Given the occurrence and diversity of nitrogen-containing molecules, the development of new amination methods is of significant importance. Indeed, a recent study shows that 60% of the FDA approved drugs contain a nitrogen heterocycle. Undoubtedly, novel methodologies arising for uncommon intermediates for the incorporation of nitrogen atoms are needed to access more complex molecules. The present document focus on the development of new methods for the formation of C-N and N-N bonds for the synthesis of acyclic and heterocyclic products. Isocyanates are useful synthons and reactive intermediates. To overcome their toxicity and instability, blocked (or masked) isocyanates have been developed: an equilibrium generates the isocyanate in-situ, allowing for safer precursors and better control over the concentration of the reactive isocyanate. This strategy enables the development of new reactivity, particularly for heteroatom-substituted isocyanates. However, reactions of oxygen-substituted isocyanates (O-isocyanates) remained severely underdeveloped. In Chapter 2, bench-stable N-oxy-carbamates and N-oxyureas are reacted under basecatalysis or thermal conditions to form the corresponding O-isocyanate intermediate in situ. In the first part of this chapter, a survey was performed and optimum experimental conditions for the controlled formation of O-isocyanate intermediates from the block precursors were found. Gratifyingly, the known side-reactions of O-isocyanates (trimerization and 1,2-shift) were avoided and different nucleophiles and substituents were studied for the controlled formation of N-oxyureas via substitution reaction of blocked O-isocyanates. Cascade reactions provided the opportunity to further develop this controlled reactivity of O-isocyanates. Herein, the first cascade-reaction of O-isocyanates is portrayed using - and -aminoester as the partners for the synthesis of hydantoin and dihydrouracil derivatives (>30 examples). Moreover, the conditions were modified to perform the reaction with -alcohol and - thioesters. Finally, evidence for the O-isocyanate intermediate is provided.

京都大学 / 新制・課程博士 / 博士(薬科学) / 甲第23138号 / 薬科博第137号 / 新制||薬科||15(附属図書館) / 京都大学大学院薬学研究科薬科学専攻 / (主査)教授 川端 猛夫, 教授 高須 清誠, 教授 大野 浩章 / 学位規則第4条第1項該当 / Doctor of Pharmaceutical Sciences / Kyoto University / DFAM

L’objectif de cette thèse de doctorat a été la mise au point de nouvelles méthodes de synthèse pour la fonctionnalisation directe de liaison C-H d’énamide via des réactions métallo-catalysées ou métallo-assistées dans des processus chimio-, régio- et éventuellement énantiosélectifs. Dans un premier temps, nous avons développé la trifluorométhylation d’énamide sélectivement en position C3 via une catalyse au Fe(II) impliquant l’utilisation de nouvelles sources de fluor (réactif de Togni II) et dont le mécanisme radicalaire a pu être mis en avant. Dans un second temps, deux nouvelles méthodes de synthèse impliquant l’utilisation de Fe(II) et Fe(III) ont pu être mises au point pour l’azidation sélective en position C2 ou C3 d’énamide via la difonctionnalisation de ces composés. La synthèse de β-azido alcools ou α-azido esters a ainsi pu être effectuée avec un contrôle diastéréosélectif pour les composés trans. Par la suite, l’étude de la réactivité des nitrènes sur des substrats énamides a permis de mettre au point et de valoriser les réactions d’oxyamidation et de C-H amination via l’insertion sélective de ces nitrènes respectivement sur la double liaison C=C ou bien en position C4 d’énamide. La compétition entre ces deux réactions a alors pu être associée à la nature des substituants présents sur les substrats de départ et plusieurs énamides γ-aminées ainsi que des β-amino éthers ont pu être synthétisés. / The aim of this Ph.D thesis was the development of new synthetic methods for the metal-catalysed direct CH functionalization of enamide with chemo-, regio- and possible enantioselectivity. First, we have developped a C3-selective trifluoromethylation of enamide with Fe (II) catalyst involving new sources of fluoride (Togni’s reagent II) with a radical mechanism. Secondly, two new synthetic methods with Fe(II) and Fe(III) were promoted for the selective azidation of enamides respectively at C2 and C3 position involving difunctionalization of the C=C double bond. β-azido alcohols and α-azido esters were then synthesized by controlling the diastereoselectivity for the trans isomer. Finally, studies on the reactivity of nitrenes on enamides allowed us to develop oxyamidation reaction and CH amination with a selective insertion of nitrenes respectively on the double bond C=C or at C4 position. The outcome of the reaction is highly substrate-dependent and several γ-amino enamides and β-amino ethers have been synthesized.

