The first project in this thesis describes our research reacting arynes with tertiary allyl amines to generate functionalised anilines via a benzyne induced aza-Claisen reaction. This process works in good to excellent yields and the methodology can be further applied to make benzannulated medium sized ring amine systems. The second project covered in this thesis details our studies in the generation of benzyne from benzoic acid. This process utilises palladium catalysis involving an ortho C-H activation of benzoic acid which generates a 5 membered palladacycle. This palladacycle then spontaneously decomposes with heat to generate palladium bound benzyne and carbon dioxide. The yield of benzyne was monitored by observing the amount of triphenylene formed in the process. Further synthetic applications in this process were limited, but it was shown that the benzyne could be reacted with alkynes to generate phenanthrene and naphthalene products. The third project in this thesis details our work on the insertion of benzyne into the C–S bond of thioesters. Using palladium catalysis and an o-trimethylsilylphenyl triflate benzyne precursor, a variety of thioethers were produced. The yields for this reaction were moderate to good but it was found that only aromatic substituents were tolerated on the thioester.

This thesis is divided into two main chapters, which are focused on two separated and uncorrelated research areas. The first part of this thesis is dedicated to the research I carried out in benzyne chemistry and the second part is focused on catalytic C-H bond activation. In the first place, a novel insertion reaction of arynes into the nitrogen-carbonyl σ-bond of amides has been investigated as a rapid and powerful approach for the preparation of valuable ortho-disubstituted arenes. Readily available aromatic amides undergo smooth insertion when treated with O-triflatophenyl silane aryne precursors, producing versatile anthranilic derivatives in good to excellent yields. The process is entirely metal-free and has been expanded to the synthesis of biologically active heterocycles such as acridones and acridines. Secondly, the synthesis of medium-sized ring systems by intramolecular oxidative CH bond coupling has been explored. Despite the abundance of biologically active natural products featuring mediumsized rings, the synthesis of such ring systems using classical synthetic routes faces many challenges and has led to a dearth of medium ring compounds in medicinal chemistry. In contrast to the more facile 5-membered ring synthesis by oxidative C-H coupling, medium ring synthesis has not been previously reported using this approach. The chemistry, which requires zero pre-functionalisation of the substrates, is catalysed by palladium and has been exemplified using heteroaromatic substrates at the core of numerous biologically active molecules. The mechanism of the reaction has also been studied and a catalytic cycle has been proposed.

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.

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.

Catalyst-Controlled Divergent C–H Functionalization of Unsymmetrical 2-Aryl Cyclic 1,3-Dicarbonyl Compounds with Alkynes and Alkenes A problem faced within the area of C–H functionalization is achieving siteselectivity when several similar C–H bonds are present within a given compound. One solution to this problem is the development of reactions that employ different catalytic systems to control the required selectivity. Herein, it is shown that such catalyst-controlled selectivity could be achieved on 2-aryl cyclic 1,3-dicarbonyl compounds where there exist two potential, non-adjacent sites for C–H functionalization. Examples demonstrate the palladium- and ruthenium-catalysed oxidative annulations of the 2-aryl cyclic 1,3-dicarbonyl substrates with alkynes, as well as with alkenes, where initial C–H bond cleavage occurs at one of two potential sites, depending on the catalyst used, which give unique products. 1,4-Rhodium(III) Migration in the One-Carbon Oxidative Annulations of 2-Arylphenols, Benzamides, and Benzoic Acids with 1,3-Enynes Oxidative annulations of 2-arylphenols, benzamides, and benzoic acids with alkynes and enynes are precedented and provide a range of heterocyclic products. However, in these examples, either the alkyne or enyne acts as a two-carbon annulation partner, reacting only across the alkynyl moiety. Herein, a more expansive scope of a previously published process in which 1,3-enynes, possessing allylic hydrogen atoms cis to the alkyne, undergo oxidative annulations with the three aforementioned classes of substrates as a one-carbon annulation partner is described. Proposed to occur via the 1,4-migration of a rhodium(III) species, annulated products were formed from a range of 1,3-enynes and substrates possessing a variety of functional groups.

Catalytic, selective C-H bond activation for the oxidative hydroxylation RH → ROH of simple or complex compounds is of significant interest in synthetic organic chemistry. One of the major classes of enzymes used for C-H bond activation are cytochrome P450 monooxygenases (EC 1.14.X.X), which can promote chemo-, regio- and stereoselective oxidations under mild reaction conditions. For the current study, catalytically self-sufficient forms of biocatalyst P450cam-RhFRed were investigated. These self-sufficient P450 systems were previously created by fusing the reductase domain of P450 RhF (CYP116B2, RhFRed from Rhodococcus sp.) with the catalytic domain of P450cam (CYP101A1, Pseudomonas putida), thus mimicking the natural fusion of P450 RhF. The generation of 93 P450cam-RhFRed variants has expanded the synthetic toolbox to serve as a basis for exploring the substrate scope towards ethylbenzenes, substituted alkylbenzenes, 4-ethylphenol and (+)-pleuromutilin. To select for active mutants from this library of 93, high throughput screening methods were developed. A pooling approach was applied in order to express P450s and analyse them against a panel of non-natural substrates, such as ethylbenzene, 4-ethylphenol and (+)-pleuromutilin in whole cell biotransformation reactions. The concentration of P450 enzymes was determined using CO difference spectroscopy in whole cells. The assay was significantly improved both in terms of speed and safety by using carbon monoxide releasing molecules as a source of CO rather than the gas CO itself. These screening studies served as starting point to identify P450cam-RhFRed mutants for specific reactions. In particular, a systematic investigation of this library showed mutants that generated chiral benzyl alcohols with good enantioselectivities. To interpret these results on a structural basis, molecular dynamics simulations were used to estimate enantioselectivity of selected mutants for the regio-isomers of methylated ethylbenzene derivatives. The results from the molecular dynamics simulations were broadly consistent with experimentally determined data and identified the importance of conformational changes and flexibility of mutant-substrate complexes to enforce enantioselectivity.

