In this thesis we report the development of biaryl azepinium salts (e.g. 83, Figure i) and their application in the enantioselective epoxidation of tri-substituted alkenes. These iminium salts appear to exist as a mixture of two conformers at room temperature. The observed enantiocontrol in the epoxidation reactions investigated appears to result from the chiral amine biasing the reactivity of one biaryl azepine conformation over the other towards attack of a nucleophilic oxidant. This leads to the epoxidation proceeding preferentially via one diastereoisomer of the oxaziridinium intermediate. t-Bu t-Bu Figure i. We also report the development of biaryl azepinium salts (e.g. 112, Figure ii) and their application in the highly enantioselective alkylation and Michael addition of glycine imines. It would appear that these salts exist in a single biaryl azepine conformation. Favourable ion- pair interaction between the quaternary ammonium and the glycine imine enolate in the transition state of the reactions result in the high enantioselectivities observed. t-Bu t-Bu Figure ii. We report preliminary studies into the application of biaryl azepines as part of bifunctional catalysts, for application in conjugate addition reactions (142) and in direct aldol reactions (152) (Figure iii). Figure iii. These results idicate that the novel tertiary amine salt 152 is capable of delivering both high diastereo- and enantioselectivity in the direct aldol reaction of 4-nitrobenzaldehyde 134 with 2-cyciohexanone 133 (Scheme i). 133 Scheme i. 134 o OH N02 138: 95%, 98% de, 98% ee The synthesis of a range of biaryl azepines with a chiral centre in the azepine ring is reported (Figure iv). Figure iv. These amines all appear to exist in a single biaryl azepine conformation. They were synthesised via a highly atropodiastereoselective direct arylation, as their corresponding trifluoroacetamide derivatives. Azepines (+)-155 and (+)-185, act as chiral relays and switch their conformation on removal of the trifluoroacetamide protecting group. Azepine (-)-211 can only exist in one conformation, and as such has the same conformation as its corresponding trifluoroacetamide derivative. Preliminary investigations into the potential of these chiral amines as precursors to asymmetric catalysts are reported. In this thesis, we also report the development of quaternary ammonium salts formed form combining a chiral amine with complex fragments that do not exhibit axial chirality. This study identified a novel quaternary ammonium salt 257, which is capable of delivering moderate levels of enantioselectivity in the Michael addition of glycine imine 10 to MVK (Scheme ii). Scheme ii. 10 K2C03, PhMe, 5h, MVK x.o, 92%, 52% ee Finally, we report the development of tetra-butyl ammonium borates (e.g. 283, Scheme iii) and their application in Suzuki-Miyaura cross-coupling reactions involving no additional water or base. Scheme iii. CI-Q-N02 280 Pd(OAch (3 mol%), IPA, 85 cc, 0.17 h ) < }-N02 282: 96% The quaternary ammonium borate reagents are capable of transferring a range of aryl groups and can react with a range of aryl halides in excellent yields. No additional base is required and reactions proceed with sub-stoichiometric quantities of water. These represent very useful reagents, particularly if one of the substrates is either water or base sensitive.

This thesis describes the study of a condensation-cyclisation-1,3-dipolar cycloaddition cascade to tricyclic amines.

No description available.

A series of bis(thioureido) ligands have been synthesised, which show anion binding in acetone-d(_6). Their structures have been determined by X-ray crystallography and some exhibit hydrogen bonding interactions with the π-electrons of the the thiocarbonyl bond. This hydrogen bonding interaction has been investigated for the general thiocarbonyl and carbonyl bond using the CSD, and a marked difference in the interaction of hydrogen bond donors with the π-electrons of carbonyl and thiocarbonyl bonds has been shown. The bis(thioureido) ligands have been coordinated to platinum group metals and the differing binding modes of the ligands investigated. The reaction of ligands with 2 carbon atoms between thiourea groups with [{Ru(n(^6)-С(_6)Н(_4)МеСН(Ме)(_2))С1(μ- Cl)}(_շ)], yields a mixture of products that may be consolidated into a single product with a water wash. The water instigates a deprotonation of an NH group that allows nitrogen coordination to ruthenium, yielding a S,S,N terdentate Ru(II) half-sandwich complex, with four- and seven-membered adjoining metallacycles. A chiral metal centre is formed and in the solid state, opposite enantiomers hydrogen-bond to each other through chloride counter-ions. Ruthenium complexes with an interaction from the pyridyl nitrogen in ligands containing pyridyl binding moieties have also been characterised. Bidentate S,S coordination is observed for the reaction of bisthiourea ligands with [Pd(dppe)Cl(_2)], forming nine- and ten-membered metallacycles. A similar binding mode is observed in a Pt(II) analogue. A polymer analogue of the bisthiourea ligands has been synthesised, and has been tested to extract metals from mixed metal solutions. Using well-defined metal salts in methanol, ruthenium(II) may be loaded onto the polymer from a single metal solution, acetontrile solvent inhibits the uptake of platinum group metals from mixed metal solutions, the polymer is selective for Cu(II) even when acetonitrile solvent is present and in the absence of Cu(II) or acetonitrile, can selectively extract Pt(II) over Ru(II), Fe(II), Cr(III) and Ni(II). The ruthenium loaded resin may be stripped of Ru(II) effectively using concentrated nitric acid solution in two hours. Testing the bisthiourea polymer in an acetic acid mixed metal solution demonstrated that the polymer was not suitable for platinum group metal extraction from the acetic acid medium, when compared to a commercially available resin.

