Rozprawy doktorskie na temat „C-C bonds”

This thesis describes the formation of new C-C bonds from the direct oxidative coupling of two C-H bonds, through the use of metal catalysts for activation. First, three different oxidative Cross-Dehydrogenative-Coupling (CDC) reactions will be presented. Initially, through the use of an organic co-catalyst, N-hydroxyphthalimide (NHPI), oxygen could be utilized as the terminal oxidant for the metal catalyzed alkylation of benzylic C-H bonds with 1,3-dicarbonyls and ketones in Chapter 2. The reaction was found to be feasible for a variety of substrates with readily enolizable C-H bonds. Next, the 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) mediated alkynylation of sp3 C-H bonds was studied. A novel copper (I) triflate catalyzed CDC reaction of unactivated benzylic C-H bonds and terminal aromatic alkynes is presented in Chapter 3. After further studies, the alkynylation of benzylic ethers could also be realized in the presence of a catalytic amount of silver (I) triflate, as described in Chapter 4. Both procedures were found to be amendable for aromatic terminal alkynes, however could not be extended to aliphatic alkynes. Finally, a palladium catalyzed Minisci-type reaction will be described in Chapter 6. Peroxide generated α-hydroxyalkyl radicals could be reacted with azines in moderate to good yields. A stoichiometric amount of acid, used in the traditional Minisci reaction, was replaced by a catalytic amount of palladium dichloride.
Cette thèse décrit la formation de nouvelles liaisons C-C par activation oxydative directe de deux liaisons C-H grâce à l'utilisation de métaux de transition comme catalyseurs. La première partie présentera trois différentes réactions de Cross-Dehydrogenative-Coupling (CDC) oxydantes. Dans un premier temps, sera présentée dans le chapitre 2, la réaction d'alkylation de liens C-H benzylique par 1,3-dicarbonyles et cétones. Ce system a démontré son efficacité sur une large variété de substrats contenant des liaisons C-H enolysable. De plus il a été rendu possible, grâce à l'utilisation d'un co-catalyseur organique, le N-Hydroxyphthalimide (NHPI), d'utiliser l'oxygène moléculaire comme oxydant terminal. Dans un second temps, nous étudierons l'utilisation du 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) comme médiateur pour l'alkynylation de liaisons sp3 C-H. Une nouvelle CDC réaction catalysée par le triflate de cuivre (I) sera présentée dans le chapitre 3, entre un alcyne et une liaison C-H benzylique. Le chapitre 4 présentera le développement de cette réaction à l'alcynation d'éthers benzyliques en présence d'une quantité catalytique de triflate d'argent (I). Ces deux procédures sont seulement applicables pour les alcynes vrais aromatiques. Finalement, le chapitre 6 portera sur la réaction de Minisci catalysée par le palladium. Le peroxyde radical α-hydroxyalkyl généré lors de la réaction est capable de réagir avec les azines. La quantité stœchiométrique d'acide nécessaire lors de la traditionnelle réaction de Minisci, a été remplacée par une quantité catalytique de dichloro palladium.

Reduction of amides to amines is an important transformation in organic synthesis, which has been identified as among the 'top ten most important reactions' by a consortium of pharmaceutical companies. Presently achieved by hydride or borane reagents, it is both hazardous and generates excessive volumes of effluent and waste. Similarly, chemoselective reduction of C=C bonds, particularly conjugated double bonds, also presents a significant challenge in organic synthesis. Electrochemical synthesis using a flow reactor offers an environmentally benign and energy efficient technology for producing key intermediates in the synthesis of candidate drug molecules; its benefits include: improved control of reaction parameters, reproducibility and scalability. The first part of the thesis describes a study on the kinetics of the selective electrochemical reduction of C=C maleimide derivatives using a rotating disc electrode system. The resulting data was used to define the reactor's operating conditions. Subsequently, the chemoselective and stereoselective reduction of maleimide derivatives were carried out in the electrochemical flow reactor with a graphite felt cathode and the rate of reactant depletion, monitored by UV-visible spectroscopy. In the second part, amide reduction was studied in an electrochemical flow reactor using vitreous carbon and boron-doped diamond cathodes. The reduction of N,N- dimethylbenzamide produced the corresponding amine, benzaldehyde and benzyl alcohol. The selectivity of the reaction was investigated as a function of reaction conditions, and a mechanism for the reduction was proposed. Subsequently, a range of functionalised amides were subjected to electrochemical reduction under optimised conditions, to further assess the scope of the methodology as a tool for organic synthesis. The influence of electron donating and withdrawing groups incorporated in to N-benzoylpyrrolidine derivatives were investigated, as well as the pattern of substitution on the amides. The result revealed observable trends in the product distribution between the corresponding amine, benzaldehyde and benzyl alcohol compounds.

The regioselective activation of C-H bonds and subsequent transformation into desirable functional groupS is an attractive prospect in organic synthesis. We have developed two novel C-H functionalisation reactions; the first is an intramolecular, sulfonamide directed, C-H amination reaction for the synthesis of 3_phenylisoindolinone derivates and the second is a sulfonamide directed ortho C-H acetoxylation reaction. Both isoindolinones and phenol derivatives of sulfonamides are important motifs in numerous pharmaceutically relevant compounds. The Cull-catalysed intramolecular C-H amination reaction for the synthesis of substituted 3-phenylisolindolinone derivatives (Scheme i) was found to be tolerant to substitution on both aromatic rings, however, no reaction was observed on exchanging the tethered aryl group for an alkyl group. Mechanistic investigations revealed that C-H cleavage was not part of the rate-determining step which is likely to be coordination of the copper catalyst to the sulfonyl amide. Substitution of the tethered phenyl ring (R2 ) and a subsequent Hammett analysis indicated that this coordination may be accelerated by a cation-IT interaction between CU11 and the pie system of the aryl group.

Thesis advisor: Amir H. Hoveyda
Chapter 1. The development of chiral monodentate N-heterocyclic carbenes (NHCs) is presented. Structurally varied twenty-eight new chiral imidazolinim salts, NHC precursors, were synthesized and characterized. Chapter 2. The first example of Cu-catalyzed enantioselective conjugate additions of alkyl- and arylzinc reagents to unactivated cyclic enones is presented. Transformations are promoted in the presence of 2.5-15 mol % of a readily available chiral NHC-based Cu complex, affording the desired products bearing all-carbon quaternary stereogenic centers in 67-98% yield and in up to 97% ee. Catalytic enantioselective reactions can be carried out on a benchtop, with undistilled solvent and commercially available (not further purified) Cu salts. Chapter 3. A new class of enantioselective conjugate addition (ECA) reactions that involve aryl- or alkenylsilylfluoride reagents and are catalyzed by chiral non-C2-symmetric Cu-based NHC complexes are presented. Transformations have been designed based on the principle that a catalytically active chiral NHC-Cu-aryl or NHC-Cu-alkenyl complex can be accessed from reaction of a Cu-halide precursor with in situ-generated aryl- or alkenyl-tetrafluorosilicate. Reactions proceed in the presence of 1.5 equivalents of the aryl- or alkenylsilane reagents and 1.5 equivalents of tris(dimethylamino)sulfonium difluorotrimethylsilicate. Desired products are isolated in 63-97% yield and 73.5:26.5-98.5:1.5 enantiomeric ratio (47%-97% ee). Chapter 4. An efficient Cu-catalyzed protocol for enantioselective addition of a dimethylphenylsilanyl group to a wide range of cyclic and acyclic unsaturated ketones, esters, acrylonitriles and dienones is presented. Reactions are performed in the presence of 1-5 mol % of commercially available and inexpensive CuCl, a readily accessible monodentate imidazolinium salt as well as commercially available (dimethylphenylsilyl)pinacolatoboron. Cu-catalyzed 1,4- and 1,6-conjugate additions afford the enantiomerically enriched silanes in 72%-98% yield and 90:10->99:1 enantiomeric ratio (er) with up to >25:1 of Z:E selectivity. Chapter 5. A Cu-catalyzed method for enantioselective boronate conjugate additions to trisubstituted alkenes of acyclic a,b-unsaturated carboxylic esters, ketones, and thioesters is presented. All transformations are promoted by 5 mol % of a chiral monodentate NHC-Cu complex, derived from a readily available C1-symmetric imidazolinium salt, and in the presence of commercially available bis(pinacolato)diboron. Reactions are efficient (typically, 60% to >98% yield after purification) and deliver the desired boryl carbonyls in up to >98:2 enantiomer ratio (er). In addition, metal-free, nucleophilic activation of a B-B bond has been exploited in the development of a highly efficient method for conjugate additions of commercially available bis(pinacolato)diboron to cyclic or acyclic a,b-unsaturated carbonyls. Reactions are readily catalyzed by 2.5-10 mol % of a simple NHC. A variety of cyclic and acyclic unsaturated ketones and esters can serve as substrates. Transformations deliver boryl carbonyls bearing tertiary as well as quaternary B-substituted carbons in up to >98% yield
Thesis (PhD) — Boston College, 2010
Submitted to: Boston College. Graduate School of Arts and Sciences
Discipline: Chemistry

Transition metal catalysis has emerged as one of the most versatile methods for the selective formation of carbon–carbon and carbon–heteroatom bonds. In particular, oxidative carbon–carbon bond forming reactions have been widely studied due to their atom economic feature. This thesis has been focused on the development of new palladium(II)-catalyzed carbocyclization reactions under oxidative conditions. The first part of the thesis describes the palladium(II)-catalyzed oxidative carbocyclization-borylation and -arylation of enallenes. In these reactions, the (σ-alkyl)palladium(II) intermediate, which was shown previously to undergo β-hydride elimination, could be trapped in situ by organoboron reagents (B2pin2 and arylboronic acids) to form new carbon–boron and carbon–carbon bonds. Through these two protocols, a range of borylated and arylated carbocycles were obtained as single diastereomers in high yields. The second part deals with a palladium(II)-catalyzed oxidative diarylative carbocyclization of enynes. The reaction was proposed to start with a syn-arylpalladation of an alkyne, followed by insertion of the coordinated alkene. Subsequent arylation afforded a series of valuable diarylated tetrahydrofuran and tetrahydropyran products. The final part of the thesis advances the previously developed palladium(II)-catalyzed oxidative carbocyclization-borylation of enallenes in an enantioselective manner. C2-symmetric chiral phosphoric acids were used as the novel co-catalyst to trigger the enantioselective formation of intramolecular carbon–carbon bonds. By using this chiral anion strategy, a number of enallenes were converted to the borylated carbocycles with high to excellent enantioselectivity.

At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 4: Manuscript.

