces molécules sont une annelation [3+2] irido-catalysée d’acides o-formylarylboronique et de 1,3-diènes, la synthèse de Leimgruber-Batcho pour obtenir des indoles et une séquence d’alkylboration-protodéboration. A partir de cela 3 stratégies ont été évaluées, montrant que l’accès à ce type de composé naturel est envisageable en combinant ces étapes
This thesis consists in three parts: bibliographic background, copper-catalyzed reactions for synthesis of N-containing compounds, approach to the synthesis of raputindoles.The first part introduces the domino reactions and their applications, then, copper-mediated reactions for construction of C-N bond formation are reviewed including Ullmann, Goldberg and Chan-Lam coupling, oxidative C-H activation/C-N formation, insertion of nitrenes and carbenoids, and hydroamination of multi-C-C bonds. This can be used as guides to design domino reaction. Following these copper-mediated single C-N bond formation reactions, recent developments of copper-catalyzed domino reactions for synthesis of heterocycles are described.The second part can be divided into three sections: 1) synthesis of benzimidazoles, 2) synthesis of imidazoles and 3) synthesis of guanidines. Each section summarizes the existing methods used for their synthesis. Following it, our synthetic work involving copper-catalyzed C-N bond formation domino reactions is discussed in detail. Our objectives include the synthesis of benzimidazoles through copper-catalyzed sequential reaction of benzamidines and boronic acids, synthesis of imidazoles via copper-catalyzed domino reaction of benzamidines and acetylenes, and synthesis of guanidines and 2-aminobenzimidazoles by Cu-catalyzed three-component reaction of cyanamides, boronic acids and amines. These copper-catalyzed domino reactions show high efficiencies from readily available and simple starting materials.The last part is about the total synthesis of raputindoles. The structure and bioactivities of raputindoles and key reactions for the total synthesis of raputindoles are introduced first, the synthetic strategies are then proposed on basis of relative synthetic methods. The key reactions we use for the synthesis of raputindoles are iridium catalyzed [3+2] annulation of o-formylarylboronic acids and 1,3-dienes, Leimgruber-Batcho indole synthesis, transition-metal catalyzed SN2 substitution and alkylborylation-protondeborylation. According to the three strategies we proposed, lots of relative reactions were investigated. The results show that it is possible to synthesize the raputindole molecules based on the iridium catalyzed [3+2] annulation of 2-formylarylboronic acids and 1,3-dienes

Organometallic aryl-CuIII species have been proposed as key intermediates in Ullmann-type reactions. However, such species have long remained elusive and mechanistic investigations of a plausible catalytic cycle remained ambiguous and speculative. The first part of this thesis deals with the reactivity of well-defined aryl-CuIII macrocyclic complex in presence of activated methylenes (Hurtley-type coupling) and terminal acetylenes (Stephens-Castro-type coupling). The subsequent part deals with the synthesis and fully characterization of well-defined aryl-NiII complex, which is analogous to aryl-CuIII complex. The strength of the Ni-C bond precludes their direct reactivity with nucleophiles via reductive elimination. Nevertheless, we have proved their reactivity in the presence of a 2 e- redox oxidant as an electrophilic CF3+ source. In the last part, we turned our attention to the standard Cu-catalyzed Ullmann-type reactions by studying the effect of the ligand choice on the chemoselectivity of a multiple combinations of amides, amines and phenols in competitive reactions
Les espècies aril-CuIII han estat proposades com les espècies a través de les quals operen els acoblaments tipus Ullmann. No obstant, aquestes espècies són molt reactives i difícilment detectables en els processos fonamentals que governen aquests acoblaments. La primera part d’aquesta tesi es centra en l’estudi de la reactivitat de complexes ben definits aril-CuIII davant de metilens actius (Reacció de Hurtley) i acetilens terminals (Reacció de Stepens-Castro). La següent part es centra en la síntesi i caracterització de complexes ben definits aril-NiII, anàlegs als de coure. La curta distància de l’enllaç Ni-C dissenteix la seva reactivitat davant diversos nucleòfils via eliminació reductiva. Per contra, aquestes espècies són reactives en presència de fonts electrofíliques de CF3+. En l’última part, ens centrem en l’estudi de les propietats estèriques dels lligands auxiliars coordinats al centre de coure i la selectivitat que presenten envers diferents nucleòfils en els sistemes estàndards de tipus Ullmann

