Doctor of Philosophy(PhD), / This thesis describes the synthesis of terminal and internal amino and amidoalkynes and their hydroamination (cyclisation) catalysed by the complex (bis(N-methylimidazol-2-yl)methane)dicarbonylrhodium(I) tetraphenylborate (1). A series of analogous palladium complexes were also prepared and investigated for catalytic hydroamination. The scope of the rhodium(I) complex (1) for the intramolecular hydroamination of more complex amino and amidoalkyne substrates was investigated. This was made possible with the synthesis of aliphatic substrates, namely, 4 pentyn 1 amide (3) and 5 hexyn 1 amide (4) and a number of aromatic substrates, namely, 1, 4 diamino-2, 5 diethynylbenzene (5), 1, 4-diamino-2, 5 bis(phenylethynyl)benzene (6), 2, 3-diamino-1, 4-diethynylbenzene (7), 2, 3-diamino-1, 4-bis(phenylethynyl)benzene (8), 1, 5-bis(acetamido)-2, 4-diethynylbenzene (9), N-(acetyl)-2-ethynylbenzylamine (10) and N-(acetyl)-2-(phenylethynyl)benzylamine (11). The rhodium(I) complex (1) catalytically cyclised the aliphatic 4 pentyn 1 amide (3) regioselectively to the 6 membered ring, 3, 4 dihydro 2 pyridone (64) as the sole product. Attempts to cyclise 5 hexyn 1 amide (4) to produce either the 6 or 7 membered ring were unsuccessful. Compounds 5, 6, 7 and 8 were doubly cyclised to 1, 5 dihydro pyrrolo[2, 3 f]indole (71), 1, 5-dihydro-2, 6-diphenyl-pyrrolo[2, 3 f]indole (73), 1, 8-dihydro-pyrrolo[2, 3 g]indole (74) and 1, 8-dihydro-2, 7-diphenyl-pyrrolo[2, 3 g]indole (75) respectively. The aromatic amides with terminal acetylenes 9 and 10 cyclised to give 1, 7 diacetyl pyrrolo[3, 2 f]indole (76) and N (acetyl) 1, 2 dihydroisoquinoline (77) respectively. However, attempts to cyclise 11 were unsuccessful. Thus the rhodium(I) complex (1) successfully catalysed via hydroamination both terminal and internal acetylenic amine and amide substrates, to give pyridones, indoles and isoquinolines. Cationic and neutral palladium complexes incorporating the bidentate heterocyclic nitrogen donor ligand bis(N-methylimidazol-2-yl)methane (bim; 2) were synthesised: [Pd(bim)Cl2] (15), [Pd(bim)2][BF4]2 (17) [Pd(bim)(Cl)(CH3)] (14), [Pd(bim)(CH3)(NCCH3)][BF4] (16). All of the complexes were active as catalysts for the intramolecular hydroamination reaction, using the cyclisation of 4 pentyn 1 amine (21) to 2 methyl 1 pyrroline (22) as the model test reaction. Percentage conversions, turnover numbers and reaction profiles for each complex were compared to the rhodium(I) complex (1). These studies have shown that the catalytic activity was not significantly dependent on the bim donor ligand or the choice of metal. Substitution of the bim (2) ligand with the COD ligand and the use of methanol as the solvent did impact significantly on the efficiency of the hydroamination reactions.

