<p dir="ltr">Vinylidenes are highly reactive intermediates that undergo a variety of chemical reactions. Our group has pioneered the in-situ generation of vinylidenes from bench stable 1,1-dichloroalkenes using transition metal catalysts and an exogenous reductant.</p><p dir="ltr">Herein, we demonstrate the intramolecular insertion of vinylidenes into Si–H bonds for the synthesis of unsaturated silacycles of different ring sizes. It is well known that the replacement of carbon for silicon are of significant interest to medicinal chemists as a strategy for improving the potency or pharmacokinetic properties of biologically active compounds. This method provides convenient access to trisubstituted vinyl silanes which are synthesized intermolecularly, including those that can be used as nucleophilic partners in Hiyama cross-coupling reactions. Finally, deuterium isotope labelling experiments reveal interesting mechanistic features of the reaction.</p><p dir="ltr">The second chapter of the thesis further highlights the reactivity of vinylidenes through utilizing a cobalt catalyst. Vinylidene complexes can be added into an alkyne intramolecularly followed by a cobalt to zinc transmetalation step. The resulting organozinc intermediate can be trapped with various electrophiles. Further, by altering the reaction condition, the cobaltacycle intermediate can be accessed using π systems to form different cycloadducts.</p>

<strong>Introduction – Dearomatisation of Heteroaromatic Compounds</strong> The introduction provides a survey of dearomatisation reaction of heteroaromatics, with a particular focus on pyridines/pyridinium salts and furans. The mechanism, scope, and limitations of various approaches are covered, along with the goals of this project. <strong>Results and Discussion – Dearomatisation of Electron-Deficient Heteroaromatics</strong> This chapter initially explores the asymmetric addition of organometallic nucleophiles to pyridinium salts bearing a chiral counterion. Unfortunately, this approach ultimately proved unsuccessful, due to low observed enantioselectivities, and the low solubility of such salts. The second part of this chapter concerns the attempted asymmetric addition of dicarbonyl nucleophiles to electron-deficient furans, under conditions of chiral phase-transfer catalysts, affording bicyclic products in moderate enantioselectivity. Various alternative routes were also explored for the dearomatisation of furans and benzenoid systems. <strong>Introduction – Hydrogen Borrowing Alkylation Reactions with Alcohols</strong> The introduction surveys the range of methods available for the alkylation of various nucleophiles with alcohols under transition metal-catalysed conditions. Related methodologies are also explored, along with methods for the dehydrogenation of methanol. <strong>Results and Discussion - Rhodium-catalysed Methylation of Ketones Using Methanol</strong> This chapter describes the development of a novel ketone α-methylation using methanol. The development of reaction conditions is explored, followed by expansion of the substrate scope, including limitations of the methylation reaction. Mechanistic investigations support a methanol oxidation, aldol reaction/elimination, conjugate reduction pathway. Investigations into the role of O2 in the methylation reaction proved inconclusive. The utility of the reaction was also expanded via one-pot dialkylation reactions (work by Di Shen), Baeyer-Villiger oxidation of the products, and an attempted asymmetric transfer-hydrogenation. <strong>Results and Discussion - Interrupted Hydrogen Borrowing Reactions of Methanol</strong> This chapter looks to intercept intermediates from the α-methylation reaction. The selective methylenation of ketones is described, and a range of nucleophiles are screened for further functionalisation of ketones. Finally, a number of nucleophiles, including nitroalkanes, amines, peroxides and boronic acids are applied to one pot methylenation/conjugate addition protocols, affording complex products after two steps in one reaction vessel. <strong>Experimental</strong> Full experimental procedures and spectroscopic characterisation of compounds are provided.

