Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

It is over 100 years since scientists first postulated the existence of arynes as reactive intermediates. Their use in organic synthesis is now well-established and investigations into novel methods for their generation and utility in carbon-carbon bond forming reactions continue to this day. In 1983 Kobayashi and co-workers introduced a novel method of generating benzyne under mild conditions, using a fluoride induced decomposition of 2-(trimethylsilyl)phenyl triflate 1. This development has opened the door to employing arynes in a variety of transitionmetal mediated carbon-carbon bond forming processes. Intermolecular carbopalladation, in particular, stands out as a powerful methodology for the construction of diverse 1,2-functionalised arenes through multi-component coupling processes. Initial benzyne carbopalladation with an organopalladium species produces the arylpalladium intermediate 3, which can then undergo a second coupling to any one of the vast numbers of nucleophiles that have been demonstrated to work in palladium cross coupling. Presented herein are investigations towards the realisation of such methodology. Initial efforts focussed on its application to the Heck reaction, using acryates as the nucleophilic component. The chemistry has been developed to incorporate a variety of organo-halides in order to generate a variety of molecular architectures; the resultant 1,2-substituted diaryls being useful in the synthesis of both natural products and medicinal chemistry targets. Following successful development of the Heck reaction, investigations of other palladium catalysed couplings were also undertaken, in particular the Buchwald reaction. Initial mechanistic studies are also discussed.

Palladium catalyzed Heck coupling with aryl and alkenyl halides has become a powerful means of carbon-carbon bond formation. This standard synthetic method has been developed to a high level of utility using various catalysts, conditions and substrates. Yet significant drawbacks remain, including poor reactivity, the need for high temperatures and base, limited substrate generality, and selectivity. Mixed products often suffer from olefin migration following insertion. N-Heterocyclic carbenes (NHC) have proven to be electron-rich donors which provide higher stability and reactivity than phosphines. In a previous paper reported by our research group the imidazolium-palladium carbene has proven to be highly efficient for the Suzuki-Miyaura cross couplings. The most active bis-2,6- diisopropylphenyl dihydroimidazolium chloride ligand 1 in that series together with palladium acetate were employed as the catalyst, to efficiently catalyze the Heck coupling of aryl diazonium ions with olefins with useful yields at room temperature. Added base is not needed either to form the carbene catalyst or for alkene product formation. Phase-Transfer Catalysis (PTC) is a very useful approach and has been widely used in synthetic organic chemistry. A novel class of fluoroanthracenylmethyl PTC catalysts were synthesized and explored for asymmetric glycolate and glycine alkylation. Phosphorous pentoxide was used for the challenging electron-deficient electrophilic aromatic substitution step. These new catalysts proved to have high selectivities for glycine alkylation under mild conditions.

Aza-heterocycles such as pyridines, imidazoles, piperidines, etc. are ubiquitous structural motifs found in various natural products and pharmacologically active compounds. Thus, they are of unparalleled importance to synthetic, medicinal, and materials chemists. Despite their structural significance, organic transformations available for the functionalization of these heterocycles remain underdeveloped. The development of several synthetic methods to construct aza-heterocyclic building blocks is described in this thesis, which, in turn, should facilitate the assembly of more elaborate frameworks present in bioactive molecules. An intramolecular palladium catalyzed Mizoroki-Heck cyclization of 4-alkylidene dihydropyridines with tethered aryl iodide electrophiles is demonstrated. This provides access to substituted isoindolinones and oxindoles in high yields. An asymmetric variant of this reaction using chiral phosphine ligands delivers enantioenriched oxindoles and isoindolinones. Additionally, an intramolecular Mizoroki-Heck reaction for the synthesis of 2-substituted pyridine derivatives is also developed. An array of fused isoindolinones is constructed as a mixture of diastereomers and further manipulated using chemical transformations to yield the corresponding pyridine and piperdine derivatives. Moreover, a formal [3+2] cyclocondensation of alkylidene dihydropyridines and aryl diazonium salts has been discovered for the synthesis of triazole derivatives. Tertiary amides deliver substituted 1,2,4-triazolium salts, whereas, secondary amides provide substituted, neutral 1,2,4-triazoles in excellent yields, under mild reaction conditions. Furthermore, an intramolecular direct arylation of 2- and 4-substituted alkylpyridines is developed for the synthesis of 2,3- and 3,4-cyclized pyridines. It is shown that 4-alkylpyridines tethered to aryl halides participate in a palladium catalyzed direct arylation to give fused 7-membered lactams in excellent yields. Lastly, an intramolecular cyclization of 1,2-alkylimidazoles is reported. Alkylidene imidazolines tethered to electrophilic keto-amide sidechains participate in an aldol-like reaction to yield γ-lactam products in good yields as mixtures of diastereomers.

<p>The Heck reaction is one of the most appreciated methods for carbon-carbon bond formation. Due to its mildness and ability to be tuned by additives, it often leaves few alternative competitive reactions. It has also proven easy to develop the reaction conditions in an environmentally benign direction. Through the introduction of palladium chelating groups in olefinic precursors for the Heck reaction, it has been possible to direct the substitution in the following Heck arylation in favor of the terminal position with good regioselectivity. In this thesis, the concept has been utilized to produce a small array of drug-like compounds at useful yields under fast microwave-enhanced conditions utilizing the thermostable Herrmanns palladacycle. During the last decade, this, together with other palladacycles has become commonly employed as precatalyst for the Heck reaction. However, there have been conflicting opinions regarding the mechanisms governing its catalytic effect. A Pd^II-Pd^IV catalytic cycle has been suggested to be operative, in contrast to the classical Pd⁰-Pd^II cycle. In order to clarify the presence of such a mechanism, a set of Heck reactions was performed with the advent of different palladium precatalysts (classical and palladacycles), which revealed that the regiochemicαal substitution pattern is highly conserved, regardless of which precatalyst was employed, and thus, the same mechanism seems to be operative. This is also supported by data from ESI-MS investigations where all the reactions investigated gave rise to the same set of oxidative addition complexes. A crafted route to 3-aryl-1,2-cyclohexandiones has been developed in which 1,2-cyclohexandione is produced <i>is situ</i> from 2,3-epoxycyclohexanone, followed by Heck arylation. A diverse array of aryl bromides encompassing electron-rich, electron-poor, neutral and sterically hindered repressentatives has been successfully utilized to produce the corresponding products at useful yields.The intramolecular Heck reaction offers a route to quaternary carbonic centersand is being increasingly exploited in synthetic endeavors. However, the use of electron-rich olefinic precursors is only reported in a few cases. The implementation of one capto-dative and five electron-rich olefins has therefore been successfully subjected to Heck reaction conditions rendering the corresponding spiro compounds.</p>

The mechanism of carbon coupling reactions is traditionally represented in a very broad schematic. This thesis seeks to explore the mechanism of these reactions by focusing on Heck olefination. The Heck reaction has become a powerful tool in synthetic labs but the mechanism of this reaction has remained a topic of debate since the reaction's discovery. The catalytic cycle that has come to be accepted, while accurate in its own right, is not nearly as detailed as the complexity of the various stages of the Heck reaction suggest it should be. This study seeks to elucidate the nature of the oxidative addition of aryl halide to a palladium catalyst using a ligand that has been shown to have high activity in facilitating oxidative addition of aryl chlorides and bromides in other coupling reactions. This information is then compared to other studies in the field so that conclusions can be drawn about the oxidative addition. Also, selectivity studies seek to determine the nature of the migratory insertion of an olefin into the Pd-Ar bond. Again, comparison of results obtained in this study are compared to previous results so that a more definitive conclusion can be drawn about the oxidative addition.

