This thesis describes the development of the conjugate addition/nitro-Mannich reaction and its use in the synthesis of useful molecules like pyrrolidin-2-ones and piperazin-2-ones. The introductory chapter of this thesis outlines the literature related to the nitro-Mannich reaction, describing the different existing methodologies for performing the reaction in diastereo- and enantioselective manner. The synthetic applications of the reaction are also described, especially its uses in the synthesis of biologically active natural products. Moreover, the syntheses and uses of two classes of compounds, pyrrolidin-2-ones and piperazin-2-ones are briefly discussed. The results and discussion chapter starts by presenting the use of a one-pot conjugate addition/nitro-Mannich/lactamisation reaction in the synthesis of densely functionalised pyrrolidin-2-ones. The development of an asymmetric protocol, as well as some functionalisations of the pyrrolidinone core are also described. Our efforts to synthesise human neutrophil elastase inhibitor GW311616A using the developed methodology are then detailed. The next part of the results and discussion chapter portrays the development of a conjugate addition/nitro-Mannich reaction of non-zinc nucleophiles to ethyl 3-nitroacrylate and β-nitrostyrene. The scope and limitations of the reaction were investigated using a variety of different nucleophiles including amines, thiols, phosphines, alcohols, enolates and nitriles. Finally, our work towards synthesising the biologically active piperazin-2-one piperazirum, using the nitro-Mannich methodology is described. The diastereoselective synthesis and characterisation of a densely functionalised piperazin-2-one was accomplished. A detailed description of the experimental details and analytical data for all novel compounds is described in the experimental section. Tables of coupling constants and X-ray crystallographic data are presented in the appendices section, followed by a list of literature references.

The thermal decomposition (dediazoniation) of i5N-labelled benzenediazonium tetrafluoroborate in 2, 2, 2-trifluoroethanol has been studied. At atmospheric pressure the reaction proceeded with a significant accompanying amount (w8%) of isotopic rearrangement, and under 300 atm of unlabelled nitrogen approximately 3% of "external" nitrogen was incorporated in the residual diazonium ion after 65% dediazoniation. Dediazoniation kinetics at high pressure showed that nitrogen was a chemical entity in the exchange reaction at 300 atm pressure. These results have been interpreted in terms of a "molecule-ion" pair and a phenyl cation intermediate. The reverse step of the formation of the phenyl cation and nitrogen is the first example of the reaction of nitrogen molecules with a purely organic reagent in solution. The relatively small influence of para-substituents (4-OCH , 4-CH , 4-NO ) on the amount of isotopic rearrangement and exchange with external nitrogen indicates that these reactions are mechanistically of the same type as the solvolysis, namely addition of a nucleophile (nitrogen) to the phenyl cation. An investigation into the mechanism of formation of aryl radicals from the reaction of 1, 3-diaryltriazenes with amyl nitrite in benzene has been carried out. The proposed reaction mechanism is analogous to the chain reaction mechanism suggested by Ruchardt for the radical decomposition of N-nitrosoacetanilide in benzene. Interest in the intermediacy of the benzenediazotate radical (PhN2O-) led to an esr study of the triazene reaction. The reaction of 1, 3-diphenyltriazene with pentyl nitrite in bromotrichloromethane has also been studied and the results compared with those of similar reactions of Nnitro soac etanilide. The participation of benzenediazonium chloride has been demonstrated in both reactions and a mechanism involving formation of the diazonium chloride has been offered. This mechanism is based on the transient intermediacy of radical-derived trichloromethyl benzenediazotate (Ph-N=N-QDCC13) which decomposes into benzenediazonium chloride and phosgene.

In recent years, polymer-assisted solution-phase synthesis has become a prevalent method because of its various advantages over conventional solution-phase chemistry, such as the ease of separation of the supported species from a reaction mixture by filtration and washing, the opportunity to use an excess of the reagent to force the reaction to completion, and the adaptability to continuous-flow processes. Peroxycarboxylic acids are common oxidants in a wide range of chemical transformations, but their use is often limited because of the associated handling risks. Some relatively stable peracids, such as <i>meta</i>-chloroperoxybenzoic acid, are commercially available, but quenching of unreacted species followed by extractions and/or chromatography separation is often required. The immobilisation of this type of reagent on a solid support can offer distinct advantages with respect to handling and stability. Carboxylic ion-exchange resins, such as acrylic macroporous matrix, can be oxidised to give highly functionalised supported peroxycarboxylic acids. The polymer-supported peracid generated from Dowex MAC-3^® proved to be the best in terms of oxidation capacity among the supports and reaction conditions tested. The new high-loading polymer-supported peracid was stable under standard laboratory practice, also when it was crushed or heated, and it was used successfully in the oxidation of sulfides, alkenes, and pyridines, giving the products with high yields and purities without the need for any additional purification step.