L’un des axes de recherche du laboratoire Synthèse Métallo-Induites consiste en le développement de nouveaux complexes métallacycliques à chiralité planaire. Le défi majeur de cette thèse, a été l’élaboration de nouvelles approches sélectives de synthèse de complexes cationiques et neutres métallacyliques à chiralité planaire dont le métal chélaté est un centrestéréogène pseudo-tétraédrique.Le projet de thèse fut initié lors de l’étude d’une réaction inhabituelle de cycloruthénation d’un ligand dérivé de la 2-phénylpyridine qui était capable de produire un complexe ruthénacyclique OC-6 triscationique, homobinucléaire et à chiralité planaire comme produit secondaire en une seule étape à partir de substrats simples. Ce type de produit homobinucléaire ne peut se former uniquement que lorsqu’un groupement fortement donneur comme le N,N-diméthylamino (-NMe2) est présent sur le ligand départ. C’est donc à la lumière de ce résultat que nous avons engagé une étude systématique de la synthèse de nouveaux composés iridacycliques à chiralité planaire. Les fragments métalliques positivement chargés (Cp*Ir2+, Cp*Ru+) et neutre (Cr(CO)3) pourraient p-coordiner un fragment aryle riche en électrons d’un composé cyclométallé suivant un cours stéréochimiqueconditionné par la nature des entités ainsi introduites. Une des conséquences inattendues de ces recherches est l’émergence du concept de chiralité constitutionnelle déportée qui a surgi lors de l’étude du comportement conformationnel du complexe endo dicationique IrIr(NMe2) dont les groupes méthyles portés par le substituant N,N-diméthylamino dénotent une diastéréotopicité remarquable en spectroscopie de RMN 1H.A cette quête fondamentale de sélectivité s’est aussi greffée une exploration des propriétés catalytiques de nos complexes qui se sont révélés comme d’excellents précatalyseurs pour la promotion de réactions comme l’oxydation de l’eau et l’hydroamination/hydrosilylation d’alcynes vrais. / One of the main research domain in the laboratory of «Synthèse Metallo-Induites» consists in the development of new planar chiral metallacycles complexes. The challenge of this thesis was the development of new selective approaches for the synthesis of new cationic and neutral planar chiral metallacycles complexes in which the chelated metal is a pseudotetrahedral stereogenic center.The thesis project was initiated by the study of the unusual cycloruthenation of a 2-phenylpyridine ligand which was able to produce a tris-cationic homobimetallic planar chiral ruthenacycle as secondary product in a one step reaction starting from simple substrates. This type of homobimetallic product is only formed when a strong electrodonationg group as NMe2 is present on the starting ligand. In view of this result, we engaged a systematic study by synthesizing new planar chiral iridacycles compounds. The positively charged metal fragments (Cp*Ir2+, Cp*Ru+) and neutral (Cr(CO)3) may p-coordinate the electronic rich aryl fragment of the iridacyclic compound by virtue of the coulombic imbalance in the coordination sphere of the chelated metal center. One of the unexpected consequence of this research is the emergence of the concept ″deported constitutional chirality″, which appeared during the study of the conformational behaviour of an endodicationiciridacyclic complex where the methyl groups carried by the N,N-dimethylamino substituent diastereotopicity.To this fundamental quest for selectivity an explanation of the catalytic proprieties of our complexes was added. They were found to be good precatalysts for the promotion of the water oxidation catalysis and to be promising catalysts for tandem hydroamination/hydrosilation of terminal alkynes.

The last decade has been marked by a large increase of demand for green chemistry processes. Consequently, chemists have focused their efforts on the development of more direct routes toward different classes of targets. In that regard catalysis has played a crucial role at enabling key bond formations that were otherwise inaccessible or very energy and resources consuming. The central theme of this body of work concerns the formation of C–N bonds, either through transition metal catalysis or organocatalysis. These structural units being highly recurrent in biologically active molecules, the establishment of more efficient routes for their construction is indispensable. The first part of this thesis describes a new method for the synthesis of isoquinolines from the oxidative coupling/annulation of alkynes with N-tert-butyl benzaldimines via Rh(III) catalysis (Chapter 2). Preliminary mechanistic investigations of this system pointed to the involvement of Rh(III) in the C–H bond cleavage step as well as in the C–N bond reductive elimination that provides the desired heterocycle. Following this oxidative process, a Rh(III)-catalyzed redox-neutral approach to isoquinolones from the reaction of benzhydroxamic acids with alkynes is presented (Chapter 3). The discovery that an N–O bond contained in the substrate can act as an internal oxidant was found to be very enabling. Indeed, it allowed for milder reaction conditions, broader scope (terminal alkyne and alkene compatible) and low catalyst loadings (0.5 mol%). Mechanistic investigations on this system were also conducted to identify the nature of the C–N bond formation/N–O bond cleavage as well as the rate-determining step. The second part of this work presents mechanistic investigations performed on a recently developed intermolecular hydroamination reaction catalyzed through tethering organocatalysis (Chapter 4). This transformation operates via the reversible covalent attachment of two reactants, a hydroxylamine and an allylamine, to an aldehyde catalyst by the formation of a mixed aminal. This allows a difficult intermolecular Cope-type hydroamination to be performed intramolecularly. The main kinetic parameters associated with this reaction were determined and they allowed the generation of a more accurate catalytic cycle for this transformation. Attempts at developing new families of organocatalysts are also discussed.