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemistry, 2003.
Vita.
Includes bibliographical references.
New methods for Pd-catalyzed cross-coupling reactions of aryl halides or arenesulfonates are described. Key to the success of these transformations is the proper choice of ligand and reaction conditions. Palladium catalysts supported by bulky, monodentate phosphine ligands with a biaryl backbone or the bidentate ligand, Xantphos, effectively promote the formation of ca-aryl carbonyl compounds. Base-sensitive functional groups are better tolerated when a weak base, such as K3PO4, is used. One of the most difficult transformations in Pd catalysis, the intermolecular C-O bond formation between primary alcohols and electron-neutral or even electron-rich aryl halides, was effectively promoted by the use of a new generation of ligands, 3-methyl-2-di-t-butylphosphinobiaryl. The one-step synthesis of ligands from cheap starting materials, as well as the mild reaction conditions employed for the coupling reactions, enables the practical use of Pd catalysis to access aryl alkyl ethers for the first time. Continuing study of Pd-catalyzed C-N bond-forming processes using biaryl monophosphine ligands led to the discovery of a structural derivative of these ligands, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl. This ligand, in combination with a Pd source, produces a catalyst system with both a greater degree of activity and of stability than those that use our previous ligands. Substrates that were not amenable to Pd catalysis previously are reexamined using this new catalyst system, and excellent results are obtained.
by Xiaohua Huang.
Ph.D.

Els complexos organometàl·lics de coure, plata i or juguen un paper fonamental com espècies reactives en diverses transformacions químiques. Aquesta tesi aporta coneixement sobre el comportament d’aquests complexos en la formació d’enllaços C-C i/o C-N. En concret, estudiem: i) el mecanisme de reacció a través del qual els complexos de coure co-catalitzen un acoblament oxidant en el context de sistemes bimetàl·lics de rodi i coure; ii) el potencial de nucleòfils de plata com a agents transmetal·lants en reaccions de trifluorometilació catalitzades per pal·ladi; iii) el mecanisme de reacció de sistemes bimetàl·lics de Pd/Ag emprant un sistema model; i iv) el comportament de complexos bis(trifluorometil) cuprat, argentat i aurat com a nucleòfils. En aquesta tesi, on s´han combinat estudis experimentals i computacionals, s’ha adquirit nou coneixement sobre els processos estudiats, i s’ha contribuït al camp de la recerca química basada en el coneixement.
Los complejos organometálicos de cobre, plata y oro juegan un papel fundamental como especies reactivas en diversas transformaciones químicas. Esta tesis aporta conocimiento sobre el comportamiento de estos complejos en la formación de enlaces C-C y/o C-N. En concreto, estudiamos: i) el mecanismo de reacción por el cual complejos de cobre co-catalizan un acoplamiento oxidante en el contexto de sistemas bimetálicos de rodio y cobre; ii) el potencial de nucleófilos de plata como agentes transmetalantes en reacciones de trifluorometilación catalizadas por paladio; iii) el mecanismo de reacción de sistemas bimetálicos de Pd/Ag usando un sistema modelo; y iv) el comportamiento de complejos bis(trifluorometil) cuprato, argentato y aurato como nucleófilos. En esta tesis, donde se han combinado estudios experimentales y computacionales, se ha adquirido nuevo conocimiento sobre los procesos estudiados, y se ha contribuido al campo de la investigación química basada en el conocimiento.
Organometallic coinage metal complexes are be key reactive species for promoting a wide variety of chemical transformations. This thesis improves the understanding the behavior of these complexes in relevant C-C and/or C-N bond-forming reactions. Specifically, we have explored: i) the mechanistic intricacies of copper species as co-catalyst in the context of rhodium/copper-catalyzed oxidative coupling reactions; ii) the capability of silver nucleophiles as transmetalating agents in palladium-catalyzed trifluoromethylation reactions; iii) the reaction mechanism of Pd/Ag bimetallic reactions using a model system as probe; and, iv) the study of bis(trifluoromethyl) coinage metallates as nucleophiles. The fundamental insights gathered in this Thesis, encompassing both experimental and computational approaches, improve our understanding of the processes under study and make a contribution to the general field of knowledge-driven research in Chemistry.