The fearsome reputation of primary phosphines, many of which are toxic and highly reactive towards atmospheric oxygen, has constrained the use of these versatile compounds in synthetic chemistry. However, a few examples of user-friendly stable primary phosphines have been reported which owe their stability to high steric encumbrance or is as yet unexplained. Recently an electronic stabilisation has allowed for the synthesis of novel MOPtype phosphorus ligands with previously inaccessible architectures that have potential applications in homogeneous asymmetric catalysis; an introduction into the topic is given in Chapter 1. The first air-stable chiral primary phosphines 1a,b were developed in our labs. We subsequently simplified and improved the synthetic approach to afford these and previously unreported synthons on a multigram scale, which is described in Chapter 2. Phosphiranes are highly strained heterocycles with a small sum of bond angles at the phosphorus (Σ°(P): <260). They act as ligands with interesting properties upon metal complexation due to the unusual electronics they possess as a result of the imposed ring strain; this leads to high s-character at the phosphorus and both lowered HOMO and LUMO energy levels compared to their acyclic counterparts. In Chapter 3 we report the synthesis of chiral binaphthyl-phosphirane ligands 14a,b offering high thermal and air stability, as well as the synthesis and solid state structures of their platinum(II) dichloride complexes. Initial findings for the application of the phosphiranes in the palladium catalysed asymmetric hydrosilylation of styrene are discussed. Furthermore, we were able to synthesise MOP-dimethylphosphine, MOP-bis(dimethylamino) phosphine and MOP-dimethylphosphonite ligands in one-pot reactions from 1a,b. Their peculiar structural and electronic parameters, in addition to those of MOP-phosphiranes 14a,b, are discussed in Chapter 4. The coordination chemistry of these compounds was investigated on platinum(II) and palladium(II) metals elucidating their cis/trans influences III and aryl side-on coordination respectively. We also carried out comparative studies in the allylic alkylation of (rac)-(E)-1,3-diphenylallyl acetate and the hydrosilylation of styrene, utilising palladium complexes of those MOP-type ligands as asymmetric catalysts. In Chapter 5 we report the efficient synthesis of novel MOP-phosphonite hybrid ligands 33a,b and 34a,b which incorporate two binaphthyl groups around the single phosphonite P-donor. We present their methallylpalladium complexes, which were studied in detail both in the solid-state and in solution. The palladium catalysed asymmetric hydrosilylation of styrene was again carried out and the results analysed in view of the molecular structure of the ligands. Furthermore, rhodium complexes of the same ligands were investigated, in particular with a view to examining their binding behaviour towards the metal. An unusual aromatic side-on binding mode was revealed by X-ray crystallography and further elucidated in solution by extended NMR experiments. Solution NMR studies also revealed a dynamic behaviour of these complexes, triggered by the hemilabile binding of the ligands towards the metal centre. Finally, we describe the synthesis of novel MOP-phosphonodichalcogenoite and MOP-phosphaalkene ligands in Chapter 6. Their corresponding gold(I) complexes were prepared and representative examples were characterised by X-ray diffraction. For the MOP-phosphonodiselenoite derivatives we also report the characteristic 77Se NMR data.

Recently, cationic ‘coordinately unsaturated’ square planar transition metal group Lewis acid complexes of the type [M(Ligand)]2+ (M = Pt, Pd,) have been shown to exhibit a number of advantageous features, which include well defined coordination geometries and wide functional group tolerance. They have proven to be efficient catalysts for a host of important enantioselective transformations including Diels-Alder reactions and 1,3-dipolar cycloadditions, as well as cycloisomerisations and various cyclisations. The supporting ligands and the metal centre each assert significant effects on the reactivity of the catalyst where, in particular, those complexes based on biaryl diphosphines such as BINAP, BIPHEP, MeO-BIPHEP, and NUPHOS are established as highly efficient catalysts for various couplings and cyclisations. The Doherty group has recently synthesised the novel biaryl-like R2-CATPHOS class of diphosphines and showed enantiopure (S)-Me2-CATPHOS to be markedly efficient ligand for rhodium catalysed asymmetric hydrogenation of dehydroamino esters and (E)-β-aryl-β-(enamido)phosphonates. This thesis reports details of a systematic evaluation of the efficiency of Lewis acid platinum and palladium metal complexes of enantiopure (S)-Me2-CATPHOS as catalysts for the asymmetric carbonyl-ene and Friedel-Crafts reaction and a comparison with their BINAP-based counterparts. The performance of R2-CATPHOS (R = H, Me, MeO) diphosphines as ligands for the palladium catalysed Suzuki-Miyaura cross-coupling, the Buchwald-Hartwig amination as well as a tandem carbopalladation-carbonylation sequence has also been investigated. Gold(I) complexes of R2-CATPHOS have also been shown to form efficient Lewis acid catalysts for the cycloisomerisation of a range of propargylamides. A range of platinum, palladium, and gold(I) precatalysts have been prepared and spectroscopically characterised, and catalytic conditions optimised in order to establish the extent to which R2-CATPHOS biaryl-like diphosphines are surrogates for their more conventional biaryl based counterparts such as BINAP and BIPHEP. The performance of catalysts based on R2-CATPHOS has also been compared for selected reactions to establish the influence of R on catalyst efficiency. This thesis evaluates the performance of R2-CATPHOS-based Lewis acid catalysts in chiral and achiral transformations with not only palladium and platinum but also with relatively new bis-gold catalysts that have only recently emerged in catalysis and offer great research potentials due to the unique properties of gold.

