Part 1: Transition-metal-catalyzed direct transformations of aromatic C-H bonds are emerging as valuable tools in organic synthesis. These reactions are attractive because of they allow for inherently efficient construction of organic building blocks by minimizing the pre-activation of substrates. Of these processes, direct arylation has recently received much attention due to the importance of the biaryl core in medicinal and materials chemistry. Also, alkyne hydroarylation has garnered interest because it allows for the atom-economical synthesis of functionalized alkenes directly from simple arenes and alkynes. Described in this thesis are number of advancements in these areas. First, palladium catalyzed direct arylation of azine N-oxides using synthetically important aryl triflates is described. Interesting reactivity of aryl triflates compared to aryl bromides was uncovered and exploited in the synthesis of a compound that exhibits antimalarial and antimicrobial activity. Also reported is the efficient, direct arylation enabled (formal) synthesis of six thiophene based organic electronic materials in high yields using simple starting materials. Additionally, the site-selective direct arylation of both sp2 and sp3 sites on azine N-oxide substrates is described. The arylation reactions are carried out in either a divergent manner or a sequential manner and is applied to the synthesis of the natural products, Papaverine and Crykonisine. Mechanistic investigations point towards the intimate involvement of the base in the mechanism of these reactions. Next, the rhodium(III)-catalyzed hydroarylation of internal alkynes is described. Good yields are obtained for a variety of alkynes and arenes with excellent regioselectivity for unsymmetrically substituted alkynes. Mechanistic investigations suggest that this reaction proceeds through arene metalation with the cationic rhodium catalyst, which enables challenging intermolecular reactivity. Part 2: Access to single enantiomer compounds is a fundamental goal in organic chemistry and despite remarkable advances in enantioselective synthesis, their preparation remains a challenge. Kinetic resolution of racemic products is an important method to access enantioenriched compounds, especially when alternative methods are scarce. Described in this thesis is the resolution of tertiary and secondary alcohols, which arise from ketone and aldehyde aldol additions. The method is technically simple, easily scalable, and provides tertiary and secondary alcohols in high enantiomeric ratios. A rationale for the unique reactivity/selectivity associated with (1S,2R)-N-methylephedrine in the resolution is proposed. Organocatalysis is a rapidly developing, powerful field for the construction of enantioenriched organic molecules. Described here is a complimentary class of organocatalysis using simple aldehydes as temporary tethers to perform challenging formally intermolecular reactions at room temperature. This strategy allows for the enantioselective, intermolecular cope-type hydroamination of allylic amines with hydroxyl amines. Also, interesting catalytic reactivity for dichloromethane is revealed.

The chemistry of late first row transition metals supported by dipyrromethane and dipyrromethene ligands bearing sterically bulky substituents was explored. Transition metal complexes (Mn, Fe, Co, Ni, Zn) of the dipyrromethane ligand 1,9-dimesityl-5,5-dimethyldipyrromethane (dpma) were prepared. Structural and magnetic characterization (SQUID, EPR) of the bis-pyridine adducts \((dpma)Mn(py)_2\), \((dpma)Fe(py)_2\), and \((dpma)Co(py)_2\) showed each tetrahedral divalent ion to be high-spin, while square planar \((dpma)Ni^{II}(py)_2\) and tetrahedral \((dpma)Zn(py)_2\) were shown to be diamagnetic. Electrochemical experiments revealed oxidative events at common potentials independent of metal identity or spin state, consistent with ligand-based oxidation. Dipyrromethene ligand scaffolds were synthesized bearing large aryl \((Ar = 2,4,6-Ph_{3}C_{6}H_{2}, Mes = 2,4,6-Me_{3}C_{6}H_{2})\) or alkyl \((^{t}Bu = CMe_3, Ad = 1-adamantyl)\) flanking groups to afford three new disubstituted ligands \((^{R}dpme, 1, 9-R_2-5-mesityldipyrromethene, R = Ar, Mes, ^{t}Bu, Ad)\). While high-spin \((S=2)\), four-coordinate iron complexes of the type \((^{R}dpme)FeCl(solv)\) were obtained when R was Mes, tBu, or Ad, use of the sterically encumbered aryl-substituted ligand gave a three-coordinate high-spin \((S=2)\) complex \((^{Ar}dpme)FeCl\). Intramolecular C−H amination was discovered in the reaction of organic azides with \((^{Mes}dpme)FeCl(thf)\), though no intermediate was observed by UV/Vis, IR, or \(^{1}H\) VT-NMR experiments. Reaction of \((^{Ad}dpme)FeCl(OEt_2)\) with alkyl azides resulted in the catalytic amination of C–H bonds or aziridination of olefins at room temperature. Reaction of \(p-^{t}BuC_{6}H_{4}N_{3}\) with \((^{Ar}dpme)FeCl\) permitted isolation of a high-spin \((S=2)\) iron complex \((^{Ar}dpme)FeCl(N(p-^{t}BuC_6H_4))\), featuring a terminal imidyl radical antiferromagnetically coupled to high-spin \(Fe^{III}\), as determined by \(^{1}H\) NMR, X-ray crystallography, and \(^{57}Fe\) Mössbauer. A three-coordinate CoI complex \((^{Ar}dpme)Co(py)\) was synthesized and characterized by \(^{1}H\) NMR, SQUID magnetometry, and X-ray crystallography. Reaction of \((^{Ar}dpme)Co(py)\) with \(^{t}BuN_3\) afforded an isolable three-coordinate Co imide complex \((^{Ar}dpme)Co(N^{t}Bu)\) that exhibits spin crossover from a singlet to a quintet. Reaction of \((^{Ar}dpme)Co(py)\) with mesityl azide produces a spectroscopically observed intermediate, consistent with an \(S=1\) terminal imide complex, that converted via benzylic C–H activation into the metallacycloindoline \((^{Ar}dome)Co(\kappa^{2}-NHC_{6}H_{2}-2,4-Me_{2}-6-CH_2)\). / Chemistry and Chemical Biology

