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Halogen bonding (XB), the interaction between electron deficient halogen compounds and electron donors, is an established non-covalent interaction in the solid and gaseous phases. Understanding of XB in the solution phase is limited. This thesis describes experimental studies of XB interactions in solution, and the application of XB interactions in anion recognition. Chapter 1 is a brief review of current understanding of XB interaction: theoretical models, studies of XB in solid and gaseous phases and examples in biological systems are discussed. At the end of this chapter, halogen bonding in the solution phase is discussed, along with applications of halogen bonding in organic syntheses. In chapter 2, linear free energy relationships involving the thermodynamics of halogen bonding of substituted iodoaromatics are studied. The utility of substituent constants and calculated molecular electrostatic potential values as metrics of halogen bond donor ability are discussed. Density Functional Theory (DFT) calculations are shown to have useful predictive values for trends in halogen bond strength for a range of donor-acceptor pairs. Chapter 3 describes the development of new multidentate anion receptors based on halogen bonding. Bidentate and tridentate receptors were found to exhibit significantly higher binding constants than simple monodentate donors. These receptors show selectivity for halide anions over oxyanions. Using 19F NMR spectra at different temperature, the enthalpies and entropies of anion bindings for monodentate and tridentate receptors were determined. The results indicate a positive entropy contribution to anion binding for both mono and tridentate receptors in acetone solvent. Finally in chapter 4, some mesitylene based receptors with 3-halopyridinium and 2-iodobenzimidazolium donors are introduced. The receptors perform halide anion recognition in aqueous solvent system through charge-assisted XB interactions. These findings can allude to utility in organic synthesis, supramolecular chemistry and drug design.

This work improved the radiosynthesis of a known M2 muscarinic receptor imaging agent, [18F]FP-TZTP, and subsequent syntheses and in vitro evaluation of several novel TZTP derivatives highlighted a lead compound which exhibited M4 potency and selectivity, the thioether fluoro-polyethyleneglycol, which was then adapted for radiolabelling (23% radiochemical yield (uncorrected), >99% radiochemical purity, reaction time of 37 minutes). The present study also seeked to utilize aziridines as intermediates in [18F]-radiolabelling chemistry for the facile radiosynthesis of [18F]-labelled beta-blockers. Novel [18F]-labelled amines were synthesized via ring-opening and deprotection to yield the [18F]-1-fluoro-2-propanamine moiety (85%) favourably over the regioisomer [18F]-2-fluoro-1-propanamine (15%). Subsequent attempts to use these amine synthons in the synthesis of the beta-blocker [18F]Exaprolol resulted in poor radiochemical yields (1-3%). The chemistry of aziridine ring-opening with 19F-fluoride sources was thoroughly explored in order to understand the fundamentals of this chemistry, and the 1-fluoro-2-propanamine moiety was characterized by X-ray crystallography and NMR spectroscopy.

In 1908, H. Emil Fisher attempted to prepare glycinal, an unprotected amino aldehyde, which he found to be inherently unstable and prone to polymerization. This instability arises from the propensity of amines to condense with aldehydes. Accordingly, amino aldehydes require protection of the amine functional group. On the contrary, aziridines do not condense with aldehydes; the aziridine ring-strain precludes the formation of an iminium ion. Predicated upon this orthogonal reactivity, a stable class of unprotected amino aldehydes has been prepared, and an in-depth investigation into their chemical reactivity has been undertaken. Reactions designed to utilize both their nucleophilic (amine) and electrophilic (aldehyde) centres have demonstrated their capacity to forge multiple bonds in a single transformation, and have been implemented in the synthesis of complex heterocycles and cyclic peptides.

Texte remanié : Thèse : Théologie : Friedrich-Wilhems Universität : 1994. / Bibliogr. p.[427]-448. Index.

Alkenes are remarkably versatile motifs as they can be further functionalized by a vast array of addition, reduction, and oxidation reactions. Thus their efficient synthesis is highly desired. Over the past 35 years, the Suzuki-Miyaura cross-coupling reaction has emerged as a powerful synthetic tool for the formation of carbon-carbon bonds. Herein is described the development of a one-pot two-step protocol for the synthesis of (E)-alkenes comprising palladium-catalyzed Suzuki-Miyaura cross-coupling of aryl or heteroaryl halides, including chlorides, with alkenyl pinacolboronates, prepared in situ via solvent-free zirconium-catalyzed hydroboration of terminal alkynes. Avoiding isolation of intermediates saves time and reduces waste. The regio- and stereochemistry of the alkene is set by initial hydrozirconation of the alkyne. Addition of water to the second step deactivates the zirconocene catalyst, which is otherwise deleterious to cross-coupling. Thus this sequence exploits the water tolerance of the Suzuki-Miyaura reaction.

Alkenes are remarkably versatile motifs as they can be further functionalized by a vast array of addition, reduction, and oxidation reactions. Thus their efficient synthesis is highly desired. Over the past 35 years, the Suzuki-Miyaura cross-coupling reaction has emerged as a powerful synthetic tool for the formation of carbon-carbon bonds. Herein is described the development of a one-pot two-step protocol for the synthesis of (E)-alkenes comprising palladium-catalyzed Suzuki-Miyaura cross-coupling of aryl or heteroaryl halides, including chlorides, with alkenyl pinacolboronates, prepared in situ via solvent-free zirconium-catalyzed hydroboration of terminal alkynes. Avoiding isolation of intermediates saves time and reduces waste. The regio- and stereochemistry of the alkene is set by initial hydrozirconation of the alkyne. Addition of water to the second step deactivates the zirconocene catalyst, which is otherwise deleterious to cross-coupling. Thus this sequence exploits the water tolerance of the Suzuki-Miyaura reaction.