C-H functionalisation reactions aim for the selective cleavage of C-H bonds, and formation of a new carbon or heteroatom bond, often with the use of a transition metal catalyst. These reactions offer potential for functionalisation of hydrocarbons in fewer steps than conventional methods, and with high atom efficiency. They are therefore a subject of intense research in organic synthesis. Carbon-heteroatom bond forming reactions are particularly sought after, and useful in the efficient synthesis of many biologically significant groups such as oxazolidinone rings, 1,2 or 1,3 amino alcohols and amino acid analogues. An efficient, cheap and robust method for C-H amination would also be adaptable to varied syntheses of important large molecules. The necessity for complex and efficient transformations with a minimal number of steps means that heteroatom ring closures are also attractive and widely used reactions in such large molecule syntheses. The nitroso group is a highly reactive species which is normally generated in situ by oxidation of a hydroxylamine, for carbon-nitrogen bond forming reactions including the nitroso Heteroatomic Diels Alder reaction, nitroso ene reaction, and nitroso aldol reaction. Nitroso group reactions often show high stereo- and regioselectivity, and have formed key components of the syntheses of important biological molecules. Enantioselectivive protocols for the nitroso-ene reaction and, to a lesser extent, the nitroso HDA reaction, are poorly developed, however, and the range of available intramolecular nitroso reactions is limited. We aimed to establish efficient single-step intermolecular C-H amination reactions, to give 1,2 and 1,3 heteroatom functionalised molecules, and to develop the capacity for enantioselective induction in this reaction, if possible. Having synthesised a model set of unsaturated hydroxycarbamates, we identified a suitable system for nitroso generation, using a catalytic metal and stoichiometric oxidant. This resulted in in situ generation of cyclised product, with the olefin functionality intact. This cyclisation was then optimised and used to obtain a range of new heterocycles. The possibility of enantioselective induction via chiral catalysts was explored, as well as catalytic systems to increase the stereoselectivity of the reaction. In summary, a cheap, novel and reliable method was developed for formation of oxazolidinone rings from unsaturated hydroxycarbamates using an original intramolecular nitroso ene reaction, and a range of unsaturated heterocycles were synthesised in fairly good yields. Distereoselectivity of the nitroso ene cyclisations was optimised. However, to-date, we were unable to develop an enantioselective varient of the reaction. Several related aminations, as well as transformations of N-hydroxyoxazolidinone products, were also attempted during the project.

<div><p>Nitrenes are reactive intermediates that are known to generate high interest organic molecules. Due to their inherent instability, nitrenes are often stabilized by introducing them to transition metal complexes. Many transition metal stabilized nitrenes (M=NR₂) have been reported and some of these complexes have been shown to control nitrene reactivity and selectivity. Transition metal nitrene reactivity can be categorized into two main groups: bond-insertion and group transfer reactions. In the reference to the former, chapter one of this dissertation highlights using unique dinuclear Nicatalysts to generate nitrenes from aromatic azides. These Ni₂ nitrenes are used towards selective C(sp²)−H bond amination in order to generate indole and carbazole derivatives. This work highlights the unique properties of the Ni₂ imide that enable a 1,2-addition pathway, which contrasts known bimetallic nitrene insertion reactions. A detailed mechanistic study, primarily using density functional theory (DFT) is the focus of this chapter.</p> <p>Chapter two of this dissertation focuses on nitrene group transfer. In particular, this chapter highlights the ability of the dinuclear Nicatalyst [<i>ⁱ</i>^-PrNDI]Ni₂(C₆H₆) to react with aromatic azides to perform N=N coupling. A large scope of functional groups are tolerated in high yield with short reaction times. Catalyst comparison studies, studies on relevant catalytic intermediates for N=N coupling and reaction kinetics are shown in this chapter. Lastly, chapter three showcases the expansion of the nitrene group transfer ability of [<i>ⁱ</i>^-PrNDI]Ni₂(C₆H₆) to generate high molecular weight azopolymers from aromatic diazides. These azopolymers are generated from monomers often used in organic semi-conducting materials. End group control and post polymer functionalization are highlighted in this chapter. Lastly, this work showcases a new polymer, polyazoisoindigo, as the first organic semiconducting material that reversibly transitions from a colored to colorless state upon reduction.</p><br></div>