Tot i que el camp de l'acoblament creuat ha desenvolupat increïbles avenços, la gran majoria de processos encara es basen en l'ús d'halurs d'aril. No obstant, aquest tipus d’electròfils presenten una toxicitat intrínseca i, al mateix temps, la seva síntesis resulta tediosa, especialment quan es tracta d'halurs d'aril altament funcionalitzats. A causa d'això, la comunitat sintètica s'ha bolcat en la recerca d'alternatives a l'ús d'halurs d'aril en química d'acoblament creuat. Grans esforços s'han desenvolupat en la última dècada per implementar els derivats del fenol en aquest tipus de transformacions a causa de l'abundància natural i comercial d'aquests compostos i a la seva baixa toxicitat en comparació amb els organohalurs. No obstant, l'alta energia d'activació necessària per trencar els enllaços C-O ha limitat considerablement l'ús de derivats de fenol en reaccions d’acoblament creuat, sobretot si es tracta d'éters de metil. Actualment la gran majoria de mètodes basats en aquesta família d’electròfils s'utilitzen en la formació d'enllaços C-C. Altrament, gairebé no existeixen tècniques per obtenir enllaços Cheteroàtom probablement a causa de la baixa reactivitat dels nucleòfils, on la densitat de càrrega negativa resideix en un heteroàtom. La present tesi doctoral s'ha centrat en el desenvolupament de noves metodologies per a la creació d'enllaços de tipus C-heteroàtom mitjançant l’activació catalítica d'enllaços C-O amb complexes de Ni. S'han descrit nous mètodes de sililació i borilació d'ésters i metil éters d’aril i benzil. Aquests mètodes suposen una via alternativa per a la síntesis de silans i boronats, els quals són intermedis de gran utilitat en síntesis orgànica. A més, el descobriment d'unes condicions totalment inusuals per activar enllaços de tipus C-OMe ha obert noves perspectives sobre la reactivitat d'aquest tipus d'enllaços i, alhora, ha suggerit l'existència de nous mecanismes d'activació.
A pesar de que el campo del acoplamiento cruzado ha desarrollado increíbles avances, la gran mayoría de procesos todavía se basa en el uso de halogenuros de arilo. Sin embargo, este tipo de electrófilos presentan una toxicidad intrínseca y, a su vez, su síntesis resulta tediosa, especialmente cuando se trata de halogenuros de arilo altamente funcionalizados. Debido a ello, la comunidad sintética se ha volcado en la búsqueda de alternativas al uso de halogenuros de arilo en química de acoplamiento cruzado. Un gran esfuerzo se ha desarrollado en la última década para implementar los derivados del fenol en este tipo de transformacions debido a la abundancia natural y comercial de dichos compuestos y a su baja toxicidad en comparación con los organohalogenuros. Sin embargo, la alta energía de activación necesaría para romper los enlaces C-O ha limitado considerablemenete el uso de derivados del fenol en reacciones de acomplamineto cruzado, sobre todo si se trata de éteres de metilo. Actualmente la gran mayoría de métodos basados en esta familia de electrófilos se utilizan en la formación de enlaces C-C. De lo contrario, apenas existen técnicas para obtener enlaces C-heteroátomo probablemente debido a la baja reactividad de los nucleófilos donde la densidad de carga negativa reside en un heteroátomo. La presente tesis docotoral se ha centrado en el desarrollo de nuevas metodologías para la creación de enlaces de tipo C-heteroatomo mediante la activción catalítica de enlaces C-O con complejos de Ni. Se han descrito novedosos métodos de sililación y borilación de ésteres y metil éteres de arilo y bencilo. Dichos métodos suponen una via alternativa para la síntesis de silanos y boronatos, los cuales son intermedios de gran utilidad en síntesis orgánica. Además, el descubrimiento de unas condiciones totalmente inusuales para activar enlaces de tipo C-OMe ha abierto nuevas perspectivas sobre la reactividad de este tipo de enlaces y, a la vez, ha sugerido la existencia de nuevos mecanismos de activación.
While the field of cross-coupling has reached remarkable levels of sophistication, the vast majority of processes are still being conducted with organic halide counterparts. Drawbacks associated to their toxicity and the limited accessibility of densely functionalized aryl halides have prompted chemists to develop powerful, yet practical, alternatives. Among these, the utilization of phenol derivatives as coupling partners via C-O bond cleavage would be particularly rewarding due to their readily availability and benign nature. However, the high activation energy required for effecting C–O bond cleavage has become a daunting challenge when devising catalytic techniques using phenol derivatives, specially always-elusive aryl methyl ethers. At present, the vast majority of cross-coupling reactions using phenol derivatives remains confined to C–C bond formation, whereas the formation of C-heteroatom bonds has been poorly studied, likely due to the less reactivity of heteroatom-based nucleophiles. This doctoral thesis has focused on the development of new methodologies for forging C-heteroatom bonds via Ni-catalyzed C-O bond cleavage. It has been described new protocols for the silylation and borylation of aryl and benzyl esters and methyl ethers. These methodologies can be used as useful alternatives towards the synthesis of aryl and benzyl silanes and boronates, incredible important intermediates in organic synthesis. Furthermore, the discovery of unusual, yet surprising, conditions for the cleavage of C-OMe bonds have opened up new vistas towards the reactivity of aryl and benzyl methyls ethers while suggesting new activation pathways.