A brief description of Supramolecular Chemistry, followed by a literature review on the chemistry of calix[n]arene derivatives (n = 4-6) concerning the work carried out in this thesis are included in the Introduction Section. A fully detailed investigation on structural and thermodynamic aspects of calix[n]arene amide derivatives (n= 4-6) with metal cations (alkali, alkaline earth, transition and heavy metal cations) were carried out in different media at 298.15 K. The information were obtained using the appropriate techniques and The successful syntheses of 5,11,17,23-tetra-(1,1-dimethylethyl)-25,26,27,28-tetra-{N,N-diethylamide)-ethoxy-calix[4]arene (L1), 5,11,17,23,29 penta-tert-butyl 31,32,33,35-penta hydroxyl calix[5]arene (L2) and 5,11,17,23,29,35-p-tert-butyl-37,38,39,40,41,42- hexadiethylacetamide-calix[6]arene (L3) was confirmed by 1H NMR and elemental analysis. The solution thermodynamics for L1 and L3 were investigated and the degree of solvation of these macrocycles on different media relative to acetonitrile was derived from the ?tG&deg;(s1-s2) from one solvent relative to acetonitrile 1H NMR studies for L1 in different media at 298 K gave valuable information on the conformation that this ligand adopts in these solvents. The interaction of L1 with metal cations in deuterated solvents was analysed by 1H NMR at 298 K. Information on the binding sites was also obtained from these experiments. Conductometric titrations in acetonitrile and methanol at 298.15 K were performed to establish the stoichiometry of complex formation for L1 and L3 with metal cations. This was followed by calorimetric and potentiometric titrations with metal cations at 298.15 K to determine the thermodynamic parameters of complexation. The medium effect on the complexation processes was assessed for L1 and monovalent metal cations in one solvent relative to another at 298.15 K. This was investigated taking into account the thermodynamic parameters of transfer of the reactants and the product from acetonitrile relative to methanol. A comparative study involving the three ligands was discussed on the basis of the experimental data obtained for each of these macrocycles in their complexation with metal cations. Conclusions and suggestions for further investigations are given.

In this project the use of amides as precursors for imidoyl radicals in heterocyclic chemistry has been developed. Amides were converted to thioamides, which function as precursors for imidoyl radical equivalents. Also, a novel protocol for the synthesis of imidoyl selanides was developed for the purpose of using these as imidoyl radical precursors. The precursors were used in a study of intramolecular oxidative cyclisation of imidoyl radicals onto electron deficient pyrroles and indoles. The imidoyl radical equivalents derived from thioamides did not cyclise onto heteroarene double bonds. In contrast, imidoyl radicals derived from imidoyl selanides did cyclise 6-exo onto activated heteroarenes, but yields were generally low due mainly to competing reduction of the imidoyl radical, but also due to adduct formation with isobutyronitrile radicals originating from the initiator.

Reaction of Ph2PCl with R(NH2)n (n = 1, 2 or 4) in the presence of NEt3 affords a series of mono-, di-, tetra- and octadentate (phosphino)amines, {Ph2PN(H)}nR or {(Ph2P)2N}nR (n =1, 2 or 4; R = functionalised aromatic group bearing methyl, keto, ester, ether, vinyl or thiazole substituents). Oxidation of these new (phosphino)amines with sulfur, selenium or hydrogen peroxide yields the corresponding phosphorus(V) compounds. Mixed phosphorus(III)/phosphorus(V) compounds containing P(III) and E donor centres are also described. The coordination chemistry of these new ligands towards various transition-metal centres (e.g. ruthenium, rhodium, palladium, platinum and gold) have been extensively studied. Thermal C–H activation of [PtMe2{PPh2N(H)R}2] or [RhCl2(η5-C5Me5){Ph2PN(H)R}] affords first examples of orthometallated (phosphino)amine complexes containing a five-membered ring M–P–N–C–C metalloring. Characterisation of a number of these novel compounds was achieved using single crystal X-ray analysis, revealing, in many cases, the presence of an intramolecular N–H···O hydrogen bond.

