I do thank my PhD directors Prof. Dr. Laurent EL Kaïm for welcoming me to join his group, and giving me an opportunity to work as a member of his research group. He always gives me lots of help whenever I needed him during my doctoral programme. He is very understanding and kind, he takes the time to get to know his students as individuals and for that I am sincerely grateful. I thank him from the bottom of my heart for his keen guidance and efforts he has put into me in the scientific training field.

My sincere thanks to M. Philippe Dauban for agreeing to act as the president of the jury, I also thank to members of the jury and rapporteur of this thesis M. Maxime Vitale and Mme.

Laurence Grimaud, I sincerely thank them for reading this thesis and evaluating critically.

Their comments have been instrumental in making this thesis more effective and I am grateful for their valuable suggestion and information they have shared with me.

I want to thank Vincent Jactel for helping me analyze the HRMS of all my synthesized compounds.

I also thank Aurélie Dos Santos, researcher Sébastien Prévost, Dr. Noisette Narboni, Mansour Dolè Kerim, Dr. Alaa Zidan and other PhD students, Postdoctors and visiting students. They really gave me a lot of support in the lab.

Finally, I thank the CSC (China Scholarship Council) for founding of my all research in France.

Résumé

Résumé 6

Les réactions multicomposants (MCRs) sont des transformations utiles qui permettent à au moins trois composés de réagir en une seule étape pour former un seul produit final, qui comprend la totalité ou la plupart des atomes des produits de départ (figure 1). Elles impliquent généralement une séquence d'étapes élémentaires conduisant à la formation et à la rupture de différentes liaisons, qui se déroulent séquentiellement jusqu'à atteindre une étape irréversible permettant d'obtenir le produit final.

Les réactions multicomposants associées à leurs réactions de post-condensation constituent une stratégie de synthèse particulièrement intéressante pour la construction de structures complexes. La grande diversité structurales et la facilité d'accès à des librairies de composés organiques de taille importante associées au développement de nouvelles techniques de « screening haut débit » ont joué un rôle important dans la mise au point de nouveaux médicaments au cours des vingt dernières années.

Un grand nombre de MCRs ont été décrites dans la littérature. Les réactions de Mannich sont probablement les reactions à trois composants les plus importantes, alors que les MCRs à base d'isonitriles sont mieux connues en raison de la grande efficacité des réactions d'Ugi.

Dans le cadre de cette thèse, nous nous sommes intéressés à l'utilisation de la réaction de Passerini, un couplage à trois composants à base d'isonitriles. Nous avons ensuite développé une nouvelle réaction de Mannich des hydrazones. La dernière partie de la thèse a été consacrée à une nouvelle réaction de Tsuji-Trost des dérivés nitrés.

La réaction de Passerini fournit un accès rapide aux α-acyloxycarboxamides (schéma 1). La réaction est très générale, donnant des produits d'addition avec des rendements élevés lorsque les réactions sont effectuées à température ambiante et à forte concentration (molaire ou sans solvant).

L'intérêt synthétique de ces réactions peut encore être augmenté par de simples transformations des adduits de Passerrini (appelées post-condensations) conduisant à des structures plus intéressantes telles que des composés hétérocycliques biologiquement actifs.

Le groupe de recherche de l'ENSTA a récemment lancé un programme visant à évaluer le potentiel des adduits d'Ugi dans des réactions intermoléculaires afin d'étendre la diversité structurale accessible par cette réaction. Nous avons été particulièrement intéressés par des additions de Michael sur à la position peptidique des adduits d'Ugi. Malgré la capacité de modifier la nucléophilie du produit d'addition d'Ugi en sélectionnant correctement le partenaire aldéhyde de départ, nous n'avons observé aucun produit addition. Néanmoins, une cycloaddition de type [3 + 2] de ces derniers avec de l'acrylonitrile conduisant à des dérivés du pyrrole a été découverte (schéma 2). Nous avons ensuite décidé d'explorer le comportement des adduits de Passerini dans des réactions similaires. Cette étude a conduit à une nouvelle préparation de -butyrolactones, elle fait l'objet de la première partie de la thèse.

Dans ce contexte, une bibliothèque de produits d'addition de Passerini a été préparée en faisant varier les 3 composants de la réaction. Les -acyloxycarboxamides ont été obtenus avec des rendements allant de 77 à 99%. Nos essais d'additions de Michael nous ont montré qu'il n'était pas possible de conserver la fonction ester en milieu basique, l'alcool se formant très vite en milieu basique. L'addition d'acrylonitrile sur ce dernier n'a pu être observée dans des conditions douces. Néanmoins, en travaillant avec un large excès d'acrylonitrile (5 équivalents) et au microonde à 130°C, il nous a été possible d'obtenir la formation d'un adduit de Michael en partant directement de l'adduit de Passerini. Dans ce cas, l'utilisation de 2.2 équivalents de Cs 2 CO 3 permet de réaliser la saponification et l'addition de Michael dans une même séquence réactionnelle. En exploitant ces conditions, nous avons pu réaliser la synthèse d'une famille d'hydroxynitriles avec des rendements variant de 61 à 95% (schéma 3). Bien que la formation de l'alcool 1 avec perte du fragment acétate ne soit pas bon en termes de diversité, il offre une opportunité intéressante pour la préparation de butyrolactones par cyclisation de l'alcool sur le groupe nitrile.

De manière surprenante la cyclisation des hydroxynitriles s'est révélée difficile à réaliser.

Nous avons pu néanmoins observer la formation des -butylactones attendues en chauffant les hydroxynitriles à température élevée dans un solvant relativement acide comme le trifluoroéthanol et en présence d'une quantité catalytique de triflate de zinc. Les rendements obtenus sont bons allant de 50 à 92% (schéma 4).

Dans la deuxième partie de la thèse, nous nous sommes intéressés à la réaction de Mannich des hydrazones. La réaction de Mannich est une préparation classique de β-amino-cétones et d'aldéhydes (bases de Mannich) à partir d'aldéhydes ou de cétones enolisables et d'amines.

Décrite pour la première fois avec des cétones enolisables, la réaction a été étendue à divers nucléophiles au cours des décennies suivantes.

La réaction de Mannich des hydrazones N-H a été proposée pour la première fois par Keil et Ried en 1959. La réaction avait été décrite uniquement avec du formaldéhyde et des N-H hydrazones relativement acides susceptibles d'être déprotonées facilement par une amine dans les conditions de la réaction. Contrairement au comportement habituel des anions hydrazonyles dans des alkylations par des halogénures d'alkyles, la réversibilité des attaques sur l'azote de l'hydrazone conduit à une fonctionnalisation au niveau du carbone de l'hydrazone (schéma 5).

Une tautomérie azo-hydrazone irréversible est indispensable pour l'efficacité du procédé, cette isomérisation n'est observée qu'en milieu basique. Ceci explique la nécessité de substituer l'hydrazone par des groupements attracteurs (cétone, ester ou groupement pyridyle en  de la fonction azo) afin d'augmenter l'acidité de l'intermédiaire azoïque. Compte tenu de ces limitations, nous avons envisagé qu'une NH-hydrazone dérivée du trifluoroacétaldéhyde puisse être suffisamment acide pour être impliquée dans des couplages de type Mannich efficaces. Les adduits de Mannich résultant de cette réaction pourraient par la suite être convertis en différents composés hétérocycliques trifluorométhylés (schéma 6). Ces réactions conduisent à de bons rendements principalement avec des amines cycliques secondaires. Dans le cas des amines primaires telles que 1'allylamine ou la 4-méthoxybenzylamine, nous avons pu observer la formation d'une famille de 1,2,4-triazines trifluorées par chauffage de la 4-nitrophénylhydrazone issue du trifluoroacétaldéhyde avec deux équivalents de formaldehyde (schéma 8).

Les applications potentielles des adduits de Mannich obtenus sont principalement associées à la capacité de ces produits de fournir des azoalcènes trifluoromethylés par chauffage à une temperature suffisante pour éliminer l'amine. La formation des azoalcènes à principalement été observées à partir d'hydrazones chlorées ou bromées par réaction d'élimination 1,4 en présence d'une base (schéma 9). La plupart des azoalcènes pauvres en électron sont instables, ils réagissent particulièrement bien dans des réactions de Diels-Alder avec des dienophiles riches en électron.

Bien que moins décrite, la préparation des azoalcènes directement à partir d'hydrazonoamines est aussi possible. Elle est en générale observée dans des conditions thermiques (température supérieure à 100°C) et avec des amines volatiles afin d'éviter une réaddition de Michael de l'amine conduisant au produit de départ. Malgré le point d'ébullition relativement élevé de nos amines secondaires, nous avons pu observer la formation d'azoalcènes et leur réaction avec des cétoesters dans des réactions de cycloadditon de type Diels-Alder conduisant à la formation de 1,2-diazines avec des rendements allant de 58 à 90% (schéma 10). Les cétoesters, ont été utilisés en solvant, ceci permet de pieger l'amine libérer lors de la formation de l'azoalcène tout en formant une enamine plus nucléophile que le cetoester de depart.

Les résultats expérimentaux ont confirmé nos hypothèses mécanistes initiales: l'élimination thermique de la morpholine permet la formation d'un intermédiaire d'énamine engagé dans une addition de Michael avec l'azoalkène. La cyclisation et l'élimination de la morpholine donnent finalement la 4-hydropyridazine (schéma 11).

Dans la dernière partie de la thèse, nous avons exploré le potentiel des dérivés nitrés dans les réactions de Tsuji-Trost. L'allylation de nucléophiles carbonés catalysée par le palladium avec des composés allyliques via des complexes π-allylpalladium est appelée réaction de .

Il est proposé que le palladium coordonne la double liaison du groupe allyle formant un complexe η2 π-allyl-Pd0. Dans l'étape suivante d'addition oxydante, le groupe partant est expulsé avec inversion de configuration et un η3 π-allyl-PdII est créé (étape également appelée ionisation). Le nucléophile s'additionne ensuite en régénérant le complexe η2 π-allyl-Pd0. Enfin, la dissociation des espèces actives libérent à la fois le produit désiré et le catalyseur au palladium qui intervient à nouveau dans le cycle catalytique (schéma 13).

Les nitroalcanes représentent une des familles chimiques les plus polyvalentes et les plus précieuses de la synthèse organique en raison des modifications fonctionnelles très simple du groupe nitro (réduction, oxydation) et du caractère fortement électronégatif de ce dernier. En effet, les nitroalcanes ont tendance à donner, dans des conditions basiques douces, des carbanions stabilisés (anions nitronates) qui sont d'excellents nucléophiles et conduisent à la formation de liaisons carbone-carbone, dans des réactions telle que la réaction de Henry, ou les additions de Michael ou de Mannich. Contrairement à ces réactions importantes décrites il y a plusieures décennies, la transformation des composés nitro catalysée par des métaux de transition a peu progressé, se limitant principalement à la transformation réductrice du nitro en dérivés d'amines par différents donneurs d'hydrogène. Ceci est particulièrement vrai pour les réactions catalysées par le palladium aussi bien sur les composés nitrés aromatiques que les aliphatiques. Il existe cependant quelques rapports dans la littérature où des dérivés nitrés allyliques et benzyliques réagissent avec un catalyseur au palladium (0) pour conduire à l'insertion du métal dans la liaison carbone-NO 2 et au remplacement du nitro par divers dérivés nucléophiles tels que les dérivés malonyles.

Bien que ces réactions de Tsuji-Trost des produits nitrés permettent d'accéder à des dérivés hautement fonctionnalisés, ces réactions ont été peu exploitées en synthèse. Stimulés par notre intérêt pour les réactions de Tsuji-Trost, nous avons envisagé qu'en l'absence d'un groupe nucléophile potentiel, l'intermédiaire π-allylique dérivé de composés nitro pourrait offrir dans des conditions basiques un accès intéressant à différents composés diènique (schéma 15). Associé à la formation préalable de composés nitrés, ce processus d'élimination pourrait fournir une stratégie de synthèse précieuse pour la formation de diènes fortement fonctionnalisés. Le travail de mon collègue Mansour Dolè Kerim a ainsi démontré la pertinence de cette approche sur des dérivés nitrés issus de la cyclohexanone (schéma 15). Il ne nous a malheureusement pas été possible de valoriser les diènes formés dans ce cas dans des réactions ultérieures aboutissant à la formation de produits polycycliques.

