Dissertations / Theses on the topic 'Heterocyclic chemistry : Pyridine'

The synthesis of the nitrogen containing heterocyclic compounds is one of the leading research areas throughout the organic chemistry due to their significant activities in biological systems. Among the various biologically active molecules, pyridine-fused ring systems are of prime importance on the grounds of their proven clinical roles. The coupling reactions with 6-membered heterocyclic compounds and diazepines gave rise to new pharmalogical compounds in recent years. Therefore, our object was the synthesis of pyridine-fused 6- and 7-membered heterocycles. Starting from bromopyridine, two different methods were applied for the synthesis of target compounds. In the first part of the this thesis, coupling products were synthesized using Sonogashira coupling reaction. After synthesis of the coupling derivatives, ring-closure under the basic conditions generated the heterocyclic units without using any catalyzer. In the second part of study, nicotinic acid and pyridopyranone derivatives were synthesized by using intramolecular cyclization reactions. The formed products were conscientiously purified and characterized by means of spectroscopics method.

The decomposition mechanisms of various coal constituents undergoing pyrolysis are of great concern in environmental circles (especially those coal constituents containing nitrogen). Most methods of burning coal that are efficient involve doing so at high temperatures. This invariably results in a large portion of non-combusting coal being heated to high temperatures also causing pyrolysis of the original coal constituents. The end result of such pyrolysis is the production of a number of noxious gaseous products. If we are to design methods of reducing the amount of toxins that are produced from the industrial use of coal, it is necessary to understand the pyrolysis process mechanistically. Due to the great number of coal constituents, a reasonable approach to such a mechanistic study is to use a simpler model. Pyridine makes an excellent starting model upon which to build. Our study focuses on interpretation of proposed reaction channels from experimental work on pyridine, quinoline and isoquinoline shock-tube decomposition in light of new ab initio energy calculations using Gaussian 98. The pathways thus determined support the proposed pyrolysis mechanisms and agree with experimental evidence obtained from independent groups of researchers performing shock tube pyrolysis.

Pyridazines are heterocyclic compounds with an N-N bond in their ring structure. Heterocyclic aromatic compounds are of great interest as a result of their novel properties and commercial applications. Our current research is focused on the potential role of pyridazines in next generation electronic devices that utilize organics as the semiconducting material. The synthesis of 5, 6-fused ring pyridazines beginning from fulvenes (Scheme 1) is described herein. These fused heterocycles will serve as synthetic models and building blocks for potential organic or organometallic conducting polymers. Our goal was to modify the route of Snyder et al. previously reported for the direct synthesis of pyridazine 2. This required improved synthesis of fulvene 1 and higher yields of 5. Additionally, a thorough analysis of the x-ray data was obtained to better understand the 3D aspects of this compound (pyridazine 2).This route was quite general and features an efficient and convenient synthesis. Single crystal X-ray analysis confirms the molecular structure of pyridazine 2. Full synthesis and characterization of newly formed pyridazine 2 and Fulvene 1 are reported.

