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The arylation of readily accessible N-tosyl hydrazones has been achieved using arynes generated in situ under mild conditions. The resulting N-tosyl-N-aryl hydrazones undergo a one-pot Fischer indole reaction on the addition of acid, giving a synthesis of protected indoles that avoids handling unstable intermediates and arylhydrazines. A new route to functionalised 2-(trimethylsilyl)phenyl triflate aryne precursors via Suzuki cross-coupling has been developed. The method allows the incorporation of a wide range of aryl and heteroaryl groups and reactions of arynes generated from these novel precursors have been demonstrated, including a cyclotrimerisation and a fluorenone synthesis. Work was also undertaken on aryne σ-insertion reactions. The addition of benzyne to ynamides was found to result in its net insertion between the nitrogen and acetylene species. The reaction proceeds from attack at the terminal carbon in an analogous manner to C(sp)–O insertions.

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.

This thesis documents the development of novel methodologies for access to sulfur-containing compounds, including sulfones, sulfonamides and benzoisothiazoles. <b>Chapter 1</b> provides an overview of the applications and the synthesis of sulfonyl-containing compounds. A comprehensive introduction to the development of sulfur dioxide surrogates and their applications in transition metal-catalysed organic chemistry is given. <b>Chapter 2</b> describes the development of a one-step copper(I)-catalysed sulfonylative Suzuki-Miyaura cross coupling reaction. A wide range of aryl and alkenyl boronic acids are coupled with aryl and alkenyl iodides to give the corresponding sulfones. A two-step one-pot sulfination/derivatisation method was also developed, allowing access to compounds including β-hydroxy sulfones, sulfonamides and sulfonyl fluorides. <b>Chapter 3</b> illustrates a one-step copper(II)-catalysed sulfonamide synthesis using boronic acids, amines and SO2. Various aryl and alkenyl boronic acids as well as amines and anilines are compatible, including active pharmaceutical ingredients such as amoxapine and desloratadine. <b>Chapter 4</b> details an aryne-based selective formation of substituted benzoisothiazoles. Different substitution pattern of the aryne precursor and the thiadiazole are employed, with the target heterocycles being obtained in good to excellent yields. <b>Chapter 5</b> summarises the research and the future work. <b>Chapter 6</b> documents the experimental procedures and data.

It is over 100 years since scientists first postulated the existence of arynes as reactive intermediates. Their use in organic synthesis is now well-established and investigations into novel methods for their generation and utility in carbon-carbon bond forming reactions continue to this day. In 1983 Kobayashi and co-workers introduced a novel method of generating benzyne under mild conditions, using a fluoride induced decomposition of 2-(trimethylsilyl)phenyl triflate 1. This development has opened the door to employing arynes in a variety of transitionmetal mediated carbon-carbon bond forming processes. Intermolecular carbopalladation, in particular, stands out as a powerful methodology for the construction of diverse 1,2-functionalised arenes through multi-component coupling processes. Initial benzyne carbopalladation with an organopalladium species produces the arylpalladium intermediate 3, which can then undergo a second coupling to any one of the vast numbers of nucleophiles that have been demonstrated to work in palladium cross coupling. Presented herein are investigations towards the realisation of such methodology. Initial efforts focussed on its application to the Heck reaction, using acryates as the nucleophilic component. The chemistry has been developed to incorporate a variety of organo-halides in order to generate a variety of molecular architectures; the resultant 1,2-substituted diaryls being useful in the synthesis of both natural products and medicinal chemistry targets. Following successful development of the Heck reaction, investigations of other palladium catalysed couplings were also undertaken, in particular the Buchwald reaction. Initial mechanistic studies are also discussed.

We report a palladium-catalyzed, norbornene mediated synthesis of tetrahydroisoquinolines via a domino ortho-alkylation/Heck reaction sequence. The desired products are obtained in moderate to excellent yields starting from readily available aryl iodides. The reaction conditions can be extended to the formation of tetrahydroisoquinolinones and tetrahydrobenzo[c]azepines. The reaction allows for sequential intermolecular and intramolecular ortho-alkylations. However, the product yields are higher with ortho-blocked aryl iodides, which simplify the domino process to one intramolecular ortho-alkylation and a Heck reaction. The Lautens group has previously reported diastereoselective aryne Diels-Alder reactions of benzyne with dienes supporting a chiral auxiliary at its terminal carbon. In an effort to extend this work and allow access to a wider variety of 1,4-dihydronaphthalenes, we attempted the synthesis of dienes supporting a chiral auxiliary at a central carbon. Chiral pyridyne precursors were also synthesized, in an attempt to vary the source of chirality in diastereoselective cycloadditions.