En els darrers anys, la funcionalització catalítica d´enllaços C-C ha suscitat un gran interés, essent una de les disciplines amb més potencial en química organometàlica. Aquesta tesi doctoral es basa en el repte de dissenyar nous mètodes catalítics de functionalitazió d´enllaços C-C en anells de cuatre baules. Específicament, s´ha demostrat la viabilitat per preparar cetones γ-arilades via rotura d´enllaços C-C catalitzada per Pd en anells de tert-ciclobutanol utilitzant clorur d´aril i tosilats (Capítol 2). La transformació presenta una gran generalitat amb càrregues de catalitzador molt baixes. Tanmateix, s´ha trobat que fosfines riques en electrons i impedides estèricament permeten evitar processos destructius de β-eliminació d´hidrògen. Amb els precedents del capítol 2, s´ha extés satisfactòriament la generalitat de la reacció de rotura d´enllaços C-C d´anells de tert-ciclobutanol mitjançant l´acoplament amb haloacetilens per donar lloc a cetones amb grups alquins en posició γ (Capítol 3). Curiosament, els substituents del grup alquí tenen una gran influencia en la reacció. És certament remarkable l´interés potencial de la metodologia ja que els productes finals poden ser transformats fàcilment en productes d´alt valor afegit mitjançant reaccions d´acoplament creuat. Al Capítol 4, s´ha pogut extendre les metodologies de trencament d´enllaços C-C en anells de cuatre baules mitjançant el desenvolupament d´una metodologia catalitzada per Ni entre benzociclobutanones i diens per donar lloc a cicloadicions [4+4]. El mètode va mostrar una preferència específica per la formació d´anells de vuit baules respecte la formació d´anells de sis baules. Aquesta tesi doctoral també ha estudiat el disseny de metodologies de fixació de CO2 i formació d´enllaços C-F mitjançant activació catalítica d´enllaços C-C (Capítol 5). Tot i que no s´han trobat condicions de reacció òptimes, el nostre grup de recerca està actualment involucrat en el disseny de metodologies semblants i s´espera que aquesta recerca permeti el disseny de processos de fixació de CO2 i formació d´enllaços C-F mitjançant trencament C-C en un futur no molt llunyà.
Recientemente la funcionalización catalítica de enlaces C-C ha suscitado un gran interés en la comunidad científica a pesar de los retos que conlleva. Esta tesis doctoral se ha basado en diseñar nuevos procesos catalíticos para la funcionalización de enlaces C-C en anillos de cuatro miembros. Específicamente, se ha demostrado la viabilidad de preparar cetonas con grupos arilo en posición γ usando precatalizadores de Pd para promover la rotura de enlaces C-C en anillos de tert-ciclobutanol utilizando cloruros de arilo y tosilatos como agentes arilantes (Capítulo 2). La transformación se caracteriza por su amplia generalidad y baja carga de catalizador. La selectividad de la reacción puede ser fácilmente controlada por la naturaleza del ligando, en la que fosfinas con grupos ricos en electrones y voluminosos dan los mejores resultados, evitando la β-eliminación de hidrógeno de las especies organometálicas intermedias. Considerando los precedentes del Capítulo 2, se ha extendido esta metodología al acoplamiento con haloacetilenos para preparar cetonas con grupos alquino en posición γ (Capítulo 3). Curiosamente, los substituyentes del grupo alquino juegan un papel fundamental en la reactividad, pudiéndose controlar mediante la utilización de un cierto ligando. En el Capítulo 4, se ha desarrollado una nueva transformación basada en una reacción catalizada por compuestos de Ni para efectuar la síntesis de anillos de ocho eslabones mediante una reacción formal de cicloadición [4+4] de benzociclobutanonas y dienos simples. Curiosamente, dicho método muestra una especial preferencia para formar anillos de ocho eslabones sobre los, a priori, anillos de 6 eslabones que son más estables termodinámicamente. En la presente tesis doctoral se ha estudiado también la viabilidad de llevar a cabo una fijación catalítica de CO2 y la formación de enlaces C-F mediante una rotura de enlaces C-C (Capítulo 5) aunque no se han encontrado las condiciones óptimas para llevar a cabo tales transformaciones.
The means to promote catalytic C-C bond-functionalization has gained a considerable attention in recent years and probably can be considered one of the most challenging and vibrant subjects in organometallic chemistry. This PhD thesis deals with the design of new metal-catalyzed functionalization of C-C bonds in four-membered ring frameworks. Specifically, we have demonstrated the viability of preparing γ-arylated ketones via Pd-catalyzed cleavage of C-C bonds in tert-cyclobutanol using aryl chloride or tosylate counterparts (Chapter 2). The transformation possesses a wide substrate scope and remarkable low catalyst loadings. Selectivity was controlled by the ligand in which electron-rich and sterically-hindered phosphine ligands provided a unique reaction outcome that avoided the proclivity of alkyl metal species towards destructive β−hydride elimination. Prompted by the precedents in Chapter 2, we successfully extended the scope of the metal-catalyzed C-C bond-cleavage of tert-cyclobutanols by using halo acetylene counterparts giving γ-alkynylated ketones (Chapter 3). Interestingly, substituents on the alkyne motif showed a remarkable influence on reactivity. Of particular interest is the application profile of such methodology since γ-alkynylated ketones could promote consecutive metal-catalyzed transformations into valuable synthetic intermediates. In Chapter 4, we extended the interest for C-C bond-cleavage beyond the use of tert-cycñobutanols. Specifically, we developed a Ni-catalyzed C-C bond-cleavage event in benzocyclobutenones for preparing eight-membered rings via formal [4+4]-cycloaddition with dienes (Chapter 4). The method shows a specific preference for eight-membered rings over thermodynamically more stable six-membered rings. This PhD thesis has also studied the development of catalytic CO2 fixation and C-F bond-formation via C-C bond-cleavage (Chapter 5). While we have not found reaction conditions to effect the desired transformations, our research group is actively involved in related catalytic endeavors and it is expected that such research will shed light into the targeted CO2 fixation or C-F bond-forming reactions via C-C bond-cleavage.

Aquesta tesi doctoral es basa principalment amb la síntesis de molècules petites potencialment útils per investigacions avançades. S'han utilitzat diferents metodologies per obtenir-les: 1) Cicloaddicions intramoleculars entre un alkí i una azida lliures de coure per l'obtenció de derivats de benzodiazepines. Obtenint-se una gran varietat de triazols fusionats a heterocicles de set membres. Posteriorment, s'han dut a terme proves d'activitat biològica. 2) a) Trencament d'enllaços carboni-carboni no activats d'amino alcohols i utilització d'aquest com a nucleòfil juntament amb bromurs d'aril en una reacció d'acoplament catalitzada per pal.ladi per l'obtenció de dibenzil amines. S'ha dut a terme una gran optimització dels diferents paràmetres de reacció; base, dissolvent, electròfil, temperatura, catalitzador i lligand. b) Trencament d'enllaços carboni-carboni no activats de N-alil amino alcohols i utilització d'aquest com a nucleòfil juntament amb bromurs d'aril en una reacció d'acoplament catalitzada per pal.ladi per l'obtenció d'aldehids arilats en la posició beta. S'ha dut a terme la síntesis d'un gran nombre d' amino alcohols nous i aquests han estat sotmesos a les condicions optimitzades de reacció. Demostrant que aquest transformació és útil per un gran ventall de substrats (bromurs d'aril i amino alcohols).L'enamina resultant de la reacció d'acoplament s'ha aconseguit alquilar amb vinil metil cetona amb bons rendiments però pobres diastereoselectivitats tot i així s'ha demostrant que la reacció és factible. Per finalitzar, s'ha aconseguit desenvolupar la versió enantioselectiva de l’anterior transformació obtenint bons excessos enantiomerics tot i que baixos rendiments.
Ésta tesis doctoral está basada principalmente en la síntesis de moléculas pequeñas potencialmente útiles para investigaciones avanzadas. Se han empleado diferentes metodologías para obtenerlas: 1) Cicloadiciones intramoleculares entre un alkino y una azida libres de cobre para la obtención de derivados de benzodiazepinas. Se han obtenido una gran variedad de triazoles fusionados a heterociclos de siete miembros. Posteriormente se han realizado pruebas de actividad biológica de las moléculas resultantes. 2) a) Escisión de enlaces carbono-carbono no activados de amino alcoholes y utilitzación de éstos como nucleófilos conjuntamente con bromuros de arilo para una reacción de acoplamiento catalizada por paladio para la obtención de derivados de dibenzil aminas. Se ha realizado una gran optimización de las condiciones de reacción; base, disolvente, electrófilo, temperatura, catalizador y ligando. b) Escisión de enlaces carbono-carbono no activados de N-alilo amino alcoholes y la utilización de éste como nucleófilo conjuntamente con bromuros de arilo en una reacción de acoplamiento catalizada por paladio para la obtención de aldehídos arilados en posición beta. Se ha realizado la síntesis de un gran numero de amino alcoholes nuevos y éstos se han sometido a las condiciones optimizadas de reacción. Demostrando que ésta transformación es útil para una gran variedad de sustratos (bromuros de arilo y amino alcoholes). La enamina resultante de la reacción de acoplamiento se ha alquilado con vinil metil cetona con buenos rendimientos pero pobres diastereoselectividades aunque se ha demostrado que la reacción es factible. Para finalizar, se ha desarrollado la versión enantioselectiva de la anterior transformación obteniendo buenos excesos enantioméricos aunque con bajos rendimientos.
This PhD thesis is based basically on synthesis of small molecules potentially useful for further investigations. Different strategies have been used to obtain them; 1) Copper free intramolecular cycloadditions between an azide and an akyne for the obtention of benzodiazepine derivatives. A wide range of triazoles fused to seven membered heterocycles rings have been obtained. Later, biological studies have been carried out. 2)a) Carbon-carbon bond cleavage of amino alcohols has been carried out with the subsequent use of them as a nucleophile together with aryl bromides to develop a cross-coupling reaction for the obtention of dibenzyl amines. A wide optimization of the reaction parameters was carried out; base, ligand, catalyst, electrophile, temperatura, and solent. b) Carbon-carbon bond cleavage of N- allyl amino alcohols has been carried out with the subsequent use of them as a nucleophile together with aryl bromides to develop a cross-coupling reaction for the obtention of beta arylated aldehydes. An important number of new amino alcohols have been synthesized and these have been subjected to the optimized reaction conditions. It has been demonstrated that this transformation is useful for a wide range of substrates (amino alcohols and aryl bromides). The resultant enamine has been alkylated with methyl vinyl ketone with good yields but poor diastereoselectivity. To finish the enantioselective version of beta functionalization of aldehydes has been developed obtaining good enantioselectivity but poor yields

This thesis describes a series of studies directed towards the use of aerobic aldehyde C-H activation for the construction of C-C and C-N bonds by the process of hydroacylation. Chapter 1 provides an introduction to the research project and an overview of strategies for hydroacylation. Chapter 2 describes the application of aerobic aldehyde C-H activation for the hydroacylation of vinyl sulfonates and sulfones. A discussion on the mechanism of the transformation, the effect of using aldehydes with different oxidation profiles and the application of chiral aldehydes is also included. Chapter 3 describes the functionalisation of γ-keto sulfonates with particular emphasis on an elimination/conjugate addition strategy, which provides an indirect approach to the hydroacylation of electron rich alkenes. Chapters 4 and 5 describe the application of aerobic aldehyde C-H activation towards the hydroacylation of α,β-unsaturated esters and vinyl phosphonates, respectively. An in-depth discussion on the mechanism and aldehyde tolerance of each transformation is also included. Chapter 6 describes acyl radical approaches towards C-N bond formation with particular emphasis on the synthesis of amides and acyl hydrazides.

This thesis is focused on the development of new palladium and copper- mediated reactions for functionalization of alkenes and propargylic alcohol derivatives. The synthetic utility of the 1,2-diborylated butadienes synthesized in one of these processes has also been demonstrated. We have developed an efficient procedure for the synthesis of allenyl boronates from propargylic carbonates and acetates. This was achieved by using a bimetallic system of palladium and copper or silver as co-catalyst. The reactions were performed under mild conditions for the synthesis of a variety of allenyl boronates. Furthermore, the synthesis of 1,2-diborylated butadienes was achieved with high diastereoselectivity from propargylic epoxides. The reactivity of the 1,2-diborylated butadienes with aldehydes was studied. It was found that the initial allylboration reaction proceeds via an allenylboronate intermediate. The allenylboronate reacts readily with an additional aldehyde to construct 2-ethynylbutane-1,4-diols with moderate to high diastereoselectivity. We have also studied the copper-mediated trifluoromethylation of propargylic halides and trifluoroacetates. It was also shown that a transfer of chirality occurred when an enantioenriched starting material was used. In the last part of the thesis, we have described a method for palladium-catalyzed functionalization of allylic C-H bonds for the selective synthesis of allylic silanes. The protocol only works under highly oxidative conditions which suggest a mechanism involving high oxidation state palladium intermediates.

At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 1: Accepted.