AbstractRuthenium-Catalyzed C-C Bond Formation via Functional-Group Directed C-H Bond ActivationXiangyu GuoAdvisor: Prof. Chao-Jun LiMcGill UniversityThis thesis is an investigation on the formation of carbon-carbon (C-C) bonds in the presence of ruthenium catalyst.In the first part of this thesis, oxidative dehydrogenative coupling reactions for carbon-carbon (C-C) bond formation are described. A ruthenium-catalyzed dimerization of 2-phenylpyridine derivatives is demonstrated to synthesize biaryls using iron(III) chloride as the terminal oxidant. In addition, the oxidative cross coupling of arenes and cycloalkanes is also illustrated, achieving a unique para-selectivity.In the second part of the thesis, a ruthenium-catalyzed olefination via decarbonylative addition of aldehydes to terminal alkynes is described. Conjugated and isolated C=C bonds can be chemoselectively generated in two catalytic systems starting from aromatic and aliphatic aldehydes. The method provides an alternative synthesis of C=C bonds from direct C-H bond addition to triple bonds.
RésuméRuthenium-Catalyzed C-C Bond Formation via Functional-Group Directed C-H Bond ActivationXiangyu GuoSuperviseur: Prof. Chao-Jun LiUniversité McGillCette thèse est le résultat de la recherche sur la formation de liaisons carbone-carbone (C-C), catalysé par le ruthénium. La première partie de cette thèse expose les résultats sur la formation de liaison carbone-carbone (C-C) par la réaction de couplage oxydant par déshydrogénation. La synthèse de composés biaryl par l'utilisation d'un catalyseur de ruthénium a permis la dimérisation des dérivés de la 2-phénylpyridine en présence de chlorure de fer (III) comme oxydant terminal. En outre, l'oxydative cross-coupling entre arènes et cycloalcanes, a montrer une notable, para-sélectivité. La seconde partie de cette thèse, décrit les résultats obtenue sur la réaction d'oléfination decarbonylative entre un aldéhyde et un alcyne vrai, catalyser par le ruthénium. En partant d'aldéhydes aromatiques ou aliphatiques et par l'utilisation de deux systèmes catalytiques, la synthèse chemioselective de double liaison C=C conjuguée ou isolée ont pu être réalisé. Cette réaction fournit ainsi, une intéressante alternative à la synthèse de doubles liaisons C=C par la directe addition de liaison C-H sur une triple liaison.

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.

This thesis is concerned with the use of palladacyclic complexes as catalysts for C-C and C-heteroatom bond-forming reactions in which an oxidation state change of the metal centre is not part of the catalytic cycle. To this end, the investigation of a range of known K²-C,L-based palladacycles in the allylation of aldehyde and imine substrates using stannanes, as well as the 1,4-conjugate arylation of enones and imines using arylboronic acids under mild conditions is described. In each case the commercially available phosphite-based dimeric palladacycle is found to be the most active complex capable of achieving excellent conversions (>90%) at the 0.5 - 2.5mol% loading range. Three previously unknown phosphinite and amidophosphinite palladium pincer complexes are also synthesised, characterised (including crystallographically) and tested in the 1,4-conjugate addition of phenylboronic acid to chalcone and found to be inactive.

