The development of new strategies to access pyridinium salts are highly sought out due to their advantageous structures, which have diverse applications across materials science, biological processes, and organic synthesis. As synthetic intermediates, these scaffolds can be used as precursors to valuable piperidine derivatives and have recently emerged as important cross coupling handles for metal-catalyzed processes. Unfortunately, current methods to access pyridinium salts are limited; they require harsh conditions, rely on the presence of an amine functional handle, and are not amenable to diverse structural variation. In Chapter 1, a summary of various syntheses and the reactivity of pyridinium salts is provided. This dissertation provides new strategies to access pyridinium salts. The first method is via aminolactonization of alkenoic acids, resulting in 1° pyridinium salts (Chapter 2). The second method is a regioselective synthesis of 3-aminopiperidine salts via diamination of olefins (Chapter 3). Both methods are promoted by nitrogen-ligated hypervalent iodine reagents (N-HVIs). These novel class of reagents serve as “heterocyclic group transfer reagents,” incorporating diverse pyridinium salts under mild conditions and in excellent yields. Heterocyclic Group Transfer reactions have resulted in new classes of pyridinium salts that can be further functionalized via simple known methods to access diverse piperidine motifs, providing an innovative approach to substitution patterns that were previously challenging to synthesize. These strategies have also enabled pyridinium salts to be viewed as a synthetic platform for diversity-oriented amine synthesis. Chapter 4 will elaborate on the synthesis of different classes of 3-aminopiperidine motifs using hypervalent iodine reagents; these motifs have been previously synthesized using transition metal catalysis. / Chemistry

This thesis concerns the use of various potent oxidants in organic synthesis. The main focus is directed at selectively introducing trifluoromethyl groups into compounds containing double or triple bonds. All reactions proceed under mild conditions and can in most cases be performed on the bench-top. We have developed three different procedures for transformations of activated alkenes and alkynes as well as quinones. In paper I the selective introduction of a trifluoromethyl group together with an oxygen functionality to double and triple bonds is demonstrated. Paper II is focused on the related chemoselective cyanotrifluoromethylation in which a cyano group is added instead of the oxygen functionality. Paper III describes a new procedure for C–H trifluoromethylation of quinones. Our studies on the mechanistic aspects of the above reactions are described in Paper IV. In these studies we investigated the ligand and substituent effects in Cu-catalyzed reactions. Paper V is focused on a conceptually new palladium-catalyzed allylic C–H acyloxylation of olefins under oxidative conditions. The procedure uses an inexpensive, safe and environmentally benign oxidant, sodium perborate, which is activated with acetic anhydride. / <p>At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 4: Submitted.</p>

Transition-metal-catalyzed cross-coupling reactions are reliable tools for forging C–C bonds. The Engle Lab has previously pioneered the intermolecular difunctionalization of unactivated alkenes facilitated by nickel catalysis, where regioselectivity is controlled through the use of a bidentate directing group. A limitation of existing methods is that allyl groups have not yet been successfully incorporated, as the electrophile scope has been limited to alkyl and aryl species. Fundamentally, C–C p-bonds have served as key building blocks for the assembly of complex molecules, and the ability to introduce allyl moieties in a controlled manner enables diverse, downstream functionalization in multi-step synthesis. This work focuses on the use of diverse azaheterocycle directing groups connected to non-conjugated alkenes. Through the use of nickel catalysis, we have been able to successfully introduce and preserve allyl and cinnamyl species at the g-position and alkyl zinc nucleophiles at the b-position with high yield under mild conditions. This novel, 1,2-allylalkylation can accommodate a vast array of substituents with different electronic and steric properties (>20 examples). Our efforts have shifted to exploring different monodentate directing groups and to conduct mechanistic studies to shed light on the catalytic cycle. Interestingly, electron-rich electrophiles provide nearly quantitative NMR and isolated yields, whereas electron-poor electrophiles lead to lower yields. We report a competition experiment to further elucidate this mechanism. While isolated yields were generally higher for electron-rich groups, a competition between p-OMe and p-CF3 electrophiles led to preferential incorporation of the trifluoromethyl-substituted coupling partner, which supports oxidative addition as the product-determining step.