Thesis advisor: Amir H. Hoveyda
Chapter 1. Part A: N-Heterocyclic Carbenes Catalyzed Enantioselective Boryl Conjugate Additions to α,β-Unsaturated Ketones, Esters, Weinreb Amides and Aldehydes. The first broadly applicable enantioselective boryl conjugate addition reactions to a variety of α,β-unsaturated carbonyls are reported. Transformations are promoted by 5.0 mol % of a chiral Lewis basic N-heterocyclic carbene. The distinctive feature of the reactions in chemoselectivity of the method compared to the Cu-catalyzed variants has been illustrated. Part B: Enantioselective Synthesis of Boron-Substituted Quaternary Carbon Stereogenic Centers through N-Heterocyclic Carbenes Catalyzed Boryl Conjugate Additions to Cyclic and Acyclic Enones The first examples of Lewis base catalyzed enantioselective boryl conjugate additions that afford products containing boron-substituted quaternary carbon stereogenic centers are presented. The carbon–boron bond forming reactions are promoted by 1.0–5.0 mol % of a chiral N–hererocyclic carbene. Cyclic or linear α,β–unsaturated ketones can be used as suitable substrates and the desired products are obtained in 63–95% yield and 91:9 to >99:1 enantiomeric ratio. The utility of the Lewis base-catalyzed approach is demonstrated in the context of an enantioselective formal synthesis of antifungal natural product crassinervic acid. Chapter 2. Enantioselectivity Fluctuations in Phosphine–Cu-Catalyzed Enantioselective Boron-Allyl Addition to Aryl-Substituted Olefins. Catalytic enantioselective multicomponent processes involving B2(pin)2, aryl or heteroaryl monosubstituted olefins, and allylic phosphates or carbonates are disclosed. Transformations promoted by a chiral Cu–phosphine complex afford products that contain a primary C–B(pin) bond and an allyl-substituted tertiary carbon stereogenic center in up to 84% yield and 98:2 enantiomeric ratio. The utility of the approach is showcased in the enantioselective formal synthesis of biologically active heliespirones A and C. Based on mechanistic and computational studies, we show that enantioselectivities variations can depend on electronic and/or steric factors of the alkene substrate and the allyl electrophile as well as their concentration. In most cases, selectivity loss can be minimized and that the resulting insights are also applicable to reactions involving Cu–H species. Chapter 3. Synthesis of Vicinal Diboronate Compounds through Practical Phosphine–Copper Catalyzed Three-Component Processes. The phosphine–Cu-catalyzed multicomponent processes have been developed for a practical and direct synthesis of vicinal diboronate compounds. Reactions of alkenyl–boronates, allylic phosphates, and diboron reagents are promoted by 2.5–10 mol % of a Cy3P–Cu complex affording a wide range of desirable vicinal diboronate products. The ability for easy access to either regioisomers of the products with a C–B(pin) and an adjacent C–B(dan) bond that can be site-selectively functionalized is a noteworthy feature of the method
Thesis (PhD) — Boston College, 2016
Submitted to: Boston College. Graduate School of Arts and Sciences
Discipline: Chemistry

Thesis advisor: Amir H. Hoveyda
Catalytic enantioselective reactions are of great importance in synthetic organic chemistry. Thus, development of efficient, selective and easily accessible catalyst for various bond formations is the main task in our laboratories. First, we have developed the first broadly applicable enantioselective boryl conjugate addition reactions to a variety of α,β-unsaturated carbonyls, promoted by a chiral Lewis basic N-heterocyclic carbene. The valuable β-boryl carbonyls were further used in complex molecule syntheses. The mechanism of these C–B bond formations was studied in details. We have also developed a practical method for enantioselective addition of an allene unit to aryl-, heteroaryl- and alkyl-substituted Boc-aldimines. These efficient C–C bond formations, catalyzed by an aminophenol-derived boron-based catalyst, were further utilized in succinct syntheses of anisomycin and epi-cytoxazone. Finally, chiral NHC–Cu complexes were employed for site-, diastereo- and enantioselective silyl conjugate additions to acyclic and cyclic dienones and dienoates. The precious enantiomerically enriched allylsilane obtained can be converted into a ketone-aldol type product, which is difficult to access through alternative methods
Thesis (PhD) — Boston College, 2015
Submitted to: Boston College. Graduate School of Arts and Sciences
Discipline: Chemistry

The main focus of this thesis has been directed towards preparation and oxidative carbocyclization of en-, dien- and aza-enallenes. In the first part of this thesis, a stereoselective oxidative carbocyclization of dienallenes was realized. By employing cheap and readily available palladium trifluoroacetate we were able to efficiently cyclize a variety of dienallenes into hydroxylated carbocycles in high yield and high selectivity. This oxidative process was compatible with two different reoxidation protocols: one relying on p-benzoquinone (BQ) as the oxidant and the other employing molecular oxygen as the oxidant. In the second part of the thesis the carbocyclization methodology was extended to include carbocyclization of aza-enallenes. This was achieved in two distinct steps. First, a copper-catalyzed coupling of allylic sulfonamides with bromoallenes was developed, giving access to the corresponding aza-enallenes. Subjecting these substrates to catalytic amounts of palladium acetate, along with BQ as the oxidant, rendered N-heterocycles in good yield. The reactivity of these N-heterocycles towards activated dienophiles was later exploited in a tandem (aerobic) oxidative carbocyclization/Diels-Alder reaction. The third topic involves efficient oxidative arylative/borylative carbocyclization of enallenes. These reactions, catalyzed by palladium acetate, relies on transmetallation of a (σ-alkyl)palladium(II) intermediate with diboranes or arylboronic acids. With this novel methodology we were able to obtain an array of arylated or borylated carbocycles, as single diastereomers, in high yield. Finally, we developed a palladium(II)-catalyzed cyclization of allylic carbamates. This mild, operationally simple, and scalable catalytic reaction opens up access to an array of oxazolidinones in high yield and excellent diastereoselectivity.

At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 6: Manuscript.

This thesis describes a broad range of coordination and organometallic chemistry on a series of ruthenium and rhodium complexes towards the aim of activating unsaturated N Ξ N, C=O, and C=C bonds. The dinitrogen complex [RuTp(pzP)(N2)]BPh4 (5) (where Tp= tris(pyrazolyl)borate, and PzP= 1-(2-diphenylphosphinoethyl)pyrazole) was synthesized via displacement of the chloride ligand from the complex [RuTp(pzP)Cl] (1). It was found that N2 coordination proceeded through an unusual oxidation/reduction cycle with the Ru(III) intermediate, [RuTp(pzP)CI]BF4 (6), isolated upon reaction of 1 with AgBF4 in THF. Investigations of the coordination chemistry of the related Tp complex [RuTp(Bp)PPh3] (4) (where Bp= bis(pyrazolyl)borate), resulted in several unusual reactions occurring on the Bp chelate. Reaction of 4 with AgBF4 gave the unusual product [RuTp(BpF')PPh3] (6), which had the Bp B-hydride substituents replaced by fluoride substituents from the BF4 anion, (i.e. BpF,). Alternatively, reaction of 4 with AgOTf, or SOCb, led to the synthesis of the products [RuTp(BpoH)PPh3]OTf (34), and [RuTp(BpoH)PPh3]Cl (35), respectively, which have a single hydroxyl substituent substituted in place of the two B-hydrides to yield a highly unusual neutral borane chelate (BpOH). A series of ruthenium tris(pyrazolyl)methane (Tpm) complexes [RuTpm(PPh3)2Cl]BPh4 (44.BPh4) RuTpm(PPh3CI2] (46), [RuTpm(PPh3)2CI]BPh4 (44.BPh4) [RuTpm(PPh3)(MeCN)Cl]BPh4 (50), [RuTpm(PPh3HMeCN)](BF4)2 (51), [RuTpm(PPh3)(MeCNh](BF4)2 (52), and [RuTpm(MeCNhCI]BPh4 (54.BPh4) were synthesized. These complexes varied in the number of labile acetonitrile ligands they contained, the net charge of the complex, and the presence or absence of strongly coordinating phosphine coligands on the complex. The influence of these properties on the catalytic activity of the complexes for the transfer hydrogenation of acetophenone was investigated. It was shown that the net charge and number of labile MeCN donors on the complex had little influence on the activity of the catalyst. It was also observed that the catalyst [RuTpm(MeCN)2CI]BPh4 (54.BPh4), which does not contain a strongly coordinating PPh3 ligand, would rapidly decompose during catalysis. A series of bis(tert-butylthiomethyl)pyridyl (SNS tBU ) pincer complexes [Ru(SNStBU)(PPh3)Cb] (65), [Ru(SN StBU)(PPh3)(MeCN)CI]BPh4 (66), [Ru(SNStBU)(PPh3)(MeCN)2](BF4h (67), and [Ru(SNStBU)(MeCN)Cb] (68) were synthesized and their as catalysts for the transfer hydrogenation of acetophenone was investigated. The activity of these complexes for as transfer hydrogenation catalysts was shown to increase as the number of labile coligands on the complex increased, with an extremely high transfer hydrogenation activity obtained using 68. The catalytic activity of 68 is one of the fastest to be reported in the literature, achieving a superlative TOF (turnover frequency) of 87360 h- I. The coordination of SNStBu in 66 and the related complexes [Ru(SNS (MeCN)2CI]BPh4 (70), and [Ru(SNS)(MeCN)2CI]2[??-Ag(MeCN)2]2(BF4)4(71) was observed to yield a range of different conformational isomers. These isomers were studied in detail using low temperature NMR and 20 NOESY and COSY IH_1H correlation experiments. The complex 71 was also characterized crystallographically and was shown to have an unusual tetrametallic macrocyclic structure with two [Ru(SNS)(MeCN)2C1r moieties bridged by two [Ag(MeCN)2r ions through a chloro and thioether donor group. The hydrogenation of unsaturated olefinic bonds was achieved using a series of Rh N-heterocyclic carbene (NHC) complexes of the type [Rh(L)(COD)]BPh4 (where L= and NHC-pyrazolyl chelate). A series of NHC-pyrazoly ligands (L) were synthesized that contained varying degrees of steric bulk on the pyrazolyl and NHC donor group. The influence of these steric parameters on the rhodium complex structure and activity of the complexes as catalysts for the hydrogenation of styrene was investigated. It was found that increasing the steric bulk around Rh decreased the activity of the catalyst.

The formation of C-C and C-N bonds in modern organic synthesis is a key target for methodological advancement. Current methods of C-C and C-N bond formation often involve the use of expensive catalysts, or sub-stoichiometric reagents, which can lead to the generation of undesirable waste products. This thesis describes a novel and environmentally benign set of reaction conditions for the formation of C-C and C-N bonds by hydroacylation and this is promoted by mixing two reagents, an aldehyde and an electron-deficient double bond, under freely available atmospheric oxygen at room temperature Chapter 1 will provide an introduction to the thesis and mainly discusses methods for C-C bond formation, in particular, radical chemistry and hydroacylation. Chapter 2 describes the hydroacylation of vinyl sulfonates and vinyl sulfones (C-C double bonds) with aliphatic and aromatic aldehydes with a discussion and evidence for the mechanism of the transformation. Chapter 3 details the synthesis of precursors for intramolecular cyclisations and studies into aerobic intramolecular cyclisations. Chapter 4 describes the hydroacylation of vinyl phosphonates (C-C double bonds) and diazocarboxylates (N-N double bonds) with aliphatic and aromatic aldehydes bearing functional groups. In addition, the hydroacylation of diazocarboxylates with chiral aldehydes will be discussed. In conclusion, a new, facile and clean set of reaction conditions for the formation of C-C and C-N bonds has been developed via aerobic C-H activation of aldehydes providing access to unsymmetrical ketones.

Density Functional Theory (DFT) is an effective tool for studying diverse metal systems. Presented herein are studies of a variety of metal systems, which can be applied to accomplish transformations that are currently difficult/impossible to achieve. The specific topics studied utilizing DFT include: 1) C–H bond activation via an Earth-abundant transition metal complex, 2) C–H bond deprotonation via an alkali metal superbase, 3) and amination/aziridination reactions utilizing a CuI reagent. Using DFT, the transformation to methanol (CH3OH) from methane (CH4) was examined. The transition metal systems studied for this transformation included a model FeII complex. This first-row transition metal is an economical, Earth-abundant metal. The ligand set for this transformation includes a carbonyl ligand in one set of complexes as well as a phosphite ligand in another. The 3d Fe metal shows the ability to convert alkyls/aryls to their oxidized counterpart in an energetically favorable manner. Also, “superbasic” alkali metal amides were investigated to perform C—H bond cleavage. Toluene was the substrate of interest with Cs chosen to be the metal of interest because of the highly electropositive nature of this alkali metal. These highly electrophilic Cs metal systems allow for very favorable C—H bond scission with a toluene substrate. Finally, the amination and aziridination of C–H and C=C bonds, respectively, by a CuI reagent was studied. The mechanism was investigated using DFT calculations. Presently, these mechanisms involving the use of coinage metals are debated. Our DFT simulations shed some insight into how these transformations occur and ultimately how they can be manipulated.

Chapter one provides a general review of the metal catalysed diboration of alkynes, 1,2- and 1,3-dienes, a,ß-unsaturated carbonyl compounds, and alkenes, as well as the metal catalysed borylation of alkane and arene C-H bonds. Chapter two is divided into two main sections. The first section introduces a high yield, highly selective catalytic synthesis of vinylboronate esters VBEs, including 1,1-disubstituted VBEs, from alkenes without significant hydrogenation or hydroboration, using the catalyst precursor, trans- [RҺС1(СО)(РРhз)2], and the diboron reagents В2РІП2, В2ПЄОР2 and HBpin. The second section addresses the synthesis of VBEs via microwave-assisted catalysis and these results are compared with those from the conventional, thermal reactions. Chapter three investigates regioselectivity in the synthesis of pyridinyl and bipyridinyl botónate esters via C-H activation using the catalyst precursor, [Іг(СОВ)(ц-ОМе)]2, and 4,4'-'Bu2-2,2'-bipyridine as the ligand. Several the pyridinyl and bipyridinyl boronate esters were coupled with aryl halides by Suzuki-Miyaura cross-coupling reactions in one pot. Examples include msiture-sensitve heteroaryl 2-boronate esters. Chapter four shows the utility of the transition metal catalysed borylation of C-H bonds in the synthesis of biologically active retinoic acid analogs.