This thesis is focused on two main areas of organic synthesis, palladium-catalyzed functionalization of alkenes and allylic alcohols, as well as development of new allylboration reactions. We have developed a palladium-catalyzed selective allylic trifluoroacetoxylation reaction based on C−H functionalization. Allylic trifluoroacetates were synthesized from functionalized olefins under oxidative conditions. The reactions proceed under mild conditions with a high level of diastereoselectivity. Mechanistic studies of the allylic C−H trifluoroacetoxylation indicate that the reaction proceeds via (η3-allyl)palladium(IV) intermediate. Palladium-catalyzed regio- and stereoselective synthesis of allylboronic acids from allylic alcohols has been demonstrated. Diboronic acid B2(OH)4 was used as the boron source in this process. The reactivity of the allylboronic acids were studied in three types of allylboration reactions: allylboration of ketones, imines and acyl hydrazones. All three processes are conducted under mild conditions without any additives. The reactions proceeded with remarkably high regio- and stereoselectivity. An asymmetric version of the allylboration of ketones was also developed. In this process chiral BINOL derivatives were used as catalysts. The reaction using γ-disubstituted allylboronic acids and various aromatic and aliphatic ketones afforded homoallylic alcohols bearing two adjacent quaternary stereocenters with excellent regio-, diastereo- and enantioselectivity (up to 97:3 er) in high yield. The stereoselectivity in the allylboration reactions could be rationalized on the basis of the Zimmerman-Traxler TS model.

No description available.