We report a palladium-catalyzed, norbornene mediated synthesis of tetrahydroisoquinolines via a domino ortho-alkylation/Heck reaction sequence. The desired products are obtained in moderate to excellent yields starting from readily available aryl iodides. The reaction conditions can be extended to the formation of tetrahydroisoquinolinones and tetrahydrobenzo[c]azepines. The reaction allows for sequential intermolecular and intramolecular ortho-alkylations. However, the product yields are higher with ortho-blocked aryl iodides, which simplify the domino process to one intramolecular ortho-alkylation and a Heck reaction. The Lautens group has previously reported diastereoselective aryne Diels-Alder reactions of benzyne with dienes supporting a chiral auxiliary at its terminal carbon. In an effort to extend this work and allow access to a wider variety of 1,4-dihydronaphthalenes, we attempted the synthesis of dienes supporting a chiral auxiliary at a central carbon. Chiral pyridyne precursors were also synthesized, in an attempt to vary the source of chirality in diastereoselective cycloadditions.

We give an overview of quantum chemical methods with a particular emphasis on the development of high-accuracy quantum chemical models. The reliability of these methods often hinges on whether enough electron correlation is included in the truncated wave function. As an example, we investigate the structures of m-benzyne and its fluorinated derivative, tetrafluoro-m-benzyne where the inclusion of triple excitations is paramount to correctly describe through-bond delocalization of the monocyclic form. At the CCSDT/6-31G** level of theory, the C1–C3 distance of the minimum energy form of m-benzyne is 2.0°A and the profile of the PES along the C1–C3 distance is that of an asymmetric, single-well, in agreement with previous density-functional theory and coupled cluster studies. In addition, the calculated CCSD(T) fundamental frequencies are in excellent agreement with the measured infrared frequencies, thus confirming the monocyclic form of m-benzyne. For tetrafluoro-m-benzyne, however, the increased eclipsing strain between the ring-external Câ X bonds stabilizes the bicyclo[3.1.0]hexatriene form: the C1–C3 distance is calculated at the CCSD(T)/cc-pVTZ level to be approximately 1.75 °A, which is in the range of elongated CC bonds. Computed harmonic vibrational frequencies compare reasonably well with the experimental neon-matrix difference spectrum and provide further evidence for the existence of a bicyclic form. We also report an extension of the coupled cluster iterative-triples model, CC3, to excited states of open-shell molecules, including radicals. We define the method for both spin-unrestricted Hartree-Fock (UHF) and spin-restricted open-shell Hartree-Fock (ROHF) reference determinants and discuss its efficient implementation in the PSI3 program package. The program is streamlined to use at most O(N7) computational steps and avoids storage of the triple-excitation amplitudes for both the ground-and excited-state calculations. The excitation-energy program makes use of a Lowdin projection formalism (comparable to that of earlier implementations) that allows computational reduction of the Davidson algorithm to only the single- and double-excitation space, but limits the calculation to only one excited state at a time. However, a root-following algorithm may be used to compute energies for multiple states of the same symmetry. Benchmark applications of the new methods to the lowest valence 2B1 state of the allyl radical, low-lying states of the CH and CO+ diatomics, and the nitromethyl radical show substantial improvement over ROHF- and UHF-based CCSD excitation energies for states with strong double-excitation character or cases suffering from significant spin contamination. For the allyl radical, CC3 adiabatic excitation energies differ from experiment by less than 0.02 eV, while for the 2§+ state of CH, significant errors of more than 0.4 eV remain. Finally, ground- and excited-state dipole moments are derived diagramatically and were recently developed within the PSI3 quantum chemistry package. However, convergence problems with computing the left-hand excited-state has prevented us from reporting any meaningful results. Thus, future work includes solving this convergence problem before the effects of triple excitations on one-electron properties can be reported with certainty. / Ph. D.