Thesis (S.M.)--Massachusetts Institute of Technology, Dept. of Chemistry, 2012.
Cataloged from PDF version of thesis.
Includes bibliographical references (p. 26-27).
A method for the nickel-catalyzed cross-coupling between benzoxazole and secondary halides was explored. This method was to make use of the activated C-H bond found in benzoxazole at the 2-position to generate the nucleophilic species in situ. After an extensive survey of parameters no such method could be found. However, it was found that copper(I) salts promoted the coupling of benzoxazole and benzylic bromides in high yield, albeit in a racemic fashion. Additionally a method to cross-couple terminal alkynes with secondary halides employing nickel-catalysis was explored. After surveying a number of alkynylmetal species, generated in situ, alkynyl borates were found to cross-couple with allylic chlorides to furnish product with the best enantioselectivity (enantiomeric excess ca. 70%), however in low yield.
by Nicholas Ernest Bencivenga.
S.M.

Presented herein is the development, optimization and mechanistic investigation of an Cu catalytic system for the oxidation of sp 3 C-H bond of simple arenes to form C-N bond in a direct manner. Due to the prevalence of nitrogen containing molecules among biologically active synthetic and natural compounds, synthetic chemists have always been motivated to develop new efficient ways to directly transform ubiquitous carbonhydrogen (C-H) bonds into carbon- nitrogen (C-N) bonds. Recent advances in transition metal catalyzed C-H amination has demonstrated that it is not only possible but also practical to functionalize C-H bonds that are often considered inert in one step, circumventing more classical, sequential functional group interconversion approaches. Existing catalytic systems that promote the transition metal-catalyzed, amination of sp 3 C-H bonds displayed certain limitations, especially the lack of built-in versatility and stability in their amination reagents. To overcome these drawbacks of these existing catalytic system, our group developed a new Cu amination protocol that deployed versatile hydroxylamine-based with general structure RSO 2 NH-OAc as amination reagents. Although the reactivity of the catalytic system ranges from moderate to good, the catalytic system provided promising results using simple arene substrates. Further detailed mechanistic studies revealed that the reaction undergoes an unprecedented two subsequent cycles divided by a major intermediate PhCH 2 (NTsOAc). The proposed mechanism is consistent with radical clock experiments, observed reaction profiles, the need for excess of substrate, and the documented role of the ligand in the catalytic system. The exciting proposed mechanism led to a new type of copper catalyzed amination reaction using N- fluorobenzenesulfonimide (NFSI) as oxidant, which overcomes the need to use an excess of substrate. A wide range of unactivated amines HNR 1 R 2 , including sulfonamide and benzamide, can be used as amine sources, which enables the installation of different nitrogen groups on benzylic sp 3 C-H bond of a variety of substrates in moderate to excellent yield. Moreover, mechanistic experiments and critical analysis of related reactivity in the literature provide insight into the catalytic cycle, resulting in a proposal that details the role of both oxidant and amine source in the new system.

In this PhD thesis recent developments in Iron and Ruthenium Catalysts for the Reduction of C=O and C=N bonds are reported. In Part A the synthesis and reactivity of new iron complexes promoting the reduction of C=O and C=N bonds is reported. The state of the art in homogenous iron catalyzed hydrogenations is introduced in Chapter 1 followed by the results obtained with each class of iron complexes. Chapter 2 shows the synthesis, characterization and reactivity of BINOL-derived tetra isonitrile iron complexes. Two different families were designed differing in the length of the arm bearing the isonitrile group. Those complexes proved to promote asymmetric transfer hydrogenation (ATH) and asymmetric hydrogenation (AH) of acetophenone under basic conditions. Although the initial results were encouraging, the further attempts to improve the performances were mostly ineffective. Lack of activity, enantioselectivity and reproducibility issues convinced us to not proceed further. Chapter 3 reports a new class of isonitrile-phosphine ligands called PCCP: a chelating system bearing phosphine and isonitrile groups in the same BINOL-derived scaffold. Design, synthesis and characterization of the PCCP ligand are here reported. Once the corresponding iron complex was obtained, ATH of acetophenone was performed but only racemic 1-phenylethanol was yielded. Synthesis of the second generation of PCCP is still undergoing. Chapter 4 is mainly dedicated to the synthesis and the catalytic properties of the (cyclopentadienone)iron pre-catalyst [bis(hexamethylene) cyclopentadienone] iron complex 81. In the first part of the chapter the synthesis of 81 by the reaction of cyclooctyne with Fe(CO)5 and the investigation of its catalytic properties in C=O bond reduction is reported. As a result of the peculiar reactivity of cyclooctyne, 81 was formed in good yield (56%) by intermolecular cyclative carbonylation/complexation with Fe(CO)5. 81 was fully characterized and its crystal structure was determined by using XRD. Catalytic tests revealed that, upon in situ activation with Me3NO, 81 promotes the hydrogenation of ketones, aldehydes, and activated esters as well as the transfer hydrogenation of ketones and shows a higher activity than the classical “Knölker complex” 30. Studies on the hydrogenation kinetics in the presence of 81 and 30 suggest that this difference in activity is probably caused by the better stability of the 81-derived complex than that of the in situ generated Knölker–Casey catalyst. In the second part of Chapter 4 the first catalytic transfer hydrogenation of non-activated imines promoted by a Fe-catalyst 81 in the absence of Lewis acid co-catalysts is reported. Use of the (cyclopentadienone)iron complex 81 allowed to reduce a number of N-aryl and N-alkyl imines in very good yields using iPrOH as hydrogen source. The reaction proceeds with relatively low catalyst loading (0.5-2 mol%) and, remarkably, its scope includes also ketimines, whose reduction with a Fe-complex as the only catalyst has little precedents. Based on this new methodology, we developed a one-pot catalytic transfer hydrogenation protocol for the reductive amination of aldehydes/ketones, which provides access to secondary amines in high yield without the need to isolate imine intermediates. Chapter 5 is focused on the catalytic performances of BINOL-derived (cyclopentadienone)iron complexes recently synthesized in our group. Those iron complexes showed good activity in asymmetric hydrogenation of ketones and although the ee values are clearly inferior to the best literature examples of ketone asymmetric hydrogenation, they still represent the best results obtained so far with chiral (cyclopentadienone)iron complexes. Their reactivity in imine reduction (AH and ATH) was investigated and the results are reported. Both pre- and in situ formed imines were screened and promising results were obtained for acetophenone-derived imines. Part B of this thesis is focused on the use of ruthenium and Trost Ligand as catalyst for asymmetric hydrogenation of ketones. This research was carried out during my Erasmus+ Placement in LIKAT (Leibniz Institute for Catalysis, Rostock, Germany) under the supervision of Prof. Dr. J.G. de Vries and Dr. Sandra Hinze. In Chapter 6, we described the use of Trost ligand as ligand in the AH of ketones. Trost ligand was screened in the presence of several metal salts and found to form active catalysts when combined with ruthenium sources in the presence of hydrogen and a base. Reaction optimization was carried out by screening different Ru sources, solvents and bases. Under the optimized conditions, the complex formed by combination of Trost ligand with RuCl3(H2O)x in the presence of Na2CO3, is able to promote the AH of several ketones at r.t. with good yields and up to 96% ee. The reaction kinetics measured under the optimized conditions revealed the presence of a long induction period, during which the initially formed Ru species is transformed into the catalytically active complex by reaction with hydrogen.

This thesis describes cyclometallation at Pd, Mn and Co: functionalisation of C H and C≡C bonds involving cyclisation, rearrangement and isomerisation processes. The use of NaNO2/NaNO3 as an oxidant in oxidative Pd-catalyzed processes has recently been reported as a complementary co-catalyst to other common oxidants (e.g. CuII/AgI salts). In view of this (Chapter two) the synthesis of a series of palladacyclic complexes containing a C^N ligand backbone, and the geometry and linkage isomerism at NO2 Pd, has been studied. The geometry about the Pd(II) centre shows the crucial role played by bulky ligands in creating hindrance and affecting phosphine dissociation. Mn-catalysed C-H bond activation is a powerful strategy for the functionalisation of organic compounds containing metal-directing groups. Chapter three of this thesis reports the characterisation of a highly reactive 7-membered MnI species which acts as anvil point between protonation and reductive elimination to deliver alkenylated and/or pyridinium products respectively. Both processes are exemplified through the reactions of a substrate containing a 2-pyridyl directing group and electron-deficient 2-pyrone motif at MnI, where C-H bond activation occurs regioselectively at C3 within the 2-pyrone. An unprecedented regioselective Diels-Alder reaction also occurs on both the pyridine and 2-pyrone ring systems. These findings provide a unique insight into MnI-mediated C-H bond activation processes, especially how relatively minor changes in substrate structure influence the product distribution. The study shows that MnI-based metallocycles warrant further study more generally in organic and organometallic chemistry The intermolecular Pauson-Khand (PK) reactions of sterically comparable (2-pyridylethynyl)-heteroaromatic compounds with norbornene, mediated by Co2(CO)8 to give cyclopentenone products, were examined in Chapter four of this thesis. The π-deficient heteroaromatic substrate, 2-pyrone, favoured the -position while the π-rich heteroaromatics such as 2-thiophene favour the β-position. The position of the nitrogen in pyridyl-containing alkyne substrates also affects the regiochemical outcome of the PK reaction. A 2-pyridyl alkyne, possessing a proximal nitrogen atom, influences the regioselectivity relative to a 4-pyridyl variant, quite dramatically, favouring the β-position in the newly formed cyclopentenone ring. Overall, the type of heteroaromatic group greatly influences PK regioselectivity. The PK cycloadducts undergo a 6π-electrocyclisation–oxidative aromatisation reaction in the presence of light, which is promoted by a LED UV-light controlled system, affording benzo[h]indeno[1,2-f]isochromene type products.

Les alcools sont des partenaires électrophiles attractifs pour des réactions de substitution nucléophile puisque l'eau est le seul sous-produit de la réaction en présence de nucléophiles protiques. Malgré le fait que la réaction soit fortement intéressante, la portée des transformations catalytique reste limitée à une combinaison spécifique alcool/nucléophile, ce qui rend l’emploi d’un ensemble général de conditions catalytiques fortement élusif. Cette thèse décrit le développement d'un système général de catalyse doux pour l'activation d'une large gamme d’alcools π-activés ainsi que d’alcools aliphatiques abordant ainsi les limitations clés dans le domaine. B(C6F6)3•H2O, un acide de Brønsted fort quand il est combiné avec le nitrométhane, a été découvert comme étant un système catalytique idéal pour la substitution chimiosélective d'alcools en présence de fonctionnalités et de groupements protecteurs sensibles aux conditions acides sans le compromis typique entre vitesse de réaction, réactivité substrat/nucléophile et quantité de catalyseur. Plus particulièrement, un effet co-catalytique de composés nitro est décrit pour la réaction d’azidation des alcools aliphatiques tertiaires en employant B(C6F6)3•H2O, permettant, pour la première fois, un turnover catalytique. Sur la base des investigations cinétiques, électroniques et spectroscopiques qui ont été menées, des agrégats de composés nitro et d’acides liés par des intéractions hydrogènes sont proposé comme étant l’espèce catalytiques responsables de la cinétique de la catalyse observée. L'utilité des nouvelles conditions catalytiques a été étendue au-delà de l'activation d'alcool et appliquée au clivage des liaisons fortes C-F dans les réactions de Friedel-Crafts défluorinatives de fluorures aliphatiques tertiaires
Alcohols are attractive electrophilic partners for nucleophilic substitution reactions as water is the only by-product in a reaction with protic nucleophiles. Despite being a highly desirable reaction, the scope of useful catalytic transformations remains limited to specific alcohol-nucleophile pairs and a general set of catalytic conditions remains elusive. This thesis describes the development of a general and mild catalyst system for the activation of a broad range of π-activated and aliphatic alcohols to address key limitations in the field. B(C6F6)3•H2O, a strong Brønsted acid, when combined with nitromethane has been found as a widely useful catalyst system for chemoselective alcohol substitution in the presence of acid sensitive functionalities and protecting groups without the typical compromises in reaction rates, substrate/nucleophile scope and catalyst loading. In particular, a co-catalytic effect of nitro compounds is described for the B(C6F6)3•H2O catalyzed azidation of tertiary aliphatic alcohols, enabling catalyst turnover for the first time. On the basis of kinetic, electronic, and spectroscopic investigations, higher order hydrogen-bonded aggregates of nitro compounds and acids are proposed as kinetically competent Brønsted acid catalysts at the origin of the enhanced reactivity. The utility of the new catalytic conditions has been extended beyond alcohol activation and applied to the cleavage of strong C–F bonds in defluorinative Friedel-Crafts reactions of tertiary aliphatic fluorides

The main electrophilic source used in radiolabelling is [18F]F2, which is highly reactive, toxic and requires specialist equipment for safe handling. The Gouverneur group has initiated a research programme focused on the preparation of new stable and easy-to-handle N-18F reagents. In the development of [18F]radiolabelling reactions it would be extremely valuable to develop a library of selective N-18F reagents possessing reactivity tailored to the desired chemical transformation. The aim of this thesis is to further assess the scope of electrophilic N- 18F reagents in new transformations for the construction of C-18F bonds.