Lors de ce travail de thèse qui visait à développer une méthode générale d’introduction d’halogénures et de pseudo-halogénures en se basant sur l’utilisation de réactifs d’iode hypervalent en tant que promoteurs d’umpolung, diverses avancées ont pu être accomplies. Tout d’abord, une réaction d'alkoxybromation régiosélective mettant en jeu des sels de bromure et du PIDA a été mise au point. Un des intérêts de cette réaction réside dans l'utilisation de LiBr peu coûteux comme source d'halogène électrophile (par inversion de polarité : umpolung). En outre, l'introduction de deux groupements de manière chimio- et régiosélective est possible sans recourir à l'utilisation d’un catalyseur métallique. Une large gamme d'énamides a été testée et les rendements sont généralement excellents (au dessus de 75 %) et les réactions rapides (moins d’une heure). En outre, la diastéréosélectivité oscille entre modérée et excellente. Ces produits éthoxybromés se sont aussi montrés très polyvalents et permettent l’accès à de nombreux motifs structuraux. Une version asymétrique de cette réaction en faisant intervenir des dérivés d’iode hypervalent chiraux n’a pas été couronnée de succès tout comme l’introduction de copules chirales. Le but initial était de mettre au point une méthode générale de difonctionnalisation d’énamides avec l’insertion d’halogénures. C’est pourquoi, notre stratégie a ensuite été étendue au chlore et une réaction d’éthoxychloration a été développée avec des rendements moyens à très bons (de 36% à 86%) un temps de réaction rapide (généralement autour de 30 minutes) et une diastéréosélectivité moyenne à très bonne (de 55/45 à 92/8). Les deux réactions d’éthoxybromation et d’éthoxychloration ont fait l’objet d’une investigation mécanistique (notamment par spectrométrie de masse) et il semblerait que le mécanisme soit ionique. Nous avons alors voulu appliquer cette méthodologie au fluor, élément dont l’introduction sélective sur un substrat est rarement triviale. En accord avec la littérature, nous avons conclu que le fluor ne pouvait être transféré directement en tant qu’électrophile. Enfin, une version d’éthoxyiodation a été validée et est en cours d’optimisation au laboratoire. Concernant les pseudo-halogénures, nous nous sommes uniquement intéressés aux azotures. Ayant réalisé qu’une réaction d’éthoxyazidation ne serait pas possible, une étude poussée des différents paramètres réactionnels adossée à la compréhension des mécanismes mis en jeu a été entreprise. Deux méthodologies ont alors pu être mises au point : une réaction de diazidation dont les rendements sont modérés ( entre 20% et 52%), les temps de réaction courts (environ 1 h) et des diastéréosélectivités moyennes à bonnes (entre 75/25 et 90/10) ainsi qu’une réaction d’oxyamination qui se montre bien plus efficace avec des rendements moyens à très bons (de 31% à 95%), des temps de réaction assez rapides (autour de 2 h), des diastéréosélectivités souvent excellentes (supérieures à 67/33) et un champ d’application bien plus large (Schéma 245). Ces deux méthodes réunies représentent un outil utile pour l’obtention de composés à la fois azotés et azidés. Dans ce cas, les intermédiaires réactionnels semblent être radicalaires même si des études complémentaires restent à effectuer.L’intérêt synthétique de ces deux types de composés a aussi fait l’objet de diverses études. Si la réduction du groupement azido en amine n’a pas pu être systématiquement accomplie, des réactions de cyclisation d’Huisgen sur les produits diazidés ont cependant fonctionné (les produits oxyaminés semblant trop encombrés stériquement). Quant au groupement TEMPO il a notamment pu être oxydé en cétone. Ainsi, des outils méthodologiques ont été développés lors de cette thèse, pour la difonctionnalisation oxydante d’énamides par des dérivés d’iode (III) hypervalent et en particulier, l’introduction d’halogénures et d’azotures. / Hypervalent iodine compounds such as (diacetoxyiodo)benzene (PIDA) are non-toxic and mild reagents that can behave in similar fashion to transition-metal complexes. Indeed, around the central iodine atom, ligands can be exchanged and then transferred through a formal reductive elimination. Following this strategy, halides can be used as ‘ligands’, in which case an umpolung of the salt can occur to give birth to electrophilic halogen species. Using LiBr, ethanol and PIDA, a variety of enamides underwent a regioselective ethoxybromination with high yields, short reaction time and good to excellent diastereoselectivity. One of the main interests of this reaction lies in the use of a cheap and widely available bromide salt (LiBr) to generate electrophilic halogen species by umpolung. Moreover, despite the