Toutes les formes de vie assemblent et désassemblent continuellement des composés chimiques via un processus de consommation d'énergie appelé métabolisme. Le métabolisme est généralement modélisé en chimie et biologie par un cycle. Ce modèle dynamique traduit la transformation de composés de base en une cascade de produits appelés métabolites. Celui-ci est comparable à un ouragan à l’échelle moléculaire. De manière analogique et imagée un cyclone est constitué de deux éléments, l'air et l'eau, et transforme l’environnement qui l’entoure par un processus endothermique (consommateur d’énergie). Traditionnellement, la recherche chimique sur les origines de la vie est concentrée principalement sur la synthèse de composés chimiques sans suffisamment apprécier leur place dans la plus grande organisation biochimique de la vie. La vie construit toutes ses molécules à partir du dioxyde de carbone, pourtant elle manque étonnamment d'innovation à cet égard. Malgré presque 4 milliards d'années d'évolution, les organismes autotrophes utilisent seulement six voies différentes pour construire leurs molécules à partir du CO2. Parmi elles, deux voies – la voie de l’acétyle CoA (aussi appelée voie Wood-Ljungdahl) et le cycle du rTCA (également appelé le cycle de Krebs inverse) - sont considérées comme primitives, et contiennent les cinq molécules servant de précurseurs chimiques universels pour toute la biochimie. Comment et pourquoi les voies de l’acétyle CoA et du rTCA sont-elles apparues? Pour répondre à cette question, une recherche systématique a été effectuée afin de trouver des catalyseurs chimiques non-enzymatiques ou des minéraux simples, ainsi que des réactifs pouvant promouvoir les réactions d'anabolisme principal, particulièrement la voie de l’Acétyle CoA et le cycle de rTCA. A l’origine, pour créer les molécules organiques complexes comme les enzymes il a fallu que des molécules plus simples avec un moins grand nombre de carbone se forme sur terre et cela à partir du CO2. On peut donc supposer que les premiers produits à plusieurs carbones sont issus de synthèse totalement inorganique comme celles développer dans notre laboratoire, plutôt que d’une évolution chimique et organométallique simultanée, c’est-à-dire une interaction efficace entre une molécule carbonée et un ou plusieurs métaux à l’instar de certains enzymes. Après avoir trouvé autant de façons possible de promouvoir individuellement chaque étapes des cycles catalytiques étudiés, seules les conditions réactionnelles mutuellement compatibles (à savoir des conditions permettant de produire l’ensemble des métabolites dans le bon ordre) ont été retenu
All life forms continuously build up and break down its constituent chemical building blocks, through an energy consuming process called metabolism. Just like a hurricane’s dynamic patterns and its building blocks (air and water) as being equally fundamental to its nature, so too should metabolism’s dynamic chemical patterns and chemical building blocks be viewed as equally characteristic. Traditionally, much chemical research on the origins of life is overly focused on the synthesis of chemical building blocks without sufficiently appreciating their place in life’s larger biochemical self-organization. Life ultimately builds all of its molecules from carbon dioxide, yet it is surprisingly lacking in innovation in this respect. Despite nearly 4 billion years of evolution, autotrophic organisms use only six pathways to build their molecules from CO2. Two of these pathways – the acetyl CoA pathway (also known as the Wood-Ljungdahl pathway) and rTCA cycle (also known as the reverse Krebs cycle) - are thought to be ancestral, with just five molecules within them serving as the universal chemical precursors for all of biochemistry. How and why did these pathways get their start? To answer this question, a systematic search was designed to find simple, non-enzymatic chemical or mineral catalysts and reagents, that can promote the reactions of core anabolism, particularly the acetyl CoA pathway and the rTCA cycle. After finding as many ways as possible to promote each reaction, they could be narrowed down to mutually compatible conditions where many reactions can occur in sequence. The more of core anabolism that can be achieved under a single set of purely chemical conditions, the more likely it is to have constituted early prebiotic chemistry rather than a later product of chemical and biological evolution