Nature provides fascinating and complicated molecular structures which offer synthetic organic chemists amazing opportunities for the design of new strategies for natural product synthesis. Among these, nitrogen containing aza-heterocycles are of unparalleled importance in natural product, bioorganic, and medicinal chemistry. Pyridine and its derivatives in particular are the most common aza-heterocycles encountered in natural products, medicinal and materials chemistry. Pyridine derivatives also serve as precursors to functionalized piperidines, which are likewise common structural motifs in bioactive and functionalized materials. Thus, developing synthetic methods suitable for the manipulation of pyridine ring systems remains an important objective in synthetic organic chemistry. The functionalization of pyridine derivatives via manipulation at the benzylic position has been investigated. First, the nucleophilicity of the benzylic position of the 4-alkyl pyridine substrates was used to engage in Brønsted acid-catalyzed aldol-like cyclizations with attached carbonyl electrophiles. These conditions afforded substituted pyridines with functionalized lactams. These substrates underwent an unusual dehydration/oxidation reaction when treated with thionyl chloride. In a similar study, 1,2-dialkylimidazoles afforded nucleophilic 2-alkylidene imidazolines upon treatment with an electrophilic activating group such as Boc2O. Positioning a ketone electrophile with in an N1-alkyl side chain results in cyclization at the imidazole 2-position to afford fused ring imidazoles through an aldol-like cyclization reaction. The stereoselective synthesis of a tricyclic analogue of the bis(piperidine) alkaloid xestoproxamine C was also investigated. Dearomatization of a tricyclic pyridine derivative afforded an alkylidene dihydropyridine (anhydrobase) intermediate which was subjected to catalytic heterogeneous hydrogenation to install the correct relative stereochemistry about the bis(piperidine) ring system. Other key features of these model studies included development of an efficient ring-closing metathesis procedure to prepare macrocyclic derivatives of 3,4-disusbstituted pyridines, intramolecular cyclizations of alkylidene dihydropyridines to establish pyridine-substituted pyrrolidines and piperidines, successful homologation of pyridine-4-carboxaldehydes using formaldehyde dimethyl thioacetal monoxide (FAMSO), and application of B-alkyl Suzuki coupling to assemble substituted pyridines. Lastly, a study was done to assess the feasibility of synthesizing one of the two chiral precursors needed for the asymmetric synthesis of xestoproxamine C via enzyme catalyzed transesterification of symmetric 1,3-diols. This resulted in successful transesterification of a symmetric 1,3-diol substrate with high enantioselectivity.

The development of novel selective 5-HT6 and 5-HT7 receptor antagonists is an ever-growing area of interest among medicinal chemists. The potential of developing a therapeutic agent useful as an antipsychotic or antidepressant, as well as the possibility to develop a drug for Alzheimer’s disease and obesity has led to an increase in synthesis of possible lead compounds. The synthesis of unfused biheteroaryl derivatives is described within. The derivatives have been evaluated for binding affinity at 5-HT2A, 5-HT6 and 5-HT7 receptors. The most potent 5-HT6 receptor antagonists include a benzene ring, a hydrophobic group and a protonated nitrogen atom. The most potent and selective compound synthesized is 1-[3-butyl-5-(thienyl)phenyl]-4-methylpiperazine. The binding site of the 5-HT7 receptor is similar to that of the 5-HT6 receptor and the most selective and potent 5-HT7 receptor antagonist also contains a potonated nitrogen atom and a hydrophobic group. The difference in selectivity between the 5-HT6 and 5-HT7 receptor antagonists is the aromatic ring. The most potent 5-HT7 receptor antagonist synthesized contains a pyridine ring instead of benzene, as in the 5-HT6 receptor antagonist. The most potent and selective 5-HT7 receptor antagonist is 1-[4-(3-furyl)-6-methylpyridin-2-yl]-4-methylpiperazine. The need to increase selectivity for both 5-HT6 and 5-HT7 receptors has led to the synthesis of flexible-chain linked derivatives and the results are described within.

New methodology for the synthesis of several 4H-pyrido[1,2-a]pyrimidin-4-ones has been developed from commercially available 2-aminopyridines and β-oxo esters catalysed by Montmorillonite under solvent-free conditions in good yields. This methodology was expanded for the synthesis of 4H-pyrimido[1,2-a]pyrimidin-4-one derivatives from 2-aminopyrimidine and different β-keto esters. The new methodology for the synthesis of N-alkylated 6-methyl 2-pyridones and N-alkylated 2-methyl 4-pyridones, from commercially available starting materials was developed. For the synthesis of N-alkylated 6-methyl 2-pyridones, 2-methoxy-6-methyl pyridine and a number of different alkylating reagents have been employed as starting materials. For the synthesis of N-alkylated 2-methyl 4-pyridones, 4-chloro 2-methyl pyridine was used successfully to make the desired pyridone in 3 steps. Selective mono-metallation at the 6-methyl substituent of N-alkylated 6-methyl 2-pyridones and N-alkylated 2-methyl 4-pyridones with n-BuLi/KHMDS at -78 °C proceeded smoothly, and the reactivity of the lithiated intermediates towards a wide range of electrophile (diketones, aldehydes, alkylating reagents) was studied. A straightforward synthesis of desirable 4H-quinolizin-4-one scaffolds by condensation of N-benzyl 6-methyl 2-pyridones with dicarbonyl compounds, and the formation of the desired quinolizinone after the condensation step was achieved. An unexpected quinolizinone bearing a fused β-lactam ring was isolated and its structure confirmed by single crystal X-ray diffraction analysis.