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Nitrogen is a vital element for the existence of life, as shown by its frequent presence in essential biomolecules, and inclusion into valuable drugs. Sulfonamides and their heterocycle counterpart, sultams, are N-containing functional groups and metabolically stable amide isosteres. Sulfa drugs, which contain these moieties, have a broad spectrum of medical applications. The industrial value of sultams has prompted the development of novel methods for their synthesis, and metal-catalyzed C-H amination reactions with nitrene precursors have recently shown promise. The current thesis presents a survey of conditions for benzo[d]sultam synthesis via intramolecular C-H amination of N-acyloxysulfonamides. Initially, using Ru(Bpy)3(PF6)2 as a photocatalyst and Et3N as a base enabled benzo[d]sultam formation by tertiary C-H amidation. The photoredox conditions were optimized to accommodate other 2,6-disubstituted-N-acyloxysulfonamides upon omission of the base, which consistently gave sulfonamide byproducts. Control reactions indicated that a thermal base-induced reaction was simultaneously occurring, both enabling productive C-H amidation and byproduct formation. Systematic optimization of base-induced conditions enabled sultam synthesis from 2,6-dialkyl- and tertiary ortho-monoalkyl-precursors in moderate yield, but sulfonamide formation still impeded the reaction.   An additional control reaction indicated that a thermal Ruthenium-catalyzed C-H amidation reaction was possible. Indeed, heating N-acyloxysulfonamides in the presence of Ru(Bpy)3(PF6)2 and in the absence of light and base enabled efficient C-H amidation, particularly with DCE as a solvent. A representative scope of 12 benzo[d]sultams was then synthesized including entries derived from ortho-monoalkyl-N-acyloxyarylsulfonamides. Aside from optimizing an efficient reaction for the synthesis of benzo[d]sultams through the cyclization of N-acyloxyarylsulfonamides, including the challenging primary C-H amidation of orthomonomethyl-substrates, the unique reaction conditions developed in this thesis set precedent for future investigation of hydroxylamine derived nitrene precursors. The optimization and design of superior ruthenium catalysts could allow for more challenging C-H amination reactions with hydroxysulfonamide derivatives and similar N-oxy nitrene precursors.

De précédentes études dans notre groupe ont montré que l'α-1-C-nonyl-1,5-didésoxy-1,5-imino-D-xylitol était un inhibiteur puissant de la β-glucocérébrosidase, enzyme impliquée dans la maladie de Gaucher. Il a été supposé que la conformation chaise inversée de ce composé pouvait expliquer en partie sa forte affinité avec la glycosidase cible. L'objectif ce travail de thèse était la synthèse d'une nouvelle classe d’iminosucres, basée sur un squelette 1-azaspiro[3.3]heptane, possédant deux cycles à 4 membres, analogue conformationnellement contraint de notre "lead" en série iminoxylitol. La première stratégie de synthèse envisagée a permis de mettre en avant une nouvelle réaction tandem d'ouverture d'azétidines conduisant à des spirocyclopropyl γ-lactames. La seconde stratégie testée a conduit dans un premier temps à la formation hautement stéréosélective d'un cyclobutane tétrasubstitué par une réaction radicalaire induite par le SmI2 − permettant ainsi la synthèse des premiers exemples de carbasucres à 4 membres − puis à la formation du carbone azaspiranique de notre cible par une réaction de C-H amination catalysée par des complexes de rhodium. / Previous studies in our group has shown that α-1-C-nonyl-1,5-dideoxy-1,5-imino-D-xylitol was a strong inhibitor of β-glucocerebrosidase, the enzyme involved in Gaucher disease. It was supposed that the inverted chair conformation of this compound could partially explain its high affinity with the target glycosydase.The goal of this PhD work was the synthesis of a new class of iminosugars based on 1-azaspiro[3.3]heptane structures, as conformationally strained analogues of our lead in the iminoxylitol series. During the course of our synthetic study, new azetidine ring-opening tandem reaction leading to spirocyclopropyl γ-lactames has been discovered. The most promising strategy evaluated led to the highly stereoselective formation of a tetrasubstituted cyclobutane via a SmI2-mediated radical reaction − leading to the synthesis of the first exemples of 4-membered carbasugars − then to the formation of the azaspiranic carbon of our target by way of rhodium-catalyzed C-H amination reaction.