Thesis (Ph.D.)--Massachusetts Institute of Technology, Dept. of Chemistry, 1999.
Includes bibliographical references.
New methods for the palladium-catalyzed amination of aryl halides are described. Key to these is the development of new catalysts and reaction conditions for these transformations. Initially, P(o-tol)3 ligated palladium catalysts were investigated but gave way to systems that used chelating phosphine ligands which substantially expanded the scope of the catalytic amination methodology. Palladium catalyst systems based on BINAP ((2,2'-diphenylphosphino)-1, 1 '-binaphthyl) allowed for the transformation of a much wider range of amines and aryl halide substrates, as well as aryl triflates. Of practical significance was that the use of cesium carbonate as a base at 100 °C substantially increased the functional group tolerance of the method. Palladium catalysts supported by novel, bulky, electron-rich phosphine ligands are exceptionally effective in the C-N, C-0, and C-C coupling procedures. For some substrate combinations, these palladium catalysts are effective for the room-temperature catalytic amination of aryl chlorides. These palladium catalysts are also highly effective for Suzuki coupling reactions of aryl bromides and chlorides at room temperature. Suzuki coupling reactions of aryl bromides and aryl chlorides are effective at very low catalyst loadings (0.000001-0.005 mol % Pd for ArBr, 0.02-0.05 mol % for ArCI) at 100 °C, and reactions of hindered aryl halides or boronic acids are effected at moderate catalyst loadings (1 mol % Pd). The high reactivity of these catalysts towards aryl chlorides challenges the conventional dogma that chloride substrates cannot be transformed under mild conditions with palladium catalysts, and significantly expands the pool of substrates available for cross-coupling chemistry.
by John P. Wolfe.
Ph.D.

The functionalisation of C-H bonds has been widely studied in organic synthesis. This work presents the results of investigation into two areas of current research, copper-catalysed aromatic C-H functionalisation and rhodium-catalysed hydroacylation. Chapter 1 presents the development of palladium- and copper-catalysed aromatic C-H functionalisation with particular attention paid to regiocontrol. Chapter 2 describes the development of copper-catalysed cross-coupling of perfluorinated arenes and alkenyl halides along with efforts to expand this methodology to a more general reaction. In Chapter 3 the development of chelation-controlled rhodium-catalysed hydroacylation is discussed. Chapter 4 outlines the utilisation of amino acid derived N-methylthiomethyl aldehydes in rhodium-catalysed hydroacylation methodology.

Transition metal-catalyzed C-H bond activation allows direct functionalization of the ubiquitous C-H bonds in organic molecules to increase the molecular complexity. Since Murai's pioneering work in ruthenium catalyzed regioselective arene-alkene coupling reaction, a number of transition metal catalysts have been developed for C-C bond formation via C-H bond activation. However, metal-catalyzed C-H functionalization faces a number of long-standing challenges such as the control over regio- and stereoselectivity and harsh reaction conditions. Presented herein is our research on the development of ruthenium(II)-based catalysts for new and improved methods in C-C bond formations by formal activation of sp2 C-H bonds and subsequent coupling with alkyne substrates. Chapter 1 introduces the background of alkyne hydroarylation initiated by transition metal-catalyzed C-H bond activation and the significance to develop new strategies to overcome the limitations of current methods. In Chapter 2 and Chapter 3, ruthenium(II)-N-heterocyclic carbene (NHC) catalyst systems were developed for efficient [3+2] carbocyclization between N-H aromatic ketimines or aromatic ketones and internal alkynes under very mild conditions. This process incorporates the ortho-directing imine and ketone groups for C-H bond activation into the overall transformation in a tandem manner and enables efficient access to indenyl amines and alcohols in high yields. Chapter 4 describes the development of bis-cyclometalated ruthenium(II) complexes with readily available N-H aromatic ketimine and ketone ligands as a new class of catalyst precursors for C-C coupling reactions. The catalytic activity of the bis(imine) complex is evaluated in several catalytic coupling reactions of alkene and alkyne substrates. The coupling reactions are proposed to proceed by Ru(II)/Ru(IV) catalytic cycles involving C-C bond formation by oxidative cyclization. Chapter 5 details the development of a decarboxylative alkyne hydroarylation process to synthesize arylalkenes with controlled and versatile regiochemistry of aromatic substituents. Following a tandem sequence of C-H bond activation and alkyne coupling, the subsequent decarboxylation is facilitated by the newly installed ortho-alkenyl moiety and is compatible with various aromatic substituents at para-, meta- and ortho-positions. This new decarboxylation strategy eliminates the prerequisite of substrate activation by ortho-substitution and allows a broad scope of substituted benzoic acids to serve as aromatic building blocks for alkyne hydroarylation.