For the purpose of incorporating indoles into organometallic complexes for catalysis, as well as in the generation of new heterocyclic systems, various reactions have been carried out at C2, C6 and C7 of the indole system. In order to achieve this, 3-substituted 4,6-dimethoxyindoles and 6-hydroxy- 4-methoxyindoles were necessary as starting materials. Consequently, a lithium-bromide-templated one-pot procedure for the synthesis of some 3-substituted 4,6-dimethoxyindoles and a selective demethylation procedure for 3-substituted 6-hydroxy-4-methoxyindoles were developed. Various kinds of novel methylene-bridged bi-, tri-, and tetradentate pyridyl-indole ligands were synthesised via Vilsmeier-Haack, Friedel-Crafts or electrophilic addition reactions on the indole heterocycle. However, their metal complexing properties were generally weak and variable. Nevertheless, some of the tridentate pyridylindole ligands showed strong anion binding to halides, whereas a remarkable ligand transformation occurred with a bidentate 2-pyridylindole ligand and zinc(II), giving a substituted indolo[2,3-c]pyrrolo-[3,2,1-ij]quinoline system. Two new types of tetradentate Schiff base ligands were prepared from 2-formyl-indoles and 7-formyl-6-hydroxyindoles, and diamines. These preformed ligands were reacted with first- and second-row transition metals to give neutral metal complexes. Novel heterocyclic systems such as 4H-pyrrolo[3,2,1-ij]quinolines, 3H-pyrrolo-[1,2-a]indoles, and 1H-furo[2,3-g]indoles were synthesised from 2-formyl-, 7-formyl-, and 6-hydroxyindoles, utilising mainly intra-molecular Wittig reactions, Claisen-Schmidt condensations or acid- and base-catalysed cyclisations. A common feature of the prepared 4H-pyrrolo[3,2,1-ij]quinolines and 3H-pyrrolo-[1,2-a]indoles was their intense fluorescent character, which was examined as well.

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.

http://www.pharmacol.usyd.edu.au/thesis This thesis is primarily concerned with a class of chemical compounds known as pyridazinediones, being 6-membered aromatic rings containing two adjacent nitrogen atoms (pyridazine), doubly substituted with oxygen. In particular, the work focuses on pyridazine-3,6-diones, derivatives of maleic hydrazide (1). Understanding of the chemistry of these compounds is extended, using theoretical and synthetic techniques. This thesis is also concerned with two very important classes of receptors which bind amino acids in the brain: firstly, the inhibitory GABA receptor, which binds g-aminobutyric acid (GABA) (2) in vivo, and for which muscimol (3) is an agonist of the GABAA subclass; secondly, Excitatory Amino Acid (EAA) receptors, which bind glutamate (4) in vivo, and in particular the AMPA subclass, for which (S)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) (5) is an agonist. The connection between pyridazinediones and amino acid receptors is the design, synthesis, and evaluation of structures based on pyridazinediones as potential GABA and EAA receptor ligands. Techniques of theoretical chemistry, molecular modelling, synthetic chemistry, and in vitro pharmacology are used to explore pyridazine-3,6-dione derivatives as ligands.

Les cancers représentent un problème majeur de santé public d'où la nécessité de rechercher de nouvelles classes de médicaments. Parmi les pistes pour développer de nouveaux traitements, deux ont retenu notre attention et celle de nos collaborateurs : la modulation de l’épissage par des composés comme le NVS-SM2, et l’inhibition de l’oncogène KRAS par des dérivés de produits naturels, les flavaglines. Dans ce contexte, nous avons développé la première synthèse robuste du NVS-SM2, qui peut satisfaire la demande globale de cet agent pour examiner en détail son potentiel thérapeutique dans différents types d’affection. En outre, la stratégie de synthèse rapportée ici pourrait être étendue à de nouveaux analogues de ce composé. D’autre part, nous avons synthétisé de nouvelles flavaglines qui sont en cours d'étude pour leurs effets sur l’inhibition de KRAS. Au cours de cette étude, nous avons découvert de nouvelles réactions, notamment une inversion de configuration d’amines induite par du chlorure de diméthylcarbamoyle
Cancers represent a major public health problem hence the need to use new classes of medicines. Among the opportunities for developing new treatments, two have caught our attention and that of our collaborators: the modulation of splicing by compounds such as NVS-SM2, and the inhibition of the oncogene KRAS by derivatives of natural products, the flavaglines.In this context, we have developed the first robust synthesis of NVS-SM2, which can satisfy the global demand of this agent to examine in detail its therapeutic potential in different types of disorders. In addition, the synthetic strategy reported here could be extended to new analogues of this compound. Furthermore, we have synthesized new flavaglines that have been examined for their effects on KRAS inhibition. During this study, we discovered new reactions, including a dimethylcarbamoyl chloride-induced amine inversion of configuration

Le travail décrit dans ce mémoire concerne l'étude de la métallation régiosélective de deux bicycles fusionnés complexes : les furo[3,2-b]- et [2,3-c]pyridines. L'influence de la nature du système basique sur le cours de la réaction et sur la régiosélectivité de la lithiation a été étudiée avec différentes bases : n-BuLi, LTMP, LDA et [n-BuLi/LiDMAE]. D'un point de vue fondamental, cette étude nous a permis d'établir quelques règles pour la fonctionnalisation des hétérocycles complexes, ce qui nous a conduit à l'obtention efficace et rapide d'une vaste chimiothèque de furo[3,2-b]- et [2,3-c]pyridines polyfonctionnalisés et refonctionnalisables. Quelques composés préparés ont ainsi été mis en jeu dans des réactions de couplage catalysées par les métaux de transition (Pd, Ni). Les difficultés rencontrées au cours de ce travail nous ont permises de mettre en évidence une séquence de double fonctionnalisation des hétérocycles ?-déficients par une séquence "one-pot" combinant le piégeage d'un intermédiaire lithié par un électrophile et l'addition nucléophile d'une espèce réactive générée in-situ. Le développement de cette séquence nous a conduits à l'obtention directe de pyrazines, pyridines et furo[3,2-b]pyridines disubstituées
The work described in this PhD thesis concerns a regioselective metalation study of two fused heterocycles : the furo[3,2-b]- et [2,3-c]pyridines. The influence of the lithiated agent on the reaction course and on the selectivity of the lithiation has been studied with several bases : n-BuLi, LTMP, LDA and [n-BuLi/LiDMAE]. From a fundamental point of view, this study allowed us to establish some rules concerning the functionalisation of fused heterocycles, and then, a chemical library of polyfunctionalised furo[3,2-b]- and [2,3-c]pyridines has been designed. Some of the compounds obtained in this way were engaged in metallo-catalysed coupling reactions. The difficulties we met during this work allowed us to discover a double functionalisation sequence of ?-deficient heterocycles via a cascade process combining the trapping of lithiated intermediates and the nucleophilic addition of some in-situ released species. The development of this sequence afforded direct access to difunctionalised pyrazines, pyridines and furo[3,2-b]pyridines

Synthèse et caractérisation de differents complexes solides. Structures de MG CH3OH6 BR::(2), (MGPY::(4)CL::(2)), (MGPY::(4)BR::(2))PY::(2) (MG(H::(2)O)::(4)PY::(2))CL::(2), (MG(H::(2)O)::(3)PY::(3)) BR::(2)PY::(2) ET (MG(H::(2)O)::(2)PY::(4))I::(2)PY::(2). Analyse des spectres IR de M(ROH)::(6) X::(2), M(ROH)::(4)X::(2) (AVEC M = MG,CA; R = CH::(3),C::(2)H::(5); X = CL,BR) ET DE MG(PY)::(4) CL::(2) ET M(PY)::(4)X::(2)PY::(2) (M = CA,MG)

Le travail décrit dans ce mémoire concerne l'étude de la métallation régiosélective d’un bicycle fusionné: la furo[3,2-B]pyridine. L'influence de la nature du système basique sur le cours de la réaction et sur la régiosélectivité de la lithiation a été étudiée avec différentes bases : n-BuLi, LiTMP, LiDA et [n-BuLi/LiDMAE]. D'un point de vue fondamental, cette étude nous a permis d'établir quelques règles pour la fonctionnalisation des furopyidines, ce qui nous a conduit à l'obtention efficace et rapide d'une vaste chimiothèque de furo[3,2-B]pyridines polyfonctionnalisées et refonctionnalisables. Quelques composés préparés ont ainsi été mis en jeu dans des réactions de couplage catalysées par les métaux de transition (Pd, Ni). Deux séquences originales de lithiations en « one-Pot » ont également été développées et permettent l’obtention de squelettes furopyridiniques hautement fonctionnalisés avec d’excellents rendements
The work described in this PhD thesis concerns the regioselective metalation study of a fused heterocycle : the furo[3,2-B]pyridine. The influence of the basic system on the reaction and on the regioselectivity of the lithiation has been studied with several bases : n-BuLi, LiTMP, LiDA and [n-BuLi/LiDMAE]. From a fundamental point of view, this study allowed us to establish some rules concerning the functionalization of furopyridines and to obtain a chemical library of various polyfunctionalized furo[3,2-B]pyridines, in good overall yields. Some of the compounds synthesized in this way, were engaged as substrate in metallo-Catalysed cross-Coupling reactions. Two efficient one-Pot multiple lithiations processes have been developed and lead to highly substitued furopyridinic scaffolds in excellent yields

Benzimidazole and its derivatives have attracted many organic chemists due to their interesting biological activities. These include activities against viruses such as, HIV, RNA, herpes (HSV-1), influenza, and cytomegalovirus (HCMV); antimicrobial and antitumor activities. Even though a lot of research has been conducted on the synthesis of benzimidazoles, factors such as, drug resistance present a need for synthesis of more structural analogues of these compounds. In chapter three, the synthesis of 2-aryl-1Hbenzimidazoles (46a-c) and 2-aryl-1-arylmethyl-1H-benzimidazoles (49a-d) is described. The yields for these products ranged from 44-79 % and 62-72 %, respectively. The synthesis of novel bisbenzimidazole derivatives is described in chapter four. Direct condensation of 3,3'-diaminobenzidine (1 mmol) with 2-thiophenecarboxyaldehyde (2 mmol) afforded 2, 2’-di-2-thienyl-5,5-Bi-1H-benzimidazole (52) in 65 % yield. Except in the case of 2-furancarboxyaldehyde, the acid catalyzed condensation of 3,3'- diaminobenzidine (1 equivalent) and heteroaromatic aldehydes (4 equivalents) gave novel bisbenzimidazoles where the aldehyde added three times to 3,3'-diaminobenzidine. The four times addition product, 1,2-di-2-furanylmethyl-2,2-di-2-furanyl benzimidazole (53) was obtained in 53 % yield. On the other hand, the three times addition product, 1,2-di-2- pyrrolylmethyl-2,2-di-2-pyrrolyl (54); 1,2-di-2-thienylmethyl-2,2-di-2-thienyl (55); and 1,2-di-2-pyridylmethyl-2,2-di-2-pyridyl benzimidazoles (56) were obtained in 85, 12 and 10 %, respectively. Full characterization of bisbenzimidazoles (54-56) was achieved by 1H, 13C NMR and LCMS spectra. Although benzimidazoles have been proven to be active against various cancers, their use as ligands for platinum (II) has been reported to enhance this activity. Three new benzimidazole Pt (II) complexes were synthesized. N, N, N-bound Pt (II) complexes of 2- quinolyl-1-quinolylmethyl-1H-benzimidazole (60) and 2-pyridyl-1-pyridylmethyl-1Hbenzimidazole (63) were obtained in excellent yields of 82 and 72 %, respectively. S, Nbound Pt (II) complex of 2-thienyl-1-thienylmethyl-1H-benzimidazole (64) was isolated in 63 % yield. From 195Pt NMR spectra analysis, it was concluded that the method reported by Morgan and Burstall is more efficient for the synthesis of these complexes. In addition to 195Pt NMR, platination was also confirmed using 1H and 13C NMR spectra.
Thesis (PhD.)-University of KwaZulu-Natal, Pietermaritzburg, 2010.

Transition metal mediated [2 + 2 + 2] cyclizations have been well researched over the past several years. As a well-developed methodology, [2 + 2 + 2] chemistry has been employed as a major pathway to various carbo- and heterocyclic synthetic targets. Numerous transition metals have been applied as catalysts for these cyclizations. Previous work in our group developed cobalt(I) catalyzed inter- and intramolecular [2 + 2 + 2] cyclizations of two alkynes and a nitrile, leading to the preparation of tetrahydro-naphthyridines. Pyridazines could be generated if the cyclization could be accomplished with two nitriles and an alkyne, which would be a novel way to synthesize 1,2-diazines through the formation of the N-N bond. To this end, metal-catalyzed intramolecular [2 + 2 + 2] cyclizations between an alkyne and two nitriles were investigated. The intramolecular nature of the reaction provided the entropic advantage to successfully assist the formation of the critical N-N bond. Optimal conditions were achieved with cobalt(I) catalysts under microwave irradiation in chlorobenzene, producing the desired pyridazines in moderate to good yields. This success led to the preparation of a series of annulated pyridazines. The use of two tethering nitrogens in the preparation of the cyclization precursors incorporated points for further diversification, the next step in the development of this chemistry. This ring closure through N,N-bond formation allowed the construction of annulated pyridazine scaffolds that were utilized further in a small molecule library synthesis. Using this methodology, sixteen new annulated pyridazines were prepared. Inverse electron demand Diels-Alder (IEDDA) reactions of arynes and 1,2,4-triazines were also investigated for the generation of isoquinoline core structures. The results showed that only triazines with electron withdrawing groups participated in the IEDDA reactions with benzyne as a partner after screening of several different arynes, which limited the scope of the reaction. Liebeskind–Srogl reactions of 3-methylthiotriazines and boronic acids were investigated during the diversification of triazines, and microwave irradiation with palladium and copper catalysts were found to be the optimal conditions for the coupling. The chemistry allowed for further triazine diversification.

L’importance des produits naturels dans le développement de nouveaux médicaments est indéniable. Malheureusement, l’isolation et la purification de ces produits de leurs sources naturelles procure normalement de très faibles quantités de molécules biologiquement actives. Ce problème a grandement limité l’accès à des études biologiques approfondies et/ou à une distribution sur une grande échelle du composé actif. Par exemple, la famille des pipéridines contient plusieurs composés bioactifs isolés de sources naturelles en très faible quantité (de l’ordre du milligramme). Pour pallier à ce problème, nous avons développé trois nouvelles approches synthétiques divergentes vers des pipéridines polysubstituées contenant une séquence d’activation/désaromatisation d’un sel de pyridinium chiral et énantioenrichi. La première approche vise la synthèse de pipéridines 2,5-disubstituées par l’utilisation d’une réaction d’arylation intermoléculaire sur des 1,2,3,4-tétrahydropyridines 2-substituées. Nous avons ensuite développé une méthode de synthèse d’indolizidines et de quinolizidines par l’utilisation d’amides secondaires. Cette deuxième approche permet ainsi la synthèse formelle d’alcaloïdes non-naturels à la suite d’une addition/cyclisation diastéréosélective et régiosélective sur un intermédiaire pyridinium commun. Finalement, nous avons développé une nouvelle approche pour la synthèse de pipéridines 2,6-disubstituées par l’utilisation d’une réaction de lithiation dirigée suivie d’un couplage croisé de Negishi ou d’un parachèvement avec un réactif électrophile. Le développement de transformations chimiosélectives et versatiles est un enjeu crucial et actuel pour les chimistes organiciens. Nous avons émis l’hypothèse qu’il serait possible d’appliquer le concept de chimiosélectivité à la fonctionnalisation d’amides, un des groupements le plus souvent rencontrés dans la structure des molécules naturelles. Dans le cadre précis de cette thèse, des transformations chimiosélectives ont été réalisées sur des amides secondaires fonctionnalisés. La méthode repose sur l’activation de la fonction carbonyle par l’anhydride triflique en présence d’une base faible. Dans un premier temps, l’amide ainsi activé a été réduit sélectivement en fonction imine, aldéhyde ou amine en présence d’hydrures peu nucléophiles. Alternativement, un nucléophile carboné a été employé afin de permettre la synthèse de cétones ou des cétimines. D’autre part, en combinant un amide et un dérivé de pyridine, une réaction de cyclisation/déshydratation permet d’obtenir les d’imidazo[1,5-a]pyridines polysubstituées. De plus, nous avons brièvement appliqué ces conditions d’activation au réarrangement interrompu de type Beckmann sur des cétoximes. Une nouvelle voie synthétique pour la synthèse d’iodures d’alcyne a finalement été développée en utilisant une réaction d’homologation/élimination en un seul pot à partir de bromures benzyliques et allyliques commercialement disponibles. La présente méthode se distincte des autres méthodes disponibles dans la littérature par la simplicité des procédures réactionnelles qui ont été optimisées afin d’être applicable sur grande échelle.
The importance of natural products in the development of new drugs is undeniable. Unfortunately, the isolation and purification of those products from their natural sources provides normally very small amounts of the desired bioactive molecules. Consequently there is largely limited access to in-depth biological studies and/or to the large scale distribution of the bioactive compound. For example, the piperidine family contains a large diversity of bioactive compounds isolated from natural sources in very limited quantities (on the order of milligram scale). To address the issue, we have developed three new divergent synthetic approaches towards polysubstituted piperidines containing an activation/dearomatization sequence from a chiral and enantioenchired pyridinium salt. The first approach aims towards the synthesis of 2,5-disubstituted piperidines by the use of an intermolecular arylation reaction on 2-substituted 1,2,3,4-tetrahydropyridines. Then, we have developed a synthetic method for indolizidines and quinolizidines starting from secondary amides. The second approach leads to the formal synthesis of non-natural alkaloids via a highly diastereoselective and regioselective addition/cyclization from a common pyridinium intermediate. Finally, we have found a new approach for the synthesis of 2,6-disubstituted piperidines by the use of a directed lithiation sequence followed by either a Negishi cross-coupling reaction or a quench with an electrophilic reagent. The development of highly chemoselective and versatile transformations are crucial to organic chemists. We have issued the hypothesis that it could be possible to apply the chemoselectivity concept towards the functionalization of amides, one of the most encountered subunits in the structures of natural products. In the specific context of the thesis, the highly chemoselective transformations are realized on functionalized secondary amides. The method relies on the activation of the carbonyl function of the amide by triflic anhydride in presence of a weak base. Firstly, the activated amide can be selectively reduced to imine, aldehyde, or amine oxidation state in the presence of a poorly nucleophilic hydride source. Alternatively, a carbon nucleophile could also be employed in order to allow the synthesis of ketones or ketimines. By combining an amide with a pyridine derivative a cyclization/dehydration reaction was used for the synthesis of polysubstituted imidazo[1,5-a]pyridines. Moreover, we have briefly applied the activation conditions to the interrupted Beckmann rearrangement of ketoximes. We have finally developed a new synthetic pathway for iodoalkynes by using a one-pot homologation/elimination reaction from commercially available benzylic and allylic bromides. The present method is distinctively different from literature precedents by the simplicity of the reaction procedures and purifications which were optimized in order to be applied to large scale synthesis