oxidative nature of the reaction conditions, a wide scope of functional groups (olefins, esters, alcohols…) is tolerated. This reaction provides α-bromo-hemiaminals which are highly versatile synthons. For instance, various nucleophiles can be incorporated on the hemiaminal moeity and then engaged in further transformations. The development of an asymmetric variant of this transformation using chiral pool or chiral hypervalent iodine was unsucceful. This methodoly has been extended to the umpolung of other salts as chlorine with moderate to good yields (from 36% to 86%) and a moderate to very good diastereoselectivity (from 55/45 to 92/8) with a short reaction time (30 minutes). Mechanistic investigation for both reactions has been performed and an ionic parthway has been priviledge. The introduction of fluorine as an electrophile was not possible according to the litterature.Finally, the last halide, iodine can be tansfered and an ethoxyiodation reaction is under optimisation. Concerning the pseudo-halides, we devot a special attention to azides. Two methodologies has been set up : a diazidation reaction which yields are moderate (betwwen 20% and 52%), short reaction times (around 1 h) and moderate to good diastereoselectivity ratios (between 75/25 and 90/10) and an oxyamination reaction whiwh shows to be much more efficient with moderate to very high yields (from 31% to 95%), short reaction times (around 2 h), excellent diastereoselectivity ratio (superior to67/33). These two gathered reactions represent a useful tool for the introduction of a nitrogen. For the diazidation reaction, the intermediatories seem to be radicals whereas for the oxyamination reaction probably ionic species. . Thus, synthetic tools have been developped during this thesis for the difunctionnalisation of enamides by hypervalent iodine and particulary introduction of halides and azides

La chimie du fluor a connu un essor considérable ces dernières années en raison des caractéristiques remarquables de cet halogène et de l'influence qu'il exerce sur les propriétés physicochimiques des molécules organiques l'incorporant. De nombreuses molécules fluorées sont désormais utilisées comme médicaments ou en agriculture. Au laboratoire, nous nous sommes intéressés au développement de nouvelles stratégies directes et efficaces pour incorporer un groupement trifluorométhyle sur une double liaison carbone-carbone. Pour cela, des procédés faisant intervenir la catalyse photoinduite ont été employés.Tout d'abord, la synthèse d'amines β-trifluorométhylées a été mise au point en utilisant des enecarbamates comme substrats de départ. Une deuxième approche a consisté à utiliser des styrènes, commerciaux ou plus facile d'accès, et d'introduire l'atome d'azote par addition concomitante du nucléophile et du groupement CF₃. Cette stratégie a été ensuite étendue à d'autres nucléophiles carbonés ou halogénés de façon obtenir une grande diversité structurale. Enfin, la réactivité inattendue des 2-vinylbenzaldéhydes nous a permis d'appliquer nos méthodologies photocatalysées à la synthèse de phthalanes, composés présents dans un grand nombre de produits naturels ou biologiquement actifs. / Over the past decade, organic fluorine chemistry has attracted wide interest due to the unique nature of this halogen which modifies the physicochemical properties of molecules. Numerous fluorinated compounds are nowadays used in medicine and crop science. These features have stimulated the development of new strategies for the efficient introduction of fluorine, especially the trifluoromethyl group into organic molecules. Among the contemporary methods, visible-light photoredox trifluoromethylation of alkenes is an efficient and attractive strategy. This first aim was to develop a methodology giving rise to original β-trifluoromethylamines. We could efficiently perform a photocatalyzed α-β-difunctionalization of enecarbamates through a three-component reaction between enecarbamates, Togni reagent, and a nucleophile: alcohol, cyanide or azide. Another approach uses styrenes, which are commercially available compounds or easily accessible. The nitrogen atom was introduced by concomitant addition of a CF₃ group and an azido or amino function. The second project of my PhD was to extend this methodology to aromatic or heteroaromatic nucleophiles leading to the formation of 1,1 diarylalkane derivatives, which are present in many biologically active products. Changing the nucleophilic partner to halogen (chlorine, bromine or iodine) is also very effective. Finally, the photoredox-mediated process has been applied to the synthesis of 1,3-dihydroisobenzofurans, commonly named phthalans and their nitrogen analogs: 1,3-isoindolines.