In the present Thesis we continued a previous study of the nucleophilic character of titanium(IV) enolates. Particularly,we focused our attention on the analysis of substrate-controlled Michael additions to enones and other acceptors.Thus, the Michael addition of (S)-2-benzyloxy-3-pentanoneto enones was thoroughly evaluatedin Chapter 1. In the case of vinyl ketones, the best reaction conditions involved the use of two TiCl4 equivalents and afforded the 2,4-antiadducts as single diastereomers in excellent yields. In addition, the developed methodology was also evaluated with β- substituted enones, whose optimised conditions using TiCl4 and SnCl4 afforded the 2,4- anti-4,5-antiadducts with diastereoselectivities above 90:10 in all cases with good yields. Furthermore, the Michael addition of (S)-2-benzyloxy-3-pentanoneto α,β- unsaturated nitroalkenes was alsoanalysed inChapter 1. The use of two equivalents of TiCl4and aromatic nitroalkenes led to the 2,4-anti-4,5-syn adducts with excellent yields and diastereoselectivities. In turn, aliphatic nitroalkenes needed optimised conditions using TiCl4 and SnCl4 to afford the 2,4-anti-4,5-syn adducts in good diastereoselectivities and yields. Finally, the nitro group was converted into other useful functional groups. Another objective of the first part of this thesis wasto re-evaluate the synthesis of the tetrahydropyran ring from the C1-C9 fragment of herboxidiene/GEX1A. Thus, in Chapter 2 we analysed the initial retrosynthesis of the C1-C9 fragment and studied the oxa-Michael cyclization. Finally, we designed two parallel sequences to improve the first synthetic approach.The stereoselective synthesis of the tetrahydropyran ring was successfully accomplished following two different approaches. In approach 1, the number of steps was increased, but the sequence pursued a fully stereoselective pathway taking advantage of the great selectivity offered by a dimethylpyrrole amide under acidic conditions attaining a 54% yield (46% for the original approach). In approach 2, the original sequence of reactions was followed, but the suppression of unnecessary purification operations and a final isomerisation step increased notably the yield up to 58% (39% for the original approach). Keepingin mind the biradical character of certain titanium enolates, the second objective of this Thesis was to examine the uncommon radical reactivity of titanium enolates derived from chiral N-acyl oxazolidinones when exposed to radical reagents. In Chapter 3, the aminoxylation of chiral N-acyl oxazolidinones was improved using a chiral tert-butyl oxazolidinethionederived from tert-leucine. This chiral auxiliary provided the aminoxylated products as single diastereomers in all cases with excellent yields. Finally, the resulting adducts were transformed into synthetical useful intermediates. Furthermore, in Chapter 3 we also reported a highly stereoselective oxidation of titanium enolates from chiral N-acyl oxazolidinones with molecular oxygen. The direct hydroxylation of biradical titanium(IV) enolates derived from chiral oxazolidinones with O2 proved to be feasible. Thus, we described a novel approach for the synthesis of enantiomerically pure α-hydroxy carboxylic derivatives. We describe in Chapter 4 a comprehensive search of compounds capable of participating in radical reactions, which involved a brief exploration of photoredox catalysis. Finally, such research led to the discovery of a new and highly stereoselective alkylation with aliphatic diacyl peroxides. Decarboxylation of the diacyl peroxides from aliphatic acids promoted by the titanium enolates produced primary and secondary radicals and triggered the formation of the alkylated adducts as single diastereomers with excellent yields.
En la presente Tesis continuamos un estudio previo sobre el carácter nucleófilo de los enolatos de titanio(IV) en adiciones de Michael con control por sustrato. Así, la adición de Michael de (S)-2-benciloxi-3-pentanona a enonas y nitroalquenos se evaluó a fondo en el Capítulo 1. En el caso de las vinil cetonas, las mejores condiciones de reacción implicaban el uso de dos equivalentes de TiCl4 o un equivalente de TiCl4 y otro de SnCl4 y proporcionaban los aductos 2,4-anti-4,5-anti con rendimientos excelentes y diastereoselectividades superiores a 90:10. Además, la metodología desarrollada también se empleó con nitroalquenos α,β-insaturados, conduciendo a proporcionar los aductos de 2,4-anti-4,5-syn con buenas diastereoselectividades y rendimientos. En el Capítulo 2 se reevaluó la retrosíntesis inicial del anillo tetrahidropiránico del fragmento C1-C9 del herboxidieno/GEX1A. La síntesis estereoselectiva del anillo de tetrahidropirano se logró con éxito siguiendo dos enfoques diferentes. En el primer enfoque, se aumentó el número de pasos, pero la secuencia siguió una ruta completamente estereoselectiva aprovechando la gran selectividad ofrecida por una dimetilpirrolamida en condiciones ácidas. En el segundo enfoque, se siguió la secuencia original, pero la supresión de operaciones de purificación innecesarias y la inclusión de una etapa de isomerización final aumentaron notablemente el rendimiento. El segundo objetivo de esta Tesis fue examinar la reactividad radical poco común de enolatos de titanio derivados de N-acil oxazolidinonas quirales cuando se exponen a reactivos radicalarios. Así, en el Capítulo 3, la aminoxilación de N-acil oxazolidinonas quirales se mejoró usando una tiazolidintiona de tert-butilo quiral derivada de tert-leucina que proporcionó los productos aminoxilados como únicos diastereómeros con rendimientos excelentes. Además, en el Capítulo 3 también llevamos a cabo una hidroxilación directa altamente estereoselectiva de enolatos de titanio a partir de N-acil oxazolidinonas quirales con oxígeno para la síntesis de derivados α-hidroxicarboxílicos enantioméricamente puros. En el Capítulo 4 describimos una búsqueda exhaustiva de compuestos capaces de participar en reacciones radicales, lo que implicó una breve exploración de la catálisis fotoredox. Finalmente, tal investigación llevó al descubrimiento de una nueva alquilación altamente estereoselectiva con peróxidos de diacilo alifáticos que conducía a la formación de los aductos alquilados como diastereómeros únicos con rendimientos excelentes.

This thesis is centred around sequential C-C bond forming processes using oxygenated electrophiles. A major part of this research focuses on the constructive deoxygenation of 2-methoxyphenol (guaiacol), a major breakdown product of the renewable feedstock, lignin. 1,2-dielectrophiles are known to be challenging substrates for catalysis if both leaving groups are of similar reactivity, however high selectivity was observed in the palladium- catalysed Grignard cross-coupling of 2-methoxyphenyl-1H-imidazole-1-sulfonate. The previously untested Grignard cross-coupling catalyst, [PdCl₂(Xylyl-Phanephos)], was found to be highly active. A 2-benzoxazolyl functionality was shown to be an excellent directing group for the chelation-controlled nucleophilic aromatic substitution of aryl methyl ethers. However, this modified Meyers reaction is limited to aryl ethers containing an ortho-chelating group. To expand the ether scope, nickel-catalysed Grignard cross-coupling was studied. [NiCl₂(PⁿBu₃)2] showed increased activity in the Grignard cross-coupling of challenging ortho-substituted anisoles compared to the well-renowned [NiCl₂(PCy₃)2] and several Ni0 -NHC systems, with a ligand steric effect demonstrated. The success of [NiCl₂(PⁿBu₃)2] was extended to more activated methoxynaphthalene substrates, in which the lowest reported catalyst loadings (0.1-0.25 mol%) were reported. Induction periods at 0.1 mol% suggested the requirement of inorganic Lewis-acidic magnesium salts to be formed in situ before any considerable activity was observed. Further work is required to increase reaction and ether scope, but this work provides a basis for exploiting lignin- derived phenols as a framework in the synthesis of functionalised chemicals of higher value. The final results chapter concerns an alternative sequential C-C bond forming process using another oxygenated electrophile. [PdCl₂((S)-Xylyl-Phanephos)] was used to accomplish a Grignard cross-coupling of vinyl tosylate, with the product then subjected to a highly enantioselective methoxycarbonylation using the same catalyst. This lead to a concise synthesis of (S)-Flurbiprofen.

Thesis: Ph. D. in Organic Chemistry, Massachusetts Institute of Technology, Department of Chemistry, 2015.
Cataloged from PDF version of thesis. Vita.
Includes bibliographical references.
Chapter 1. Palladium-Catalyzed Cross-Coupling of Aryl Chlorides and Triflates with Sodium Cyanate: A Practical Synthesis of Unsymmetrical Ureas. An efficient method for palladium-catalyzed cross-coupling of aryl chlorides and triflates with sodium cyanate is reported. The protocol allows for the synthesis of unsymmetrical N,N'-di- and N,N,N'-trisubstituted ureas in one pot, and is tolerant of a wide range of functional groups. Insight into the mechanism of aryl isocyanate formation is gleaned through studies of the transmetallation and reductive elimination steps of the reaction, including the first demonstration of reductive elimination from an arylpalladium isocyanate complex to produce an aryl isocyanate. Chapter 2. Palladium-Catalyzed Synthesis of N-Aryl Carbamates. An efficient synthesis of aryl carbamates was achieved by performing palladiumcatalyzed cross-coupling of ArX (X = CI, OTf) with sodium cyanate in the presence of alcohols. The use of aryl triflates as electrophilic components in this transformation allowed for an expanded substrate scope for the direct synthesis of aryl isocyanates. This methodology provides direct access to major carbamate protecting groups, Sthiocarbamates, and diisocyanates, which are precursors to polyurethane materials. Chapter 3. Structural Reevaluation of the Electrophilic Hypervalent Iodine Reagent for Trifluoromethylthiolation. Hypervalent iodine [lambda]3-benziodoxoles are common electrophilic transfer reagents known for their enhanced stability compared to their non-cyclic analogues. Here we present data showing that chlorobenziodoxole reacts with two different thiolate nucleophiles (thiocyanate and trifluoromethylthiolate) resulting in the formation of stable thioperoxy complexes rather than the expected benziodoxole derivatives. We further report a revised structure for the earlier described electrophilic trifluoromethylthiolation reagent (1), previously believed to contain the benziodoxole framework. Our findings, which are based on a combination of analytical techniques, including the recently introduced crystalline sponge method for X-ray analysis, unambiguously demonstrate that 1 is a thioperoxy compound both in solution and the solid state. Chapter 4. Organometallic Palladium Reagents for Cysteine Bioconjugation. Organometallic palladium reagents for the selective S-arylation of biomolecules are described. This new bioconjugation toolkit provides a highly versatile technique for the fast functionalization of cysteine with aromatic scaffolds under a broad range of reaction conditions (e.g., pH, solvent, temperature). The resulting bioconjugates are stable under basic and acidic conditions, as well as in the presence of external thiol nucleophiles. The substitution pattern on the aryl ring can be varied to achieve high levels of stability toward oxidation. Lastly, new types of bio-therapeutics - stapled peptides and linker-free antibody-drug conjugates - could be synthesized using the new method.
by Ekaterina V. Vinogradova.
Ph. D. in Organic Chemistry

Thesis advisor: Amir H. Hoveyda
Formation of C-C bonds is an invaluable tool for the construction of materials, pharmaceuticals, natural products, and the building blocks of life. Although great strides in this area have been made, there remain several limitations in regio-, site-, and enantioselective additions of carbon-based nucleophiles. Solving these challenges by expanding the scope, efficiency, and selectivity of alkyl, aryl, heteroaryl, vinyl, and alkynyl additions to carbon-based electrophiles is the topic of this dissertation
Thesis (PhD) — Boston College, 2013
Submitted to: Boston College. Graduate School of Arts and Sciences
Discipline: Chemistry

Reactions of fluorinated anilines with stoichiometric Ti(NMe2)4 in mesitylene (typically for 23 h at 120 °C) afforded moderate to high yields of the corresponding N,N-dimethyl-o-phenylenediamine derivatives resulting from defluoroamination of a fluorine atom ortho to the NH2 of the starting aniline. Reactivity increased with additional ring fluorination in general accordance with established regiochemical (activating and deactivating) trends. Based on results, we propose a metal-mediated, SNAr-based mechanism. We report the scope and limitations of this reaction and discuss trends in reactivity according to a putative mechanistic scheme.
Master of Science
This thesis describes reactions of fluorinated anilines with titanium amides to make fluorinated 1,2-phenylenediamines. The reaction gives high to moderate yields, and is highly selective for ortho substitution. The scope of the reaction, trends in reactivity among substrates, product characterization, and reaction mechanism are discussed. This reaction is of interest because fluorinated aniline derivatives are a privileged structural motif in pharmaceuticals and agricultural chemicals. The first chapter presents an overview of C-F bond activation and key background information. Chapter 2 is a description of the experiments and an in-depth analysis of their results. Chapter 3 presents detailed characterization data for substances generated in this research. Chapter 4 comprises some concluding remarks and plans for possible future extensions of the research.