Les hétérocycles azotés sont d’une importance considérable dans le domaine pharmaceutique. En effet, ces composés se retrouvent dans de nombreuses structures bioactives brevetées dans les dernières années. Malgré l’utilité de ces motifs, leur synthèse nécessite souvent plusieurs étapes ou encore l’utilisation de matériaux de départ fonctionnalisés. Le présent mémoire décrit de nouvelles méthodologies pour accéder à ces structures de façon douce, chimiosélective et efficace par l’activation d’amides avec l’anhydride trifluorométhanesulfonique. Dans un premier temps, une méthode en deux étapes pour accéder aux 3-aminoindazoles à partir des amides aromatiques correspondants a été développée. La séquence comprend l’activation de l’amide, suivie de l’addition d’une hydrazine protégée pour former un intermédiaire de type amino hydrazone. Cet intermédiaire peut ensuite être cyclisé dans une réaction de type amination de liens C-H en présence d’un catalyseur de palladium pour former le 3-aminoindazole désiré. Plusieurs 3-aminoindazoles ont été ainsi obtenus dans des rendements modérés à bons. Ensuite, une nouvelle méthodologie pour la synthèse des 3-amino imidazo[1,2-a]pyridines a été étudiée. Des amides contenant un motif 2-aminopyridine ont été traités avec l’anhydride trifluorométhanesulfonique afin d’obtenir l’hétérocycle désiré dans d’excellents rendements. Les produits ainsi obtenus ont pu être davantage fonctionnalisés en utilisant des réactions d’arylation de liens C-H catalysées par des composés de ruthénium et de palladium.
Nitrogen-containing heterocycles are of considerable importance in the pharmaceutical area. These types of compounds are indeed found in numerous bioactive structures patented in the last few years. Although these motives are useful, their synthesis often necessitates multiple steps or the use of highly functionalized starting materials. The present thesis describes new methodologies to access these synthetically challenging structures in a mild, chemoselective and step-economic fashion by amide activation using trifluoromethanesulfonic anhydride. First, a two-step method to access 3-aminoindazoles from the corresponding aromatic amide has been developed. The sequence includes a one-pot trifluoromethanesulfonic anhydride-mediated amide activation to form the corresponding iminium trifluoromethanesulfonate, followed by the addition of a protected hydrazide to access the amino hydrazone intermediate. This intermediate can then undergo cyclization through a palladium-catalyzed C-H amination reaction to afford the desired 3-aminoindazole. Various 3-aminoindazoles could be obtained in moderate to good yields. Moreover, a new methodology for the synthesis of 3-amino imidazo[1,2-a]pyridines was developed. 2-Aminopyridine-containing amides were treated with trifluoromethanesulfonic anhydride to afford the desired heterocycles in good to excellent yields. The products thus obtained could then be further functionalized using ruthenium and palladium catalyzed C-H arylation reactions.