The last decade has been marked by a large increase of demand for green chemistry processes. Consequently, chemists have focused their efforts on the development of more direct routes toward different classes of targets. In that regard catalysis has played a crucial role at enabling key bond formations that were otherwise inaccessible or very energy and resources consuming. The central theme of this body of work concerns the formation of C–N bonds, either through transition metal catalysis or organocatalysis. These structural units being highly recurrent in biologically active molecules, the establishment of more efficient routes for their construction is indispensable. The first part of this thesis describes a new method for the synthesis of isoquinolines from the oxidative coupling/annulation of alkynes with N-tert-butyl benzaldimines via Rh(III) catalysis (Chapter 2). Preliminary mechanistic investigations of this system pointed to the involvement of Rh(III) in the C–H bond cleavage step as well as in the C–N bond reductive elimination that provides the desired heterocycle. Following this oxidative process, a Rh(III)-catalyzed redox-neutral approach to isoquinolones from the reaction of benzhydroxamic acids with alkynes is presented (Chapter 3). The discovery that an N–O bond contained in the substrate can act as an internal oxidant was found to be very enabling. Indeed, it allowed for milder reaction conditions, broader scope (terminal alkyne and alkene compatible) and low catalyst loadings (0.5 mol%). Mechanistic investigations on this system were also conducted to identify the nature of the C–N bond formation/N–O bond cleavage as well as the rate-determining step. The second part of this work presents mechanistic investigations performed on a recently developed intermolecular hydroamination reaction catalyzed through tethering organocatalysis (Chapter 4). This transformation operates via the reversible covalent attachment of two reactants, a hydroxylamine and an allylamine, to an aldehyde catalyst by the formation of a mixed aminal. This allows a difficult intermolecular Cope-type hydroamination to be performed intramolecularly. The main kinetic parameters associated with this reaction were determined and they allowed the generation of a more accurate catalytic cycle for this transformation. Attempts at developing new families of organocatalysts are also discussed.

New synthetic routes to nitrogen- and phosphorus-containing polymers have been investigated. These routes rely on amine- and phosphine-containing monomers bearing pendant alkyne substituents, and subsequent hydroamination, oxidation, or hydrophosphination polymerization. A series of primary amines of the form H2NC6H2R2C≡CR’ (R = H or iPr; R’ = Ph, SiMe3, nBu, or p-C6H4Me) is reported. These amines are deprotonated with nBuLi to give lithium amides, which react with zirconocene compounds to provide amidozirconium complexes. Characterization is achieved by multinuclear NMR spectroscopy, IR spectroscopy, high-resolution mass spectrometry, elemental analysis, X ray crystallography, and DFT calculations. Three routes were attempted towards nitrogen-containing oligomers: (1) thermolysis of amidozirconium complexes to afford [2+2] cycloaddition polymers; (2) Ti(IV)-catalyzed hydroamination of H2NC6H4C≡CPh; (3) chemical oxidation of H2NC6H4C≡CPh. The latter two strategies resulted in distinct nitrogen-containing oligomers. The oligomer formed by Ti(NR2)4-catalyzed hydroamination (R = Me, Et) contains up to 15 repeat units in the chain, with both imine and enamine moieties, and is capped by a molecule of HNR2 (R = Me or Et) originating from the catalyst. The oligomer formed by chemical oxidation contains up to 9 repeat units in the chain. A series of phosphines of the form X2PC6H2R2C≡CR’ is reported (X = NEt2, Cl, H; R = Me, iPr; R’ = Ph, SiMe3). Characterization is achieved by multinuclear NMR spectroscopy, IR spectroscopy, high-resolution mass spectrometry, elemental analysis, and X-ray crystallography. The primary phosphines, H2PC6H2R2C≡CR’, are relatively “user-friendly” in that they are not particularly malodorous, they are isolated as solids or highly viscous liquids, and they are stable when stored under N2 in the solid state and in solution. The primary phosphine H2PC6H2iPr2C≡CPh serves as a precursor for a zirconium phosphinidene and for the secondary phosphines RP(H)C6H2iPr2C≡CPh (R = CH2iPr, CH2Ph). Hydrophosphination polymerization gives cyclic P(III)-containing oligomers, which are converted to P(V)-based macromolecules by treatment with sulfur. The oligomers contain ca. 5 to 10 repeat units, and heating to 800 °C gives rise to phosphorus-containing ceramics. The mechanism of hydrophosphination is discussed with the use of DFT calculations.

