Two methods of C-H functionalisation of sp2 C-H bonds via ruthenium catalysis have been developed in this thesis. The first methodology is the preparation of meta-sulfonated heteroaromatics. Individual substrate optimisations were performed on various nitrogen containing heteroaromatics such as 2-phenylpyridine, 1-phenylpyrazole and benzo[h]quinoline. It was discovered that 2-phenylpyridine was the best substrate for C-H sulfonation with aryl sulfonyl chlorides and gave yields of 4 – 63% and provided functional handles allowing for further synthetic manipulations. The second methodology developed is a ruthenium(II) catalysed ortho-C-H acylation of heteroaromatics. Initial optimisation was performed on 2-phenylpyridine with ortho-toluoyl chloride for C-H acylation and it was found tricyclohexylphosphine was the best ligand for this reaction. Unfortunately, the scope of this reaction is limited, as only a couple of aryl acid chlorides were compatible for the acylation of 2-phenylpyridine. This methodology was then applied to 1-phenylpyrazole and demonstrated the first example of C-H acylation of 1-phenylpyrazole with acid chloride as the coupling partner. C-H acylation of 1-phenylpyrazole is more versatile than 2-phenylpyridine, as the reaction scope is much broader. Various aryl and alkyl acid chlorides were compatible for the acylation of 1-phenylpyrazole derivatives and gave yields of 4 – 91%. Sterically hindered acid chlorides provided the higher yields, which is indicative of a steric acceleration during the reductive elimination step. Ruthenium-substrate complexes were synthesised and employed in stoichiometric experiments under the meta-sulfonation and ortho-acylation conditions independently, to attempt to elucidate the mechanistic pathways of these two reactions. 1H NMR spectroscopy on the meta-sulfonations of 1-phenylpyrazole and benzo[h]quinoline complexes indicated the formation of sulfonated ruthenium-substrate complexes, where the sulfone is substituted para to the ruthenium-carbon bond. C-H activation of 1-phenylpyrazole with a ruthenium-phosphine complex was attempted, and found it was difficult to synthesise the C-H activated substrate-ruthenium complex in the presence of phosphine ligands.

1. C–H Functionalisation of 2 Aryl Cyclic 1,3-Dicarbonyl Compounds Two enolate-directed C–H functionalisation protocols have been developed using 2-aryl cyclic 1,3-dicarbonyl compounds as substrates. Reactions with activated alkenes, under ruthenium or palladium catalysis produced benzopyrans in most cases, in moderate to good yield. Alternatively, an oxidative annulation of 2-aryl cyclic 1.3-dicarbonyls with 1,3-enynes was facilitated under rhodium catalysis, forming functionalised spiroindene structures in most cases, in generally good yields and high regioselectivity. During the investigation, the serendipitous formation of spirodialin structures was also observed. 2. Enantioselective Rh(I)-Catalysed Cyclisation of Arylboron Compounds onto Ketones Chiral tertiary alcohols, bearing aza-, oxa- and carbocyclic core structures of varying ring size were successfully formed from arylboron substrates under rhodium catalysis. In general the reactions proceeded with good yield and with moderate to high enantioselectivity. A protocol for the formation of a bicyclic lactam system was also achieved in moderate yield and enantioselectivity.

Chapter 1 is a brief review on some of the recents developments in palladium-catalysed C-H functionalisation chemistry. The synthesis and functionalisation of heterocycles using these methodologies was particularly emphasised. Chapter 2 presents our efforts to identify a new catalytic system to promote the intramolecular coupling of vinyl bromides with unfunctionalised aryl C-H bonds for the formation of benzofurans. Dihydrobenzofurans were obtained efficiently under mild conditions in the presence of Pd(OAc)₂, X-Phos and K₂CO₃ in DMA at 80 °C and a subsequent one-pot isomerisation under acidic conditions afforded the desired benzofurans. A new strategy has also provided access to more complex benzofurans by functionalisation of the exocyclic alkene isomer in both a chiral and achiral manner. In Chapter 3, mechanistic studies were performed on the benzofuran formation reaction. The analysis of substituent effects on the aromatic ring is in accordance with an electrophilic aromatic substitution mechanism (SEAr); however, the existence of both intra and intermolecular kinetic isotope effects suggest a SE3 type pathway rather than a pure SEAr. In Chapter 4, the intramolecular coupling of vinyl bromides with unfunctionalised aryl C-H bonds was further extended to the synthesis of six-membered heterocycles by direct arylation of alkenyl bromide derivatives in the presence of Pd(OAc)₂, dppf and K₂CO₃ in DMA at 120 °C. The synthetic utility of this methodology was exemplified by the synthesis of substituted isoquinolines in six steps. Moreover, we have applied our methodology to the direct arylation of sulfonamides, leading to an interesting synthesis of widely used sultams. Both these new routes are currently being investigated and should provide access to a variety of differently substituted cyclic sulfonamides and isoquinolines. Finally, Chapter 5 presents a new strategy for the synthesis of benzo[b]furan was briefly investigated. It consists in consecutive Tsuji-Trost and C-H functionalisation reactions. This methodology requires simpler and more versatile substrates, allowing access to various heteroaromatics in a single step. We successfully proved the viability of this reaction through the synthesis of a range of benzofurans in modest yields. To our knowledge, this is the first example of a single palladium catalyst performing these different reactions in tandem in a simple procedure.