Part 1: Transition-metal-catalyzed direct transformations of aromatic C-H bonds are emerging as valuable tools in organic synthesis. These reactions are attractive because of they allow for inherently efficient construction of organic building blocks by minimizing the pre-activation of substrates. Of these processes, direct arylation has recently received much attention due to the importance of the biaryl core in medicinal and materials chemistry. Also, alkyne hydroarylation has garnered interest because it allows for the atom-economical synthesis of functionalized alkenes directly from simple arenes and alkynes. Described in this thesis are number of advancements in these areas. First, palladium catalyzed direct arylation of azine N-oxides using synthetically important aryl triflates is described. Interesting reactivity of aryl triflates compared to aryl bromides was uncovered and exploited in the synthesis of a compound that exhibits antimalarial and antimicrobial activity. Also reported is the efficient, direct arylation enabled (formal) synthesis of six thiophene based organic electronic materials in high yields using simple starting materials. Additionally, the site-selective direct arylation of both sp2 and sp3 sites on azine N-oxide substrates is described. The arylation reactions are carried out in either a divergent manner or a sequential manner and is applied to the synthesis of the natural products, Papaverine and Crykonisine. Mechanistic investigations point towards the intimate involvement of the base in the mechanism of these reactions. Next, the rhodium(III)-catalyzed hydroarylation of internal alkynes is described. Good yields are obtained for a variety of alkynes and arenes with excellent regioselectivity for unsymmetrically substituted alkynes. Mechanistic investigations suggest that this reaction proceeds through arene metalation with the cationic rhodium catalyst, which enables challenging intermolecular reactivity. Part 2: Access to single enantiomer compounds is a fundamental goal in organic chemistry and despite remarkable advances in enantioselective synthesis, their preparation remains a challenge. Kinetic resolution of racemic products is an important method to access enantioenriched compounds, especially when alternative methods are scarce. Described in this thesis is the resolution of tertiary and secondary alcohols, which arise from ketone and aldehyde aldol additions. The method is technically simple, easily scalable, and provides tertiary and secondary alcohols in high enantiomeric ratios. A rationale for the unique reactivity/selectivity associated with (1S,2R)-N-methylephedrine in the resolution is proposed. Organocatalysis is a rapidly developing, powerful field for the construction of enantioenriched organic molecules. Described here is a complimentary class of organocatalysis using simple aldehydes as temporary tethers to perform challenging formally intermolecular reactions at room temperature. This strategy allows for the enantioselective, intermolecular cope-type hydroamination of allylic amines with hydroxyl amines. Also, interesting catalytic reactivity for dichloromethane is revealed.

Part 1: Transition-metal-catalyzed direct transformations of aromatic C-H bonds are emerging as valuable tools in organic synthesis. These reactions are attractive because of they allow for inherently efficient construction of organic building blocks by minimizing the pre-activation of substrates. Of these processes, direct arylation has recently received much attention due to the importance of the biaryl core in medicinal and materials chemistry. Also, alkyne hydroarylation has garnered interest because it allows for the atom-economical synthesis of functionalized alkenes directly from simple arenes and alkynes. Described in this thesis are number of advancements in these areas. First, palladium catalyzed direct arylation of azine N-oxides using synthetically important aryl triflates is described. Interesting reactivity of aryl triflates compared to aryl bromides was uncovered and exploited in the synthesis of a compound that exhibits antimalarial and antimicrobial activity. Also reported is the efficient, direct arylation enabled (formal) synthesis of six thiophene based organic electronic materials in high yields using simple starting materials. Additionally, the site-selective direct arylation of both sp2 and sp3 sites on azine N-oxide substrates is described. The arylation reactions are carried out in either a divergent manner or a sequential manner and is applied to the synthesis of the natural products, Papaverine and Crykonisine. Mechanistic investigations point towards the intimate involvement of the base in the mechanism of these reactions. Next, the rhodium(III)-catalyzed hydroarylation of internal alkynes is described. Good yields are obtained for a variety of alkynes and arenes with excellent regioselectivity for unsymmetrically substituted alkynes. Mechanistic investigations suggest that this reaction proceeds through arene metalation with the cationic rhodium catalyst, which enables challenging intermolecular reactivity. Part 2: Access to single enantiomer compounds is a fundamental goal in organic chemistry and despite remarkable advances in enantioselective synthesis, their preparation remains a challenge. Kinetic resolution of racemic products is an important method to access enantioenriched compounds, especially when alternative methods are scarce. Described in this thesis is the resolution of tertiary and secondary alcohols, which arise from ketone and aldehyde aldol additions. The method is technically simple, easily scalable, and provides tertiary and secondary alcohols in high enantiomeric ratios. A rationale for the unique reactivity/selectivity associated with (1S,2R)-N-methylephedrine in the resolution is proposed. Organocatalysis is a rapidly developing, powerful field for the construction of enantioenriched organic molecules. Described here is a complimentary class of organocatalysis using simple aldehydes as temporary tethers to perform challenging formally intermolecular reactions at room temperature. This strategy allows for the enantioselective, intermolecular cope-type hydroamination of allylic amines with hydroxyl amines. Also, interesting catalytic reactivity for dichloromethane is revealed.

