Techn. Hochsch., Diss., 2003--Aachen.

Universiẗat, Diss., 2003--Kassel.

Techn. Universiẗat, Diss., 2005--Berlin.

Universiẗat, Diss., 2004--Düsseldorf.

Techn. Hochsch., Diss., 2004--Aachen.

Optimized methods for the regioselective and stereospecific synthesis of both trisubstituted and tetrasubstituted olefins as single isomers from E-β-chloro-α-iodo-α,β-unsaturated esters have been developed from previous work done in the Ogilvie lab. These optimized methods have led to the synthesis of trans isomeric enediynes that can be photoisomerized to their respective cis isomers and subsequently undergo microwave-assisted Bergman cycloaromatizations. Furthermore, both cis and trans isomeric enediynes that have propargyl ether substituents have been found to be able to undergo photoactivated Bergman cyclizations without the need for an intermolecular hydrogen donor. A mechanism study has confirmed that the Bergman cyclization products that form without the presence of an intermolecular hydrogen donor undergo a series of 1,5-hydrogen shifts as intermediates. A series of optimizations to these reactions were carried out, in part by utilizing electron-donating or electron-withdrawing functional groups to help stabilize the resulting radicals that form on the intermediates, and thus increase the yield of the associated Bergman cyclization products.

The last decade has been marked by a large increase of demand for green chemistry processes. Consequently, chemists have focused their efforts on the development of more direct routes toward different classes of targets. In that regard catalysis has played a crucial role at enabling key bond formations that were otherwise inaccessible or very energy and resources consuming. The central theme of this body of work concerns the formation of C–N bonds, either through transition metal catalysis or organocatalysis. These structural units being highly recurrent in biologically active molecules, the establishment of more efficient routes for their construction is indispensable. The first part of this thesis describes a new method for the synthesis of isoquinolines from the oxidative coupling/annulation of alkynes with N-tert-butyl benzaldimines via Rh(III) catalysis (Chapter 2). Preliminary mechanistic investigations of this system pointed to the involvement of Rh(III) in the C–H bond cleavage step as well as in the C–N bond reductive elimination that provides the desired heterocycle. Following this oxidative process, a Rh(III)-catalyzed redox-neutral approach to isoquinolones from the reaction of benzhydroxamic acids with alkynes is presented (Chapter 3). The discovery that an N–O bond contained in the substrate can act as an internal oxidant was found to be very enabling. Indeed, it allowed for milder reaction conditions, broader scope (terminal alkyne and alkene compatible) and low catalyst loadings (0.5 mol%). Mechanistic investigations on this system were also conducted to identify the nature of the C–N bond formation/N–O bond cleavage as well as the rate-determining step. The second part of this work presents mechanistic investigations performed on a recently developed intermolecular hydroamination reaction catalyzed through tethering organocatalysis (Chapter 4). This transformation operates via the reversible covalent attachment of two reactants, a hydroxylamine and an allylamine, to an aldehyde catalyst by the formation of a mixed aminal. This allows a difficult intermolecular Cope-type hydroamination to be performed intramolecularly. The main kinetic parameters associated with this reaction were determined and they allowed the generation of a more accurate catalytic cycle for this transformation. Attempts at developing new families of organocatalysts are also discussed.

In modern synthetic organic chemistry, chemists are driven to develop efficient methods for important C-C and C-N bond formation reactions. The challenge lies with establishing new uses for readily available substrates. In this regard, the synthesis of β-aminocarbonyl compounds from alkenes remains a long-standing challenge. Innovation in reaction discovery often requires finding new reagents, or rare reagents with underappreciated value in synthesis. In Chapter 1, N-isocyanates and other heterocumulenes are introduced as versatile amphoteric reagents. Their amphoteric properties are valuable in the discovery of new synthetic approaches, especially in cycloaddition reactions. While C-isocyanates are bulk industrial chemicals, the formation and reactivity of N-isocyanates remains underexplored. Chapter 2 describes the development of reactivity with rare imino-isocyanates. This includes methods to access the reagent in situ with a blocking group approach, and the establishment of intermolecular cycloaddition reactivity with a variety of alkenes. This stereospecific reaction provides complex N,N’-cyclic azomethine imines, and enables access to β-aminocarbonyl compounds from alkenes. β-Amino amides and esters, pyrazolidinones, and pyrazolones were accessed by reductive derivatization of the aminocarbonylation products. Exploration into the limits of this reactivity gave insight into fundamental properties of imino-isocyanates. This includes the first detection of imino-isocyanates by IR spectroscopy. A kinetic resolution of the azomethine imines obtained from this alkene aminocarbonylation reaction was then developed, which gave access to enantioenriched β-amino carbonyl compounds (Chapter 3). This was accomplished by Brønsted acid catalysed reduction, with a selectivity factor of 13-43. This was the first example of the enantioselective reduction of azomethine imines, and represents a new activation mode for reactions of N,N’-cyclic azomethine imines. Using this reductive method, both enantiomers of the β-amino amide could be obtained from a racemic azomethine imine in ≥ 97% ee. The discovery of new reactivity of imino-isocyanates with imines in described in Chapter 4, which allowed the synthesis of eight new azomethine imines with the triazolone core. Our initial scope studies revealed different trends with imines than with alkenes, including increased reactivity, which led to investigation of the mechanism of this reaction. In addition, this was shown to be a valuable new approach for the synthesis of triazolones from imines.

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