Nous avons envisagé qu'avec un autre noyau benzénique fusionné avec le 1-(nitrométhyl) cyclohex-1-ène, et donc en travaillant avec des dérivés de la tétralone, il nous serait possible d'accéder à des dérivés de naphtalènes plus intéressants sur le plan synthétique (schéma 16).

Mon travail sur ce sujet a donc consisté à étendre la formation de diènes mise au point par Mansour sur des dérivés de tétralone. Si les composes niters de depart se sont révélés plus difficile à former que dans le cas des dérivés de la cyclohexanone, nous avons pu réaliser très facilement l'élimination du groupement nitro dans des conditions proches de celles mises au point par Mansour. Une série de dérives naphthalènique a ainsi pu être préparée avec des rendements allant de 66 à 87% (schèma 17).

Cette approche a principalement été développée sur des dérivés du naphtalène. Nous avons pu cependant démontrer qu'il était possible de modifier le noyau aromatique de ce système pour obtenir des indoles fonctionnalisés par cette méthode. Faute de temps, un seul exemple a été réalisé mais ceci démontre la généralité de l'approche et son potentiel en synthèse hétérocyclique (schéma 18).

List of Abbreviations

General introduction

The past few decades witnessed the development of organic chemistry. A large group of organic molecules exhibited various biological activities which is basis of life and society.

However, chemists are still facing a challenge of designing chemical reactions that are highly capable in providing most of the elements of structural complexity and diversity with minimum synthetic steps for the particular molecules with interesting properties.

Multicomponent reactions served an access to this "ideal synthesis" with high atoms economy and other advantages.

One major target of this thesis is to discover some new multicomponent reactions and further develop them in heterocyclic synthesis; the other one is to synthesize naphthalene derivatives via palladium catalyzed Tsuji-Trost elimination sequences.

The first chapter will give a brief introduction of isocyanides and multicomponent reactions.

In chapter two, we will illustrate the reactivity of Passerini adducts and their application toward butyrolactones via a Passerini/Michael pathway. The Passerini adducts of aromatic aldehydes act as nucleophiles in Michael additions with acrylonitrile. The reaction proceeds together with hydrolysis of the ester. The resulting γ-hydroxynitrile can be cyclized under acidic conditions to afford γ-butyrolactones.

The third chapter will investigate the Mannich reaction of trifluoromethyl directed hydrazones. The NH-aryl hydrazones derived from trifluoroacetaldehyde hemiacetal can be involved in efficient Mannich type reactions with formaldehydes and aromatic aldehydes.

The resulting hydrazones are useful building blocks for the preparation of trifluoromethyl substituted 1,2-diazine derivatives under heating with β-ketoesters.

In chapter four, we will explore the possibility of obtaining naphthalene through Tsuji-Trost reaction. This reaction may involve the formation of a palladium p-allyl complex followed by a base promoted β-hydride elimination. This reaction combined with the condensation of fused cyclic ketones with nitromethane and the functionalization of the resulting nitrocycloalkenes (Michael, Mannich...) constitute a very powerful synthetic tool for the formation of 1-substituted naphtalenes.

The last part of this context will include the experimental part involving all the procedures employed for the different syntheses, the spectral data and interpretations for all of the organic compounds prepared during the whole study of this thesis.

Chapter I Isocyanides and multicomponent reactions 1. Multicomponent reactions (MCRs)

Advantages of multicomponent reactions (MCRs)

Over the past decades, organic-chemical syntheses have reached a high degree of skillfulness. 1 It proposed a challenge of obtaining chemical compounds, especially some natural products and drugs, with high efficiency and sustainability. In conventional way, the structural complexity of the molecules often requires multiple synthetic steps, diversified substrates and reagents, harsh reaction conditions and difficulties in the isolation and purification of products, leading to extremely laborious and costly experimental procedures. 2 Hence, the need for an alternative method to conventional multistep synthesis is compulsory.

A number of multicomponent reactions (MCRs) meet the "ideal synthesis" (figure1-1)

requirement such as atoms economy, steps with high chemical yields, the use of convergent one-pot reactions, less aggressive reactions conditions to the environment, accessible and cheap substrates, easy operation together with a considerable advantage of this methodology, the ability to quickly build a library of varied and structurally complex compounds. 3

Principles of multicomponent reactions

Multicomponent reactions (MCRs) are useful transformations that allow at least three starting materials combined together in only one reaction to form a single final product, which include all or most of the atoms of the starting components (figure 12).

They consist of a sequence of elementary stages involving bond breaking and bond formations, which proceed sequentially till reaching an irreversible final step to afford the final product.

They can be considered as a special class of tandem reactions as they just allow all starting substrates mixed and react with each other in a single reaction flask without additional modifications of the reaction conditions.

Multicomponent reactions together with their post condensation reactions constitue a particularly attractive synthetic strategy. They provide rapid and efficient accessibility to large libraries of organic compounds with different substituents. Such diversity and easy accessibility to a large number of organic compounds along with the available screening techniques play a significant role in the drug discovery processes.

History of multicomponent reactions

It has been more than 180 years since the first description of a multicomponent reaction was documented by Laurent and Gerhardt, in 1838, who isolated the compound 2 from the intermediate 1 α-aminonitrile which was obtained from reaction between benzaldehyde, hydrocyanic acid and ammonia (scheme 1-1). 4In 1850, Strecker synthesized α-amino acids from α-aminonitriles obtained from condensation of an aldehyde with ammonium chloride in presence of potassium cyanide (scheme 1-2). 5After Strecker reaction, lots of different MCRs have been developed over the decades allowing the access to various complex structures. In 1882, Hantzsch synthesized dihydropyridine from an aldehyde, ammonia and twofold of ethyl acetoacetate (scheme 1-3).6

At the same time, Debus-Radziszewski obtained 1,4,5-trimethyl-1H-imidazole from condensation of biacetyl, formaldehyde, methanamine and ammonia (scheme 1-4). 7In 1891, Biginelli synthesized 3,4-dihydropyrimidin-2(1H)-ones from ethyl acetate, an aryl aldehyde(such as benzaldehyde), and urea (scheme 1-5). 8 The Mannich reaction was discovered in 1912, consists of an amino alkylation of an enol with aldehyde and amine (scheme 1-6). 9

In 1921, Passerini reaction, an efficient access to α-acyloxycarboxamides, was reported (scheme 1-7). 10

The Ugi reaction, disclosed in 1959, involves a ketone or aldehyde, an amine, an isocyanide and a carboxylic acid to give a bis-amide (scheme 1-8

Isocyanides

Isocyanides (also called isonitriles or carbylamines) are organic compound possessing the functional group -N≡C. It is the isomer of the related cyanide (-C≡N), hence the prefix iso.

The organic fragment is connected to the isocyanide group via the nitrogen atom, not via the carbon. Usually, they spread strong penetrating, unpleasant odor, thus, isocyanides have been recognized as potential non-lethal weapons. 12 Isocyanide functional group exists in only few naturally occurring compounds. The first isolated natural product containing isocyanide group, Xantocillin, which was used as an antibiotic, was extracted from the mold Penicillium notatumin in 1950 (figure 1-3).

12 C. Pirrung, S. Ghorai, R. Ibarra-Rivera, J. Org. Chem. 2009,74, 4110.

Synthesis of isocyanides

Isocyanides were first described in the literature by Lieke in 1859, 13 he was surprised to obtain a product with sharp odour which upon hydrolysis gave N-allylformamide instead of the corresponding carboxylic acid. Few years later, in 1869, Gautier proved that this allylation reaction gave allyl isocyanide and demonstrated isomeric relationship between isocyanides and nitriles (scheme 1-9). 14

In 1867, Hofmann developed a new approach to isocyanide through the condensation of a primary amine with dichlorocarbene, which generated in situ by heating chloroform in presence of a base such as potassium hydroxide (scheme 1-10). 15 Despite it looks simple, it is not considered as a general method for the isocyanides synthesis because of the low yields obtained and the difficulties of separating the isocyanides from amines.

In 1972, Weber, Gokel and Ugi modified Hofmann's approach by using a biphasic medium (water/dichloromethane) in the presence of a quaternary ammonium salt as a phase transfer catalyst (PTC). This improved the selectivity of the amine attacking the dichlorocarbene, but it still suffers from the formation of byproducts (scheme 1-11). 16 This method could be used to synthesize isocyanides in large-scale even though the yield is moderate, and it is the most frequently applied in our laboratory for preparing the starting isocyanide substrates.

In 1958, Corey and Ugi reported another approach to isocyanides via dehydration of N-monosubstituted formamides, which could be readily prepared by the condensation of a primary amine with methyl formate or formic acid (scheme 1-12). 17

Various dehydrating agent such as diphosgene (C 2 Cl 4 O 2 ), 18 diphosphorus pentoxide (P 4 O 10 ), phosphorus oxychloride (POCl 3 ) or thionyl chloride (SOCl 2 ) 19 in the presence of different bases like pyridine, triethylamine, or DABCO could be used. 20 Few examples are shown in scheme 1-13.

16 (a) W. Weber, G. Gokel, Tetrahedron Lett. 1972, 11, 1637. (b) P. Weber, W. Gokel, I. Ugi, Angew. Chem. 1972, 84, 587. 17 (a) W. Hertler, J. Corey, J. Org. Chem. 1958, 23, 1221. (b) I. Ugi, R. Meyr, Angew. Chem. 1958, 70, 702. 18 G. Skorna, I. Ugi, Angew. Chem., Int. Ed. Engl. 1977, 16, 259. 19 I. Ugi, R. Meyr, Chem. Ber. 1960, 93, 239. 20 R. Obrecht, R. Hermann, I. Ugi, Synthesis 1985, 400. This method is widely used in the synthesis of isocyanides since it is tolerable with a number of functional groups.

Isocyanides could also be prepared from isocyanide gem-dihalides. Gem-dihalide of trifluoromethyl isocyanide under the treatment of magnesium could afford trifluoromethyl isocyanide (scheme 1-14). 21 Reduction of isocyanates, isothiocyanates or dichloro ketenimine can give corresponding isocyanides. The reduction process could occur at relatively low temperature in presence of 2-phenyl-3-methyl-1,3,2-oxazaphospholidine, (diphenyl-tert-butylsilyl)lithium or a mixture of trichlorosilane-triethylamine (scheme 1-15). 22 21 (a) D. Lentz, J. Fluo. Chem. 1984, 24, 523-530. (b) D. Lentz, J. Fluo. Chem. 1985, 29, 91. (c) The formed intermediate is then trapped using various acid chlorides (scheme 1-17). 24

Among those various synthetic methods, the purification step is essential, and the horrible smells may be a nightmare for chemists. To avoid this disadvantage, in 2009, our lab published an in situ protocol for the synthesis of isocyanides starting from halogenated derivatives with silver and potassium cyanide in the presence of benzyltriethylammonium chloride as a catalyst at 80 ºC (scheme 1-18). 25 The obtained product can be used directly without further purification.

Reactivity of isocyanides

Structure of isocyanide

Isocyanides are described by two resonance structures, one with a triple bond between the nitrogen and the carbon (zwitterions form) and one with a double bond between (divalent carbon form) (scheme 1-19).

In the resonance structure 4, the carbon possess a carbene-like reactivity while in structure 3, it involves a dipolar linear resonance Based on Valence bond calculations for methyl isocyanide, it was found that the carbene-form existed in about 50 %, while the zwitterionic species in about 30 %, the 25 (a) L. Elkaïm, L. Grimaud, A. Schiltz, Synlett. 2009, 1401. (b) L. Elkaïm, L. Grimaud, A.Schiltz, Tetrahedron Lett. 2009, 50, 5235. (c) L. Elkaïm, L. Grimaud, A. Schiltz, Org. Biomol. Chem., 2009, 7, 3024. remaining 20 % structures being more complex (scheme 1-20). 26 Thus isocyanides are linear molecules since such geometry allows the resonance between the carbene and the zwitterionic structures.

Isocyanides are characterized by their high stability in basic mediums, but they are sensitive to acids. In the presence of acidic solutions, they undergo acidic hydrolysis forming formamides. Most isocyanides may polymerize as well in acidic mediums. 27

Reactivity of the terminal carbon

The terminal carbon reactivity of the isocyanide functional group could be explained on the basis of the Molecular orbital theory. The analysis of the frontier orbitals showed that the largest coefficients in both HOMO (σ) and LUMO (π*) orbitals are situated on the terminal carbon of methylisocyanide (figure1-4)

26 R. Consequently, both electrophilic and nucleophilic additions occur at the terminal carbon atom of isocyanides

After the attack of a nucleophile on the isocyanide, the divalent carbon becomes nucleophilic and attacks an electrophile and conversely, it can react first with an electrophile and followed by addition of the nucleophile.