Palladium-catalyzed reactions for carbon-carbon bond formation have had a significant impact on the field of organic chemistry in recent decades. Illustrative is the 2010 Nobel Prize, awarded for “palladium-catalyzed cross couplings in organic synthesis”, and the numerous applications of these transformations in industrial settings. This thesis describes recent developments in C(sp2)-C(sp3) bond formation, focusing on alkane arylation reactions and arylative dearomatization transformations. In the first part, our contributions to the development of intramolecular C(sp3)-H arylation reactions from aryl chlorides are described (Chapter 2). The use of catalytic quantities of pivalic acid was found to be crucial to observe the desired reactivity. The reactions are highly chemoselective for arylation at primary aliphatic C-H bonds. Theoretical calculations revealed that C-H bond cleavage is facilitated by the formation of an agostic interaction between the palladium centre and a geminal C-H bond. In the following section, the development of an alkane arylation reaction adjacent to amides and sulfonamides is presented (Chapter 3). The mechanism of C(sp3)-H bond cleavage in alkane arylation reactions is also addressed through an in-depth experimental and theoretical mechanistic study. The isolation and characterization of an intermediate in the catalytic cycle, the evaluation of the roles of both carbonate and pivalate bases in reaction mechanism as well as kinetic studies are reported. Our serendipitous discovery of an arylation reaction at cyclopropane methylene C-H bonds is discussed in Chapter 4. Reaction conditions for the conversion of cyclopropylanilines to quinolines/tetrahydroquinolines via one-pot palladium(0)-catalyzed C(sp3)-H arylation with subsequent oxidation/reduction are described. Initial studies are also presented, which suggest that this transformation is mechanistically unique from other Pd catalyzed cyclopropane ring-opening reactions. Preliminary investigations towards the development of an asymmetric alkane arylation reaction are highlighted in Chapter 5. Both chiral carboxylic acid additives and phosphine ligands have been examined in this context. While high yields and enantiomeric excesses were never observed, encouraging results have been obtained and are supported by recent reports from other research groups. Finally, in part two, the use of Pd(0)-catalysis for the intramolecular arylative dearomatization of phenols is presented (Chapter 7). These reactions generate spirocyclohexadienones bearing all-carbon quaternary centres in good to excellent yields. The nature of the base, although not well understood, appears to be crucial for this transformation. Preliminary results in the development of an enantioselective variant of this transformation demonstrate the influence of catalyst activation on levels of enantiomeric excess.

京都大学 / 0048 / 新制・課程博士 / 博士(工学) / 甲第22455号 / 工博第4716号 / 新制||工||1737(附属図書館) / 京都大学大学院工学研究科材料化学専攻 / (主査)教授 中尾 佳亮, 教授 松原 誠二郎, 教授 杉野目 道紀 / 学位規則第4条第1項該当 / Doctor of Philosophy (Engineering) / Kyoto University / DFAM

Ces dernières années ont été témoin de l'énorme développement de la chimie organique du fluor. Notamment, l'introduction de groupements fluorés émergents sur des « briques » moléculaires variées a attiré l'attention de la communauté scientifique en raison de leurs propriétés particulières. De plus, la stratégie de fonctionnalisation dirigée de la liaison C-H par catalyse par les métaux de transition, a conduit à une révolution dans le développement de méthodologies synthétiques originales. Par conséquent, la conception de nouvelles approches synthétiques pour l'introduction de groupements fluorés par fonctionnalisation de la liaison C-H catalysée par les métaux de transition est particulièrement attirante. Dans cette thèse, nous nous sommes concentrés sur le développement de nouvelles méthodologies d'introduction directe des groupements fluorés sur des arènes et des oléfines par fonctionnalisation directe de liaison C(sp2)-H catalysée par les métaux de transition. En particulier, nous avons tourné notre attention sur le 2-bromo-3,3,3-trifluoropropène (BTP), un réactif fluoré bon marché et provenant de déchets de l'industrie. Ce dernier est utilisé comme agent de remplacement de halon pour la suppression des incendies et, utilisé comme « brique » moléculaire en synthèse organique (Chapitre 1). La première partie de cette thèse est dédiée au développement de nouvelles méthodologies pour l'introduction directe du groupement CF3-vinyl sur des arènes et des oléfines par fonctionnalisation de la liaison C(sp2)-H catalysée par le palladium. Ensuite, cette approche a été étendue à la fonctionnalisation d'esters α,β- insaturés, bien qu'un mécanisme différent soit probablement impliqué (Chapitre 2). Dans la seconde partie de cette thèse, nous avons développé une nouvelle méthodologie pour l'introduction directe du groupement SCF3 sur des arènes et des oléfines par fonctionnalisation de la liaison C(sp2)-H catalysée par le palladium, utilisant le réactif de Munavalli (Chapitre 3). / Recent years have witnessed a great development of the organofluorine chemistry field. In particular, the introduction of emergent fluorinated moieties onto various scaffolds has attracted attention of the scientific community because of their special properties. Besides, transition metal-catalyzed directed C-H bond functionalization strategy has brought a revolution in the development of original synthetic methodologies, since it allows straightforward and more atom-economical processes. Thus, the design of new synthetic approaches for the introduction of fluorinated moieties by transition metal-catalyzed C-H bond functionalization pathway is particularly appealing. Therefore, in this Ph.D. thesis, we focused on the development of new methodologies for the direct introduction of fluorinated moieties onto arenes and olefins by transition metal catalyzed directed C(sp2)-H bond functionalization. In particular, we turned our attention to the 2-bromo-3,3,3-trifluoropropene (BTP), an inexpensive fluorinated reagent coming from industry waste, used as a potential halon replacement for fire suppression and as a fluorinated building block in organic synthesis (Chapter 1). The first part of this Ph.D. thesis was dedicated to the development of new methodologies for the direct introduction of a CF3- vinyl moiety onto arenes and olefins by a Pd-catalyzed directed C(sp2)-H bond functionalization with BTP. Then, this approach was extended to the functionalization of α,β-unsaturated esters, although a different reaction pathway is probably involved (Chapter 2). In the second part of this Ph.D. thesis, we developed a new methodology for the direct introduction of the SCF3 group onto arenes and olefins by Pd-catalyzed directed C(sp2)-H bond functionalization using the Munavalli reagent (Chapter 3).