The work in this thesis describes the development of new heteroarylation methodology based on transition metal-catalysed C-H functionalisation and the properties of organomain group compounds. The underlying reaction mechanisms and reactivity patterns of the (hetero)arene substrates are also investigated. The selective C2-H arylation indoles, which are key pharmaceutically-relevant units, was achieved using N-pyrimidyl directing groups, RuII catalysis and arylboronic acids as the coupling reagents (paper I). The use of this set of conditions enabled a remarkable functional group tolerance, highlighted by the preservation of halide substituents on both coupling partners. Mechanistic experiments suggest that cleavage of the C2-H bond occurs through an electrophilic aromatic substitution type pathway. The dehydrogenative C2-H silylation of unprotected gramine and tryptamine alkaloids and other related heteroarenes using hydrosilanes under Ru0 catalysis is described in paper II. The protocol does not require protecting groups and undirected C2-H silylation of heteroarenes is possible at higher temperatures. Significantly, H/D-exchange studies revealed deuterium incorporation at the C4 and C7 positions of the indole unit, apart from C2-H silylation. This study represents the first account of C4-H activation using an electron-rich metal catalyst. Paper III describes an unexpected and profound influence of boronate substituents on the regioselectivity of aryne trapping reactions. The boronates may be introduced easily to the backbone of established fluoride-activated precursors via Ir-catalysed C-H functionalisation. Optimisation and mechanistic studies on the unprecedented level of regioselectivity control these substituents permit using external additives is presented.

Dans cette thèse, nous avons entrepris une aventure pour découvrir une application plus large de la chimie du xanthate dans la construction de cycles fusionnés et l'alkylation directe des hétéroarènes. Au chapitre II, nous avons abordé le problème de la préparation de l'azaindane en tirant parti de la capacité des xanthates à agir à la fois sur l'addition intermoléculaire et la cyclisation intramoléculaire. Au chapitre III, une étude sans précédent sur la fonctionnalisation directe des pyrazines a été décrite, conduisant à des pyrazines hautement fonctionnalisées avec de bons rendements et une bonne régiosélectivité. Enfin, au chapitre IV, nous avons développé une méthode de méthylation et de fluorométhylation des hétéroarènes. / In this thesis, we have undertaken an adventure to discover wider application of xanthate chemistry in the construction of fused cycles and direct alkylation of heteroarenes. In Chapter II, we have tackled the problem of preparation of azaindane by taking advantage of the ability of xanthates to mediate both intermolecular addition and intramolecular cyclisation. In Chapter III, an unprecedented investigation into the direct functionalization of pyrazines was described, leading to highly functionalized pyrazines in good yields and good regioselectivity. Finally, in Chapter IV, we have developed a method for the methylation and fluoromethylation of heteroarenes.

This thesis centres on the synthesis of taxol analogues via late-stage hydroxylation with P450 enzymes. To accomplish this, the taxane core, specifically taxa-4(5),11(12)-dien-2-one, was synthesised by classical synthetic methods, and subsequently oxidised using P450_BM3 mutants. Chapter 1 introduces enzymatic catalysis, and the advantages and disadvantages of its application to organic synthesis. Additionally, an overview of taxol, including its discovery, mode of action, biosynthesis and large-scale production, and a summary of the previously reported approaches to the taxane core are described. Chapter 2 details the problems encountered and solutions implemented when reproducing Baran's route to taxa-4(5),11(12)-dien-2-one. Furthermore, approaches to some of its intermediates and an alternative route to taxa-4(5),11(12)-dien-2-one, which is based on Baran's, are discussed. Chapter 3 describes the development of a new, practical and short synthetic route to taxa-4(5),11(12)-dien-2-one which, ultimately, led to 1,3-di-epi-taxa-4(5),11(12)-dien-2-one. Additionally, the application of this route to the synthesis of a model compound and attempts to convert this racemic synthesis into an enantioselective route are reported. Finally, the enzymatic oxidation of taxa-4(5),11(12)-dien-2-one and related molecules using P450_BM3 mutants is explored in Chapter 4. A preliminary study to determine the substrate enantioselectivity of the mutants is also described, along with the biological assays of the oxidised compounds produced during the study.

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