The generation of new chemical entities (NCEs) for use in chemical biology and drug discovery is of wide interest to both academia and the pharmaceutical industry. In order to generate NCEs, this project focused on development of new synthetic methodologies using transition-metal mediated [2+2+2] cyclotrimerisation of alkynes and unsaturated molecules to form bi- and tricyclic heterocyclic derivatives, some with structural resemblance to the quinocarcin family of natural products. Three different dialkynes (1,5-di(prop-2-yn-1-yl)pyrrolidin-2-one 2.117a, 1,6-di(prop-2-yn-1-yl)piperidin-2-one 2.118a and 4-benzyl-1,6-di(prop-2-yn-1-yl)piperazin-2-one 2.120a) were successfully synthesised. Several cyclotrimerisations were attempted, with the best yields being obtained when diethylacetylene dicarboxylate 2.113a was used as the monoalkyne and Cp*Ru(cod)Cl as the catalyst in refluxing toluene. New heterocyclic compounds with potential for diversification were synthesised using a diversity-oriented synthesis approach; specifically the build/couple/pair strategy for the synthesis of small molecules. Racemic nitrogen and oxygen building blocks were coupled with acrylonitrile, bromoacetonitrile and acyl chlorides. The pair step involved the intramolecular ring closure using transition-metal catalysed [2+2+2] cyclotrimerisations using microwave assisted radiation. The best catalyst for this approach was found to be CpCo(CO)2 at 150 ºC (300 W) in chlorobenzene. This provided a new methodology with potential for synthesising a diverse set of small molecules for biological testing. 20 compounds were subjected to chemosensitivity testing using the MTT assay. Several compounds were shown to possess activity in bladder (RT112) and breast (MCF-7) cancer cell lines. As these two cell lines are known to express extra-hepatic cytochromes P450 enzymes, it is possible that these are involved in generating cytotoxic metabolites that may damage DNA.

The phosphazene ligands spiro(biph)tetrakis(2-oxypyridine)cyclotriphosphazene (L1), spiro(biph)tetrakis(4-methyl-2-oxypyridine)cyclotriphosphazene (L2), and spiro(biph)tetrakis(6-methyl-2-oxypyridine)cyclotriphosphazene (L3 In solution, [CuL) have been synthesised and characterised as small molecule templates for the polymeric analogues. Complexes of each ligand with selected transition metals have been synthesised and characterised. Where X-ray crystal structures have been obtained, the predominant geometry is a five-coordinate trigonal bipyramidal (TBP) form, though variations exist. 2Cl2] retains the TBP form whereas [CoL2Cl2 ] rearranges to a tetrahedral geometry. In order to elucidate this behaviour, diamagnetic complexes were synthesised and variable temperature NMR (VTNMR) studies conducted. The complexes [ZnL2Cl2], [CdL2Cl2] and [HgL2Cl2] exhibit fluxional behaviour as monitored by VTNMR studies. The X-ray structure of [CdL2Cl2] contains three molecules in the unit cell that demonstrate what is thought to be the first evidence for a fluxional mechanism in phosphazene compounds. The complex [ZnL2Cl2 ] exists at low temperature as discernable major and minor species. Polyphosphazene analogues have been synthesised and complexed with selected transition metals. The polymer complexes display variations in solubility and stability which is postulated to be due to the ratio of side group substitution, position of the pyridyl methyl group and the nature of the complexing metal. A number of the polymers degrade prior to workup, possibly as a result of base-promoted attack on the backbone by the pyridyl nitrogen atoms. Electronic spectra reveal that where soluble, the Co(II) polymer complexes have a tetrahedral geometry, whereas the Cu(II) polymer complexes distort between TBP and square-based pyramidal dependent on the ratio of metal used. Polymer complexes with Zn(II) demonstrate fluxional behaviour.