La recherche de petites molécules bioactives et la quête de diversité moléculaire sont des sources d’inspiration infinies pour les chimistes de synthèse. Dans ce contexte, l’objectif de ma thèse a été de développer de nouvelles voies de synthèse pour accéder aux squelettes de molécules naturelles complexes, et à élaborer une méthodologie de synthèse polyvalente et modulable permettant l’accès à des composés hétéroaromatiques polyazotés. La première partie de ce manuscrit concerne le développement d’une stratégie de synthèse, vers une plateforme de type amincyclopentitol, dont les représentants naturels, la pactamycine et la jogyamycine, présentent un potentiel pharmacologique établi. Ce projet implique l’utilisation de transferts catalytiques de nitrènes dans des réactions d’aziridination et d’amination C-H. La deuxième partie décrit une approche en synthèse totale d’une nouvelle classe de produits naturels, les raputindoles. L’étape clé est une réaction de cycloaddition [3+2] iridocatalysée permettant de préparer des indanes possédant deux centres asymétriques dont la stéréochimie peut être contrôlée. Enfin, la troisième partie relate le développement d’une réaction domino multi-composant, catalysée par le cuivre, pour la synthèse de composés hétéroaromatiques. Les quinazoline-4(3H)-imines, les quinazoline-4-ones et les benzimidazo[1,2-c]quinazolines peuvent être obtenues via l'assemblage d'un cyanamide, d'un acide boronique et d'une amine, promu par un système catalytique unique. / The search for small bioactive molecules and molecular diversity are constant sources of inspiration for organic chemists. In this context, major developments in the design of always more effective, flexible and environment-friendly synthetic methods were described, in particular thanks to organometallic catalysis. Within this context, this Thesis project deals with the development of synthetic approaches towards natural molecules or simplified analogues, and the development of a new methodologies for the synthesis of nitrogen-containing heteroaromatic compounds.The first part of this manuscript concerns the development of a synthetic strategy towards a cyclopentitol platform, found in the natural products pactamycin and jogyamycin which show a great pharmacological potential. This project involves the use of catalytic nitrene transfers within aziridination and C-H amination reactions.The second part of the project describes a total synthesis approach towards a new class of natural products, the raputindoles. The key step is a [3+2] cycloaddition reaction, catalysed by an iridium complex, to prepare indanes possessing two asymmetric centres whose stereochemistry can be controlled. Finally, the third part is devoted to the development of a domino multicomponent reaction, catalysed by copper, for the synthesis of heteroaromatic compounds. Quinazolin-4(3H)-imines, quinazolin-4-ones and benzimidazo[1,2-c]quinazolines can be obtained from the same catalytic system, by the assembly of a cynamide, a boronic acid and an amine with an unique catalytic system.