The asymmetric reduction of imino bonds is a well known and utilised method of chiral amine synthesis. Chapter 1 gives an insight into the published methods for a range of substrates via hydrogenation and transfer hydrogention systems. This thesis presents a range of novel iridicycles, all of which contain chiral oxazoline and imidazoline ligands. The synthesised complexes demonstrate a variety of electronic and steric properties. Their activities are presented in the latter chapters for the asymmetric reduction of C=N bonds. Chapter 3 demonstrates the activity of the 4,5,6-trimethoxyimidazoline iridium complex for direct asymmetric reductive amination. High activity, yielding up to quantitative product is reported, under unusually mild conditions, in both aqueous and organic solvent systems. The enantioselectivites achieved were moderate to high for the substrates screened. The use of a bulky 2,4,6-tri-iso-propyloxazoline iridium complex is reported for the asymmetric reduction of quinolines, via transfer hydrogenation conditions. The tetrahydroquinolines were produced in high yields and moderate enantioselectivities. The addition of co-solvents to the aqueous system yielded improved enantioselectivies and conversions. For the reduction of pyridinium salts a bromo-dioxole imidazoline iridium complex presented high activity. This presents unprecedentedly mild conditions via a transfer hydrogenation system, producing high yields of N-benzyl piperidines. The enantioselectivites determined were high, although some could not be measured by the available means. The 2,4,6-tri-iso-propyloxazoline iridium complex further demonstrates high activity and enantioselectivity for the asymmetric hydrogenation of acyclic imines. An NMR and mechanistic study revealed the in-situ formation of a new iridium species present only in TFE.

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 focus of this thesis is on C-O bonds activation by transition metal atoms. Lignin is a potential alternative energy resource, but currently is an underused biomass species because of its highly branched structure. To aid in better understanding this species, the oxidative cleavage of the Cβ-O bond in an archetypal arylglycerol β-aryl ether (β–O–4 Linkage) model compound of lignin with late 3d, 4d, and 5d metals was investigated. Methoxyethane was utilized as a model molecule to study the activation of the C-O bond. Binding enthalpies (ΔHb), enthalpy formations (ΔH) and activation enthalpies (ΔH‡) have been studied at 298K to learn the energetic properties in the C-O bond cleavage in methoxyethane. Density functional theory (DFT) has become a common choice for the transition metal containing systems. It is important to select suitable functionals for the target reactions, especially for systems with degeneracies that lead to static correlation effects. A set of 26 density functionals including eight GGA, six meta-GGA, six hybrid-GGA, and six hybrid-meta-GGA were applied in order to investigate the performance of different types of density functionals for transition metal catalyzed C-O bond cleavage. A CR-CCSD(T)/aug-cc-pVTZ was used to calibrate the performance of different density functionals.

Thesis advisor: Masayuki Wasa
Cooperative catalysis has been developed for transformations where at least two reactants are activated in situ by acid or base sensitive catalysts to form the reactive species and subsequent bond formation leads to desired product. This thesis focuses on the development of ɑ-amino C-H alkynylation and β-amino C-H deuteration through the use of cooperative catalysts. In the alkynylation reaction, N-alkylamines and trimethylsilyl substituted alkynes were used to synthesize propargylamines by the cooperative actions of Lewis acid catalysts, B(C₆F₅)₃ and copper complex. The reaction between in situ generated iminium ion and copper alkyne complex afforded the product. The method is applicable to the late-stage functionalization of bioactive amine drug molecules and has been shown to tolerate different functional groups on trimethylsilyl-substituted alkynes. In addition, an enantioselective and diastereoselective version of the method was also developed through the use of chiral copper complex. In the second part, selective deuteration of β-amino C-H bonds of various acylic and cyclic alkyl amines will be introduced. B(C₆F₅)₃ and Brønsted base work cooperatively to afford enamine and deuterated ammonium ion as reactive intermediate. Deuteration of enamine at the β-position and hydride reduction at the ɑ-position gave the selectively deuterated products. Acetone-d₆ was the found to be the optimal source of deuterium. This method was able to incorporate deuterium atoms up to 99% and can be applied in a gram scale reaction without compromising the yield or d-incorporation level
Thesis (MS) — Boston College, 2020
Submitted to: Boston College. Graduate School of Arts and Sciences
Discipline: Chemistry

In the laboratory under the direction of Prof. Roberto Ballini (where I carried out my PhD work), an ''in-progress'' research project has been under way for the past few years. This project, in the field of eco-friendly chemical processes, aims to develop new synthetic methods which could reduce waste and guarantee cleaner reactions. In the team, my task involved studying new reduced environmental impact processes in C-C and C-X bonding. These new processes have been achieved through solid heterogeneous catalysis and domino reactions, and both these methods are in accordance with Green Chemistry guidelines ''Green Chemistry is the design of chemical products and processes that reduces or eliminates the use and generation of hazardous substances'' In this context, by means of solid heterogeneous catalysis, it is possible to reduce complicated work-up to a simple filtration or to a direct loading onto chromatographic column, avoiding the usage of aqueous layer, extraction with organic solvents and, above all, the application and the formation of salts, like Na2SO4 and NH4Cl. Further, the catalyst is weakly corrosive, shows very low toxicity, provides reaction without the use of any solvent (i.e. the most toxic element in a reaction) and, sometimes, it can be recycled. Domino reactions, defined as: ''the processes of two or more bond forming transformations under widely identical conditions in which the subsequent reactions take place at the functionalities obtained in the former transformation'', offer several advantages, in terms of environmental protection and lowering of costs, that lead to an advance toward eco-friendly systems. In fact, the possibility of producing two or more bonds in the same reaction conditions, instead of isolating every intermediate, diminishes the number of steps and consequently entails a reduction of work-up and purification processes. At the end, besides shortening the whole operation span, it provides a cut in the usage of solvents and reagents with evident decreasing of pollution. Thesis work As mentioned above, the main task of my PhD has been to cooperate to development of new synthetic processes in order to produce new C-C and C-X bonds under eco-friendly conditions. For this purpose aliphatic nitro compounds, thanks to the strong electron-withdrowing power of the nitro group, that guarantees the access using weak conditions to stabilized carbanions and the possibility of using the same group as leaving group, have proved to be good starting materials,compatible with low environmental impact processes.

Part A: Oxo-rhenium-catalyzed Biomimetic Cyclization Biomimetic cyclizations are remarkable tools because a significant increase in molecular complexity can be obtained in a single step. In the first part of my PhD, a new method to promote biomimetic cyclizations of terpenoid-like starting materials using an oxo-rhenium complex as a catalyst is described. This proof of concept, if further explored, will give access to useful building blocks that can be employed for the total synthesis of natural products. Part B: Electrochemical C–H Oxidation The site-specific oxidation of “strong”, non-acidic C(sp3)–H bonds is a rewarding, yet difficult topic in organic synthesis. In the second part of my PhD, N-ammonium ylides are described as tunable, electrochemically driven oxidants for site-specific, chemoselective C(sp3)–H oxidation. This ylide-based approach to C–H oxidation exhibits a unique selectivity relative to other classes of chemical oxidants and can be applied to real-world problems.
Part A: Oxo-rhenium-catalyzed Biomimetic Cyclization Biomimetic cyclizations are remarkable tools because a significant increase in molecular complexity can be obtained in a single step. In the first part of my PhD, a new method to promote biomimetic cyclizations of terpenoid-like starting materials using an oxo-rhenium complex as a catalyst is described. This proof of concept, if further explored, will give access to useful building blocks that can be employed for the total synthesis of natural products. Part B: Electrochemical C–H Oxidation The site-specific oxidation of “strong”, non-acidic C(sp3)–H bonds is a rewarding, yet difficult topic in organic synthesis. In the second part of my PhD, N-ammonium ylides are described as tunable, electrochemically driven oxidants for site-specific, chemoselective C(sp3)–H oxidation. This ylide-based approach to C–H oxidation exhibits a unique selectivity relative to other classes of chemical oxidants and can be applied to real-world problems.

Ce travail de thèse présente le développement de nouvelles réactions de formation de liaisons carbone-carbone. Le premier chapitre décrit la cyanation d’arylzinciques par catalyse au cobalt à partir d’une source non toxique et bénigne, le N-cyano-N-phenyl-p-methylbenzenesulfonamide (NCTS), et conduit à de bons rendements en benzonitriles correspondants. Dans cette réaction, le cobalt sert de catalyseur non seulement pour la formation des arylzinciques mais aussi pour la formation de liaisons C-CN. Les groupements fonctionnels, cétone et nitrile, sont permis lorsque le complexe de cobalt associé au ligand bipyridine est utilisé. Le deuxième chapitre porte sur l’homocouplage Csp3-Csp3. Un simple halogénure de cobalt permet de catalyser la dimérisation des halogénures d’alkyles et des acétates d’allyles avec de bons à d’excellents rendements. L’ajout d’iodure de sodium permet d’étendre cette réaction aux chlorures et tosylates d’alkyles. Le couplage croisé entre 2 halogénures d’alkyle différents a également été testé mais les conditions doivent être optimisées. Dans le troisième chapitre, le couplage croisé catalysé au cobalt entre des bromures vinyliques et des chlorures benzyliques est présenté. Des halogénures de vinyles et de benzyles porteurs de groupements electrodonneurs ou electroattrateurs peuvent ainsi être couplés efficacement avec rétention de la configuration de la double liaison. Un mécanisme radicalaire semble être impliqué. Enfin, le dernier chapitre décrit l’arylation d’une 2-phenylpyridine avec un arylzincique par catalyse au cobalt par activation d’une liaison C-H et conduit à de premiers résultats encourageants
This thesis presents the development of cobalt-catalyzed carbon-carbon bonds formation. The first chapter describes a novel cobalt-catalyzed electrophilic cyanation of arylzinc species, employing benign and non-toxic N-cyano-N-phenyl-p-methylbenzenesulfonamide (NCTS) as the cyano source. In this reaction, cobalt catalyzes both the formation of arylzinc species and the cyanation reaction. Various benzonitriles are synthesized affording good to excellent yields. Using cobalt-bipyridine complexes instead of CoBr2, ketone and nitrile groups can be tolerated. The second chapter reports cobalt-catalyzed Csp3-Csp3 homocoupling reaction. A simple catalytic system could deliver dimers of a number of alkyl halides/pseudohalides and allylic acetates. Sodium iodide is crucial for the homocoupling of unactivated alkyl chlorides and tosylates. This method is extended to alkyl-alkyl cross-coupling; however, the conditions still need to be optimized. The third chapter describes a cobalt-catalyzed vinyl-benzyl cross-coupling. A variety of functionalized vinyl bromides and benzyl chlorides are efficiently coupled under mild conditions in good to excellent yields, with retention of Z/E configuration. A few mechanistic experiments indicate a single electron transfer involved. The last chapter discusses the progress on the cobalt-catalyzed arylation of 2-phenylpyridine with an arylzinc species by C-H activation and promising results are obtained

Thesis (Ph. D.)--University of North Carolina at Chapel Hill, 2008.
Title from electronic title page (viewed Oct. 5, 2009). "... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Chemistry." Discipline: Chemistry; Department/School: Chemistry.