Bifunctional catalysis is a well understood phenomenon in nature, with enzymes frequently using two (or more) functional groups to accomplish selective transformations on a suitable substrate. It is becoming clear however, that bifunctional catalysis is not merely of interest to explain or mimic biological efficiency and rate enhancement, but is a viable design principle for the development of new molecular catalysts. In this thesis we have prepared achiral amino-boronic acid compounds with different scaffold structures based on general structures 1 and 2.(^5). although these compounds did not show any reactivity towards the MBH and aza-MBH reaction, they were very successful as catalysts for the aldol reaction. For this reaction it was possible to select the wanted product (aldol or chalcone product) using the same bifunctional catalyst only by changing the solvent. Also with hydroxyacetone some excellent results were gained with yields between 49 to 97% for both aromatic and aliphatic aldehydes in very high regioselectivity.

Thesis (Ph. D.)--University of North Carolina at Chapel Hill, 2007.
Title from electronic title page (viewed Apr. 25, 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 advisor: James P. Morken
This dissertation will describe the development of three transition metal-catalyzed syntheses of nonracemic organoboronates. The first chapter explains the development of a palladium-catalyzed enantiotopic-group-selective cross-coupling of geminal bis(boronates) with alkenyl electrophiles. This process enables the synthesis of highly valuable nonracemic disubstituted allylic boronates. Chapter two describes a palladium-induced 1,2-metallate rearrangement of vinylboron “ate” complexes. The newly developed process incorporates an alternative route for the transmetallation step of Suzuki-Miyaura cross-couplings. Lastly, an enantioselective platinum-catalyzed hydrosilylation of alkenyl boronates is disclosed. This reaction enables the synthesis of nonracemic geminal silylboronates for the divergent synthesis of functionalized
Thesis (PhD) — Boston College, 2018
Submitted to: Boston College. Graduate School of Arts and Sciences
Discipline: Chemistry

Transition metal catalysis emerged as an essential tool in the field of organic chemistry. In this context, transition metal catalyzed C-H bond functionalization is considered as an alluring strategy as it occurs with the high atom-and-step economy. In the recent years, significant attention has been paid for the conversion of C-H bond into C-X (X = C, N, O, S, P..etc) bonds using transition metal catalysts. This thesis presents the development of new catalytic systems for the construction of C-C and C-N bonds through late transition metal-mediated C-H activation and decarboxylation reactions. Chapter 1 introduces the background of transition metal catalyzed C-H bond functionalization. This chapter provides reported catalytic methods for the conversion of arene C-H bonds into various functional groups through transition metal mediated chelation-assisted C-H bond activation. Chapter 2 describes the development of a new method for the synthesis of oxindoles via intramolecular alkene hydroarylation with N-aryl acrylamides using a Ru(II)/N-heterocyclic carbene (NHC) catalyst system. This reaction occurs with good substrate scope and synthetically useful tolerance of functional groups and does not require the assistance of additional directing group. Preliminary mechanistic results support a tandem sequence involving amide-directed aromatic C-H bond activation and intramolecular alkene arylmetalation. Chapter 3 describes ruthenium-based decarboxylative alkenylation of heteroarenes through carboxylate directed C-H bond functionalization. The decarboxylative functionalization of heteroarenes occurs with high regioselectivity and a broad range of functional group tolerance. This decarboxylation proceeds without stoichiometric amounts of bases or oxidants and it is applicable for functionalization of various heteroarenes such as indole, pyrrole, thiophene, benzothiophene, and benzofuran at both C-2 and C-3 positions. The current protocol provides a straightforward approach for the synthesis of trisubstituted olefins with heteroarenes. Chapter 4 explains the development of Rh/Ag-bimetallic catalyst system for decarboxylative amidation of ortho-substituted benzoic acids with 3-aryldioxazolones. The nature of ortho-substituents determines regioselectivity of this reaction through two forms of proposed chelation assistance: (1) A wide range of non-directing ortho-substituents led to ortho-amidation products via carboxylate-directed C-H amidation and subsequent decarboxylation. (2) 2-Pyridyl and analogous DGs led to ipso-amidation products via DG-assisted decarboxylation and subsequent amidation.