α-Acidity of the isocyanide group

Oxazoles could be synthesized from isocyanides attribute to the acidity of the protons in α-position to the isocyanide functionality, which is enhanced by the electron-withdrawing nature of such group. After α-deprotonation under basic condition, isocyanide react with an acid chloride to afford the target cyclic compound (scheme 1-21). 28 28 (a) U. Schöllkopf, R. Schröder, Angew. Chem. Int. Ed. Engl. 1971, 10, 333. (b)

Radical reaction of the isocyanides

Imidoyl radical was usually formed by the addition of a radical to the terminal carbon of the isocyanide moiety. It can fragment into a cyanide and an alkyl radical or react with an unsaturated system to finally give heterocycles (scheme 1-24).

This behavior was first described by Shaw 31 and Saegusa 32 , who exploited this reactivity for the formation of various heterocycles. In 2014, Zhu 33 and Yu 34 independently developed a practical route to access phenanthridine-6-carboxylates via a sequential oxidative radical alkoxycarbonylation and aromatization reaction of biaryl isocyanides with carbazates. The C-N bond cleavage of the carbazates with the extrusion of nitrogen gas leads to alkoxycarbonyl radical, the subsequent radical addition to the biaryl isocyanides generated the imidoyl radical intermediate, which underwent intramolecular homolytic aromatic substitution to afford the desired product (scheme 1-25).

Radical reactions involving isocyanides were also widely used in the total synthesis of alkaloid like heterocycles or natural products. 35 For instance, this sort of radical reaction plays a key step in the total synthesis of camptothecin, which is a natural product used in cancer chemotherapy (scheme1-26).

Metal-catalyzed C-H insertion reaction

Since the early 1960s, many metal-catalyzed isocyanide insertion reactions have been developed by Saegusa and Ito. 37,38 In 1990, Hessell et al. reported an isocyanide insertion which an Iron-Aryl bond generated by a CH activation of benzene (scheme 1-27). 39

In 2009, Meijere et al. synthesized 2,3-disubstituted pyrroles by the reaction of terminal alkynes with substituted methyl isocyanides. An in situ generated copper acetylide interact in this reaction with an isocyanide substituted by an electron withdrawing group.

37 (a) Y. Ito, I. Ito, T. Hirao and T. Saegusa, Synth. Commun., 1974, 4, 97;(b) Y. Ito, T. Hirao and T. Saegusa, J. Org. Chem., 1975, 40, 2981;(c) Y. Ito, T. Hirao, N. Ohta and T. Saegusa, Tetrahedron Lett., 1977, 18, 1009. 38 (a) T. Saegusa, Y. Ito, S. Kobayashi and K. Hirota, Tetrahedron Lett., 1967, 8, 521;(b) T. Saegusa, S. Kobayashi, Y. Ito, K. Hirota andY. Okumura, Bull. Chem. Soc. Jpn., 1968, 41, 1638;(c) T. Saegusa, Y. Ito, S. Kobayashi, K. Hirota and H. Yoshioka, Tetrahedron Lett., 1966, 7, 6121;(d) T. Saegusa, S. Kobayashi, Y. Ito and K. Hirota, J. Am. Chem. Soc., 1967, 89, 2240;(e) T. Saegusa, Y. Ito and S. Kobayashi, Tetrahedron Lett., 1968, 9, 935. 39 W. D. Jones and E. T. Hessell, Organometallics, 1990, 9, 718 Insertion of isocyanide into the copper-carbon bond gave the 2H-pyrrolenline-4,5-dicopper derivatives. Finally, the following 1,5-H shift and twofold protonation afforded the corresponding pyrroles (scheme 1-28). 40

Oxidation of isocyanides

Isocyanides react with halogens forming gem-dihalogenated isocyanide intermediates 41 , which can be used in the synthesis of tetrazoles, upon the reaction with sodium azide followed by a Suzuki-coupling reaction (scheme 1-29 forming dimethyl sulfide as the only byproduct (scheme 1-30). 43

Nef Reaction

In 1894, the first example about the insertion of an isocyanide into carbon-chlorine bond was described by Nef. 44 The formed intermediate imidoyl chloride after hydrolysis, afforded the corresponding α-ketoamide (scheme 1-31).

In 2009, our group reported the synthesis of ketene-imine phosphates using Nef/Perkow sequence. After the addition of trimethylsilylazide or trimethylsilyldiazomethane to the ketene-imine phosphonates, generated in situ, triazole and tetrazole phosphonates was obtained respectively (scheme 1-32).

Formal cycloaddition reactions

In 2000, our group reported the synthesis of 5-aminopyrrazoles via a [4+1] cycloaddition reaction of isonitriles and azoalkenes, generated in situ from hydrazones (scheme 1-33). 46In

Scope of Passerini reaction

Scope of acids

Based on the mechanism of the Passerini reaction, it's indicated that the carboxylic acid plays a crucial role in the course of this process, where the activation of aldehyde by the acid compound would start the reaction. Thus a carboxylic acid is normally required and it could be a limitation for the applications of this process to the synthesis of more complex scaffolds. 51 In 2006, our lab reported a three-component addition of isocyanides to phenol derivatives and aldehydes in methanol to form O-arylated compounds. group. The hydroxy group on the boron atom rearranges to the nitrilium carbon. After tautomerization and hydrolysis, α-hydroxyamide and the borinic acid were regenerated (scheme 1-41).

α-hydroxyamides could be also prepared by using various acids 55 such as hydrochloric, hydrobromic, sulfuric, nitric and phosphoric acid in stoichiometric amount and in the presence of water that acts as a nucleophile. The irreversible rearrangement of the imidate to primary amide is the key step of the reaction (scheme 1-42).

Hydrazoic acid (HN 3 ) and azide ions may also be used for the coupling of

Scope of carbonyl compounds

In 2010, Zhu and his coworkers reported a Passerini reaction starting directly with a primary alcohol. The reaction proceeds via an in situ catalytic oxidation of the alcohol (scheme 1-44). 57

In the presence of Brönsted acids or Lewis acids, the acetals can undergo Passerini coupling to give αalkoxyamides (scheme 1-45). An epoxide compound could be also introduced in Passerini reaction with an isonitrile and an acid carboxylic acid. A carbonyl derivative was obtained by rearranging the epoxide in the presence of Lewis acid (scheme 1-46). 59

In 1964, Neidlein and coworkers reported an addition of an isonitrile on an isocyanate to give N-Alkyl or N-aryl N-N'-diacyloxamides. 60 This was close to the coupling of Nef. (scheme 1-47).

Similarly, dioxoamides are obtained by the reaction of ketenes with a carboxylic acid and an isocyanide (scheme 1-48

Ugi reaction

This reaction was discovered by Ugi in 1959. 62 He extended the scope of the Passerini reactions by adding an amine. It can deliver α-amidocarboxamide derivatives via the condensation between a carbonyl group (aldehyde or ketone), an amine, a carboxylic acid and an isocyanide.

This reaction is generally carried out at room temperature and in concentrated polar protic solvents affording very high yields.

Ugi suggested an ionic mechanism involving charged intermediates for this reaction. The mechanism includes a series of reversible equilibrium and begins with formation of an imine.

The imine was activated by proton exchange with carboxylic acid, followed by nucleophilic Lately, many efforts have been conducted towards the development of Ugi reaction to extend its scope of reactivity and the accessibility to diverse libraries of compounds.

Scope of Ugi reaction

Scope of the amines

The secondary amines can be used for the Ugi reaction. In this case, the acyl transfer proceeded via [1,3]-shift towards the nitrogen atom of the isocyanide forming α,α'-diacylimide derivatives (scheme 1-50). 63 Nonetheless, using ammonia as the amine component in Ugi coupling was widely studied by a number of groups. 64 The desired Ugi adduct is often obtained with moderate yields because of the competition with several byproducts such as: the six-component coupling adduct isolated in this case (scheme 1-51 Other amine derivatives (e.g. hydrazines and hydrazides, 65 hydroxylamines and oximes, 66 as well as hydrazones 67 and ureas 68 ) can also be successfully employed as amine partners in the coupling reaction, yielding the corresponding Ugi adduct (scheme 1-52).

Scope of the acids

Since the discovery of the Ugi reaction, many approaches have been described on the acidic partner variations. In 1962, Ugi proposed the possibility of using thiocarboxylic acid as the acid component. (scheme 1-53). 69 The use of hydrogen selenide and thiosulfuric acid as acidic parts in Ugi reaction allowed the synthesis of α-aminoselenocarboxamides and α-aminothiocarboxamides respectively (scheme 1-54). 70 The carbonic acid generated in situ by bubbling carbon dioxide in methanol, can be employed in Ugi reaction to prepare methyl α-carboxamidocarbamates (scheme 1-55). 71 The use of hydrazoic acid derivatives represents a particularly important acid variant in Ugi coupling. In this case, an [1,5]-electrocyclization replaced the Mumm rearrangement resulting in the formation of 1,5-disubstituted tetrazoles.

Post-condensation reactions

For Passerini post-condensation reactions, I introduced them chapter 2. Here are just some examples performed on Ugi adducts.

Aromatic nucleophilic substitution S N Ar

In 2007, Spatz and co-workers described a synthesis of imidazo-and pyrazolo [1,5-a] 74 a) A. Keating, W. Armstrong, J. Am. Chem. Soc. 1996, 118, 2574. b) A. Keating, W. Armstrong, J. Org. Chem. 1996, 61, 8935. quinoxalines via an Ugi/S N Ar cascade, in which a bifunctional heterocyclic carboxylic acid derivative was used in the Ugi coupling together with an ortho-fluoro-substituted aniline derivative (scheme 1-59). 75

Knoevenagel condensation

In 1999, Marcaccini group described a synthesis of variously substituted pyrroles involving an Ugi/Knoevenagel cascade. Starting from cyanoacetic acid and phenacylamine hydrochloride as coupling partners in Ugi reaction, different pyrrolones were obtained. A subsequent methylation of these derivatives afforded the desired pyrroles (scheme 1-60). 76

Horner-Wadsworth-Emmons condensation

In

Passerini post-condensation reactions

In previous chapter, we introduced the Passerini reaction for rapid access to αacyloxycarboxamides (scheme 2-1), and this reaction could be utilized in the drug discovery process and total syntheses of biologically relevant natural products. 80 Passerini reactions are powerful synthetic tools for the synthesis of structurally diverse molecules. The power of these reactions can be further increased by simple transformations of the Passerrini adducts (the so called post-condensations). 81

Passerini / O-Deacylation

In 2006, Marcos et al. reported a synthesis of acylated tartronamide derivatives from glyoxylamides, isocyanides and acetic acid, after solvolysis catalyzed by zinc under ultrasound irradiation, the tartronamides were obtained. This compound can be used as a retropeptidic surrogate of hydroxyglycine, which may be regarded as a stable transition state analogue for amide bond hydrolysis (scheme 2-2). 82

Passerini / Decarboxylation

The Passerini adducts from substituted cinnamaldehydes, isocyanides and carboxylic acids were treated with SmI 2 /HMPA in dry tetrahydrofuran (THF) at room temperature, and α,β-unsaturated amides were obtained in moderate yields (scheme 2-3). 83

Passerini / N-Deprotection / Acyl Migration (PADAM)

In 2000, Banfi group reported a three-component Passerini condensation between N-Boc protected α-aminoaldehydes, isocyanides and carboxylic acids to α -acyloxy carboxamides.

N-deprotection and acyl migration were then achieved upon treatment with trifluoroacetic acid followed by triethylamine. α-Hydroxy-β-acylamino amides were obtained in good to excellent overall yields. These products can be oxidized to the corresponding α-oxo-β-acylamino amides derivatives (scheme 2-4). 84 83 H. Yu, T. Gai, L. Sun, S. Zhang, Chinese Chem. Lett., 2011, 22, 379-381. 84 L. Banfi. G. Guanti, R. Riva, Chem. Commun., 2000, 985-986.