Dans cette thèse, nous avons démontré que le complexe Ru(CO₂R)₂(p-cymene) généré in situ à partir de [RuCl₂(p-cymene)]₂ et de KCO₂R était un excellent catalyseur pour l'ortho-fonctionnalisation de liaisons C-H d'arenes contenant un hétérocycle pyridine, oxazoline ou pyrazole. Ces réactions se font à partir de dérivés chlorés généralement peu réactifs et en présence de K₂CO₃ comme base. Les réactions ont été effectuées dans le dimethyl carbonate (DEC) ou dans l'eau comme solvants au lieu de la N-methylpyrrolidone (NMP), le solvant de choix pour ce type de réactions. Il a ainsi été démontré que les catalyseurs sont plus actifs dans l'eau que dans la NMP. Nous avons également mis en évidence un nouveau catalyseur basé sur l'utilisation de [RuH(codyl)₂]BF₄/2KY(KY: KOAc, KOPiv, KPI) dans lequel Y favorise le cleavage initial de la liaison C-H. L'oléfination déshydrogénante de N-aryl pyrazoles par le styrène ou les alkyls acrylates catalysée par le complexe Ru(OAc)₂(p-cymene) en présence d'une quantité catalytique ou stœchiométrique de Cu(OAc)₂H₂O est aussi présentée. Cette réaction s'effectue à l'air et nécessite l'utilisation d'acide acétique comme solvant. Une nouvelle méthode de synthèse du produit d'homocouplage oxydant de la N-phenylpyrazole est également présentée
In this doctoral thesis, we have shown that Ru(CO₂R)₂(p-cymene) catalyst the insitu generated from [RuCl₂(p-cymene)]₂ and KCO₂R, acts as an excellent catalyst for ortho C-H bond functionalization of arenes containing an heterocycle (pyridine, oxazoline, pyrazole) with unactivated aryl chlorides in the presence of K₂CO₃ as a base. The reactions were performed in diethyl carbonate (DEC) or in water as a solvent instead of N-methylpyrrolidone (NMP), the solvent of choice used in most of ruthenium catalyzed C-H bond transformations. The activity of these catalysts is higher in water than in other organic solvents. We have also disclosed a new catalytic system based on [RuH(codyl)₂]BF₄/2KY(KY: KOAc, KOPiv, KPI) in which the ligand Y promotes the initial cleavage of C-H bonds and the efficiency of this catalytic system depends also on the nature of both substrates involved in the reaction. The directed dehydrogenative alkenylation of N-aryl pyrazoles by styrene and alkyl acrylates catalyzed by Ru(OAc)₂(p-cymene) in the presence of a catalytic or stoichiometric amount of Cu(OAc)₂ H₂O in air is also presented and it is demonstrated that the acetic acid solvent plays a key role. A new method to generate the oxidative homocoupling of N-phenylpyrazole is shown with the Ru(OAc)₂(p-cymene) catalyst

The present research project concerns the catalytic application of transition metal dicarbene complexes in aromatic C-H bond functionalisation/activation reactions. The efficiency of this kind of complexes has been mainly examined in the hydroarylation of alkynes (Fujiwara reaction), which involves the addition of arenes to a wide range of internal and terminal alkynes. It was already known that this reaction is catalysed by simple palladium(II) compounds, such as Pd(OAc)2, in a trifluoroacetic acid environment. It occurs at room temperature and is characterised by a high and quite unusual regio- and stereoselectivity: remarkably the thermodynamically less favoured cis-arylalkenes are often obtained as major products. The Fujiwara reaction appears very promising from the synthetic point of view also because both the inter- and intra-molecular versions of the reaction are known, thus expanding its applicability to the functionalisation of aromatic heterocycles and to the synthesis of coumarins. However, the possible industrial application requires the optimisation of the reaction conditions since the reaction is often quite slow, needs an excess of arene substrate, and it usually requires 1-5 mol% palladium which heavily affects the cost of the process. In the literature other metal centres, such as platinum(II), gold(I) and gold(III) have been successfully employed as alternative catalysts, but their efficiency appears to be lower than that of palladium(II). Also the use of non-noble, electrophilic metal centres has been reported, but their reactivity is lower and/or their applicability limited to aryl-acetylenes. The initial aim of the present research project was to improve the yields of the reaction and decrease the catalyst loading. N-heterocyclic carbene ligands can improve the stability of the catalyst under the reaction conditions as well as its reactivity. Monocarbene Pd(II) complexes (IPr)Pd(OAc)2 and (IPr)Pd(OOCCF3)2 (IPr = N,N’-bis(2,6-diisopropylphenyl)-imidazol-2-ylidene) are indeed the only complexes which have been reported to be active in the Fujiwara reaction in the absence of other promoters, though their activity is comparable to that of simple Pd(OAc)2. In the initial part of this research work it has been shown that dicarbene palladium(II) complexes are able to catalyse the hydroarylation of alkynes at 80 °C, with excellent conversions and selectivities at low catalyst loading (0.1 mol%) and with equimolar amounts of reagents. These dicarbene complexes have displayed a reactivity higher than simple palladium acetate and monocarbene palladium complex (12) tested in the same reaction conditions. Dicarbene platinum(II) complexes have also been employed and have performed an efficiency superior than Pt salts based systems reported in the literature. The optimised protocol has resulted quite general with respect to the alkyne, while its applicability to arene substrates is at present limited to electron-rich molecules. However this is a limitation occurring with all Pd- and Pt-catalytic systems reported in the literature for the hydroarylation reaction. Another part of the work has concerned the identification of the catalytic active species. Mechanistic studies, performed at 80 °C and made varying both the dicarbene ligand and the halide ligands at the metal, have revealed that the catalytic active species retains the dicarbene ligand in its coordination sphere. Halide anionic ligands are instead removed from the complex by exchange with the trifluoroacetate anion deriving from the acidic solvent media. The catalytic efficiency of the complex does not depend on the kind of halide ligands, but it is influenced by the nature of the dicarbene ligand. Parallel electrochemical studies have been therefore made to evaluate the electronic density at the metal centre in different dicarbene complexes. The aim is to clarify if the catalytic efficiency of the complex is predominantly influenced by its electronic or steric properties, in order to design the best catalyst for the reaction. Cyclic voltammetries have shown that the electronic density at the metal changes depending on the dicarbene ligand, but the scale of reduction potentials Pd(II)-Pd(0) is not correlated to the scale of catalytic activity. This suggests that the catalytic efficiency of such complexes in the Fujiwara reaction is predominantly influenced by the steric hindrance at the metal centre. A successive optimisation of the reaction parameters (nature of the solvent system, concentration of the reagents, reaction temperature and use of co-catalysts) has allowed to further increase the selectivity of the reaction under mild reaction conditions. It has indeed found that, in the presence of silver salts (like AgTFA) as co-catalysts, the reaction can be run at room temperature, with conversion higher than the one displayed by palladium acetate in the same reaction conditions. Differently from at 80 °C, isomerisation to the more thermodinamically stable trans-arylalkene and hydrolysis reactions of the ester functions do not occur at room temperature, so that selectivity towards the cis-arylalkene product has been significantly improved. Finally, the optimised catalytic system has been used with other substrates, such as aromatic heterocycles, obtaining also in this case high yields in products. However, the selectivity towards the desired product decreases by the formation of adducts heterocycle/alkyne 2/1. A preliminary investigation of the reaction mechanism through kinetic studies has been also started. There is indeed at present some controversy about the reaction mechanism, that could be an electrophilic arene metalation or a Friedel-Crafts-type alkenylation. The kinetic law has resulted of the first order in palladium and, in the adopted reaction conditions, of the first order also in arene or in alkyne. It remains to evaluate the dependence of the kinetic law from the concentration of the acid, which seems to have an important role in the reaction mechanism. However, it needs to be used in large excess with respect to the substrates and probably its principal role is to hydrolyse the vinyl-palladium species, invoked as catalytic intermediate in both the proposed mechanisms. Dicarbene complexes of palladium(II) and platinum(II) have been also tested in other aromatic C-H bond functionalisation reactions, such as the ortho-functionalisation of acetanilides.
Il presente progetto di ricerca riguarda l’applicazione di complessi dicarbenici di metalli di transizione in reazioni di funzionalizzazione/attivazione di legami C-H aromatici. L’efficienza catalitica di questi complessi è stata principalmente valutata nella reazione di idroarilazione di alchini (reazione di Fujiwara), che consiste nell’addizione di areni ad alchini interni o terminali catalizzata da semplici composti di palladio(II), come Pd(OAc)2. Questa reazione decorre in ambiente acido, generalmente acido trifluoroacetico, a temperatura ambiente e presenta una elevata ed inusuale regio- e stereoselettività: si ottengono infatti come prodotti principali i cis-arilalcheni, che sono le olefine termodinamicamente meno favorite. La reazione appare molto promettente dal punto di vista tecnologico, anche perché sono conosciute sia la versione inter- che quella intramolecolare, permettendo quindi la funzionalizzazione di eterocicli aromatici e la sintesi di cumarine. La potenziale applicazione industriale richiede però l'ottimizzazione delle condizioni di reazione, poichè la reazione è spesso lenta, necessita di un eccesso di arene rispetto all’alchino e viene condotta con un elevato tenore di catalizzatore (1-5%), fattore che incide pesantemente sul costo del processo. Altri centri metallici, come Pt(II), Au(I) e Au(III), sono stati impiegati come catalizzatori alternativi, ma la loro reattività sembra essere inferiore a quella mostrata dai composti di palladio(II). Sono stati utilizzati anche centri metallici elettrofilici non nobili, ma la loro reattività è inferiore e/o la loro applicabilità limitata ai soli aril-acetileni. L’obiettivo iniziale di questo progetto di tesi è stato quindi quello di migliorare le rese della reazione e diminuire il tenore di catalizzatore. Leganti carbenici N-eterociclici possono aumentare la stabilità del catalizzatore nelle condizioni di reazione e quindi la sua reattività. I complessi monocarbenici di palladio(II), (IPr)Pd(OAc)2 e (IPr)Pd(OOCCF3)2 (IPr = N,N’-bis(2,6-diisopropylphenyl)-imidazol-2-ylidene) sono infatti gli unici complessi ad essere risultati attivi nella reazione di Fujiwara senza bisogno di promotori, sebbene la loro reattività sia comparabile a quella mostrata da Pd(OAc)2. Nella prima parte di questo lavoro di ricerca è stato dimostrato che complessi dicarbenici di palladio(II) catalizzano la reazione ad 80 °C, con eccellenti conversioni e selettività a basso tenore di catalizzatore (0.1%) e con i reagenti in rapporto equimolare. Questi complessi hanno mostrato una reattività maggiore rispetto al semplice palladio acetato ed al complesso monocarbenico (12) testati nelle stesse condizioni di reazione. Sono stati impiegati in questo studio anche complessi dicarbenici di Pt(II), che si sono dimostrati più attivi dei sistemi catalitici di platino riportati in letteratura. Il protocollo ottimizzato è risultato abbastanza generale per quanto riguarda gli alchini, mentre la sua applicabilità agli areni è al momento limitata a molecole elettron-ricche. Questa è comunque una limitazione di tutti i sistemi catalitici di Pd e Pt riportati in letteratura per l’idroarilazione di alchini. Una seconda parte del lavoro ha riguardato l’identificazione della specie cataliticamente attiva. Studi meccanicistici condotti ad 80 °C, variando sia il legante dicarbenico che i leganti anionici al metallo, hanno mostrato che la specie cataliticamente attiva mantiene il legante dicarbenico nella sua sfera di coordinazione, mentre i leganti anionici vengono rimossi dal complesso attraverso uno scambio con l’anione trifluoroacetato derivante dal solvente acido. L’efficienza catalitica del complesso non dipende dal tipo di leganti anionici, ma dipenda invece dalla natura del legante dicarbenico. Sono stati inoltre effettuati studi elettrochimici per determinare la densità elettronica presente al centro metallico in complessi con diverso legante dicarbenico, con lo scopo di chiarire se l’efficienza del complesso sia principalmente influenzata dalle proprietà elettroniche o da quelle steriche di questo legante e di progettare così il migliore catalizzatore per la reazione. Le voltammetrie cicliche hanno mostrato che la densità elettronica al centro metallico varia a seconda del legante dicarbenico, ma che la scala di potenziali di riduzione Pd(II)-Pd(0) non è correlabile alla scala di attività catalitica. L’efficienza di questo tipo di complessi nella reazione di Fujiwara sembra quindi essere principalmente influenzata dall’ingombro sterico al centro metallico. La successiva ottimizzazione dei parametri di reazione (natura del solvente, concentrazione dei reagenti, temperatura di reazione ed utilizzo di co-catalizzatori) ha permesso di incrementare ulteriormente la selettività della reazione in condizioni di reazione blande. E’ stato infatti dimostrato che in presenza di sali di argento come co-catalizzatori (per esempio AgTFA) la reazione avviene anche a temperatura ambiente, con conversioni maggiori di quelle ottenute con palladio acetato nelle stesse condizioni di reazione. Diversamente che a 80 °C, le reazioni di isomerizzazione a trans-arilalchene (prodotto più stabile termodinamicamente) e le reazioni di idrolisi delle funzioni esteree non avvengono a temperatura ambiente, cosicché la selettività verso il cis-arilalchene viene notevolmente migliorata. Infine, sono state determinate le condizioni sperimentali adatte per estendere questo protocollo sintetico ad eterocicli aromatici, ottenendo anche in questo caso elevate rese nei prodotti. La selettività della reazione verso il prodotto desiderato è però diminuita dalla formazione di addotti eterociclo/alchino 2/1. Analisi preliminari di tipo cinetico hanno inoltre dato una prima indicazione sul tipo di meccanismo coinvolto nella reazione, che non è ancora del tutto chiarito e che potrebbe coinvolgere la metallazione elettrofilica dell’arene oppure una alchenilazione di tipo Friedel-Crafts. La legge cinetica è risultata essere del primo ordine in palladio e, nelle particolari condizioni dei reazione adottate, anche del primo ordine in arene o in alchino. Rimane da valutare la dipendenza della legge cinetica dalla concentrazione di acido, che sembra avere un ruolo importante nel meccanismo di reazione. Deve essere infatti utilizzato in largo eccesso rispetto ai substrati e probabilmente il suo ruolo principale è quello di idrolizzare la specie vinilica di palladio, proposta come intermedio catalitico in entrambi i cicli riportati in letteratura. I complessi dicarbenici di palladio(II) e platino(II) sono stati testati anche in altre reazioni di funzionalizzazione di legami C-H aromatici, come l’orto-funzionalizzazione di acetanilidi.