The related investigations of catalytic hydroamination as a key step in synthetic methodology development and the synthesis of new hydroamination catalysts are reported in this thesis. The first section focuses on methodology development for the application of a bis(amidate)bis(amido) titanium hydroamination precatalyst towards the synthesis of functionalized small molecules via a tandem C-N, C-C bond forming reaction sequence. The development of two tandem sequential reactions will be described, as well as their applications in the synthesis of α-cyanoamines, α-amino acid derivatives, β-amino alcohols, diamines, imidazolidinones, and β-amino acid derivatives. These tandem reactions show an expanded substrate scope and increase synthetic flexibility by allowing for alternative starting materials in the preparation of highly functionalized small molecules. The second section describes progress towards the development of an asymmetric tandem reaction sequence, including investigations into the mode of activation for the tandem reaction. It has been established that a nucleophilic activation mode is required to generate an active species for the C-C bond forming step. Furthermore, it is postulated that the coordination environment and steric congestion about the activator impacts reaction efficiency and stereoselectivity. This information will be valuable in the design of future generations of activators. The final section reports the development of two novel group 4 metal complexes for catalytic hydroamination. The synthesis and full characterization of these complexes will be described, as well as the results of the catalytic investigations. Through this investigation it has been postulated that while a change in the electronic nature of the metal complex does enhance catalytic reactivity, the degree of orbital overlap between the ligand and the metal center is also an important consideration in the design of electrophilic hydroamination precatalysts. Hydroamination catalysis is currently an attractive area of intense research. The work in this thesis has demonstrated the use of hydroamination catalysis in the synthesis of highly functionalized small molecules, and has furthered the fundamental understanding of the hydroamination reaction. This increase in understanding can then be applied towards the rational design of more powerful hydroamination catalysts and further their application in the synthesis of functionalized N-containing compounds.
Science, Faculty of
Chemistry, Department of
Graduate

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.

Benzoylformate decarboxylase (BFD) from Pseudomonas putida catalyzed the formation of 2-hydroxy-1-phenylpropanone (2-HPP), a 2-hydroxy ketone, from the kinetic resolution of rac-benzoin in the presence of acetaldehyde. The formation rate of 2-HPP via kinetic resolution of benzoin was 700-fold lower compared to the formation via direct carboligation of benzaldehyde and acetaldehyde. Further investigations revealed that BFD not only accepts (R)-benzoin but also 2-HPP as the substrate. A typical Michaelis–Menten type kinetics was observed starting from enantiopure (S)- or (R)-2-HPP. The formation of racemic 2-HPP while using benzoin as the donor in the presence of acetaldehyde and the racemization of (R/S)-2-HPP were detected. The equilibrium constant determined, showed favoured conditions towards the product side i.e. (R)-benzoin and 2-HPP. In the end, an extended reaction mechanism was proposed by supplementing the already known mechanism with the C–C bond cleavage activity of BFD towards 2-hydroxy ketones.
Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

Benzoylformate decarboxylase (BFD) from Pseudomonas putida catalyzed the formation of 2-hydroxy-1-phenylpropanone (2-HPP), a 2-hydroxy ketone, from the kinetic resolution of rac-benzoin in the presence of acetaldehyde. The formation rate of 2-HPP via kinetic resolution of benzoin was 700-fold lower compared to the formation via direct carboligation of benzaldehyde and acetaldehyde. Further investigations revealed that BFD not only accepts (R)-benzoin but also 2-HPP as the substrate. A typical Michaelis–Menten type kinetics was observed starting from enantiopure (S)- or (R)-2-HPP. The formation of racemic 2-HPP while using benzoin as the donor in the presence of acetaldehyde and the racemization of (R/S)-2-HPP were detected. The equilibrium constant determined, showed favoured conditions towards the product side i.e. (R)-benzoin and 2-HPP. In the end, an extended reaction mechanism was proposed by supplementing the already known mechanism with the C–C bond cleavage activity of BFD towards 2-hydroxy ketones
Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich