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The application of MIDA boronates (MIDA = N-methyliminodiacetic acid) in Suzuki- Miyaura reactions has increased over the last years. This is mainly because in many cases, the replacement of the boronic acid for the respective MIDA boronate has a positive result in the reaction yield. The key feature that makes MIDA boronates efficient coupling partners is that they can undergo a slow hydrolysis reaction under Suzuki-Miyaura conditions, which generates the boronic acid in situ. The control of the hydrolysis rate is crucial to keep a low concentration of the boronic acid to avoid some of the side reactions frequently observed. The kinetics of the hydrolysis reaction from a range of alkyl, aryl, and heteroaryl MIDA boronates have been determined under different reactions conditions. In addition, competition experiments and computational calculations have resulted in the proposal of three distinct mechanisms for the hydrolysis of MIDA boronates: ‘base-promoted’, ‘water-promoted’, and ‘acid-promoted’. The base and acid mediated processes occur at faster rates than the neutral pathway and involves a rate-limiting addition at the MIDA carbonyl carbon by hydroxide or water, respectively. Whilst the 'neutral' hydrolysis requires neither base nor acid and involves ratelimiting B-N bond cleavage by a water cluster. Under certain conditions the neutral mechanism can operate in parallel with the base or with the acid mediated mechanism; relative rates are easily quantified by 18O incorporation in the MIDA, after this is released from the hydrolysis reaction. This insight is expected to assist informed application and optimisation of MIDA boronates in synthesis as well as the design of new MIDA boronate derivatives.

This thesis describes the developments of new protocols for the hydrogenation of challenging substrates. Three specific substrates were highlighted for study after an initial review of the literature; benzofurans, esters and bulky ketones. Chapter 1 details a review of the hydrogenation of challenging unsaturated substrates, highlighting areas where development is still required. Chapter 2 describes studies on the hydrogenation of 2,3-benzofuran. While a benzofuran hydrogenation catalysts was optimised, severe conditions were required to facilitate the reaction, and not found to be applicable for more elaborate substrates. We therefore considered an alternative process of enantioselective hydrogenation of benzofuranyl ketones followed by heterogeneous hydrogenation. A good process for transfer hydrogenation of a range of these hitherto unstudied substrates was developed along with greater understanding. The hydrogenation of esters is another challenge in the catalytic reduction field, so was also selected for study, with the results described in Chapter 3. After screening a range of catalysts of types [RuCl₂ (diphosphine)(diamine)] and [RuCl₂ (PNX)(DMSO)], good catalysts were identified. Successful hydrogenation of a range of esters, under mild conditions was achieved using [RuCl₂ (1,3-bisdiphenylphosphinepropane)(2-aminomethylpyridine)] using high concentrations of base co-catalyst. [RuCl₂ ((2-(diphenylphosphanylbenzyl)ethane-1,2-diamine)(DMSO)] combined with 15-25 mol% of a basic co-catalyst have been shown to be active at near ambient conditions in the hydrogenation of aromatic esters. Chapter 4 related to studies where the activity of Ru, Ir and Rh complexes of the same tridentate ligand were tested in the hydrogenation of ketones that would be regarded as sluggish substrates. Highly active and selective catalysts for the hydrogenation of bulky acetophenone derivatives were found using iridium complexes of PNX ligands (formed in situ). The highest selectivity was obtained with acetophenone substrates containing iso-propyl and cyclohexyl substituents, or medicinally important piperdinyl groups. In the best cases over 90% e.e. was observed with high conversions and with only 0.1 mol% of catalyst.

This thesis investigates the use of arene chromium complexes as phenyl cation synthons in the synthesis of homochiral N-phenylamino esters, and the dianion formation of a series of complexed aryl ethers. Chapter 1 reviews the properties of arene chromium tricarbonyl complexes and discusses in detail the ability of some of these complexes to undergo nucleophilic aromatic substitution. Chapter 2 outlines the biological importance of homochiral N-phenylamino esters. The N-phenylation of a series of amino alcohols are first investigated both by direct reaction of haloarene complexes with amino alcohols and also via a Smiles rearrangement of an aryl ether derivative. In addition, methodology is developed for the synthesis of a series of homochiral N-phenyl-α-amino esters and N-phenyl-β-amino esters. The synthetic strategy is then applied to the synthesis of some N-phenyl-β-lactams, in particular (+)SCH 48461. Chapter 3 reviews the directed metallation of complexed and uncomplexed arene compounds and discusses the mechanism involved. The generation of dianions in a series of complexed aryl ethers is investigated. Regioselective deprotonation is observed using different alkyllithium bases and the degree of dianion formation is confirmed by electrophilic quench of the dianionic intermediates with CD3OD and TMSC1.

A range of highly ordered dendritic and oligomeric macromolecules, functionalised with tetrathiafulvalene (TTF) derivatives as a redox-active sub-unit were assembled. In particular, the first dendritic macromolecules incorporating TTF were constructed by the reaction of poly-acid chlorides and alcohol functionalities. Electrochemical techniques showed the novel redox-superstructures to be efficient π-electron donors that are able to undergo two reversible, multi-electron-on oxidations. The TTF-units were established to be acting independently, and the extent to which the redox groups could be oxidised was evaluated. UV studies demonstrated the redox- assemblies to be capable of forming charge-transfer complexes m solution and showed potential for the formation of conducting charge-transfer complexes. Preliminary studies showed the precursors to these compounds to be suitable for use as electrochemical detectors for dopamine. Structural variation of the core units increased the air and thermal stability of the dendritic materials, whilst retaining the characteristics of the multi-redox system. These systems formed stable aggregates of the radical cation and afforded conducting charge- transfer complexes with TCNQ. The new precursors to multi-TTF systems were then used in attempts to impart redox characteristics on [2]pseudorotaxanes and rotaxanes. Preliminary attempts were made to assemble multi-TTF systems using a TTF derivative as a core and at the periphery.

This thesis is concerned with the use of kinetic resolution strategies for the preparation of enantiomerically pure materials. Chapter 1 introduces kinetic resolution. The limitations of conventional kinetic resolutions are described and the methods used to overcome these limitations are discussed. Chapter 2 presents a double kinetic resolution strategy where the recovered reactant from the first kinetic resolution is used as starting material in a second kinetic resolution. In the second kinetic resolution the major enantiomer present in the starting material is the faster reacting enantiomer. Application of this double kinetic resolution strategy to the Sharpless epoxidation is shown to enable enhanced product enantiomeric excesses to be obtained. Chapter 3 presents an alternative double kinetic resolution strategy where the product from the first kinetic resolution is used as starting material in a second kinetic resolution. In the second kinetic resolution the major enantiomer present in the starting material is the faster reacting enantiomer. Application of this double kinetic resolution strategy using lipase mediated esterification and hydrolysis reactions is shown to enable enhanced product yields to be obtained. Chapter 4 describes the preparation of an enantiomerically pure 2-substituted monoprotected propan-1,3-diol derivative via combination of an asymmetric synthesis and a kinetic resolution. Chapter 5 describes the preparation of the pheromone sulcatol in enantiomerically pure form via combination of an asymmetric synthesis and a kinetic resolution. Chapter 6 presents an investigation into the structure of lithium(α-methylbenzyl)- benzyl amide. Chapter 7 describes an attempted dynamic kinetic resolution of 2-substituted monoprotected propan-1,3-diol derivatives. Chapter 8 describes an attempted preparation of the iron crotonyl complex E-[(η5-C5H5)Fe(CO)(PPh3)(COCH=CHCH3)] in enantiomerically pure form via enzymic kinetic resolution.

Part 1: The occurrence of bimolecular nucleophilic aromatic substitution has been established in the reaction of o-dinitrobenzene with triethyl phosphite and diethyl methylphosphonite in acetonitrile solution. There is a fine balance between the customary deoxygenation and nucleophilic substitution of aromatic nitrocompounds. The role of the o-nitro group in facilitating the nucleophilic substitution has been discussed in terms of "built-in solvation" of the reaction centres. The exclusive formation of ethyl nitrite in the reactions has been shown to be compatible with the dealkylation of a quasi-phosphonium intermediate by nitrite ions. Part 2: A series of alkyl a-hydroxyimino-p-nitrobenzyl alkylphophyl adducts have been synthesised from phosphorus-containing acids and p-nitrobenzonitrile oxide. Their solvolytic behaviour has been examined. Hydrolysis occurred in acid solution at 25°with anchimeric assistance of about 2x107 by the neighbouring oximino group, to yield the alcohol of the ester moiety. Exclusive phosphorus-oxygen fission occurred. P-Nitroaniline was formed in alkaline solution by intramolecular attack by the oximate anion, followed by a Lossen rearrangement. Evidence is presented for the intermediary of pentacovalent intermediates, and the relative reactivities of the adducts are explained by the constraints necessary for pseudo-rotation to allow further reaction to form the products in alkaline solution. The acid hydrolysis of ethyl pinacolyl methylphosphonate was shown to proceed via a unimolecular mechanism with the formation of a carbonium ion in 50% aqueous dioxin at 100 °.

Abstract: A thorough overview of esters and their reductions is presented. A large focus was placed on reductions via homogeneous catalytic hydrogenation. Although several ester hydrogenation systems have been developed, the production of highly enantioenriched alcohols has generally relied upon the usage of enantioenriched esters. A system for homogeneous asymmetric hydrogenation of esters to enantioenriched alcohols was discovered and optimized via an in-house screening method. The optimal system uses an in situ formed Ru-based catalyst made from [Ru(1-3:5,6-η5-C8H11)(η6-anthracene)]BF4, the chiral ligand (1R,2R)-N,N′-bis{2-[bis(3,5-dimethylphenyl)phosphino]benzyl}cyclohexane-1,2-diamine, and H2. This catalyst is highly active and enantioselective towards hydrogenating α phenoxy esters to β-chiral primary alcohols under mild conditions. The system operates via dynamic kinetic resolution (DKR), where the esters undergo base-assisted racemization and the catalyst preferentially reacts with one enantiomer. Specifically, NaOiPr in THF and NaOEt in DME were optimal base and solvent combinations for the DKR. The alkoxide bases participate in transesterification and catalyst activation. Under 4 atm H2 and at room temperature, the catalyst provides quantitative conversion (50 turnovers) over 1 h for α-phenoxy propionate and butyrate esters (2 mol% catalyst, 50 mol% base). The enantiomeric excesses of the resulting β chiral alcohols ranged from 79 to 93%. The hydrogenation of (±)-ethyl 2-phenoxypropionate at 0 C resulted in a 95% enantiomeric excess (ee). Under 15 atm H2 and at room temperature, the catalyst performed 950 turnovers of (±)-ethyl 2-phenoxypropionate over 9 h and resulted in a 91% ee towards (R)-2-phenoxypropan-1-ol (0.1 mol% catalyst, 20 mol% NaOEt, DME). Hydrogenation of the potential intermediate aldehyde (±) 2 phenoxypropionaldehyde and deuteration of (±)-ethyl 2-phenoxypropionate were performed to experimentally investigate the mechanism. Three Ru(II)–polypyridyl complexes were prepared for the underexplored area of photohydrogenation. [Ru(bipy)2(1,10-phenanthroline-5,6-diamine)](OTf)2 (bipy = 2,2′ bipyridine) was synthesized in 56% yield from [Ru(MeCN)2(bipy)2](OTf)2 and the bis bidentate ligand 1,10-phenanthroline-5,6-diamine in MeOH at 70 C. The dinuclear complex was not the major product. The imidazolium ligand 1-benzyl-3-(propan-2-yl)-1H-imidazol[4,5-f][1,10]phenanthroline-3-ium (bpip) was prepared in 55% yield over three steps from 1,10 phenanthroline-5,6-diamine. The complexation of bpip to the Ru–dichloride precursors cis [Ru(Cl)2(bipy)2] and cis-[Ru(Cl)2(dmbipy)2] (dmbipy = 4,4′-dimethyl-2,2′-bipyridine) proceeded smoothly in MeOH at 70 C. [Ru(bpip)(bipy)2](OTf)3 and [Ru(bpip)(dmbipy)2](OTf)3 were prepared from their respective dichloride precursors, over two steps, in 87 and 73% yields, respectively. Crystals suitable for X ray diffraction were obtained for [Ru(bpip)(bipy)2](BF4)3. The [Ru(bipy)2(1,10-phenanthroline-5,6-diamine)](OTf)2 and [Ru(bpip)(dmbipy)2](OTf)3 were incorporated into two separate known hydrogenation systems. The photohydrogenation of acetophenone was attempted with in situ catalyst formation from [Ru(bipy)2(1,10 phenanthroline-5,6-diamine)](OTf)2 and fac-[Ru((R)-BINAP)(H)(iPrOH)3]BF4 (BINAP = 2,2′ bis(diphenylphosphino)-1,1′-binaphthyl). Only ~2% of the acetophenone was converted (~10 turnovers) over 45 min (0.2 mol% catalyst, 10 mol% KOtBu, iPrOH, ~1 atm H2, rt, 15 min 400–700 nm hv). The photohydrogenation of styrene was attempted with in situ catalyst formation from [Ru(bpip)(dmbipy)2](OTf)3 and [Co(TMEDA)(CH2SiMe3)] (TMEDA = N,N,N′,N′ tetramethylethylenediamine). No detectable reaction occurred under the conditions examined (0.2 mol% catalyst, 0.2 mol% KOtBu, MeOH, ~1 atm H2, 450 nm hv, 10.5 h).

Tuberculosis continues to be a public health problem in the world, and drug resistance has been a major obstacle in its treatment. Quinoxaline 1,4-di-N-oxide has been proposed as a scaffold to design new drugs to combat this disease. To examine the efficacy of this compound, this study evaluates methyl, ethyl, isopropyl, and n-propyl esters of quinoxaline 1,4-di-N-oxide derivatives in vitro against Mycobacterium tuberculosis (pansusceptible and monoresistant strains). Additionally, the inhibitory effect of esters of quinoxaline 1,4-di-N-oxide on M. tuberculosis gyrase supercoiling was examined, and a stability analysis by ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS) was also carried out. Results showed that eight compounds (T-007, T-018, T-011, T-069, T-070, T-072, T-085 and T-088) had an activity similar to that of the reference drug isoniazid (minimum inhibitory concentration (MIC) = 0.12 µg/mL) with an effect on nonreplicative cells and drug monoresistant strains. Structural activity relationship analysis showed that the steric effect of an ester group at 7-position is key to enhancing its biological effects. Additionally, T-069 showed a high stability after 24 h in human plasma at 37 ◦C.