Synthesis of heterocycles

The condensation of isocyanides, glyoxals, and acetophosphonic acid diethylesters led to the Passerini products, which can be cyclized through a Horner-Wadsworth-Emmons reaction with LiBr and Et 3 N to afford the 5-acylamino butenolides (scheme 2-5). 85 Synthesis of 3-hydroxy-5-oxo-2,5-dihydrofuran-2-carboxamide derivatives as a nonpeptidic inhibitors of HIV-1 protease was reported by a combination of the classical three-component

Presentation of our strategy

Isocyanide based multicomponent reactions (IMCRs) offer a unique way to generate libraries of heterocycles.102 These syntheses are usually performed via two-step procedures using first an Ugi reaction as the IMCR affording the highest diversity and functional tolerance. The heterocyclic core is then obtained in a second cyclization step involving additional functionalities proper selected in the starting materials. The peptidyl position of Ugi adducts was often selected as the reactive center due to the ability to tune its acidity by proper selection of the aldehyde partner. After deprotonation which is deeply affected by aldehyde partner, a carbanion is obtained leading to cyclization with properly positioned additional functionality. 103 Most of these reactions have been described with Ugi reaction, we will make a brief summary here.

In 2007, Ivachtchenko et al. described a synthesis of 3-oxoiso-indoline-1-carboxamides via an Ugi four component reaction followed by intramolecular cyclization (scheme 2-19). 103d

In 2012, a two-step synthesis of 2,3-dihydropyrroles via a formal 5-endo cycloisomerization of Ugi 4-CR/propargyl adducts was described by Miranda group (scheme 2-20). 103e

In 2015, Ghandi and co-workers reported a one-pot synthesis of a series of spiropyrroloquinoline isoindolinone and spiropyrroloquinoline aza-isoindolinone scaffolds.

The reaction proceeds by combination of an Ugi 4CR and two intramolecular cyclizations under metal-free conditions (scheme 2-21). 103f

In 2016, Eycken group reported a facile domino Ugi/Michael approach for the synthesis of diversely substituted α,β-unsaturated γ-lactams under mild reaction conditions (scheme

2-22). 103g
We recently started a program to evaluate the potential of intermolecular reactions of Ugi adducts as a way to expand the diversity and scope of heterocycles accessible by these two-step procedures (scheme 2-23). 104

Among the various solutions explored, we discovered a [3+2] type cycloaddition of Ugi adducts with acrylonitrile leading to pyrrole derivatives, no Michael type adducts were obtained. Aware that a Thorpe-Ingold effect could favor the cyclization of our Ugi adducts, we proposed a possible mechanism (scheme 2-24).105

Gratified by this coupling but still failing to observe any Michael addition with Ugi adducts, we decided to explore the behavior of Passerini adducts in similar reactions (scheme 2-25).

A number of publications demonstrate that the ester moieties of Passerini adducts are very sensitive under basic conditions with saponification occurring readily (scheme 2-26). 105 Looking at the closet analogues of hydroxy Passerini derivatives, we could find various approaches for Michael additions of α-hydroxy keto and ester derivatives. Most examples have been performed with benzoins.

In 2005, Zhai and co-workers described a direct construction of γ,γ-difunctionalized γ-butyrolactones from benzoins promoted by 1,3-dimethyl imidazolin-2-ylidene (scheme 2-27). 106In 2014, Han group reported a synthesis of chiral tetrahydrofuran derivatives bearing multiple functional groups and stereogenic centers. The reaction proceeds with high stereoselectivity of up to 95:5 dr and 96 % ee. The high diastereomeric ratio may be due to the fact that acid promotes not only the iminium ion activation of enals but also the desymmetrization of racemic acyloins (scheme 2-28). 107 Knowing all the above information, we now wish to report a successful Passerini/Michael addition tandem with acrylonitrile and its application to new γ-butyrolactone preparation (scheme 2-29).

Results and discussion

Towards hydroxy derivatives

Optimization of reaction conditions

Our work as well as reports by others on cyclizations involving the peptidyl position of Ugi adducts showed the importance of selecting aromatic aldehydes for successful selective deprotonation/alkylation strategies. Thus, Passerini adduct II-1a was prepared in quantitative yield letting stoichiometric amount of p-chlorobenzaldehyde, cyclohexylisocyanide and acetic acid to react for two days under solvent free conditions (scheme 2-30). 108 At the onset of the study, acrylonitrile was chosen as Michael acceptor due to its higher efficiency as electrophile in our previous study on Ugi adducts. In order to get the suitable reaction conditions, the following trials were performed: Microwave conditions were then selected. When II-1a was heated in methanol at 140 °C in the presence of diisopropylamine (0.5 equiv) and large excess of acrylonitrile (6 equiv), nearly quantitative yield of alcohol II-2a was obtained after 30 min heating (entry 1, table 2-1).

Replacing methanol by acetonitrile (entry 2, table 2-1 The nature of the base and solvent were then varied working at the same temperature until we luckily observed a modest 33 % isolated yield of expected II-3a when cesium carbonate was selected as base in acetonitrile (entry 6, table 2-1). Raising the amount of base to two equivalents led us to a nice 81 % isolated yield (entry 7, table 2-1), whereas lowering the temperature to 130 °C and the excess of acrylonitrile gave us the best yield after 45 min of reaction (entry 8, table 2-1). These conditions were selected for the rest of the study.

Synthesis of Passerini/Michael adducts

The Passerini reaction has been already highlighted in Chapter 1 involving the condensation of an aldehyde, an acid and an isocyanide at room temperature for 48 hours. Thus we prepared some Passerini adducts varying the 2 components with excellent yields in most examples. And these products were tested under our selected Michael conditions. The various results are presented thereafter in (see obtained in 88 % isolated yield from isovaleraldehyde was treated with acrylonitrile under our optimized conditions for the Michael addition step, we could not isolated any addition product and only observed a saponification of the ester giving the corresponding hydroxyamide in 96 % isolated yield. Probably due to the OH group is deprotonated faster preventing the required carbanion formation for Michael addition.

When 1H-indole-3-carbaldehyde was used for Passerini reaction, we got nothing except some starting materials (scheme 2-32).

When the nitrogen atom was protected by benzyl group, only traces of the corresponding Passerini adduct was obtained. This further proved the low reactivity of indole derivatives in this reaction (scheme 2-33).

The Passerini adduct of 4-methoxybenzaldehyde behaves similarly probably due to more difficult deprotonation at the α-position. In the opposite direction, the use of 4-nitrobenzaldehyde lead to quantitative formation of Passerini adduct II-1f (Table 2-2, entry 6) but the resulting anion is probably too stabilized to give an efficient coupling with acrylonitrile affording II-3f only in a moderate 39 % isolated yield (scheme 2-34).

The furyl derivative II-1i gave us our best yield in the Michael addition step (Table 2-2, entry 9), which was a bit surprising in light of the electronrich nature of the ring and the failure of the 4-methoxyaryl group to participate in the sequence.

Finally, in the case of cinnamaldehyde derived Passerini adduct II-1j, we were delighted to observe the formation of Michael addition product II-3j in moderate yield (Table 2-2, entry 10) as such conditions were close to the one we proposed for the conversion of the same Passerini adducts into α-ketoamides (scheme 2-35).

Proposed mechanism

The formation of II-3a most probably involves an initial saponification followed by a

Michael addition of the resulting hydroxy derivative II-2a. The presence of the aryl group in the hydroxyl II-2a allows a selective CH deprotonation followed by Michael addition (scheme 2-36).

To examine our assumption, II-2a was treated under our optimized conditions, II-3a was isolated with 89 % yield (scheme 2-37), which bring further elements in support for the proposed timing of the process.

To progress further on the mechanism of the reaction and determine whether the Michael addition step could be observed before the saponification of the ester, we prepared a Passerini analogue of II-1b using pivalic instead of acetic acid. When the pivalate II-1m was treated under microwave conditions with 6.0 equiv. of acrylonitrile in acetonitrile, we couldn't indeed isolate any Michael adduct without loss of the pivalate moiety and II-3b was again obtained in a low 55 % yield (scheme 2-38). Lowering the amount of base to 1 equiv.

afforded II-3b in even lower yields supporting further the mechanistic propositions of scheme 2-36.

Towards γ-butyrolactones

Even though the formation of alcohol II-3a with loss of the acetate moiety was not a good point in terms of diversity, it offers an interesting opportunity for the preparation of butyrolactones through cyclization of the alcohol onto the nitrile group.

Optimization of cyclization reaction

Butyrolactone synthesis from 4-hydroxynitriles is well documented, 110 occurring under both acidic and basic conditions, in most cases the imidate intermediate is not observed leading directly to the butyrolactone.

In 2014, the lactones were synthesized by Citron et al. and used in bioassays in which one of the compounds was found to be a strong germination inhibitor for ash seeds, causing necroses in the plant tissue (scheme 2-39). 110b

In 2017, Daïch and co-workers synthesized 2,3-dihydro-1H-inden-1-ones and found that these compounds could be transformed into spiro-lactones (scheme 2-40). 110

Considering the literature on those cyclisations together with the rather harsh basic conditions selected for our Michael addition, the lack of cyclized products was rather a surprise in our case. Thus, the ability of II-3a to cyclize was directly tested under acidic conditions (table 23. 110 For some cyclizations to γ-lactones under basic conditions, see: a) K. The few trials performed confirmed the relative stability of II-3a, nevertheless we could observe the expected butylactone II-4a in a good 75 % isolated yield heating the alcohol under microwave conditions in trifluoroethanol as solvent and in the presence of a catalytic amount of zinc triflate (entry 9, table 2-3).

Synthesis of γ-butyrolactones

The scope of γ-butyrolactone synthesis was then evaluated on a set of different Michael adducts prepared from Passerini adducts and acrylonitrile under microwave conditions. The results are displayed in The reaction does not seem to depend much on the nature of the starting aromatic aldehydes as shown by the good yields obtained (Table 234).

The low yield with furan may be just explained by the relative sensibility of the furan ring to Lewis acid triggered ring opening and hydroxyl elimination (Table 234entry 9).

Other Michael acceptors

Except acrylonitrile, methyl acrylate was also tested for our Passerini/Michael reaction. But no Michael adducts were obtained. We tried various reaction conditions as below (see table 2345), but the reaction is not clean and we could only recover the product resulting from Probably the low reactivity of methyl acrylate, compared to acrylonitrile, prevented the coupling with the carbanion. The same situation existed in the reaction of but-3-en-2-one and II-1b (scheme 2-41).

Another Michael acceptor 2-benzylidenemalononitrile was then tested with II-1g under our Passerini/Michael reaction condition. Unfortunately, after heating, just some remaining 2-benzylidenemalononitrile could be isolated from the reaction mixture (scheme 2-42).

Steric hindrance may prevent the coupling between 2-benzylidenemalononitrile and the carbanion.

Conclusion

In this chapter, we have settled a two-step sequence for the preparation of γ-butyrolactones from Passerini adducts of aromatic and heteroaromatic aldehydes. This strategy significantly expanded the scope of the butyrolactones syntheses from benzoin derivatives with microwave conditions allowing to counterbalance the poorer electron-withdrawing group effect of the amide moiety. Further work is under progress to raise the diversity of the synthesis by performing the reaction on a larger array of Michael acceptors.

Chapter III Mannich reaction of trifluoroacetaldehyde hydrazones

The work described in this chapter has been published on Org. Biomol. Chem.:

Shuanglong Jia and Laurent El Kaim, Org. Biomol. Chem., 2018, 16, 1457-1460 1 Introduction

A brief overview of Mannich reaction

Carl Mannich, who was the first to describe the aminoalkylation of CH-acidic compounds, recognized the enormous significance of this reaction, and extended this chemistry into a broad based synthetic methodology through systematic research. Thus this reaction carries his name, and has been one of the most important C-C bond-forming reactions in organic synthesis. 111 It's a a typical method for the preparation of β-amino ketones and aldehydes (Mannich bases) and one of most important step in the synthesis of numerous natural products and pharmaceuticals.

In this reaction, enolizable aldehydes or ketones serve as the CH-acidic scaffolds. In the most important variation, the carbonyl compound react with formaldehyde and an amine hydrochloride in a protic solvent under heating. A simplified mechanism is given in scheme 3-1.

111 Reviews: a) M. It is assumed that only tiny amount of methylene iminium salts 1 are formed by a series of equilibrium reactions. Then, 1 react with the enol tautomer 2b of the carbonyl compound 2a, also present in very small amounts, to give the hydrochloride of the β-aminocarbonyl compound 3, which is called Mannich bases. These kind of compounds are versatile synthetic scaffolds, which can easily be converted into a great quantity of useful and valuable derivatives 112 (scheme 3-2).