The Heck reaction is one of the most appreciated methods for carbon-carbon bond formation. Due to its mildness and ability to be tuned by additives, it often leaves few alternative competitive reactions. It has also proven easy to develop the reaction conditions in an environmentally benign direction. Through the introduction of palladium chelating groups in olefinic precursors for the Heck reaction, it has been possible to direct the substitution in the following Heck arylation in favor of the terminal position with good regioselectivity. In this thesis, the concept has been utilized to produce a small array of drug-like compounds at useful yields under fast microwave-enhanced conditions utilizing the thermostable Herrmanns palladacycle. During the last decade, this, together with other palladacycles has become commonly employed as precatalyst for the Heck reaction. However, there have been conflicting opinions regarding the mechanisms governing its catalytic effect. A PdII-PdIV catalytic cycle has been suggested to be operative, in contrast to the classical Pd0-PdII cycle. In order to clarify the presence of such a mechanism, a set of Heck reactions was performed with the advent of different palladium precatalysts (classical and palladacycles), which revealed that the regiochemicαal substitution pattern is highly conserved, regardless of which precatalyst was employed, and thus, the same mechanism seems to be operative. This is also supported by data from ESI-MS investigations where all the reactions investigated gave rise to the same set of oxidative addition complexes. A crafted route to 3-aryl-1,2-cyclohexandiones has been developed in which 1,2-cyclohexandione is produced is situ from 2,3-epoxycyclohexanone, followed by Heck arylation. A diverse array of aryl bromides encompassing electron-rich, electron-poor, neutral and sterically hindered repressentatives has been successfully utilized to produce the corresponding products at useful yields.The intramolecular Heck reaction offers a route to quaternary carbonic centersand is being increasingly exploited in synthetic endeavors. However, the use of electron-rich olefinic precursors is only reported in a few cases. The implementation of one capto-dative and five electron-rich olefins has therefore been successfully subjected to Heck reaction conditions rendering the corresponding spiro compounds.

This essay will investigate male and female usage of four swear words: hell, heck, damn and darn. A minor part of the essay focuses on comparing real life speech (by using the Longman Corpus of Spoken American English) with scripted language in soap operas (the SOAP corpus). The main part of the essay focuses on a detailed investigation of the four swear words in the SOAP corpus to see how they are used considering gender. Preliminary hypotheses were both correct and incorrect. Even though it was true that women use the milder forms of swearing in the company of men, men however use the harsher forms in the company of women. Moreover, heck seems to be a very neutral swear word used by men and women equally. Hell was most frequently used by men, and darn was very frequent among women. Overall, there was very little female to female swearing, and the category with the highest instances of usage of three of the four swear words was in fact male to female.

Increasing attention has recently been directed toward 1,2,3-triazole-containing compounds. With their unique properties and excellent stability, 1,4-disubstituted triazoles are readily accessible via the copper catalyzed azide alkyne cycloaddition (CuAAC). As compounds containing fused triazoles become common in pharmaceutical targets and biologically active substances, new strategies to synthesize this class of molecules are highly desirable. An efficient and highly modular approach toward the synthesis of three different heterocyclic motifs containing fused 1,2,3-triazoles is reported. The synthesis involved a Pd-catalyzed annulation of 5-iodo-1,2,3-triazoles, which were prepared by a Cu(I)-catalyzed cycloaddition of iodoalkynes and azides. This work demonstrates the versatility of iodotriazoles in Heck reactions and in direct arylations.

Increasing attention has recently been directed toward 1,2,3-triazole-containing compounds. With their unique properties and excellent stability, 1,4-disubstituted triazoles are readily accessible via the copper catalyzed azide alkyne cycloaddition (CuAAC). As compounds containing fused triazoles become common in pharmaceutical targets and biologically active substances, new strategies to synthesize this class of molecules are highly desirable. An efficient and highly modular approach toward the synthesis of three different heterocyclic motifs containing fused 1,2,3-triazoles is reported. The synthesis involved a Pd-catalyzed annulation of 5-iodo-1,2,3-triazoles, which were prepared by a Cu(I)-catalyzed cycloaddition of iodoalkynes and azides. This work demonstrates the versatility of iodotriazoles in Heck reactions and in direct arylations.