Chapter 1 gives the reader a background on cross-coupling reactions, in particular palladium mediated couplings. Furthermore the importance of ligands, including phosphines and N-heterocyclic carbenes (NHC), in such cross-coupling reactions is explored. Chapter 2 provides a background to the reductive lithiation of phosphines, followed by an account of our investigation of BINAP functionalisation by means of reductive elimination.1 The reaction was examined by experimental means and through the use of density functional theory to predict 31P NMR chemical shifts. Chapter 3 provides background on the Heck reaction and selected developments over the years, with particular reference to the use of aryl chlorides in the reaction. A brief discussion of NHC based palladium complex sets the scene for our investigation of a new class of (NHC)-Pd catalysts developed by the Navarro group. Complexes of type (NHC)PdCl2(TEA) (TEA = triethylamine) have been tested for their activity in the Heck reaction, focusing on the scope of the reaction with electron-deficient aryl chlorides and electron-rich aryl bromides.2 Chapter 4 gives an account of the discovery and developments of the Sonogashira reaction. Particular attention is paid to non-classical systems such as palladium-only and copper-only protocols. Herein our investigation into the use of collaborative (NHC)-Pd and (NHC)-Cu in Sonogashira reactions is presented.3 Notable features of this system are the low catalyst loadings and the synthetically convenient conditions in which the reaction can be carried namely non-anhydrous solvents and in air. Publications: (1) Gallop, C. W. D.; Bobin, M.; Hourani, P.; Dwyer, J.; Roe, S. M.; Viseux, E. M. E. J. Org. Chem. 2013, 6522–6528. (2) Gallop, C. W. D.; Zinser, C.; Guest, D.; Navarro, O. Synlett 2014, 2225–2228. (3) Gallop, C. W. D.; Chen, M.-T.; Navarro, O. Org. Lett 2014, 3724–3727.

Methodology studies for cyclic boronate ester synthesis Figure i: Target molecules (see Abstract in pdf for image) Structures i,ii,iii represent a general depiction of cyclic boron-containing heterocyles targeted in this methodology study. These molecules will be made using a range of new organic pathways. A 1,3 nitrogen-boron relationship in selected structures will also be investigated due to its importance in pharmaceutical chemistry. In the pursuit of cyclic boranes a new method for the preparation of unsaturated ketones has been discovered, which utilises the boron chemistry outlined below. Figure ii: Reagents and Conditions: (a) tBuLi, B(OIPr)3, Et2O, -79 °C, 20 % (see Abstract in pdf for image) Novel aspects of furan chemistry It was found that the furan derivative vii, when treated with palladium salts, gave the bis-annulated benzene structure viii. This sequence gave rise to a novel method for the construction of aromatic rings. This reaction was tested on a range of substituted furans in order to examine the scope of this reaction. Figure iii: Reagents and Conditions: (a) Pd(OAc)2, K2CO3, MeCN, 80 °C, 25% (see Abstract in pdf for image).

Group 14 metal(II) alkyl complexes are very rare, with few examples being studied in great detail. To this end, a series of β-diketiminate lead(II) alkyl and aryl complexes, [{(2,6-iPr2C6H3)NC(CH3)}2CH]PbR (R = Me, iPr, sBu, Np, Bn, tBu and Ph) were synthesised and a number of computational studies were performed on them to increase the understanding of the nature of these compounds. Reactivity studies on both the lead, and the analogous tin systems, showed that they could be used as precursors to generate examples of very rare two-coordinate group 14 metal cation complexes, including the first example of a β-diketiminate two-coordinate lead(II) cation, and an analogous example of a rare low-coordinate tin(II) system. These were studied in detail by computational methods, including the stabilising effects of a coordinated solvent molecule on the metal centre. β-Diketiminate magnesium alkyl complexes were generated to investigate the +2 oxidation state metal environment without the presence of a stereochemically active lone pair, as present in the group 14 metal(II) complexes. A carbodiimide was successfully inserted into the magnesium-carbon bond, and novel magnesium phosphides were generated from the alkyl complexes. Solvent stabilisation effects on these phosphides were also studied by computational methods. A series of macrocyclic amines and amine ethers were synthesised to investigate the hydrolysis of a phosphate diester model RNA system by lead(II) salts, monitored by UV-visible kinetics. The reaction kinetics gave no reproducible results, but the syntheses of the macrocycles are presented in detail for further citation.