These derivatives include Michael acceptors 4 (elimination of the amine HNR 2 ), 1,3-amino alcohols 5 (reduction or addition of organometallic compounds) and functionalized carbonyl compounds 6 (substitution of NR 2 by nucleophiles). 113 Mannich bases and their derivatives play a significant role in plant protection and in paint and polymer chemistry (hardeners, cross-linkers, and reaction accelerators) and especially pharmaceutical products. 113 Like some examples represented in figure 3-1.

112 M. Arend, B. Westermann and N. Risch, Angew. Chem.,Int. Ed., 1998, 37, As one of the most important 3-component reactions (3-CR), Mannich reaction has all the features, such as atoms economy, accessible and cheap substrates, steps with high chemical yields, environment-friendly, easy operation and, the use of convergent one-pot reactions, the ability to quickly build a library of varied and structurally complex compounds. 114

Few typical Mannich reactions

In 2010, Ma and co-workers applied Mannich reaction as the key step to obtain the intermediate into the total synthesis of the sesquiterpene (+)-Carainterol A, that contains a exocyclic double bond in the decalin skeleton. 115 These natural products are drugs with anti-HIV, antifungal, antibacterial and anti-inflammatory activities 116 (scheme 3-3). J Nat Prod. 2004, 67, 1975-1979. b) M. Fraga, Nat Prod Rep. 2007, 24, 1350 In 2011, Yang and co-workers prepared the C19 -diterpene alkaloids racemic precursor, 117 which has several bioactivities such as analgesic, antiinflammatory, psychotropic, antitumor and anesthetic (scheme 3-4). 118 Environmentally friendly reactions are always welcomed. In 2016, Dongare and co-workers developed a serious of 7-azagramine analogues by reaction of 7-azaindole derivatives, aromatic aldehydes and heterocyclic amines in solvent-free and catalyst-free medium. These azaindole compounds have extensive biological properties, such as inhibitors of kinase and phosphodiesterase enzymes in anticancer therapies (scheme 3-5). through Barbier-type reaction. In the case of benzyl halide derivatives, the formation of organozinc occurs in situ quantitatively and the reaction proceeds rapidly. For aryl halide, a preformed ArZnBr has been employing due to its comparative low activity (scheme 3-7). 123 Recently, Ramachandran and co-workers described the synthesis of tetrahydropyridines from a reaction between aldehydes and aromatic amines with β-ketoesters using BF 3 supported on silica (BF 3 .SiO 2 ) as catalyst in methanol. The Lewis acid increass the electrophilicity of the aldehyde and favors the attack of amine to obtain the iminium ion. In addition, the BF 3 .SiO 2 assists enamine generation, which is the nucleophile of Mannich reaction, and contributes to the final formation of the pyridinetetrahydropyridine (scheme 3-8). 124 In 2002, Loh and co-workers used InCl 3 and methanol medium in synthesis of Mannich bases derived from L-Valine methyl ester (scheme 3-9). 125 Sathesh and co-workers used FeCl 3 to obtain lactams. The Fe 3+ promotes imine formation besides increasing its electrophilicity by complexing aldehyde and imine. 126 It has been also

believed that the Fe 3+ ion also catalyzes the ketone enolization step (scheme 3-10).

Chiral catalyst for enantioselectivity

In paraformaldehyde giving tertiary allylamines with the same geometry. This practical and simple method was used for the synthesis of geometrically pure naftifine, a potent antifungal agent. 135With isocyanide as nucleophile, Ugi reaction could be considered as a sort of Mannich reaction. This reaction was already described in chapter I, we won't discuss here (scheme 3-16).

In 2010, Chai and co-workers reported the cyanation of various imines at room temperature at presence of partially hydrolyzed titanium alkoxide (PHTA) catalyst together with salicyl-β-aminoalcohol as the ligand. High enantioselectivities were obtained in the case of various benzhydryl, benzyl, and N-Boc imines (scheme 3-17). 136 tripiperidines (scheme 3-19). 140 hydrazones may be used as well both as nucleophile or electrophile in Mannich reactions.

Chemistry of hydrazone

Hydrazones have been utilized in various fields, ranging from medicinal to supramolecular chemistry, due to their modularity, straightforward synthesis, functional diversity, and stability.

Synthesis of hydrazone

The simplest and most widely used synthetic method to access hydrazones N -mono -or N, N -disubstituted is the condensation of a hydrazine with a carbonyl compound (aldehyde or ketone) in ethanol (scheme 3-20). Che m. 2008Che m. , 16 , 1927Che m. -1947. . The synthesis of α-ketohydrazones by the previous conventional method gives modest yields because of the competition between the two carbonyl groups during condensation. However, the Japp-Klingemann synthesis is specifically useful for preparing these compounds. 142 It is an addition of a diazonium salt on a β-ketoester or β-ketoacid possessing activated methylene, the intermediate azo compound is rearranged to hydrazone. In the case of β-keto acids, these are likely to decarboxylate to give the expected hydrazone (scheme 3-21).

Reactivity

The reactivity of hydrazones can be interpreted in two different ways:

These are derivatives of imines which, as such, possess an electrophilic character linked to the polarization of the double bond C=N.

However, this imine polarization is counterbalanced by the presence of the second nitrogen atom which confers an aza-enamine type behavior due to the π-donor character of the terminal nitrogen (figure 3-3).

142 R. Thus the σattractor and π -donor character of the two nitrogen atoms will give on the same terminal carbon both potential nucleophilic and electrophilic reactivity.

Electrophilic behavior

The electrophilic reactivity of hydrazones is the best known and the most developed although yields are sometimes modest. The hydrazine resulting from the addition was then treated with an excess of SmI 2 allowing its conversion to primary amine (scheme 3-23). 148

Nucleophilic behavior

The reactivity of hydrazones as nucleophiles will strongly depend on their substitution at the terminal nitrogen atom. Thus hydrazone nitrogen atom can be attacked by acylating and alkylating agents, while reactions like Mannich reaction, Michael type addition and halogenation can take place readily at terminal carbon atom. 149

a. N, N -dialkylhydrazones

In 1982, Brehme described a reaction of aldehyde-N,N-dimethylhydrazones were substituted on the azomethinecarbon by the electrophilic sulphonylisocyanates (scheme 3-24). Brehme in 1976 157 described a nucleophilic addition of hydrazones with iminiums, but he got low yields (scheme 3-27).

The nucleophilic additions of N, N-dialkylhydrazones are often limited in scope giving good yields only for formaldehyde derived hydrazones.

b. N-H hydrazones

For N-H hydrazones, the additions are classically observed at the nitrogen atom which is the more reactive nucleophilic center.

157 R. Brehme, Tetrahedron 1976, 32, 731 -736.

N-acetylation and N-alkylation of N-H hydrazones

In 1949, Sharp reported a N-acetylation of hydrazones with good yields (scheme 3-28). 158 Some electrophiles with sp2 carbon atoms such as carbon disulphide, phenylisothiocyanate, chlorosulfonylisothiocyanate can also be attacked by the hydrazone nitrogen atom. 159 In

Carbon alkylation of N-H hydrazones

In opposition to the usual behavior of hydrazonyl anions in alkylation, reversible attacks on nitrogen may lead to exclusive functionalisation at the C-position of the hydrazone (scheme 3-30).

In 1959, Keil and Ried first proposed the Mannich reaction of N-H hydrazones (scheme 3-31). The reaction was described only with formaldehydes and rather acidic hydrazones prone to easy deprotonation under the conditions of the reaction. Our lab also made some contribution to N-H hydrazones chemistry. In 2000, we found that aliphatic aldehyde, secondary amines and hydrazones work well to give the new aminohydrazones in good yields. However, in all cases, the reaction remained limited to the coupling of hydrazones possessing electron-withdrawing groups on the hydrazones (R 1 = CO 2 Et, COR, CN…), no positive results were observed when simple hydrazones (R 1 = alkyl, aryl) was added in ethanol, toluene or chlorobenzene, even after prolonged heating in the presence of several equivalents of amine and aldehyde (scheme 3-33). 164 In 2003, our research group found that when hydrazone with two to three equivalents of a secondary amine and formaldehyde was mixed, the Mannich reaction of hydrazones can be performed smoothly. The new conditions allow the efficient coupling of simple hydrazones derived from aromatic and heteroaromatic aldehydes, and these new conditions widen significantly the scope and interest of the Mannich reaction of hydrazones. However, in Mannich reaction step, only formaldehyde performed well, some aromatic aldehydes only 164 V. Atlan, H. Bienaymé, L. Kaim and A. Majee, Chem.Commun., 2000, 1585-1586 react with special starting hydrazones (scheme 3-34). 165 In Mannich reaction of hydrazones, a base triggered irreversible azo-hydrazone tautomerism is required for the efficiency of the process. This explains the need for an electron-withdrawing ketone, ester or pyridyl moieties tethered at the α-position of the hydrazone in order to increase the acidity of the azo intermediate. 166 Considering these limitations we envisioned that an NH-hydrazone derived from trifluoroacetaldehyde may be sufficiently acidic to be involved in efficient Apart from some oxidative/cycloaddition cascades169 as well as several Michael additions with α,β-unsaturated aldehydes,170 the reactivity of NH-trifluoromethyl hydrazones has been poorly studied.

In 2011, Wu et al. described an example of diastereoselective 1,3-dipolar cycloaddition of NH-trifluoromethyl hydrazone with α,β-ethenyl ketones. This new method provided synthetically useful, highly substituted pyrazolidine and pyrazoline derivatives with efficiency and high diastereoselectivity (scheme 3-36). 169 In 2012, Wu and co-workers developed a facile and efficient method for the synthesis of 165 , heating in toluene or alcohol as the solvents was used to conduct the reactions.

4-Nitrophenyl hydrazone, obtained in 90 % yield from 4-nitrophenyl hydrazine, was initially selected due to its higher acidity and the reported beneficial effect of a nitro substituent in the Mannich coupling of non-fluorinated NH-arylhydrazones.

For the first trial carried out, we allowed 4-nitrophenyl hydrazine to react with stoichiometric amount of formaldehyde and diethylamine, with methanol and toluene as the solvent respectively. The mixture was refluxed under argon, and the reaction followed by TLC.

Fortunately, a good yield was obtained in toluene after 12 h. We were satisfied with this good yield, thus no further optimization was carried out (scheme 3-39).

Mannich reaction of trifluoroacetaldehyde hydrazones

We prepared a library of Mannich adducts varying the 3 components of the reaction, using toluene as the solvent, affording NH-aryl hydrazones with excellent yields in most examples.

The various results are presented thereafter in (see Table 3- In general, the products of Mannich type reaction were obtained with good to excellent yields from 47 to 99 % (see Table 3-1).

When trifluoromethyl substituted 4-nitrophenylhydrazone was added to morpholine and 4-chlorobenzaldehyde under chosen reaction conditions (equimolar amounts in refluxing toluene), we were delighted to observe a quantitative formation of a new Mannich fluorinated adduct III-2 after refluxing the mixture for 12 hours (Table 3-1, entry 2). To evaluate the potential of this coupling, different N-aryl fluorinated hydrazones were prepared and treated together with morpholine and various aldehydes (Table 3-1).

Using nitrosubstituted hydrazone, the reaction does not seem to show a strong dependence on the electronic nature of the aromatic aldehyde, both electron-rich and deficient aromatic aldehydes giving very good yields (Table 3-1, entries 4, 5, 7 and8).

However, when dihydroxyacetophenone was used, the reaction was not clean. This is probably due to both carbonyl groups reacting with morpholine, the competition leads to more by-products generation (scheme 3-40).

Heteroaromatic aldehydes may be used as well giving lower yields for electron-rich derivatives (indole, thiophene versus pyridine, Table 3-1, entries 9-11).

Indole-3-carbaldehyde failed to couple with 4-nitrophenylhydrazone and morpholine.

(scheme 3-41) but N-methyl-indole-3-carbaldehyde works well (Table 3-1,entry 11). A possible reason is that iminium 7 processing an acidic NH can isomerize into 8 which has lower reactivity. This may obstructs the coupling between hydrazone and iminium (scheme 3-42).

When N-methyl-pyrrole-2-carbaldehyde or furan-2-carbaldehyde was introduced into this Mannich reaction, no corresponding product was observed. For both of them, we just got some starting hydrazones and some color, while thiophene-2-carbaldehyde gave 48% yield (Table 3-1, entry 9). The most probable reason is that pyrrole ring and furan ring are more electron rich than thiophene ring, which decrease the electrophilicity of the carbon of carbonyl group (scheme 3-43).