Sequential intermolecular Diels-Alder/intermolecular ene reactions of electron-rich vinyl-heteroaromatics have been investigated, as the basis for a new class of three component coupling reactions. This relatively unexplored reaction sequence provides access to the biologically important scaffolds 4,5,6,7-tetrahydro-1H-benzo[d]imidazole and 2,3,4,9-tetrahydro-1H-carbazole, with high atom economy and diastereocontrol of up to 5 new stereocentres, following a two-step reaction process involving three simple molecules (a diene, a dienophile and an enophile). 2-Vinylfuran (1), 2-vinylthiophene (2), N-protected-3-vinylindole (3) and N-protected-4-vinyl-1H-imidazoles (4 and 5) were found to react as dienes in Diels-Alder reactions under thermal conditions, without the need for Lewis acid catalysis. 4 and 5 were then subjected to a program of N-protecting group and dienophile optimisation, and the resulting Diels-Alder adducts were isolated in moderate to high yields (31-79 %) as single diastereoisomers, arising from exclusively endo-cycloaddition (Scheme 1). Scheme 1. Sequential Diels-Alder/Ene reactions. The cycloadducts arising from the Diels-Alder reaction of N-trityl-4-vinylimidazole and N-phenylmaleimide (NPM) were shown to undergo hitherto unreported, facile, sterically driven N→N trityl migrations. These migrations were a key step in several novel, highly diastereoselective domino reaction sequences (Diels−Alder, [1,3]-H shift, [1,3]-trityl migration and Diels−Alder, [1,3]-H shift, [1,3]-trityl migration, Michael reaction), leading to architecturally complex molecules. Heterocycle R 1 Furan CH2OTBS 2 Thiophene CH2OTBS 3 Indole H 4 Imidazole CH2OTBS 5 Imidazole H X: O, NPh Y: CH, N R1: Trt, DMTr, Bn, BnOMe, Ts, Ns, DMAS X1=Y1: C=C, C=O, C=N, N=N, N=O, O=O | Abstract Page | iii The cycloadducts arising from the Diels-Alder reaction of 1-benzyl-4-vinyl-1H-imidazole, (E)-1-benzyl-4-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-1-yl)-1H-imidazole and N,N-dimethyl-3-vinyl-1H-indole-1-sulfonamide were obtained in high yields, and were then tested in ene reactions with a range of reactive enophiles (Scheme 1). The resulting ene adducts were successfully isolated in moderate to excellent yields (53-95%).

The synthesis and reactions of phosphoranes are reviewed, and the mechanisms of ligand permutational isomerisms of phosphoranes are discussed in terms of Berry pseudorotations (B.P.Rs.) and Turnstile rotations (T.Rs.). The factors effecting the activation energies for these pseudorotations are discussed. The synthesis and thermal reactions of phosphoranes prepared from acyclic trivalent phosphorus compounds and from 3,4-dimethylphosphol-3-enes by using N-chlorodi-isopropylamine is described. A short investigation into the preparation of phosphoranes that contain seven-membered rings suggested that these compounds are inherently unstable. The synthesis of phosphoranes from cyclic and acyclic phosphine oxides and from phosphetan oxides by using trifluoromethanesulphonic anhydride, is described. Cis-trans isomerisations in 2,2,3,4,4-pentamethylphenylphosphetan ditriflate are discussed in terms of pseudorotations of intermediate phosphoranes. The dynamic n.m.r. spectra of certain phosphoranes were recorded and, in some cases, the difference in relative apicophilicities of phenyl, methyl and methoxyl groups were determined. The preparation of phosphoranes from alkoxyphosphetanium salts resulted in Arbuzov reactions whereas the preparation of phosphoranes from alkylthiophosphetanium salts is described and the stereospecific nature of this reaction is discussed in terms of the mechanisms of substitutions in pentacoordinate phosphorus compounds. The preparation and thermal rearrangement of 2,2,3,3-tetrakistrifluoro-methyl-5-phenyl-1,4,6-trioxa-5-phospha (5Pv) spiro [4,4] nonane, i.e. the first example of a spirophosphorane containing a 1,2-oxaphospholan ring, is described. Pseudorotations of this phosphorane are discussed. The preparation of cyclic phosphoranes, containing 1,2- -oxaphospholan rings, from epoxides and ylids is discussed and attempts to adapt this reaction to spirophosphorane synthesis is described. The preparation of chlorophosphoranes by the halogenation of allenylphosphonic dichlorides is discussed and attempts to adapt this reaction to allylphosphonates are described. In some cases this reaction lead to carbon-phosphorus bond fission. Condensation reactions using diethyl azodicarboxylate (D.A.D.) and triphenylphosphine are discussed and the use of these reagents to prepare heterocyclic compounds from diols and related compounds is described.