Herbimycin A (1) belongs to the ansamycin family and is a 19-membered lactam with seven stereogenic centres, making it a synthetic challenge, which was first isolated in 1979 by Omura et al. Herbimycin A (1) exhibits a broad spectrum of biological activities: herbicidal, inhibitor of angiogenesis and of the maturation of growth factor receptor tyrosine kinases. Figure 1 - Herbimycin A (for figure see pdf) Since its discovery, only three total syntheses of Herbimycin A (1) have been described in the literature, along with the syntheses of advanced fragments. This thesis describes a new route to Herbimycin A (1), using a wide range of chemical reactions than those used in the previous routes from the literature. The main idea is to split Herbimycin A (1) into an aromatic fragment and an aliphatic fragment as shown below in Scheme 1. Scheme 1 - Retrosynthesis highlighting both aromatic and aliphatic fragments (for figure see pdf) The synthesis of aliphatic fragment (4) follows up the work of Ansell and Pietsch, past members of the Parsons group. Interesting results could be obtained and a wide range of Organic Chemistry reactions could be investigated.

For images please see Abstract in pdf trans-4-Hydroxy-L-proline (2.2) was converted to a key oxazolidinone precursor (2.1) by an improved Greenwood's procedure.47,48 The diastereofacial selective property of (2.1) led to a stereo-controlled 1,3-dipolar cycloaddition and gave a single tricyclic diastereomer (2.20). The N-O bond of the resulting isoxazoline (2.20) was cleaved by a reductive ring-opening, followed by an elimination to give enone (2.26). The enone (2.26) was converted to a b-silanol (2.33) by a nucleophillic addition with LiCH2Si(CH3)3 and then an acetylation to (2.27) was attempted. Addition of Gilman reagent to the enone (2.26) resulting a diastereoselective 1,4-nucleophillic addition and afforded the C-2,C-3 trans, C-3,C-4 cis sterically favoued bicyclic pyrrolidine (2.38) as the only diastereomer. All that remains for the synthesis of kainic acid (1.1) are olefination, ring-opening of carbamate, oxidation and deprotection.

Polysubstituted aromatics are highly desirable in medicinal chemistry for library generation and the tetrasubstituted aryl motif appears in many pharmaceuticals. Current methods to access 1,2,4,5- and 1,2,3,4- tetrasubstituted aromatics are problematic. Therefore new routes giving defined regiochemical outcomes with four different orthogonal functionalities were sought. This work took two directions; 1) the bromination and nitration of trisubstituted aryl MIDA boronates, and 2) the nitration of trisubstituted aryl bromides, both leading to the desired tetrasubstituted aromatics. MIDA boronates are boronic acids masked with N-methyliminodiacetic acid (MIDA). This allows for iterative palladium cross-coupling reactions. The first step in the work was developing a new rapid microwave-mediated method (5-15 min) towards MIDA boronates using ether poly-ethylene glycol 300, acetonitrile or dimethylformamide as a solvent. This methodology gave a library of over 20, mainly aryl or heteroaryl MIDAboronates.1,2 Trisubstituted aryl-MIDAboronates were then brominated or nitrated giving 6 novel tetrasubstituted aromatic compounds. The 3 new tetrasubstituted aryl-MIDAboronates bromides were then used in a selection of iterative Suzuki–Miyaura cross coupling reactions (SM) to show the potential uses of the compound in library generation. Three different bromo-fluorobenzaldehyde regioisomers were nitrated giving 3 different tetrasubstituted aromatics. These 3 compounds were then subjected to several different conditions to modify them i.e. nitro reduction, Sonogashira couplings, reductive aminations, Clauson-Kaas pyrrole synthesis. A number of tetrasubstituted anilines were reacted with 4-chloro-6,7-dimethoxyquinazoline to afford novel, potential kinase inhibitors.

This study commenced with an investigation into a total synthesis of the antibiotic platensimycin 1.1 in chapter one. The key reaction for accessing the synthetically challenging fused ring system involved a meta-photocycloaddition reaction and the chapter one describes our attempts at the syntheses of the key substrates. Much of the chemistry was unsuccessful however we were able to attempt a key photochemical reaction however the desired compound was not obtained. On the basis of these outcomes we refocused our efforts towards the syntheses of kainic acid 2.1 and allokaininc acid 2.2 in chapter two. We aimed to devise a stereoselective synthesis of both kainic acid 2.1 and the allokainic acid 2.2, utilising the diastereofacial selectivity inherent in the previously synthesised oxazolidinone 2.240. Oxazolidinone 2.240 was subjected to a stereo and regiocontrolled 1,3-dipolar cycloaddition to give isoxazole 2.279. Reduction, followed by dehydration of isoxazole 2.279 gave the enone 2.287 which forms the Michael acceptor in the key Michael addition reaction. The 1,4 addition on enone 2.287, gave the two diastereomers 2.328 and 2.329 which underwent sequential Wittig reaction, and Krapcho decarboxylation to give the formal synthesis of allokainic acid 2.2 and epikainate 2.346 respectively. An investigation was also conducted with the aim of altering the stereochemistry of the dicarboxylic group in compound 2.329, in order to produce a novel route to the stereoselective synthesis of kainic acid 2.1.

In the last decade substantial progress has been made in our understanding of uranium organometallic chemistry, specifically regarding the activation of small molecules by uranium(III) complexes. Research by Cloke and colleagues has employed dianionic eight- and monoanionic five-membered aromatic ligands around a uranium(III) centre to make mixed-sandwich systems, which have demonstrated novel reactivity with carbon monoxide and carbon dioxide. This thesis continues this work and furthers our understanding of the properties and reactivity of these complexes. The first part of this thesis describes the preparation of novel mixed-sandwich complexes incorporating the COT(SiiPr3)2 ligand and either a substituted cyclopentadienyl ring or a heterocyclic analogue. The steric parameters of these complexes have been quantitatively evaluated and provide insight into the molecular structures and reactivity observed. The electronic properties of the complexes have been investigated using cyclic voltammetry and complement results obtained by other researchers from the group. The second part of this thesis describes the reactivity of the novel mixed-sandwich complexes with small molecules. Whilst it was found the cyclopentadienyl complexes exhibit similar reactivity with carbon monoxide and carbon dioxide to previously reported complexes, the heterocyclic analogues provided a wealth of new reactivity, including facile cleavage of carbon monoxide at ambient temperatures, synthesis of an unusual phosphacarbonate fragment, and unprecedented synthesis of a 2,2'-bis(arsenine) species. The third part of this thesis explores the reactivity of potential precursors to uranium(II) metallocene complexes. Uranium complexes in this oxidation state have only recently been synthesised and the formation of a uranium(II) sandwich complex is desirable for its anticipated reactivity with small molecules. Reactivity studies include the attempted reduction of uranium(III) iodide precursors with potassium-based reducing agents and the synthesis of a novel uranium(II) tetraphenylborate complex.

This thesis presents the synthesis of a number of unsymmetrical SCN, N'CN, PCN and PCS pincer palladacycles. A new synthetic route has been designed towards unsymmetrical pincer ligands, involving a key Suzuki-Miyaura coupling, yielding the characteristic biaryl ligand backbone presented. New unsymmetrical SCN pincer ligands, containing a pyridine and a thioether ligand were synthesised. A number of substituents were used on the thioether ligand arm, with various steric demand and electron donating characteristics. These unsymmetrical ligands underwent C-H bond activation with palladium (II) salts, yielding the corresponding palladacycles. In order to investigate the effect of changing the sulphur donor atom, the thioether ligand arm was replaced by amines in the synthesis of N'CN pincer palladacycles, and phosphinites in the synthesis of PCN pincer palladacycles. Also changing the pyridine donor arm to a thioether was investigated, yielding a PCS pincer palladacycle. The palladacycles were tested in a number of catalytic applications: Suzuki-Miyaura coupling of sterically demanding and electronically deactivated aryl bromides; cross coupling of arylboronic acids and vinyl epoxides; and catalytic aldol condensations; revealing differences between the SCN, N'CN and PCN pincer palladacycles. In order to investigate the differences in catalytic activity, density functional theory was employed. A palladacycle formation pathway containing a key C-H bond activation step was investigated for an SCN pincer palladacycle, revealing differences in energy barriers of the C-H bond activation step depending on whetherthe thioether or the pyridine arm coordinates to the PdCl2 first. Next, the activation pathway of the palladacycles in the Suzuki-Miyaura coupling reaction was studied, identifying key transmetallation and reductive elimination steps. Differences in the overall thermodynamics and kinetics provide explanations for differences in catalytic activity. The results show that slower release of the catalytically active Pd(0) species yield a better precatalyst in the Suzuki-Miyaura coupling reaction, due to the lower propensity to form catalytically inactive palladium black. Overall this thesis provides a novel synthetic route to a family of unsymmetrical pincer palladacycles; their testing in catalytic activity in several applications, revealing differences in catalytic activity; and a theoretical study into key mechanisms, C-H bond activation, and catalyst activation in the Suzuki-Miyaura coupling reaction, which provide a rationalisation to the varying catalytic activities of the unsymmetrical pincer palladacycles.

The focus of this thesis is the synthesis and characterisation of organometallic complexes incorporating the silylated pentalene ligand, [C8H4{SiiPr3-1,4}2]2- (= Pn†), bound to more than one metal centre. In general, metals in low oxidation states from the d- and f-block of the periodic table have been selected for these bimetallic complexes, as they are potentially reactive with small molecule substrates. Chapter One introduces the pentalene molecule and its derivatives, and discusses their use as ligands in organometallic chemistry. Particular emphasis is given to the application of organometallic pentalene complexes, ranging from conducting polymers in materials chemistry to small molecule activation and catalysis. In Chapter Two the silylated pentalene ligand Pn† is used to bridge two lanthanide(II) centres in anti-bimetallic sandwich complexes of the type [Cp*Ln]2(μ-Pn†) (Ln = Yb, Eu and Sm). Magnetic measurements and electrochemical methods are used to investigate the extent of intermetallic communication in some of these systems, which show potential for the design of organometallic 'molecular-wires'. Chemical oxidation of [Cp*Yb]2(μ-Pn†) leads to dissociation into mononuclear fragments (η8-Pn†)YbCp* and [Cp*Yb]+, and reaction of [Cp*Sm]2(μ-Pn†) with CO yields (η8-Pn†)SmCp*. Rational synthetic routes to mononuclear mixed-sandwich Pn†/Cp* compounds with trivalent f-block ions (Dy, Tb and U) are also developed, and their magnetic properties are studied by SQUID magnetometry including variable-frequency ac susceptibility measurements. These studies identified (η8-Pn†)DyCp* as the first known example of a pentalene based single molecule magnet, with a closed-waist hysteresis loop observed up to 2 K. Chapter Three describes the synthesis of iron(II) complexes with silylated pentalene ligands, and efforts towards incorporating them into extended organometallic arrays and heteronuclear anti-bimetallic complexes. Six complexes have been structurally characterised including the triple-decker homobimetallic [Cp*Fe]2(μ-Pn†), and the potassium salt [Cp*Fe(η5-Pn†)][K] which is an organometallic polymer in the solid state. Chapter Four documents efforts towards the synthesis of syn-bimetallic pentalene complexes, including the first row d-block metals V, Ti and Sc. A novel synthetic route to the di-titanium bis(pentalene) 'double-sandwich' complex (Pn†)2Ti2 is developed, via chloride-bridged dimers [(η8-Pn†)Ti]2(μ-Cl)x (x = 2 and 3). The electronic and magnetic properties of the latter are investigated using EPR spectroscopy and SQUID magnetometry, and the structure and bonding in (Pn†)2Ti2 is examined using spectroscopic, crystallographic, electrochemical and computational techniques. Preliminary studies toward the synthesis of an analogous di-scandium complex were unsuccessful, however three novel complexes have been synthesised including (η8- Pn†)ScCp* which is first example of a Sc complex bearing a Pn† ligand to be characterised by X-ray diffraction. Chapter Five explores the reactivity of the double-sandwich compound (Pn†)2Ti2 prepared in Chapter Four, with small molecules which are of industrial and environmental importance. The relatively open structure of (Pn†)2Ti2 allows the formation of adducts with unsaturated small molecules CO, MeNC and CO2. In the latter case the adduct formed is unstable at room temperature and the coordinated CO2 molecule is reduced to give a bis(oxo) bridged dimer and a di-carbonyl complex. This provides the first example of small molecule activation by a di-metal bis(pentalene) double-sandwich complex. The reactivity survey of (Pn†)2Ti2 is extended in Chapter Six to other substrates; including unsaturated heteroallenes as model molecules for CO2. In the case of nonpolar heteroallenes CS2 and carbodiimide, thermally stable adducts are isolated and have been structurally characterised. Polar heteroallenes COS and organic isocyanates undergo reductive transformations to give sulfide- and carbonimidate-bridged complexes respectively. The reactivity of (Pn†)2Ti2 with organic molecules containing heteroatom-heteroatom bonds is also described; the reactions with diphenyldichalcogenides and azobenzene show the ability of the double-sandwich complex to act as a 2e- and 4e- reducing agent respectively. The rich and varied chemistry shown by (Pn†)2Ti2 is evaluated and future work is suggested.