2-Substituents are not tolerated on the aromatic ring as shown by the lack of any coupling observed with 2-nitro and 2-methoxy benzaldehydes (Table 3-1, entries 3 and 6); the steric hindrance may prevent the iminium formation, which is essential in Mannich reaction. On the other hand, due to the bulkiness of ortho-substituent, there is some angle between phenyl plan and iminium plan. This steric hindrance hindered the nuecleophilic attack from top or bottom (figure 345). The same situation exists in 2-bromo and 2-iodo benzaldehydes (scheme 3-44).

In strong contrast to its non-fluorinated hydrazone analogue, the reaction could not be extended to the coupling of simple aliphatic aldehydes such as acetaldehyde or isovaleraldehyde (Table 3-1, entries 13 and14). However, more reactive formaldehyde and trifluoroacetaldehyde (used as its hemiacetal) could give some productive couplings ( Besides morpholine, the coupling could also be easily extended to other cyclic and non-cyclic secondary amines (Table 3-1, entries 15-18 and Table 3-2, entry 7,8).

However, while diethylamine or diisopropylamine react with 4-nitrophenylhydrazone and 4-chlorobenzaldehyde, no desired results was obtained, just some starting materials remained in the reaction system. This is probably due to the higher nucleophilicity of morpholine compared to both diethylamine and diisopropylamine (scheme 3-45).

Similar situation was observed with diallylamine or dibenzylamine. Because of weaker nucleophilicity and higher steric hindrance, the reaction cannot proceed. We just got some starting materials (scheme 3-46). The lowest yield was obtained while using tryptamine. A probable explanation would be a This reaction was limited to formaldehyde, other aromatic or aliphatic aldehydes such as 4-chlorobenzaldehyde or isovaleraldehyde cannot react (scheme .

Towards 1,2,4-Triazine derivatives

Even when we preformed their iminium and reacted them directly with 4-nitrophenylhydrazone, only traces of elimination product was obtained (scheme 3-55).

Towards α-(Trifluoromethyl)pyridazine Derivatives

A brief introduction of α-(trifluoromethyl)pyridazine derivatives

The last decades witnessed an increasing interest in α-(trifluoromethyl)pyridazines in medicinal chemistry. The biologically active pyridazines could be a bioisoster of other heterocycles. Due to the influence of trifluoromethyl group on the chemical and physicochemical properties, α-(trifluoromethyl)pyridazines have been an attractive scaffold for medicinal chemists. 184 For example, BMS-911278, possessing a (trifluoromethyl)pyridazine was presented as a potent triple reuptake inhibitor which could possibly be used for the treatment of depression (figure 3456). 185 One of the first synthesis of a α-(trifluoromethyl)pyridazine was reported by Kobayashi et

Presentation of our strategy

More interestingly, aminohydrazones such as III-1 represent potential starting materials for the generation of reactive fluorinated azoalkenes. Azoalkenes are usually obtained under basic treatment by means of 1,4-elimination of a good leaving group X (frequently chloride or bromide) in the α-position with respect to a hydrazone function (scheme 3-61). 191Azoalkenes may also be prepared under simple thermal elimination of amines from hydrazonoamines. 192 Our lab synthesized pyrazoles via a [4+1] cycloaddition of azoalkenes intermediates with isocyanides (scheme 3-62).

Due to substituted electron-withdrawing groups (esters and ketones tethered on N or carbon atoms) which favour the stability and enhance the electrophilic character of the heterodiene system, azoalkenes have been widely described as efficient Michael acceptors. 193 The typical reaction of azoalkenes is region-selective nucleophilic attack at the terminal carbon atom in the 4-position of the heterodiene system by a variety of carbon and hetero nucleophiles (Nu 1 , Scheme 3-63). These Michael-type 1,4-additions produce highly functionalized hydrazones.

In this key step, together with the attacking nucleophiles, we can introduce various other nucleophile (Nu 2 , scheme 3-63) or electrophile (E, scheme 3-63) functions.

These functionalized hydrazones are potential starting materials for further interesting structural modifications through controlled regioselective reactions leading to complex heterocyclic systems. Nucleophilic sites can be either the nitrogen atom from the azo group The electron-withdrawing groups on the terminal atoms of the azo-ene system also make azoalkenes very good partners in the hetero-Diels-Alder reactions. 194 In 2015, Wang and co-workers described a highly efficient Cu(II)-catalyzed enantioselective inverse-electrondemand aza-Diels-Alder reaction of in situ formed azoalkenes with enol ethers. This methodology provides a facile entry to biologically important and enantioenriched tetrahydropyridazine analogues in good yield (up to 95 % yield) with good to excellent enantioselectivity (up to 94 % ee) (scheme 3-65). 195 The additions of β-ketoesters to azoalkenes substituted by electron-withdrawing groups are known to afford pyrroles or 1,2-diazines according to the nature and position of the electron-withdrawing groups (scheme 3-66). 196 In 2011, Favi et al. reported a synthesis of polysubstituted pyrroles through a sequential three-component reaction of primary aliphatic amines, active methylene compounds, and azoalkenes (scheme 3-67). We were interested in examining whether the trifluoromethyl group might be activating enough to allow a Michael cyclization cascade. Thus, we decided to react directly the morpholine Mannich adduct III-1 using acetylacetone as a solvent. Elimination of amines from the Mannich-type adducts of hydrazones is usually observed for amine partners with a rather low boiling point in order to limit the reverse Michael addition. Thus the temperature was fixed at 130 °C, hoping that the Mannich-azoalkene equilibrium could be shifted by the formation of an enamine intermediate between the morpholine and the diketone.

Rewardingly heating III-1 in acetylacetone (0.2 M) at 130 °C for 12 hours afforded 4-hydropyridazine in 58% isolated yields (Table 3-4, entry 1).

Optimization of reaction conditions

In order to optimize the conditions, the following trials were performed: According to the literature, Cu(II) can coordinate with morpholine to accelerate its thermal elimination. However, we found that the reaction could work nicely even without Cu(II).

entry
Using ketone as the solvent and heating the mixture to 130 o C for 12 h is a suitable reaction condition.

Study of the reaction scope

Several Mannich adducts were then treated with ketones under the optimized conditions leading to diazines in moderate to excellent yields ( The reaction does not seem to depend much on the nature of the starting arylhydrazines as

shown by the good yields obtained using nitrophenyl (Table 3-4, entries 1-4), phenyl (Table 3-4, entries 5 and 8-10), methylphenyl(Table 3-4, entry 7) or pyridyl (Table 3-

Conclusions and perspectives

The The Pd-catalyzed allylation of carbon nucleophiles with allylic compounds via π-allylpalladium complexes is called the Tsuji-Trost reaction (scheme 4-1).

In 1965, Tsuji group first demonstrated that π-allylpalladium chloride could be substituted with certain nucleophiles such as the anions derived from diethyl malonate and ethyl acetoacetate (scheme 4-2). 199

Soon after this initial report, the catalytic version of this transformation was developed by Walker's group. Only a catalytic amount of palladium complex was used in order to trigger the reaction (scheme 4-3). In 1973, Trost group first reported that alkyl-substituted π-allylpalladium complexes could be alkylated with soft carbon nucleophiles with complete regio-and stereoselectivity. However, hard nucleophiles (e.g., alkylithiums, alkylmagnesium halides) failed to react (scheme 4-4). 201 Then, the Trost group developed asymmetric variations of allylic alkylation reaction by selecting proper chiral ligands (scheme 4-5). 202 Chiral ligands are known to enhance both the enantioselectivity and diastereoselectivity under mild conditions, which contributed greatly to expand the application of this reaction.

201 M. Trost, J. Fullerton, J. Am. Chem. Soc. 1973, 95, 292-294. 202 M. Trost, E. Strege, J. Am. Chem. Soc. 1977, 1649. After that, this allylation reaction was greatly explored by chemists, because allyl moieties are easily transformed into various versatile functional groups. 203

Mechanism of Tsuji-Trost reaction

It's proposed that the palladium coordinates the double bond of the allyl group forming a η2 π-allyl-Pd 0 complex. The next step is oxidative addition in which the leaving group is expelled with inversion of configuration and a η3 π-allyl-Pd II is created (also called ionization). The nucleophile then adds to the allyl group regenerating the η2 π-allyl-Pd 0 complex. Finally, dissociation of the active species would occur to release both the desired product and the palladium which gets involved again in the catalytic cycle (scheme 4-6). 204

Reaction parameters

Many parameters affect the reaction progress, the stereochemistry as well as the regioselectivity.

Metal catalyst

A wide variety of metal complexes had been employed in Tsuji-Trost type reaction such as: palladium, 205 nickel, 206 iridium, 207 platinum, 208 rhodium, 209 iron, 210 ruthenium, 211 molybdenum 212 and tungsten 213 complexes.

The choice of the metal complex controls greatly the reaction's regioselectivity. For example, the reaction of 2-methyl-propenyl acetate with PhMgCl in the presence of NiCl 2 /dppf allows substitution selectively at the most substituted carbon atom, while using palladium catalyst (PdCl 2 /dppf) substitution occurrs at the least substituted carbon atom (figure 4-1).

Ligand

The ligands could be monodentate, bidentate or chiral. They might influence the reaction speed, the control of both regioselectivity and enantioselectivity of the reaction.

Usually, π-acceptor ligands such as phosphines enhance the nucleophilic substitution by attracting the electrons of the metal which increases the positive charge on the allylic moiety favoring the substitution.

Enantioselective extensions of Tsuji-Trost reaction were successfully achieved by introducing catalytic amounts of chiral ligands. In 1977, the first enantioselective Pd-catalyzed allylation reaction was reported by Trost group. 4 Where the racemic mixture 1 was reacted with the nucleophile, sodium salt of methyl phenylsulfonylacetate, using Pd(PPh 3 ) 4 and the chiral ligand (+)-DIOP as the catalytic system giving 2 in 77% yield. After desulfonylation, the final product 3 was obtained with 24 % ee (scheme 4-5).

Such achievement was the foundation for many asymmetric approaches of Tsuji-Trost allyl carbonates, the carbonate group undergoes decarboxylation, in the process a sufficiently basic alkoxide is formed so no extra base is needed (scheme 4-8).

When allylic reagent possesses two leaving groups, the substitution would take place selectively at the more reactive site for the reaction. For instance, when using the allyl substrate 4, nucleophilic substitution occurred at the carbon attached to the more reactive carbonate group affording selectively single product with E-configuration (scheme 4-9).

Naphthalene

A brief overview of naphthalene

There are numerous biologically active natural products possessing a naphthalene or naphthoquinone core. 221 For instance, (S)-gossypol (figure 4-2) is known to be an oral antifertility agent in men and male animals. It shows as well potential for the treatment of HIV infections, diabetic complications and cancer. Other compounds possessing prominent naphthalene motifs are the biaryl naphthylisoquinoline alkaloids such as korupensamine A (figure 4-2), which has anti-malarial properties. 223 The atropisomers of (1,1'-binaphthyl)-2,2'-diol and its derivatives (figure 4-2) have been widely used in asymmetric synthesis as chiral auxiliaries or ligands. These binaphthols have demonstrated excellent chiral induction in a number of organic transformations ranging from Diels-Alder cycloadditions to polymerisation reactions. 224 In addition, substituted naphthalene derivatives are frequently employed as starting materials for the preparation of more complex polynuclear aromatic ring systems. 225 Hence, development of new methods for the efficient synthesis of substituted naphthalenes has always been attractive.

produce polyaromatic cycloadducts from dieneynes (scheme 4-10). 226

Annulation via Fischer carbenes (Dotz reactions)

In 1986, Yamashita and Toy developed a method to synthesis substituted naphthalene from a phenyl chromium carbene complex and alkyne bearing electron withdrawing groups such as conjugated carbonyl groups. However, only moderate yields were observed, a simplified mechanism was shown as scheme 4-11. Lett., 2011Lett., , 13, 1972Lett., -1975 adducts can be employed as strategic starting materials for the preparation of more substituted nitroalkanes and/or complex structures.