This thesis outlines work carried out in the last three years concerning the development of novel, atom-economic, catalytic syntheses of amide bonds, determination of the ranges of these reactions through substrate screenings and investigations into the mechanisms by which the reactions are operating. In Chapter 1, an introduction to amide bonds is given, after which a discussion on the synthesis of amide bonds is presented, covering direct coupling methods, enzymatic methods and both non-metal catalysts and metal catalysts used for amide bond synthesis. In the Results and Discussion section, an iron catalysed coupling of nitriles and amines is presented in Chapter 2. In Chapter 3, firstly the development of an indium and zinc catalysed rearrangement of aldoximes into primary amides is discussed, followed by development of a novel, nickel catalysed coupling of aldehydes and amines. Detailed mechanistic studies using 18O labelled substrates are then presented for both of these reactions. Chapter 4 details work on a novel, hydroxylamine hydrochloride catalysed transamidation of primary amides with amines, including 1H NMR studies to attempt to elucidate the mechanism of the reaction. Finally, in Chapter 5, work investigating the direct coupling of unactivated carboxylic acids and amines is discussed, followed by an investigation into suitable catalysts to improve the efficiency of the reaction and a comparison of the rates in the catalysed and uncatalysed reactions for a wide range of substrates. In the Results and Discussion section, an iron catalysed coupling of nitriles and amines is presented in Chapter 2. In Chapter 3, firstly the development of an indium and zinc catalysed rearrangement of aldoximes into primary amides is discussed, followed by development of a novel, nickel catalysed coupling of aldehydes and amines. Detailed mechanistic studies using 18O labelled substrates are then presented for both of these reactions. Chapter 4 details work on a novel, hydroxylamine hydrochloride catalysed transamidation of primary amides with amines, including 1H NMR studies to attempt to elucidate the mechanism of the reaction. Finally, in Chapter 5, work investigating the direct coupling of unactivated carboxylic acids and amines is discussed, followed by an investigation into suitable catalysts to improve the efficiency of the reaction and a comparison of the rates in the catalysed and uncatalysed reactions for a wide range of substrates.

The development of cost-effective and sustainable catalytic methods for the production of enantiomerically pure chiral amines is a key challenge facing the pharmaceutical and fine chemical industries. There is an increasing demand for broadly applicable synthetic methods which deliver the desired amine product in high yield and enantiomeric excess (e.e.). Previously we have described the development of variants of monoamine oxidase from Aspergillus niger (MAO-N) which are able to mediate the complete conversion of racemic amines to the corresponding enantiomerically pure products in a single step. In this thesis we report a panel of MAO-N variants (D5, D9 and D11) developed in our laboratory, which are able to mediate the deracemisation of primary, secondary and tertiary amines with broad structural features. In particular, we have synthesized and subjected to deracemisation a broad range of tetrahydroisoquinolines and tetrahydro-β-carbolines checking enantioselectivity and enantiopreference of our biocatalysts. A relation between lipophilicity of the substituents and enantiopreference of the enzyme has been identified. We have also engineered a new MAO-N variant (D11) with a greatly increased substrate scope and enhanced tolerance for bulky substrates. Application of this engineered biocatalyst is highlighted by the asymmetric synthesis of the generic drugs Solifenacin and Levocetirizine as well as a number of important classes of biologically active alkaloid natural products. We also report a novel MAO-N mediated asymmetric oxidative Pictet-Spengler approach to the synthesis of (R)-harmicine.Another challenge facing the chemist in the new millennium is the development of cleaner and more efficient chemical processes. To this aim the combination of two or more catalytic systems to complete a series of cascade reactions is considered particularly appealing. We have reported a concurrent redox cascade for the deracemisation of pyrrolidines and tetrahydroisoquinolines using our monoamine oxidase-N with a biotinylated Ir-complex within streptavidin (SAV). To achieve the final goal it is necessary to shield the metal inside a host to avoid the mutual inactivation of the two catalysts. We have also described the combination of MAO-N with berberine bridge enzyme (BBE) for the synthesis of berbines (tetrahydroprotoberberines), which represent a sub-class of tetrahydro-isoquinoline alkaloids found in various plants. This bi-enzymatic cascade allows the synthesis of these structures achieving a theoretical 100% yield instead of the 50% given by the kinetic resolution using BBE itself.

This thesis describes the development of a more economical catalytic system for the N-alkylation of amines by “borrowing hydrogen” and its application in the synthesis of a variety of amines including the dopamine agonist Piribedil and the antihistamine agents Antergan and Tripelennamine. <b>Chapter 2</b> describes the development of the ruthenium-catalysed N-alkylation of primary amines with primary alcohols by “borrowing hydrogen”. <b>Chapter 3</b> describes the application of the ruthenium-catalysed N-alkylation of secondary amines with primary alcohols by “borrowing hydrogen”. The ruthenium-catalysed synthesis of dimethylamines by “borrowing hydrogen” is also described and a mechanistic proposal for the N-alkylation of alcohols with amines has been proposed. <b>Chapter 4</b> describes the role of amines in pharmaceuticals and the ruthenium-catalysed synthesis of Piribedil, Antergan and Tripelennamine by “borrowing hydrogen”.