Le sujet de cette thèse se situe dans le cadre général des arylations de nucléophiles catalysées par des complexes de métaux de transitions (Cu, Fe) ou réalisées en absence de ces derniers, dans des conditions compétitives et respectueuses de l’environnement. Ces réactions sont d’une importance majeure pour l’industrie chimique. Dans un premier chapitre est tout d’abord décrit un couplage inédit mettant en jeu un sel d’aryldiazonium et un nucléophile azoté (formation de liaison CAr-N). La méthode procède dans des conditions douces via un système catalytique au cuivre peu coûteux et peu toxique. Les produits de couplage obtenus (Ar-NHet) sont d’un intérêt central dans l’industrie pharmaceutique et agrochimique. Dans une deuxième partie nous avons présenté une méthode permettant de réaliser le couplage entre des sels d’aryldiazonium et des dérivés du styrène, à l’aide d’un système t BuOK/DMF. Cette réaction, réalisée pour la première fois en absence de catalyseurs à base de métaux de transition, permet d’accéder, via la formation de liaisons CArsp²-Csp², à des motifs stilbènes variés qui trouvent de nombreuses applications en chimie pharmaceutique. Un deuxième chapitre porte sur l’utilisation de dérivés de l’iode hypervalent permettant la fonctionnalisation de noyaux aromatiques (C-H) ou de dérivés vinyliques (C-H). Une première méthode décrit une réaction de triflimidation directe de composés acétanilides avec une sélectivité exclusive en position para. Deux conditions réactionnelles ont été mises en place pour cette fonctionnalisation. Une première utilise une quantité stœchiométrique de PhI(OAc)2 et une autre utilise une quantité catalytique d’iodotoluène (génération in-situ de l’iode(III)). Cette transformation a conduit à la formation de liaisons CAr-N en présence de bis(trifluorométhane)sulfonimide de lithium (LINTf2) comme nucléophile azoté. Dans une deuxième partie, nous avons montré que l’iodure de bisphosphoranilidène (PNPI), pouvait catalyser la trifluorométhylation vinylique sélective de dérivés du styrène en présence d’un réactif de l’iode hypervalent (l’iode(III)), le réactif de Togni II. Des travaux sont en cours pour tenter de comprendre l’influence positive de l’utilisation de PNPI dans le cas de notre réaction. Un troisième chapitre décrit des résultats préliminaires permettant d’obtenir un rendement honorable (54%) lors du couplage catalysé au fer du 4-iodotoluène avec le phényllithium. Une autre série de test décrit le couplage entre des halogénures d’aryle et des alkyllithium primaires. La méthode semble très efficace, puisque par ailleurs les travaux très récents de la littérature pour des couplages similaires faisant intervenir les mêmes partenaires réactionnels, font appel à des catalyseurs de fer ou de palladium
This thesis is part of a very general search seek to develop methodologies for environmentally sustainable conversion of small molecules into more valuable substances catalyzed by copper and iron complexes or under metal-free conditions. The work focuses on the functionalization of aromatic rings by C-C or C-N bond formation.In a first chapter, a novel coupling involving an aryldiazonium salt and a nitrogenous nucleophile (CAr-N bond formation) is first described. The method proceeds under mild conditions using a cheap and non-toxic copper catalyst system. The obtained coupling products (Ar-NHet) are of central interest in the pharmaceutical and agrochemical industry. Then in a second part, a method allowing the coupling between aryldiazonium salts and styrene derivatives, using a BuOK / DMF system is presented. This reaction, carried out for the first time in the absence of catalysts based on transition metals, makes it possible to access to various stilbene units which find numerous applications in pharmaceutical chemistry.A second chapter concerns the use of hypervalent iodine derivatives allowing the functionalization of aromatic or vinyl substrates. A first method describes a direct triflimidation reaction of acetanilide compounds with an exclusive selectivity in the para position. Two reactions conditions have been established for this functionalization. One uses a stoichiometric amount of PhI(OAc)2 and another uses a catalytic amount of iodotoluene (in-situ generation of iodine (III)). This transformation resulted in the formation of CAr-N bonds in the presence of lithium bis (trifluoromethane) sulfonimide (LINTf2) as the nitrogen nucleophile. In a second part, we have shown that bisphosphoranilidene iodide (PNPI) can catalyze a selective vinylic trifluoromethylation of styrene derivatives in the presence of a hypervalent iodine reagent (iodine (III)), Togni’s reagent II. Work is under way to try to understand the positive influence of PNPI.A third chapter describes preliminary results of an iron-catalyzed heterocoupling of 4-iodotoluene an phenylithium system allowing the obtention of an honorable yield (54%) during the coupling of 4-iodotoluene with phenyllithium. Another series of tests describes the coupling between aryl halides and primary alkyllithiums. The method seems to be very effective, since very recent work in the literature for similar couplings involving the same reaction partners involves catalysts of iron or palladium

En la present Tesi Doctoral en primer lloc s’ha completat un estudi previ de reaccions aldòliques d’α-hidroxi metil cetones, tant per a grups protectors benzílics com silílics. Així, al Capítol 1 s’ha demostrat que la tria adequada del grup protector de l’α-hidroxi cetona i l’àcid de Lewis permet accedir a aldols 1,4-anti o 1,4-sin amb bons rendiments (5697%) i diastereoselectivitats en ocasions excel•lents (fins a rd 96:4), dins el context de l’aldòlica d’acetat. Les metodologies desenvolupades també s’han avaluat amb aldehids quirals en processos doblement asimètrics. La notable capacitat d’inducció asimètrica dels enolats de titani d’α-benziloxi metil cetones ha quedat demostrada per l’obtenció dels seus aldols amb unes diastereoselectivitats excel•lents, independentment de la configuració de l’aldehid. Fins i tot, un d’aquests aldols obtingut enantiomèricament pur s’ha utilitzat en la síntesi del fragment C12C16 de l’epotilona B. A més, una seqüència de reacció aldòlica-reducció desenvolupada anteriorment al grup s’ha aplicat a l’(S)-3-tert-butildimetilsililoxi-4-metil-2-pentanona per obtenir els corresponents triols 1,2-sin-2,4-sin amb rendiments excel•lents (9192%) i un control estereoquímic que depèn, majoritàriament, de la reacció aldòlica inicial (rd 80:2094:6). Al Capítol 2 s’ha demostrat la utilitat sintètica de les reaccions aldòliques d’enolats de titani d’α-hidroxi etil cetones desenvolupades anteriorment en el grup de recerca. Aquestes metodologies s’han aplicat amb èxit en la síntesi total de l’herboxidiè, contribuint a la construcció de gran part del seu esquelet carbonat i dels estereocentres requerits. La reacció aldòlica de l’(S)-2-benziloxi-3-pentanona i la seqüència d’aldòlica-reducció de l’(R)-2-tert-butildimetilsililoxi-3-pentanona han estat etapes clau en la síntesi dels fragments C1C9 (17%, deu etapes) i C10C19 (43%, set etapes), respectivament. La unió d’aquests fragments ha permès obtenir l’herboxidiè amb un 8% de rendiment global amb la seqüència lineal més llarga de catorze etapes. Després d’haver estudiat a fons les reaccions aldòliques d’enolats de titani d’α-hidroxi cetones, s’ha explorat la reactivitat d’aquests nucleòfils en altres processos de construcció d’enllaços CC. Al Capítol 3 s’ha desenvolupat l’addició de Michael de l’enolat de titani de l’(S)-2-benziloxi-3-pentanona a cetones α,β-insaturades, amb què s’han obtingut els corresponents adductes 1,3-anti-3,4-anti amb excel•lents diastereoselectivitats (rd ≥ 89:11). Partint del mateix nucleòfil, en aquest Capítol també s’ha iniciat un estudi d’addicions de Michael a nitro alquens. L’addició de l’enolat de titani de l’(S)-2-benziloxi-3-pentanona a l’(E)-4-metoxi-β-nitroestirè ha produït el corresponent adducte de Michael amb excel•lent diastereoselectivitat (rd ≥ 97:3). Aquests primers resultats són prou esperançadors i demostren l’interès sintètic que poden arribar a tenir aquestes reaccions, que actualment constitueixen una línia activa d’investigació al grup de recerca. Finalment, prenent com a punt de partida el caràcter biradicalari de determinats enolats de titani, en aquesta Tesi s’ha iniciat un estudi de la reactivitat d’aquests substrats en reaccions de formació d’enllaços CC i CO. Així, al Capítol 4 s’ha estudiat l’al•lilació d’N-acil oxazolidinones quirals amb al•lil estannans, amb què s’han obtingut els corresponents adductes amb un control estereoquímic excel•lent (rd ≥ 97:3). D’altra banda, en la constitució d’una nova línia d’investigació al grup, en el darrer Capítol també s’ha desenvolupat l’oxidació estereoselectiva d’N-acil oxazolidinones quirals amb TEMPO. S’ha demostrat que la utilització d’aquest radical estable permet l’oxidació dels corresponents enolats de titani i condueix als α-aminoxi derivats amb rendiments i diastereoselectivitats excel•lents (9095%, rd ≥ 93:7) i, a més, s’ha descrit l’aminoxilació estereoselectiva en la posició d’enolats conjugats. L’eliminació de l’auxiliar quiral i/o el trencament reductiu de l’enllaç NO han permès arribar a derivats sintèticament útils. Per últim, s’ha descobert que es pot assolir la hidroxilació directa d’aquests substrats a través de la reacció dels seus enolats de titani amb O2.
The first Chapter of the present text deals with substrate-controlled titanium-mediated aldol reactions of chiral α-hydroxy methyl ketones. The appropriate choice of the Lewis acid and the protecting group in the α-hydroxy ketone gives access to either 1,4-anti or 1,4-syn aldol adducts in good yields (5697%) and diastereoselectivities up to ≥ 97:3 with a broad range of aldehydes. Furthermore, a sequential aldol reaction-reduction transformation from (S)-3-tert-butyldimethylsilyloxy-4-methyl-2-pentanone provides 1,2-syn-2,4-syn triols in excellent yields (9192%) and a stereochemical control which mostly relies on the aldol step of the sequence (dr 80:2094:6). The usefulness of these methodologies is proven in Chapter 2 with its application in the total synthesis of herboxidiene. Most of the carbon backbone and the required stereocentres are constructed through an aldol reaction of (S)-2-benzyloxy-3-pentanone and an aldol reaction-reduction sequence from (R)-2-tert-butyldimethylsilyloxy-3-pentanone, which are key steps in the synthesis of C1C9 fragment (17%, 10 steps) and C10C19 fragment (43%, 7 steps), respectively. Assembling of both fragments affords herboxidiene in 8% overall yield (14 steps, longest linear sequence). After a thorough study of aldol reactions of titanium enolates from α-hydroxy ketones, the reactivity of these nucleofiles is explored in other CC bond-forming reactions. In Chapter 3, the Michael addition of the titanium enolate of (S)-2-benzyloxy-3-pentanone to α,β-unsaturated ketones is developed, which provides 1,3-anti-3,4-anti adducts in excellent diastereoselectivities (dr ≥ 89:11). Finally, considering the biradical character of certain titanium enolates, in Chapter 4 the reactivity of such substrates in some CC and CO bond-forming reactions is investigated. Allylation of chiral N-acyl oxazolidinones with allyl stannanes is achieved and the corresponding adducts are obtained with excellent levels of stereocontrol (dr ≥ 97:3). Moreover, the stereoselective oxidation of chiral N-acyl oxazolidinones with TEMPO is described. The use of this stable radical leads to α-aminoxy derivatives in excellent yields and diastereomeric ratios (9095%, dr ≥ 93:7), and the stereoselective oxidation in the position of conjugate enolates is also accomplished. Elimination of the chiral auxiliary and/or reductive cleavage of the NO bond provides synthetically useful derivatives.