One example of a less familiar conversion may be illustrated by the conversion of aliphatic nitro compounds into oximes by irradiation in acetone in the presence of triethylamine (scheme 4-21). 243 Transformation of nitro compounds based on transition metal has made little progress due to the easy reduction of the nitro group into amine and hydroxylamine derivatives by low valent metals. This is particularly true for palladium catalyzed reactions working on both aromatic and aliphatic nitro compounds.

In 1984, Ehrenkaufer et al. demonstrated that various aliphatic and aromatic nitro compounds can be selectively and rapidly reduced to their corresponding amino derivatives in good yields using anhydrous ammonium formate and palladium on carbon as catalyst (scheme

4-22). 246

There are, however with palladium, a number of interesting reports where the nitro is not Michael additions are known to be easily performed with nitro compounds as nucleophiles.

Indeed, many Michael acceptors performed well in this sequence. High yields were obtained in both Michael addition step and Tsuji-Trost step. The reaction could be extended as well to five member ring system (scheme 4-26).

Thinking about potential application of this sequence, we envisioned that with another benzene ring fused with 1-(nitromethyl)cyclohex-1-ene, a naphthalene could be formed after isomerization (scheme 4-27).

Results and discussion

Preliminary test

In order to test our hypothesis, 4-(nitromethyl)-1,2-dihydronaphthalene IV-1a was prepared through condensation of 3,4-dihydronaphthalen-1(2H)-one and nitromethane in presence of N',N'-dimethylethane-1,2-diamine (20 mol%) (scheme 4-28). 249 249 R. Tamura, M. Sato, D. Oda, J. Org. Chem. 1986, 51, 4368-4375 The first trial was carried out under Mansour's diene synthesis reaction conditions: we allowed IV-1a to react with 5.0 equiv. of methyl acrylate in presence of 0.5 equiv. of DBU at room temperature for 3 h, the Michael adduct IV-2a was obtained in 98 % yield. Then IV-2a

was dissolved in DMF, followed by addition of 5 mol% Pd(OAc) 2 , 5 mol% dppe and 1.0 equiv. of Cs 2 CO 3 , the mixture was heated to 120 o C for 30 min, after completion of the reaction, naphthalene derivative IV-3a was isolated in 87 % yield. A novel Michael/Tsuji-Trost tandem reaction to synthesize naphthalene derivatives was thus settled (scheme 4-29).

The reaction mechanism

Based on all above information, we proposed a possible mechanism for this Tsuji-Trsot reaction.

Scope of Michael/Tsuji-Trost reaction

In order to explore the limitations of this reaction, various allylic nitro-compounds were prepared and tested under our selected reaction conditions.

When acrylonitrile was used for double Michael addition, the reaction performed well (scheme 4-31).

A ketal IV-2e was also prepared by 2 steps from IV-1a. IV-3f was obtained in good yield from IV-2e (scheme 4-35).

To further explore the reaction scope, IV-2f was synthesized from IV-2c. After Tsuji-Trost reaction, IV-3g was obtained in moderate yield. In this case, an interesting cascade involving two Tsuji-Trost eliminations is observed (scheme 4-36).

To further examine our assumption about the reaction mechanism, IV-1b was prepared under similar conditions of preparing IV-1a (scheme 4-37).

When IV-1b was treated under Michael reaction condition, IV-2g was obtained in 65% yield.

However, for Tsuji-Trost reaction, the reaction is not clean, we could only recover some starting materials IV-2g (scheme 4-38).

Conclusions and perspectives

Following my colleague Mansour Dolè Kerim's work on the synthesis of cyclic dienes from nitroallylic derivatives, we have reported an application of this methodology to the formation of 1-substituted naphtalenes from 1-tetralone. This reaction probably involves the formation of a palladium π-allyl complex followed by a base promoted β-hydride elimination. This reaction combined with the condensation of fused cyclic ketones with nitromethane and the functionalization of the resulting nitrocycloalkenes (Michael, Mannich...) constitute a very powerful synthetic tool for the formation of 1-substituted naphtalenes.

If we changed fused benzene ring into another one such as pyrrole, furan, thiophene etc., a series of heteroaromatic compounds would be synthesized (scheme 4-39). In fact, we have just obtained one example of such substituted indole (scheme 4-40).

General conclusion

This thesis explores various multicomponent reactions including Passerini reactions and Mannich reactions , and their applications into synthesis of heterocycles such as γ-butyrolactones and 1,2-diazine analogues. It also gives an access to synthesize naphthalene via a palladium catalyzed Tsuji-Trost elimination.

We discovered a two-step sequence for the preparation of γ-butyrolactones from Passerini adducts of aromatic and heteroaromatic aldehydes. This strategy significantly expanded the scope of the butyrolactones syntheses from benzoin derivatives with microwave conditions allowing to counterbalance the poorer electron-withdrawing group effect of the amide moiety (scheme 1).

We also explored the reactivity of trifluoroacetaldehyde NH-aryl hydrazones, which can be easily obtained from hydrazine and trifluoroacetaldehyde hemiacetal under acid conditions.

As the carbon centered nucleophile in Mannich reactions, the electron-withdrawing properties of the trifluoromethyl group are strongly associated with the success of the couplings allowing various NH-arylhydrazone derivatives to react with formaldehydes as well as different aromatic aldehydes. The resulting Mannich adducts are valuable starting materials for the generation of azoalkene intermediates and the preparation of trifluoromethyl substituted 1,2-diazine derivatives under heating with β-ketoesters (scheme 2)

Meanwhile, this reaction offers interesting opportunities for the preparation of trifluoromethylated 1,2,4-triazines (scheme 3).

The final part of the manuscript deals with the application of Tsuji-Trost elimination to the formation of 1-substituted naphtalenes from 1-tetralone. This reaction probably involves the formation of a palladium p-allyl complex followed by a base promoted β-hydride elimination.

This reaction combined with the condensation of fused cyclic ketones with nitromethane and the functionalization of the resulting nitrocycloalkenes (Michael, Mannich...) constitute a very powerful synthetic tool for the formation of 1-substituted naphtalenes (scheme 4).

Experimental part General Considerations

NMR spectra were recorded at 298 K using a Bruker AVANCE 400 spectrometer. 1 H NMR spectra were recorded at 400 MHz and residual solvent peaks were used as an internal reference (CDCl 3 δ 7.26). Data are reported as follows: chemical shift in ppm, apparent multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, p = pentet, m = multiplet or overlap of nonequivalent resonances), coupling constants, integration. 13 In a round bottom flask under Argon was added the aldehyde (10 mmol, 1 equiv.), glacial acetic acid (0.60 g, 0.57 ml, 10 mmol) and the isocyanide (10 mmol, 1 equiv.). The mixture was stirred at room temperature for two days during which times it slowly solidifies. The pure Passerini adducts II-1a to II-1l were then obtained by column chromatography on silica gel when the crude were not pure enough.

General procedure B: formation of Michael adducts

To a dried microwave tube was charged with II-1 (0.375 mmol, 100 mol%), acrylonitrile(60 mg, 1.125 mmol, 300 mol%), Cs 2 CO 3 (269 mg, 0.825 mmol, 220 mol%) and acetonitrile (1.5 ml). The tube was full of Argon and capped with a silica septum. The mixture was heated to 130 o C for 45 min under microwave condition. After completion of present reaction, the solvent was removed under reduced pressure. The residue crude was purified by column chromatography on silica gel to afford desired product II-3a to II-3j.

General procedure C: formation of butyrolactones

To a dried microwave tube was charged with II-3 (0.375 mmol, 100 mol%), Zn(OTf) 2 (14 mg, 10 mol%) and 2,2,2-trifluoroethanol (1.5 ml). The tube was full of Argon and capped with a silica septum. The mixture was heated to 110 o C for 30 min under microwave condition. After completion of present reaction, the solvent was removed under reduced pressure. The residue crude was purified by column chromatography on silica gel to afford II-4a to II-4i. 3294, 3066, 2930, 2854, 1739, 1650, 1536, 1495, 1451, 1370, 1223, 1189, 1096, 1042, 1030cm , 3429, 3062, 3019, 2937, 2858, 1746, 1681, 1594, 1575, 1525, 1473, 1452, 1438, 1373, 1256, 1228, 1152, 1112, 1047cm Following general procedure A with cinnamaldehyde (1.32 g, 10 mmol) and cyclohexyl isocyanide (1.09 g, 1.24 ml, 10 mmol), the mixture was purified by column chromatography on silica gel (eluent: PE:EA = 70:30) to afford II-1j (2.71 g, 9.0 mmol, 90 %). The spectra data are in agreement with the literature report. [1] Aspect: white solid m.p. 141.8-142. Following general procedure A with para-methoxybenzaldehyde (1.36 g, 10 mmol) and cyclohexyl isocyanide (1.09 g, 1.24 ml, 10 mmol), the mixture was purified by column chromatography on silica gel (eluent: PE:EA = 70:30) to II-1k (2.20 g, 7.2 mmol, 72 %). The spectra data are in agreement with the literature report. [1] Aspect: white solid m.p.162.5-163. , 3417, 2937, 2858, 1671, 1598, 1519, 1491, 1452, 1401, 1350, 1253, 1206, 1096, 1014cm -1 .

N , 3590, 2971, 2935, 2260, 1678, 1598, 1519, 1491, 1457, 1394, 1368, 1268, 1223, 1096 , 3590, 3426, 3007, 2937, 2839, 1676, 1613, 1514, 1491, 1465, 1303, 1251, 1176, 1096, 1035, 1014cm -1 .

2-(4-chlorophenyl)-4-cyano-N- (3,4- , 3593, 3427, 2938, 1676, 1594, 1516, 1491, 1262, 1238, 1158, 1142, 1028, 1014cm -1 . , 3287, 2937, 2858, 1670, 1593, 1573, 1517, 1468, 1452, 1437, 1395, 1350, 1253, 1214, 1154, 1137, 1094, 1052cm -1 . , 3594, 3418, 2937, 2858, 1675, 1602, 1525, 1452, 1375, 1350, 1317, 1253, 1221, 1150, 1128, 1066, 1006cm -1 . , 2937, 2858, 1788, 1677, 1598, 1521, 1490, 1452, 1403, 1351, 1286, 1255, 1222, 1186, 1173, 1156, 1095, 1061, 1015cm -1 .

(E)-2-(2-cyanoethyl)-N-cyclohexyl-
N-(tert-butyl)-2-(4-chlorophenyl)- , 3423, 2972, 2260, 1787, 1683, 1599, 1520, 1491, 1458, 1395, 1368, 1279, 1219, 1187, 1173, 1095, 1065, 1040cm -1 . , 3431, 2958, 2937, 2839, 1789, 1682, 1613, 1514, 1491, 1442, 1303, 1250, 1224, 1176, 1113, 1094, 1065, 1036cm -1 . , 3606, 3432, 3009, 2938, 2839, 1788, 1683, 1599, 1516, 1491, 1466, 1263, 1237, 1158, 1142, 1095, 1028cm -1 . 3348, 2931, 2855, 1784, 1666, 1603, 1506, 1451, 1225, 1182, 1152,

2-(4-chlorophenyl)-N-(4-methoxybenzyl)-

2-(4-chlorophenyl

N-cyclohexyl

N-cyclohexyl-5-oxo-2-phenyltetrahydrofuran-2-carboxamide (II-4g) , 2931, 2854, 1783, 1666, 1518, 1449, 1224, 1183, 1153, 1109, , 3606, 3421, 2937, 2858, 1786, 1677, 1589, 1524, 1470, 1452, 1435, 1226, 1181, 1157, 1109, 1066cm -1 .

N-cyclohexyl-2-(furan-2-yl)- -4), 48.9 (C-6), 33.0 (C-7), 32.9 (C-7), 30.2 (C-2), 28.6 (C-3), 25.5 (C-9), 24.9 (C-8), 24.9 (C-8). 2H, H-c), 6.90 (q, J =4.1Hz, 1H, H-2), 2.34(s, 3H, H-3). A solution of 2-bromopyridine (1.42 g, 9 mmol) and hydrazine hydrate (20 mmol) was placed in a three-necked flask fitted with mechanical stir, a dropping funnel and thermometer. The reaction mixture was stirred at reflux for 4h under an inert atmosphere of N 2 . The reaction mixture was next extracted at room temperature with Et 2 O (3×50 ml). The organic layer was evaporated under reduced pressure to provide, in 50% yield, the 2-hydrazinepyridye as a white oil (850 mg, 50 %). 252 2-hydrazinepyridye (1 mmol) was added to a solution of Trifluoroacetaldehyde (1.25 mmol) in EtOH (2 ml) .The stirred mixture was heated to reflux for 10 h under Ar. After completion of present reaction, the reaction mixture was concentrated under vacuum. The residue was washed by n-hexane (3×5 ml) to afford a white solid (170 mg, 90 %,159.6 o C-161.9 o C). -c), 124.9(q, J = 39 Hz, C-2), 120.9(q, J = 268 Hz, C-1), 117.7 (C-b), 108.7 (C-d).