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.

<p><font face="TimesNewRomanPSMT"> <p align="left">This thesis reports the synthesis of the imine ligands from Schiff base condensation reaction of aldehyde derivatives and equimolar quantities of aniline derivatives. The imine ligands spectrometry.</p> </font></p>

1. Benzene C-H Activation by Nickel(II) and Platinum(II) Complexes of Chelating Diarylamido Phosphine Ligands We have demonstrated an efficient intermolecular benzene C-H activation process mediated by Ni(II) complexes of ([Me-NP-iPr]Ni(L)(R)(L = Pyridine, 2,4-Lutidine, PMe3) and [iPr-NP-Ph]Ni(PMe3)(R) (R = Me, CH2SiMe3). When Lewis base is PMe3 or substituent is CH2SiMe3 more reactivity is observed. The amido diphosphine complexes [iPr-PNP]PtOTf effectively activate the benzene C-H bond in the presence of an appropriate Lewis base(NEt3 or DABCO). 2. Metal Complexes of Amido Phosphine Ligand Bearing Unsymmetric Donor Atom: Syntheses, Structures and Reactivities A series of [Ph-PNN]Ni(II)R (R = Me, Et, Ph, CH2Ph) complexes containing £]-hydrogen atoms have been prepared and characterizated. We have demonstrated an efficient intermolecular arene C-H activation process mediated by Ni(II) complexes of [Ph-PNN]NiEt at elevated temperature. A series of nickel(II) complexes featuring an unsupported, covalently bound p-donor ligand including anilide, phenolate, thiophenolate and tert-butoxide derivatives have been prepared and characterizated. Novel unsymmetric tridentate ligands (H[R-PNO], R = iPr, Ph) have been prepared and characterized. The reaction of [iPr-PNO]NiCl with Na/Hg in thf or ether at room temperature induced C-O bond activation followed by the generation of {[iPr-PNO]Ni}{[iPr-PNO*]NiMe}. 3. Amido Diphosphine Complexes of Cobalt: Syntheses, Structures and Reactivities A series of paramagnetic divalent cobalt complexes ([R-PNP]CoCl, R = iPr, Cy) supported by tridentate diarylamido phosphine ligands have been prepared and characterized. The diamagnetic monovalent cobalt-dinitrogen complexes ([R-PNP]Co(N2), R = iPr, Cy) are accessible from the reaction of [R-PNP]CoCl with LiHBEt3 in THF solution. The dinitrogen complex [Cy-PNP]Co(N2) reacts in THF with terminal alkynes, HC¡ÝCR, yielding vinylidene complexes ([Cy-PNP]Co=C=C(H)(R), R = Ph, SiMe3). The dinitrogen complex [Cy-PNP]Co(N2) and {[iPr-PNP]Co}2(£g-N2) reacts in THF with diphenylacetylene (PhC¡ÝCPh) yielding p complexes ([R-PNP]Co(h2-PhC¡ÝCPh), R = iPr, Cy). 4. Fluorinated Mono- and Diarylamido Complexes of Lithium and Group 4 Metals The synthesis of bis-ligand Group 4 metal complexes ([iPrAr-NF]2MCl2, M= Zr, Hf) are utilizing [iPrAr-NF]Li and MCl4(THF)2. The alkylation of [iPrAr-NF]2MCl2 with RMgCl (R= Me, iBu, PhCH2, Me3SiCH2) produced a series of group 4 metal complexes ([iPrAr-NF]2MR2, M= Zr, Hf) which are catalyst precursors for olefin polymerization. Deprotonation of H[iPr-NF] and H[Cy-NF] with n-BuLi in ethereal solutions at -35 ¢XC produced the lithium complexes {[iPr-NF]Li(solv)}2 (solv = THF, Et2O) and {[Cy-NF]Li(Et2O)}2, respectively. The metathetical reaction of [iPr-NF]Li(Et2O) with 1/3 equiv TiCl4(THF)2 in toluene solution produced the trianilide titanium complex [iPr-NF]3TiCl. A series of novel fluorinated bidentate (H[Mes-NP-RF], R = iPr, Ph) and tridentate ligands (H2[Mes-NPNF]) have been prepared and characterizated.

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