The synthesis of metal-redox active ligand complexes is described, along with reactivity studies aimed at facilitating novel C-N bond forming reactions. A copper bis(iminosemiquinone) structure is characterized, analyzed and its reduction series are characterized and the reactivity of the Cu(II) bis(amidophenolate) analog is investigated with tosyl azide. The identification of the major reaction product and its characterization is detailed, with reaction sensitivities and heavily distorted x-ray diffraction single crystal structure generating a complex data set. The characterization of the isolated product is ongoing, with EPR studies aimed at identifying the radical nature of the complex. Unusual solvent effects and solubility issues have been noted with these initial EPR studies and more data is necessary before analysis can be properly attempted. An ytterbium bis(amidophenolate) complex was synthesized and its reactivity studied with aryl azides. Initial reactivities generate the first documented lanthanide tetrazenes in-lieu of the targeted ytterbium imido. Reactivities and characterization of these complexes support a stable, heavily ionic tetrazene-metal complex with no observed redox nature, UV light sensitivities, or imido azide-tetrazene equilibrium observed in various tetrazene transition metal complexes. Synthesis of a sterically blocked ytterbium imido was attempted, utilizing DMAP. Initial isolation was achieved with characterization and reactivity studies supporting the imido nature of the complex. The weak coordinating of the DMAP provided instability that proved in opposition to crystallization, however, so the imido could not be confirmed. Initial reactions using alternative steric hinderance from triphenylphosphine oxide and pyridine N-oxide prove promising to increasing the stability of the presumed ytterbium imido. Organic synthesis was performed generating a potential antibacterial agent. The synthesis of cyclopropenes was initiated as antagonists for ETR proteins in fruits and plants. The intermediates proved highly sensitive to harsh chemical conditions, which was overcome utilizing a tin-mediated Barbier allylation. The cyclopropene alcohol synthon was synthesized, though protecting group optimization is necessary.

The generation of new chemical entities (NCEs) for use in chemical biology and drug discovery is of wide interest to both academia and the pharmaceutical industry. In order to generate NCEs, this project focused on development of new synthetic methodologies using transition-metal mediated [2+2+2] cyclotrimerisation of alkynes and unsaturated molecules to form bi- and tricyclic heterocyclic derivatives, some with structural resemblance to the quinocarcin family of natural products. Three different dialkynes (1,5-di(prop-2-yn-1-yl)pyrrolidin-2-one 2.117a, 1,6-di(prop-2-yn-1-yl)piperidin-2-one 2.118a and 4-benzyl-1,6-di(prop-2-yn-1-yl)piperazin-2-one 2.120a) were successfully synthesised. Several cyclotrimerisations were attempted, with the best yields being obtained when diethylacetylene dicarboxylate 2.113a was used as the monoalkyne and Cp*Ru(cod)Cl as the catalyst in refluxing toluene. New heterocyclic compounds with potential for diversification were synthesised using a diversity-oriented synthesis approach; specifically the build/couple/pair strategy for the synthesis of small molecules. Racemic nitrogen and oxygen building blocks were coupled with acrylonitrile, bromoacetonitrile and acyl chlorides. The pair step involved the intramolecular ring closure using transition-metal catalysed [2+2+2] cyclotrimerisations using microwave assisted radiation. The best catalyst for this approach was found to be CpCo(CO)2 at 150 ºC (300 W) in chlorobenzene. This provided a new methodology with potential for synthesising a diverse set of small molecules for biological testing. 20 compounds were subjected to chemosensitivity testing using the MTT assay. Several compounds were shown to possess activity in bladder (RT112) and breast (MCF-7) cancer cell lines. As these two cell lines are known to express extra-hepatic cytochromes P450 enzymes, it is possible that these are involved in generating cytotoxic metabolites that may damage DNA. / Fundação Para a Ciência e a Tecnologia (FCT)

<p>  </p> <p>A historically important reaction, the Ueno-Stork reaction promotes, through the use of toxic organotin species, the cyclization of a haloacetal onto an alkene generating bicyclic acetals. This reaction has been used over the years in several total syntheses of biologically relevant natural products, especially the prostaglandin class of natural products. Herein, will be described the development of a novel nickel-catalyzed Ueno-Stork cyclization reaction, which no toxic organotin and radical promoters are used, and instead a greener, operationally friendly, and non-toxic earth abundant nickel catalyst is applied. Optimization studies, substrate scope, scalability, relative stereochemistry of the bicyclic acetals, as well as derivatization of the products were studied. Furthermore, the newly developed reaction was applied on the total synthesis of tricyclic-PGDM Methyl ester, a prostaglandin D2 metabolite of important clinical relevance that currently suffers from material supply issues.</p> <p>Cyclopropanol ring opening reactions have different reactivity modes. Either a metal homoenolate species or a b-keto radical species can be formed after ring opening depending on the reaction conditions applied. More specifically, hydroxycyclopropanols have been studied to access several important motifs present in an array of natural products and medicinally important molecules. The Dai group has used this strategy to access several motifs through intramolecular trapping of the homoenolate species with and without the presence of carbon monoxide to generate oxaspirolactones, THF/THP-fused bicyclic lactones, and disubstituted THF/THP heterocycles. Herein, it will be discussed the application of similar concepts to access new classes of heterocycles 4-ketovalerolactones and 3-furanones. The optimization of two reaction conditions to selectively synthesize each product starting from the same starting material was studied. Furthermore, the substrate scope, scale-up, and derivatization studies of each motif will be disclosed. </p>