Domino catalysis is an ideal strategy in the synthesis of heterocyclic scaffolds, as multiple bonds can be formed under a single set of reaction conditions. In this work, we present the development of two novel domino processes which afford access to aza-analogues of the dihydrodibenzoxepine motif. Careful optimisation revealed that the Rh catalysed hydroarylation proceeds under mild conditions as compared to the C-O coupling. Furthermore, Pd was not required for the C-O bond formation when using alkenyl pyrazines as substrates. Variation of the substituents on both the heterocycle and on the boronic ester provided insight into the structural features required for successful domino reaction, and a stepwise protocol was developed for incompatible substrates. We have also developed the first multi-metal, multi-ligand domino reaction featuring both a chiral and achiral ligand in the same pot, still leading to an enantioenriched product.

Dans ce mémoire, il sera question de la formation de dérivés pipéridines en utilisant la fragmentation de Grob. Tout d’abord, une introduction sur les alcaloïdes ainsi que sur l’expertise du groupe Charette associée à leur formation démontrera l’importance de ces composés dans le domaine de la chimie organique. Cela sera suivi par un résumé de la fragmentation de Grob incluant les conditions de réactions utilisées, l’importance de la structure de la molécule initiale, les prérequis stéréoélectroniques ainsi que les modifications qui y ont été apportées. Le chapitre 2 sera dédié au développement de la méthodologie c’est-à-dire, à l’optimisation de tous les paramètres jouant un rôle dans la fragmentation de Grob. Par la suite, l’étendue de la réaction ainsi que des explications sur la régiosélectivité et la diastéréosélectivité de la réaction seront fournies. La méthodologie peut être exploitée dans un contexte de synthèse qui sera démontré dans le chapitre 3. De plus, elle servira pour une étude mécanistique qui est encore d’actualité à partir du concept d’effet frangomérique. Finalement, quelques projets futurs, notamment des améliorations possibles de la méthodologie, seront présentés dans le dernier chapitre. Le tout sera suivi d’une conclusion résumant l’ensemble des travaux effectués. / This thesis discusses the formation of piperidine derivatives using the Grob fragmentation. Firstly, an introduction of the important alkaloid family as well as previous work completed by the Charette group towards the synthesis of these compounds will be demonstrated. This will be followed by a summary of the Grob fragmentation including a discussion of the reaction conditions, molecular structures, stereoelectronic requirements and modifications of the Grob fragmentation. Chapter 2 will be dedicated to the development of the methodology and more precisely, to the optimization of all parameters necessary to the reaction. Furthermore, the scope of the reaction and some explanation of the regioselectivity and the diastereoselectivity of the reaction will be discussed. The developed methodology can be used in a total synthesis and will be demonstrated in Chapter 3. Moreover, using the frangomeric effect concept, a mechanistic study on the Grob fragmentation will be discussed. Finally, some future projects, especially possible improvement of the methodology, will be presented in the last chapter. This is followed by a conclusion and a summary of the work completed on this project.

Verdazyl radicals are a family of multicoloured stable free radicals. Aside from the defining backbone of four nitrogen atoms, these radicals contain multiple highly modifiable sites that grant them a high degree of derivatization. Despite having been discovered more than half a century ago, limited applications have been found for the verdazyl radicals and little is known about their chemistry. This thesis begins with an investigation to determine whether verdazyl radicals have a future as mediating agents in living radical polymerizations and progresses to their application as substrates for organic synthesis, an application that to date has not been pursued either with verdazyl or nitroxide stable radicals. The first part of this thesis describes the successful use of the 1,5-dimethyl-3-phenyl-6-oxoverdazyl radical as a mediating agent for styrene and n-butyl acrylate stable free radical polymerizations. The study of other verdazyl derivatives demonstrated the impact of steric and electronic properties of the verdazyl radicals on their ability to mediate polymerizations. The second part of this thesis outlines the initial discovery and the mechanistic elucidation of the transformation of the 1,5-dimethyl-3-phenyl-6-oxoverdazyl radical into an azomethine imine, which in the presence of dipolarophiles, undergoes a [3+2] 1,3-dipolar cycloaddition reaction to yield unique pyrazolotetrazinone structures. The reactivity of the azomethine imine and the scope of the reaction were also examined. The third part of this thesis describes the discovery and mechanistic determination of a base-induced rearrangement reaction that transforms the verdazyl-derived pyrazolotetrazinone cycloadducts into corresponding pyrazolotriazinones or triazole structures. The nucleophilicity, or the lack thereof, of the base employed leading to various rearrangement products was examined in detail. The final part of this thesis demonstrates the compatibility of the verdazyl-initiated cycloaddition and rearrangement reactions with the philosophy of diversity-oriented synthesis in generating libraries of heterocycles. A library of verdazyl-derived heterocycles was generated in a short amount of time and was tested non-specifically for biological activity against acute myeloid leukemia and multiple myeloma cell lines. One particular compound showed cell-killing activity at the 250 mM range, indicating future potential for this chemistry in the field of drug discovery.