No description available.

The thesis entitled “Studies on the Stereoselective Geminal and Vicinal Heterodifunctionalization of Alkenes” consists of three chapters. Chapter 1: Part A: Bromonium Ion Mediated Stereoselective Geminal Aminooxygenation of Vinylarenes In this part (part-A) of Chapter 1, the development and mechanistic studies of the first method for the non-Wacker intermolecular geminal aminooxygenation of vinylarenes (styrenes) has been presented (Scheme 1). Sheme 1 The role of the substituent on controlling the competitive vicinal and geminal addition pathways has been studied. It was found that the unsubstituted amino alcohol takes both the vicinal addition pathways, whereas, the introduction of substituent on the aminoalcohols was found to favour only the geminal addition route (Scheme 2). Scheme 2 The diastereomeric alkenes were found to show stereoconvergence on the product formation. The migration of the phenyl group in the semipinacol rearrangement was confirmed by deuterium labeling studies. This highly stereoselective oxidative geminal addition is found to involve a semipinacol rearrangement (Scheme 3). Scheme 3 Chapter 1: Part B: Bromonium Ion Mediated Stereoselective Anti-Markovnikov Geminal Diamination and Dioxygenation of Vinylarenes In this part (part-B) of Chapter 1, the development of a facile straightforward method for the stereoselective intermolecular geminal diamination of vinylarenes under the bromonium ion mediated conditions is discussed (Scheme 4). Scheme 4 The addition of unsubstituted diamine was found to follow both geminal and vicinal addition routes, while the introduction of the substituent on the diamine was found to favour only geminal addition (Scheme 5). Scheme 5 The stoichiometric geminal dioxygenation of vinylarenes using 1,2 and 1,3 -diols was also found to work well. The substituent on the nucleophile and the nucleophilicity of the heteroatom was found to control the competitive geminal and vicinal addition pathways. The stereoselectivity of geminal dioxygenation is dependent on the ring size of the product formed and on the position of the stereo-inducing substituent. Unlike the unsubstituted diamine and the unsubstituted aminoalcohol, irrespective of the substituents attached to it, the 1,2-diols furnished only the geminal addition product (Scheme 6). Scheme 6 Interestingly, the α-methyl substituted 1,3-diols provided the corresponding 2,4-disubstituted 1,3-dioxanes with very high stereoselectivity. The β-propyl substituted 1,3-diol gave the 2,5-disubstituted 1,3-dioxane as a mixture of diastereomers (Scheme 7). Scheme 7 The phenyl migration in the semi-pinacol rearrangement in the geminal addition process was confirmed from the deuterium labelling studies (Scheme 8). Scheme 8 Chapter 1: Part C: Straightforward Synthesis of 1,3-Dioxolan-4-ones through Geminal Difunctionalization of Vinylarenes The development of a straightforward method for the synthesis of important chiral synthon, 1,3-dioxolan-4-ones by the geminal addition of α-hydroxy carboxylic acids to vinylarenes has been presented in the final part of this chapter (part-C, Chapter 1) (Scheme 9). Scheme 9 The effect of substituents on the α-hydroxy carboxylic acid on controlling the stereoselectivity of the reaction has been studied. In the case of α-hydroxy carboxylic acid derived from isoleucine containing the chiral substituent at the α position, it exclusively forms a single diastereomer of the corresponding 1,3-dioxolan-4-one (Scheme 10). Scheme 10 The reactions of α-hydroxy carboxylic acids with styrenes containing a variety of substituents have been found to work well, including the styrenes containing the electron withdrawing groups and the β-substituted styrenes. The migration of the phenyl group in the semi-pinacol rearrangement in the geminal oxidative reaction has been confirmed by deuterium labelling studies (Scheme 11). Scheme 11 Simple carboxylic acids are found to form only the vicinal addition products on reaction with styrenes. However, the alcohols under the same conditions formed only the geminal addition product, thereby demonstrating the role of nucleophilicty of heteroatom being added that control the competitive vicinal and geminal addition pathways (Scheme 12 Scheme 12 Chapter 2: Reagent-Switch Controlled Metal-Free Geminal Difunctionalization of Vinylarenes In this Chapter, the development of two new methods for the geminal oxyamination of vinylarenes and the detailed studies to understand their mechanism are presented. A novel reagent-switch for the control of migrating group by controlling the two independent, distinct pathways of the two reagent systems has been reported for this geminal addition (Scheme 13). Scheme 13 We have developed the first general method for the geminal diamination of vinylarenes with excellent stereoselectivity mediated by a hypervalent iodine reagent (Scheme 14). Scheme 14 This method is also found to be very efficient for the stoichiometric metal-free geminal dioxygenation of vinylarenes (Scheme 15). Scheme 15 The substituent on the nucleophile and the nucleophilicity of the heteroatom was found to control the competitive geminal and vicinal addition pathways. Chapter 3: Studies on the Synthesis of Enantiopure Morpholine Derivatives Mediated by Dimethyl (Methylthio) Sulfonium Triflate (DMTST) In this chapter, the development of a sulfonium ion mediated cylco-etherification methodology for the construction of biologically important molecules such as morpholines, morpholine carboxylates and morpholine methylthio ethers in good yields under mild conditions using DMTST has been presented. This method was also found to work well for the synthesis of 1,4-oxazepane (Scheme 16). (For figures pl refer the abstract pdf file)

Cette thèse décrit le développement de nouvelles réactions de difonctionnalisation catalytique d’oléfines impliquant des transferts de nitrène médiés par des complexes de dirhodium(II).La première partie de ce manuscrit s’articule autour de la réactivité d’alcènes riches en électrons, c’est-à-dire substitués par un hétéroatome. L’application des conditions de transfert de nitrène catalytiques a permis la fonctionnalisation oxydante des positions C2 et C3 de l’indole. En utilisant cette stratégie, il est donc possible d’effectuer formellement des réactions d’oxyamination intermoléculaire et de diamination intramoléculaire. Dans ce dernier cas, le motif indoline formé étant présent dans certains produits naturels, la synthèse totale de la Pestalazine B a pu être initiée. Le champ d’application de ces réactions a été étendu aux énamides en collaboration avec le groupe du Professeur Isabelle Gillaizeau.La seconde partie de ce travail concerne le développement de la réaction d’oxyamination d’oléfines aromatiques et aliphatiques. Le champ d’application de cette réaction a été étudié en détail tandis que des expériences témoins et des analyses RMN ont permis de proposer un mécanisme original.Enfin, dans un dernier temps, nous avons démontré que par extension du concept, l’application des transferts de nitrène catalytiques permet de réaliser des réactions de diamination intermoléculaire d’oléfines. / This manuscript describes the development of new reactions for the difunctionalization of alkenes that involve dirhodium(II)-catalyzed nitrene transfers.The first part of the studies focuses on the reactivity of electron-rich alkenes, i.e. substituted by a heteroatom. The application of catalytic nitrene transfers has led to the development of oxidative conditions for the difunctionalization of the 2,3-π-bond of indolic derivatives. The strategy, thus, has allowed to perform formal reactions of intermolecular oxyamination and intramolecular diamination. The latter gives access to indoline skeleton found in the structure of several natural products such as Pestalazine B, the total synthesis of which has been initiated. The scope of intermolecular oxyamination has then been extended successfully to enamides in collaboration with the group of Professor Isabelle Gillaizeau.The second part of the experimental work has been aimed at applying the catalytic oxyamination to aromatic and aliphatic alkenes. The scope of the reaction has been extensively studied while test experiments and NMR analysis have allowed to propose an unexpected mechanism based on the Lewis acid character of the metallanitrene.Finally, the scope of catalytic nitrene transfers has been extended to the intermolecular diamination of alkenes with the development of bis(arenesulfonyl)imide-type reagents.