Les transferts de nitrène représentent un outil synthétique très intéressant pour former simplement une liaison C-N à partir d’une liaison C-H. Notre laboratoire a développé des précurseurs de nitrène chiraux : les sulfonimidamides. Leur utilisation a abouti, en présence de catalyseurs de rhodium, à des réactions d’amination C-H hautement diastéréosélectives. Ce projet de thèse s’inscrit dans la continuité de ces travaux. Dans un premier temps, la synthèse totale de la Dibromophakellstatine a été envisagée, impliquant comme étape clé, une étape d’amination C-H en position pseudo benzylique. Le projet n’ayant pas abouti, une séquence réactionnelle de quelques étapes a été développée à partir de l’amination C-H d’éthers d’énols et de benzocyclobutènes. Ainsi, plusieurs motifs perhydroindoles ont pu être préparés avec de bons rendements et d’excellentes diastéréosélectivités dans la plupart des cas. Dans le cadre d’une chimie plus éco-compatible, il a ensuite été envisagé de limiter l’introduction d’iode hypervalent dans les conditions de l’amination C-H. Pour cela, une première approche a consisté à utiliser les haloamines comme précurseurs de nitrène, cependant sans résultat satisfaisant. Une autre alternative a été d’introduire un oxydant, respectueux de l’environnement, permettant la réoxydation de l’iodobenzène formé en cours de réaction en une espèce de nouveau réactive (I(III)). De même, ces derniers résultats plutôt décevants ne permettent pas de s’affranchir de l’introduction de dérivé iodé en quantité stoechiométrique. / Catalytic nitrene transfers are useful tools in organic synthesis for the efficient conversion of a C-H bond into a C-N bond. In this context, our group has recently reported the use of sulfonimidamides as efficient chiral nitrene precursors in the rhodium-catalyzed stereoselective C-H amination of hydrocarbons. These PhD studies follow on from this work; it aims, on one hand, at applying the catalytic C-H amination in total synthesis, and, on the other hand, at searching for more sustainable reactions conditions. The first part of the manuscript reports our initial investigations devoted to the synthesis of Dibromophakellstatine. The strategy was based on a key step of C-H amination of a pseudo benzylic position but did not prove successful. A second application deals with the synthesis of polycyclic nitrogen compounds that relies on the catalytic C-H amination of enol ethers and benzocyclobutenes. A 3- to 4-step scheme, thus, allows the efficient access to perhydroindole scaffolds that are isolated in good yields and excellent diastereoselectivity. The second part deals with the search for sustainable reaction conditions that will avoid the use of stoichiometric amounts of hypervalent iodine reagents. These are indeed responsible for the production of excess iodobenzene. A first approach involves the use of haloamines as nitrene precursors but it did not lead to satisfying results. Attention has thus been paid to the use of benign oxidants allowing the in situ generation of an iodine(III) species from PhI. An extensive screening of reagents and reaction parameters has led to uncover a first significant result in the case of indan that, however, does not prove reproducible.

Les transferts de nitrène représentent un outil synthétique très intéressant pour former simplement une liaison C-N à partir d’une liaison C-H. Notre laboratoire a développé des précurseurs de nitrène chiraux : les sulfonimidamides. Leur utilisation a abouti, en présence de catalyseurs de cuivre et de rhodium, à des réactions d’aziridination d’oléfine et d’amination C-H hautement diastéréosélectives. Ce projet de thèse s’inscrit dans la continuité de ces travaux. Les sulfonimidamides ont pu être combinés avec des complexes scorpionate de cuivre et d’argent, au cours d’une collaboration COST avec le groupe de Pedro Pérez à Huelva, avec de bons résultats pour l’aziridination d’oléfines et l’amination C-H. De même, des nouveaux complexes de cuivre développés dans l’équipe de Didier Bourissou à Toulouse, ont pu être testés avec succès pour l’aziridination de différentes oléfines, dans le cadre d’une collaboration ANR. D’autre part, le champ d’application de la réaction d’amination C-H catalysée par le rhodium a été étendu avec d’excellents résultats à des substrats complexes comme les terpènes et différents éthers d’énol, ainsi qu’à des substrats peu réactifs comme les alcanes. Enfin, des études mécanistiques ont été menées pour tenter d’élucider la nature du transfert de nitrène. Les résultats obtenus sont en faveur d’un mécanisme concerté asynchrone, mais ils ne permettent pas d’exclure définitivement un transfert radicalaire. L’isolement d’un complexe métal-carbène étant supposé plus aisé qu’un complexe métal-nitrène, nous nous sommes tournés vers le développement de carbènes de sulfoximines, analogues carbonés des sulfonimidamides, sans résultat satisfaisant pour le moment. / Catalytic nitrene transfers are useful tools in organic synthesis, to perform the transformation of a C-H bond into a C-N bond. Our group has previously demonstrated that sulfonimidamieds are efficient chiral nitrène precursors. Combined with copper or rhodium complexes, they have allowed to uncover olefin aziridination and C-H amination that occur with high level of stereoselectivity. These PhD studies stand within the framework of this topic. Sulfonimidamides have first been combined with scorpionate copper and silver complexes developed by Pedro Perez in Huelva, to afford either aziridines or C-H amination products in very good yields. In the same way, new copper catalysts developed in the group of Didier Bourissou in Toulouse were evaluated with good results in olefin aziridination. On the other hand, rhodium catalyzed C-H amination has been applied to more complex substrates such as terpenes and enol ethers, as well as to less reactives substrates like alkanes, with excellent results in terms of regio-, chemo-, and stereoselectivity. Mechanistic studies have also been conducted. These point to an asynchronous concerted nitrene transfer, but the involvement of radicals cannot be ruled out. We have finally turned our attention to the formation of carbenes from sulfoximines, which are the carbo-analogs of sulfonimidamides, but without success so far.