New synthetic routes to nitrogen- and phosphorus-containing polymers have been investigated. These routes rely on amine- and phosphine-containing monomers bearing pendant alkyne substituents, and subsequent hydroamination, oxidation, or hydrophosphination polymerization. A series of primary amines of the form H2NC6H2R2C≡CR’ (R = H or iPr; R’ = Ph, SiMe3, nBu, or p-C6H4Me) is reported. These amines are deprotonated with nBuLi to give lithium amides, which react with zirconocene compounds to provide amidozirconium complexes. Characterization is achieved by multinuclear NMR spectroscopy, IR spectroscopy, high-resolution mass spectrometry, elemental analysis, X ray crystallography, and DFT calculations. Three routes were attempted towards nitrogen-containing oligomers: (1) thermolysis of amidozirconium complexes to afford [2+2] cycloaddition polymers; (2) Ti(IV)-catalyzed hydroamination of H2NC6H4C≡CPh; (3) chemical oxidation of H2NC6H4C≡CPh. The latter two strategies resulted in distinct nitrogen-containing oligomers. The oligomer formed by Ti(NR2)4-catalyzed hydroamination (R = Me, Et) contains up to 15 repeat units in the chain, with both imine and enamine moieties, and is capped by a molecule of HNR2 (R = Me or Et) originating from the catalyst. The oligomer formed by chemical oxidation contains up to 9 repeat units in the chain. A series of phosphines of the form X2PC6H2R2C≡CR’ is reported (X = NEt2, Cl, H; R = Me, iPr; R’ = Ph, SiMe3). Characterization is achieved by multinuclear NMR spectroscopy, IR spectroscopy, high-resolution mass spectrometry, elemental analysis, and X-ray crystallography. The primary phosphines, H2PC6H2R2C≡CR’, are relatively “user-friendly” in that they are not particularly malodorous, they are isolated as solids or highly viscous liquids, and they are stable when stored under N2 in the solid state and in solution. The primary phosphine H2PC6H2iPr2C≡CPh serves as a precursor for a zirconium phosphinidene and for the secondary phosphines RP(H)C6H2iPr2C≡CPh (R = CH2iPr, CH2Ph). Hydrophosphination polymerization gives cyclic P(III)-containing oligomers, which are converted to P(V)-based macromolecules by treatment with sulfur. The oligomers contain ca. 5 to 10 repeat units, and heating to 800 °C gives rise to phosphorus-containing ceramics. The mechanism of hydrophosphination is discussed with the use of DFT calculations.