<p dir="ltr">The separation of tellurium from cadmium telluride is examined using a unique combination of mild, anhydrous chlorination and complexation of the subsequent tellurium tetrachloride with 3,5-di-<i>tert</i>-butylcatechol. The resulting tellurium complex, Te(dtbc)₂, is isolated in moderate yield and features a 10³ to 10⁴ reduction in cadmium content, as provided by XRF and ICP-MS analysis. Similar results were obtained from zinc telluride. A significant separation between Te, Se, and S was observed after treating a complex mixture of metal chalcogenides with this protocol. These three tunable steps can be applied for future applications of CdTe photovoltaic waste.</p><p dir="ltr">We report the synthesis and characterization of the first series of tellurium and selenium complexes featuring an η⁵-cyclopentadienyl ligand. Reaction of Ph₃TeX (X = Cl, S₂CNEt₂) with MCp^R (M = Li, K; R = H, Me₄, Me₅) results in high yields of [Cp][TePh₃] (<b>1</b>), [Cp^Me4][TePh₃] (<b>2</b>), and [Cp*][TePh₃] (<b>3</b>), respectively. Similarly, reaction of Ph₃SeCl with LiCp and KCp* furnishes [Cp][SePh₃] (<b>4</b>) and [Cp*][SePh₃] (<b>5</b>). Each was characterized by X-ray crystallography, revealing similar η⁵-coordination with little distortion from an idealized half-sandwich geometry, presumably from the remaining lone pair on tellurium and selenium. The Te–centroid distances are relatively long (<b>1</b>: 2.770(3), <b>2</b>: 2.746(1), and <b>3</b>: 2.733(1) Å), suggesting a mostly ionic interaction. Se–centroid distances (<b>4</b>: 2.748(3), <b>5</b>: 2.707(2), 2.730(2) Å) were found to be surprisingly similar despite its smaller atomic radius. Compounds <b>2</b>, <b>3</b>, and <b>5</b> display rapid decomposition at room temperature, extruding a phenylated cyclopentadiene and the and the respective diphenylchalcogenide. The nature of bonding within these complexes was investigated through DFT methods and found to be primarily ionic in nature.</p><p dir="ltr">Synthesis of homoleptic zirconium and hafnium dithiocarbamate via carbon disulfide insertion into zirconium and hafnium amides were investigated for their utility as soluble molecular precursors for chalcogenide perovskites and binary metal sulfides. Treating M(NEtR)₄ (M= Zr, Hf and R= Me, Et) with CS₂ resulted in quantitative yields of homoleptic Group IV dithiocarbamates. Zr(k²-S₂CNMeEt) (<b>1</b>), Zr(k²-S₂CNEt₂)₄ (<b>2</b>), and Hf(k²-S₂CNEt₂)₄(<b>4</b>), a rare example of a crystal of a homoleptic hafnium CS₂ inserted amide species, were characterized. A computational analysis confirmed assignments for IR spectroscopy.<b> </b>To exemplify the utility of the Group IV dithiocarbamates, a solution-phase nanoparticle synthesis was performed to obtain ZrS₃ via the thermal decomposition of Zr(S₂CNMeEt)₄</p><p dir="ltr">Chalcogenide perovskites have garnered interest for applications in semiconductor devices due to their excellent predicted optoelectronic properties and stability. However, high synthesis temperatures have historically made these materials incompatible with the creation of photovoltaic devices. Here, we demonstrate the solution processed synthesis of luminescent BaZrS₃ and BaHfS₃ chalcogenide perovskite films using single-phase molecular precursors at sulfurization temperatures of 575 °C and sulfurization times as short as one hour. These molecular precursor inks were synthesized using known carbon disulfide insertion chemistry to create Group 4 metal dithiocarbamates, and this chemistry was extended to create species, such as barium dithiocarboxylates, that have never been reported before. These findings, with added future research, have the potential to yield fully solution processed thin films of chalcogenide perovskites for various optoelectronic applications.</p><p dir="ltr">Np(IV) Lewis base adducts were prepared by ligand substitution of NpCl₄(DME)₂. Using acetonitrile and pyridine, NpCl₄(MeCN)₄ (<b>1</b>) and NpCl₄(pyr)₄ (<b>2</b>), were isolated, respectively. All species were fully characterized using spectroscopic and structural analyses.</p>