A discussion of hydride shifts of an order greater than 1,2 is followed by some illustrative examples. Ethyl cyclooctylidene acetate and cyclooctylidene methyl ketone were reacted with boron trifluoride etherate, but the only reaction observed was isomerisation to cyclooct-l-ene derivatives. Sulphuric, or toluene p-sulphonic, acids treatment of either double bond isomer of the ester gave 1-oxabicyclo[6.3.0]undecan-2-one. 8-(p-Methoxyphenyl)-6,6-dimethyloct-3-en-2-one underwent a 1,5 hydride shift upon treatment with perchloric acid to give 2-(p-methoxy-phenyl)-4,4-dimethylcyclohexyl methyl ketone. Treatment of ethyl 7-(p-methoxyphenyl)-5,5-dimethylhept-2-enoate with hydrobromic acid/ acetic acid gave only 7-(p-hydroxyphenyl)-5,5-dimethylhept-2-enoic acid. Attempts to induce a 1,4 hydride shift by acid treatment of 7-(p-methoxyphenyl)hept-3-en-2-one or 7,7-bis-(p-methoxyphenyl)hept-3-en-2-one were unsuccessful. Wolff-Kishner reduction of 4-(p-anisoyl)-3,3-dimethylbutyric acid, followed by methylation with dimethyl sulphate, gave 2,4,5,6-tetrahydro-7- -(p-methoxyphenyl)-2,5,5-trimethyl-1,2-diazepin-3-one. Transannular ?-reactions and interactions in alicyclic systems are reviewed. Ethyl (cyclooct-3-enylidene) acetate reacted with boron trifluoride etherate in benzene to give an inseparable mixture of products, whereas ethyl (cyclooct-4-enylidene) acetate and cyclooct-4-enylidene methyl ketone, under the same conditions, gave 1-phenylbicyclo[3.3.1]nonane-9-carboxylic acid and its ethyl ester, and 9-acetyl-1-phenylbicyclo[3.3.1]nonane, respectively. The structure of the ester product was proved by degradation to 1-phenylbicyclo[3.3.1]nonan-9-one, whose identity was proved by rational synthesis. An authentic sample of 9-acetyl-1- -phenylbicyclo[3.3.1]nonane was prepared from 1-phenylbicyclo[3.3.1]-nonane-9-carboxylic acid. Treatment of ethyl (cyclooct-4-enylidene) acetate with boron trifluoride etherate alone, followed by esterification, gave 9-carboethoxybicyclo[3.3.1]nonane; with toluene as co-solvent l-(p-tolyl)bicyclo[3.3.1]nonane-9-carboxylic acid and its ethyl ester were produced. Nitrobenzene as a co-solvent in this reaction gave no discernible products. Under the usual reaction conditions dimethyl 3,3-(cyclooct-4'-enyl)glutarate and ethyl 2-(cyclooct-4'-enyl)-2-phenyl acetate did not react. Possible mechanisms for this reaction are discussed. A similar reaction was observed when 7-exo-methylene- bicyclo[3.3.1]non-3-enylidene acetate was treated with boron trifluoride etherate in benzene, but the products were not fully characterised.

Initial direct chlorination of quinoline in the presence of aluminium trichloride, and subsequent treatment of the tetra- and pentachloroquinolines formed with phosphorus pentachloride at elevated temperatures gave heptachloroquinoline in high yield. Earlier attempts to convert quinoline directly to heptachloroquinoline using either a mixture of sulphuryl chloride, aluminium trichloride and sulphur monochloride, or phosphorus pentachloride gave mixtures of highly chlorinated quinolines which were difficult to purify.

No description available.