<p>Numerous methodologies for efficient formation of carbon-nitrogen bonds have been developed over the decades due to the widespread importance of nitrogen containing compounds in pharmaceuticals and bulk commercial chemicals. Among many methods, hydroamination, especially, has attracted enormous attention because of its atom-economical characteristic to synthesize amine moieties. As a result, numerous publications have been reported relating the hydroamination reaction using various metal catalysts. However, the hydroamination of unactivated alkenes still remains a challenge task because of the low reactivity of the CC double bond. Recent development of superior gold(I) catalysis in many organic transformations stimulated us to develop efficient gold(I)-catalyzed methods for enantioselective intra- and intermolecular hydroamination of unactivated alkenes. </p><p>A gold(I)-catalyzed system for enantioselective intramolecular hydroamination of unactivated alkenes has been developed. For the effective gold(I)-catalyzed method, various gold(I)-catalysts have been synthesized and tested. Among the catalysts, bis(gold) complexes containing an axially chiral bis(phosphine) ligand catalyze the enantioselective intramolecular hydroamination of unactivated alkenes with carboxamide derivatives, most effectively. The method was effective for both carbamates and ureas to form pyrrolidine derivatives with up to 85 % ee.</p><p>The first enantioselective intermolecular hydroamination of unactivated alkenes was realized by a gold(I)-catalyzed method. The gold(I) catalyst system adds cyclic ureas to unactivated 1-alkenes to produce corresponding enantiomerically enriched hydroamination product in good yield with enantioselectivity up to 78 % ee. </p><p>Polymer-embedded ligands have been synthesized to demonstrate proofs of concepts for fluxional mechanocatalysis. We applied a certain shear stress using a rheometer in the course of palladium-catalyzed asymmetric allylic alkylation to examine catalytic reactivity change under the mechanical force.</p> / Dissertation

The last decade has been marked by a large increase of demand for green chemistry processes. Consequently, chemists have focused their efforts on the development of more direct routes toward different classes of targets. In that regard catalysis has played a crucial role at enabling key bond formations that were otherwise inaccessible or very energy and resources consuming. The central theme of this body of work concerns the formation of C–N bonds, either through transition metal catalysis or organocatalysis. These structural units being highly recurrent in biologically active molecules, the establishment of more efficient routes for their construction is indispensable. The first part of this thesis describes a new method for the synthesis of isoquinolines from the oxidative coupling/annulation of alkynes with N-tert-butyl benzaldimines via Rh(III) catalysis (Chapter 2). Preliminary mechanistic investigations of this system pointed to the involvement of Rh(III) in the C–H bond cleavage step as well as in the C–N bond reductive elimination that provides the desired heterocycle. Following this oxidative process, a Rh(III)-catalyzed redox-neutral approach to isoquinolones from the reaction of benzhydroxamic acids with alkynes is presented (Chapter 3). The discovery that an N–O bond contained in the substrate can act as an internal oxidant was found to be very enabling. Indeed, it allowed for milder reaction conditions, broader scope (terminal alkyne and alkene compatible) and low catalyst loadings (0.5 mol%). Mechanistic investigations on this system were also conducted to identify the nature of the C–N bond formation/N–O bond cleavage as well as the rate-determining step. The second part of this work presents mechanistic investigations performed on a recently developed intermolecular hydroamination reaction catalyzed through tethering organocatalysis (Chapter 4). This transformation operates via the reversible covalent attachment of two reactants, a hydroxylamine and an allylamine, to an aldehyde catalyst by the formation of a mixed aminal. This allows a difficult intermolecular Cope-type hydroamination to be performed intramolecularly. The main kinetic parameters associated with this reaction were determined and they allowed the generation of a more accurate catalytic cycle for this transformation. Attempts at developing new families of organocatalysts are also discussed.

The ability of gold(I) to activate many types of unsaturated bonds toward nucleophilic attack was not widely recognized until the early 2000s. One major challenge in gold catalysis is the control over regioselectivity when there are two or more possible products as a result of complicated mechanistic pathways. It is well know that the choice of ligand can have dramatic effects on which pathway is being followed but very rarely are the reasons for this selectivity understood. The synthesis of new acyclic diaminocarbenes was developed and a study of the ligand effects on the regioselectivity of a gold-catalyzed domino enyne cyclization hydroarylation reaction and a Nazarov cyclization was undertaken. New chiral acyclic diaminocarbenes were also developed and tested along side new C3-symmetric phosphite ligands in an asymmetric intramolecular hydroamination of allenes. Structure activity correlations were developed for the potential use in further rational ligand design. The synthesis of 6a,7-dihydro-5-amino-dibenzo[c,g]chromene derivatives via a gold-catalyzed domino reaction of alkynylbenzaldehydes in the presence of secondary amines was developed. These were sent to be screened for biological activity.

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