<div>Enantioselective syntheses of hexacyclic aspidoalbidine alkaloids (+)-fendleridine and (+)-acetylaspidoalbidine are described. These syntheses feature an asymmetric decarboxylative allylation and photocyclization of a highly substituted enaminone. Also, the synthesis highlights the formation of a C19-hemiaminal ether via a reduction/condensation/intramolecular cyclization cascade with the C21-alcohol. The present synthesis provides convenient access to the aspidoalbidine hexacyclic alkaloid family in an efficient manner.</div><div>A copper-catalyzed cross-coupling is described. Use of Cu(I) salts in the presence of allyl bromides and organostannyl furans were found to undergo catalytic turnover under ambient conditions and afford the coupled products in good to great yields. Model substrate screening led to conditions used in the concise formal synthesis of FR901464 analogues. Optimization of the described coupling step led to suppression of undesired isomers and byproducts affording the desired diene coupled product in high yield, stereo-, and regioselectivity on a multigram scale. Novel protection of the resulting diene moiety as an unconventional protecting group, and a facile four-step single column chromatographic stereoselective sequence are also reported.</div>

<div>The global demand for energy of mankind, the ever-increasing cost of energy, and the expected depletion of fossil energy carriers within the next centuries urge the exploration of alternative and more sustainable ways to provide energy. The current quest for energy-efficient technologies for the replacement of existing cooling devices has made the magnetocaloric effect a field of current scientific interest. Cooling technologies based on magnetic refrigerants are expected to have a better environmental impact compared with those based on the gas compression-expansion cycle. This technology provides an alternative for refrigeration applications with advantages, such as high energy efficiency, environmental friendliness, and low power consumption. In search of promising magnetocaloric materials, several rare earth-depleted transition metal-based materials were designed and investigated.</div><div>In this work, RCrxAl2-x and RZnAl (R = Gd, Tb, Dy, Ho) belonging to the ternary rare-earth transition-metal Laves phases, were chosen as the starting point to establish the effect of valence electron concentration (VEC) on the magnetic behavior and magnetocaloric effect. Our result and the results from the previously studied RTAl phases (T = Cu, Ni, Co, Fe, Mn) shows that the perturbation of the valence electron concentration at the Fermi level is found to be the driving force that dictates the crystal structure, magnetocaloric and magnetic properties of these systems. Most notably, the decrease in the valence electron concentration at the Fermi level leads to an increase in the curie temperature.</div><div>In addition, we have further extended this theory to GdNiAl2 systems. GdNiAl2 is a known magnetocaloric material which exhibits an isothermal magnetic entropy change of ΔSM = 16.0 Jkg-1K-1 at TC = 28K under a magnetic field change from 0-5T. However, the low TC limits its application as a room temperature refrigerant. We, therefore, substituted Co for (Ni/Al) in the structure of GdNiAl2, intending to substantially perturb the position of the Fermi level of Ni since that will lead to a decrease in the VEC and hence elevate the TC. The study was also extended to another Icosagenides (Ga,), which saw the substitution of Ga for Al in GdNiAl2 and its Co substituted analogs. The Ga analogs exhibit complex magnetic behavior with a cascade (multiple) of magnetic transitions, as opposed to the rather simple magnetism of their Al congeners.</div>