HRMS

HRMS: calculated for C 13 H 15 F 3 N 4 O 3 : 189.0514, found: 189.0510 I.R.(thin film): 3334,1626,1599, 1580, 1519, 1446, 1354, 1301, 1290, 1266, 1136, 1092cm -1 .

General procedure for the formation of Mannich adducts

Hydrazone (0.5 mmol) was added to a solution of secondary amine (0.5 mmol) and aldehyde (0.5 mmol) in 3ml toluene. The stirred mixture was heated to reflux under Ar for 12 h. After completion of present reaction, the reaction mixture was concentrated under vacuum. The residue was purified by column chromatography on silica gel to afford the desired product.

General procedure for the formation of 1,2,4-Triazine derivatives

Hydrazone (0.5 mmol) was added to a solution of primary amine (0.5 mmol) and aldehyde (1 mmol) in 3ml toluene. The stirred mixture was heated to reflux under Ar for 12 h. After completion of present reaction, the reaction mixture was concentrated under vacuum. The residue was purified by column chromatography on silica gel to afford the desired product.

1.4 General procedure for the formation of dihydropyridazine derivatives.

Mannich adduct (0.5 mmol) was dissolved in 3 mL diketone, and the stirred mixture was heated to 130 o C under Ar for 12 h. After completion of present reaction, the reaction mixture was concentrated under vacuum. The residue was purified by column chromatography on silica gel to afford the desired product.

III-2 was dissolved in 3 ml acetone and the mixture was heated to 130 o C under microwave condition for 1 h.

Characterization Data

(Z)-4- (3,3,3-trifluoro-2-(2-(4-nitrophenyl)hydrazono)propyl)morpholine III-1

C 13 H 15 F 3 N 4 O 3 332.28 g.mol -1
Trifluoroacetaldehyde 4-nitrophenylhydrazone (0.5 mmol, 117 mg, 1.0 eq) was added to a solution of morpholine (0.5 mmol, 44 mg, 1.0 eq) and formaldehyde (0.5 mmol, 41 mg, 37 %, 1.0 eq) in 3 ml toluene. The stirred mixture was heated to reflux under Ar for 12 h. After completion of present reaction, the reaction mixture was concentrated under vacuum. The residue was purified by column chromatography on silica gel (eluent: Et , 2838, 1595, 1511, 1377, 1338, 1325, 1258, 1207, 1124, 1111,

(

Z)-4-(1-(4-chlorophenyl)-3,3,3-trifluoro-2-(2-(4-nitrophenyl)hydrazono)propyl)morpholine III-2 C 19 H 18 ClF 3 N 4 O 3 442.82 g.mol -1
Trifluoroacetaldehyde 4-nitrophenylhydrazone (0.5 mmol, 117 mg, 1.0 eq) was added to a solution of morpholine (0.5 mmol, 44 mg, 1.0 eq) and p-chlorobenzaldehyde (0.5 mmol, 70 mg, 1.0 eq) in 3 ml toluene. The stirred mixture was heated to reflux under Ar for 12 h. After completion of present reaction, the reaction mixture was concentrated under vacuum. The residue was purified by column chromatography on silica gel (eluent: Et , 2973, 2853, 1595, 1511, 1494, 1337, 1256, 1209, 1159, 1122, 1112,

1016cm -1 (Z)-4-(3,3,3-trifluoro-1-(3-nitrophenyl)-2-(2-(4-nitrophenyl)hydrazono)propyl)morpholine III-3 C 19 H 18 F 3 N 5 O 5 453.38 g.mol -1
Trifluoroacetaldehyde 4-nitrophenylhydrazone (0.5 mmol, 117 mg, 1.0 eq) was added to a solution of morpholine (0.5 mmol, 44 mg, 1.0 eq) and 3-nitrobenzaldehyde (0.5 mmol, 76 mg, 1.0 eq) in 3 ml toluene. The stirred mixture was heated to reflux under Ar for 12 h. After completion of present reaction, the reaction mixture was concentrated under vacuum. The

I.R.(thin film)

: 3692,3094,2973,2854,2258,1595,1536,1513,1351,1338,1257,1249,1210,1160,1123,1123,1112 Trifluoroacetaldehyde 4-nitrophenylhydrazone (0.5 mmol, 117 mg, 1.0 eq) was added to a solution of morpholine (0.5 mmol, 44 mg, 1.0 eq) and 3-nitrobenzaldehyde (0.5 mmol, 76 mg, 1.0 eq) in 3 ml toluene. The stirred mixture was heated to reflux under Ar for 12 h. After completion of present reaction, the reaction mixture was concentrated under vacuum. The Trifluoroacetaldehyde 4-nitrophenylhydrazone (0.5 mmol, 117 mg, 1.0 eq) was added to a solution of morpholine (0.5 mmol, 44 mg, 1.0 eq) and 3-methoxybenzaldehyde (0.5 mmol, 68 mg, 1.0 eq) in 3 ml toluene. The stirred mixture was heated to reflux under Ar for 12 h. After completion of present reaction, the reaction mixture was concentrated under vacuum. The residue was purified by column chromatography on silica gel (eluent: Et 2 O:PE = 50:50) to afford the desired product III-5 (99 %, 216 mg).

Aspect: yellow oil

Rf: 0.38 (Et 2 O:PE = 50:50)

I.R.(thin film)

: 3692,3109,2971,2853,2838,1596,1511,1455,1336,1255,1209,1159,1122

, 1034cm -1 (Z)-4-(3,3,3-trifluoro-1-(4-methoxyphenyl)-2-(2-(4-nitrophenyl)hydrazono)propyl)morpholi- ne III-6 C 20 H 21 F 3 N 4 O 4
438.41 g.mol -1

Trifluoroacetaldehyde 4-nitrophenylhydrazone (0.5 mmol, 117 mg, 1.0 eq) was added to a solution of morpholine (0.5 mmol, 44 mg, 1.0 eq) and 3-methoxybenzaldehyde (0.5 mmol, 68 mg, 1.0 eq) in 3ml toluene. The stirred mixture was heated to reflux under Ar for 12 h. After completion of present reaction, the reaction mixture was concentrated under vacuum. The residue was purified by column chromatography on silica gel (eluent: Et

I.R.(thin film)

: 3689,2971,2853,2839,1596,1513,1457,1336,1255,1207,1157,1112,

1034cm -1 (Z)-4-(3,3,3-trifluoro-2-(2-(4-nitrophenyl)hydrazono)-1-(thiophen-2-yl)propyl)morpholine III-7 C 17 H 17 F 3 N 4 O 3 S
414.40 g.mol -1 Trifluoroacetaldehyde 4-nitrophenylhydrazone (0.5 mmol, 117 mg, 1.0 eq) was added to a solution of morpholine (0.5 mmol, 44 mg, 1.0 eq) and thiophene-2-carbaldehyde (0.5 mmol, 57 mg, 1.0 eq) in 3 ml toluene. The stirred mixture was heated to reflux under Ar for 15 h.

After completion of present reaction, the reaction mixture was concentrated under vacuum.

The residue was purified by column chromatography on silica gel (eluent: Et 4.2,0.7 Hz,1H,2H,7.12 (dd,J = 3.5,1.0 Hz,1H,6.99 (dd,J = 5.1,3.6 Hz,1H,4.59 (s,1H,3.75 (bs,4H,4H,. 2H,g),8.20 (d,J = 9.1 Hz,2H,7.73 (dd,J = 7.9,1.6 Hz,1H,7.33 (dd,J = 7.9,4.8 Hz,1H,2H,4.28 (s,1H,3.76 (bs,4H,2.49 (bs,4H,.

I.R.(thin film)

: 3689, 3039, 2973, 2916, 2895, 2854, 2836, 2768, 2446, 2233, 1595, 1513, 1456, 1337, 1264, 1209, 1159, 1123, 1112, 1035cm -1 (Z)-4- (3,3,3- = 7.9 Hz,1H,6H,f,h,i,j),4.64 (s,1H,3.77 (s,3H,3.72(bs,4H,2.60 (bs,4H,. , 2971, 2853, 1596, 1509, 1425, 1334, 1297, 1256, 1207, 1154, 1113, 1071, 1034, 1005cm -1 (Z)-4- (1,1,1,4,4,4-hexafluoro-3-(2-(4-nitrophenyl) 7.17 (m, 4H, H-g,h), 7.03 (d,J = 9.2 Hz,2H,4.09 (s,1H,2.39 (bs,4H,, 1.91-1.84 (m, 4H, H-5). , 2976, 2824, 1594, 1509, 1493, 1336, 1254, 1208, 1161, 1127, 1111 4H, H-f,g), 7.23 -7.14 (m, 2H, H-c), 4.17 (s, 1H, H-3), 2.40 (bs, 4H, H-4), 1.70 -1.50 (m, 6H, H-5,6). 3692, 2943, 2817, 1594, 1510, 1492, 1386, 1254, 1214, 1161, 1111, 7.24 (m,9H,g,j,k,l),7.16 (d,J = 8.8 Hz,2H,4.22 (s,1H,3.56 (s,2H,2.50 (bs,8H,5). , 3088, 3031, 2973, 2833, 2770, 2444, 1902, 1595, 1510, 1494, 1458, 1373, 1336, 1297, 1254, 1208, 1159, 1127, 1111, 1095, 1037cm -1 (Z)-N, N-diethyl-3,3,3-trifluoro-2-(2-(4-nitrophenyl)hydrazono)propan-1-amine III-14

C 13 H 17 F 3 N 4 O 2 318.30 g.mol -1
Trifluoroacetaldehyde 4-nitrophenylhydrazone (0.5 mmol, 117 mg, 1.0 eq) was added to a solution of diethylamine (0.5 mmol, 37 mg, 1.0 eq) and formaldehyde (0.5 mmol, 41 mg, 37 %, 1.0 eq) in 3 ml toluene. The stirred mixture was heated to reflux under Ar for 12 h.

After completion of present reaction, the reaction mixture was concentrated under vacuum.

The residue was purified by column chromatography on silica gel (eluent: CH 2 Cl 2 :PE = 50:50) to afford the desired product III-14 (89 %, 141 mg). , 3105, 2976, 2938, 2878, 2843, 2444, 1918, 1596, 1528, 1509, 1458, 1438, 1427, 1383, 1335, 1298, 1258, 1206, 1158, 1111, 1065, 1041cm -1 (Z)-4- (3,3,3-trifluoro-2-(2-phenylhydrazono)propyl)morpholine III-15

C 13 H 16 F 3 N 3 O 287.29 g.mol -1
Trifluoroacetaldehyde phenylhydrazone (0.5 mmol, 94 mg, 1.0 eq) was added to a solution of morpholine (0.5 mmol, 44 mg, 1.0 eq) and formaldehyde (0.5 mmol, 41 mg, 37 %, 1.0 eq) in

I.R.(thin film)

: 3172, 3107, 3030, 2973, 2858, 2833, 1601, 1523, 1496, 1456, 1376, 1346, 1296, 1251, 1155, 1119, 1053, 1005cm -1 (Z)-4- (1-(4-chlorophenyl)-3,3,3-trifluoro-2-(2-phenylhydrazono) Trifluoroacetaldehyde phenylhydrazone (0.5 mmol, 94 mg, 1.0 eq) was added to a solution of morpholine (0.5 mmol, 44 mg, 1.0 eq) and p-chlorobenzaldehyde (0.5 mmol, 70 mg, 1.0 eq) in 3 ml toluene. The stirred mixture was heated to reflux under Ar for 12 h. After completion of present reaction, the reaction mixture was concentrated under vacuum. 7.39-7.32(m, 6H, H-b,f,g), 7.19-7.16 (m, 2H, H-c), 7.02-6.98 (m, 1H, H-a), 4.16 (s, 1H, H-3), 3.76 (bs, 4H, H-5), 2.47 (bs, 4H, H-4). , 3169, 3031, 2971, 2916, 2883, 2855, 1599, 1514, 1493, 1456, 1364, 1245, 1210, 1164, 1119, 1096, 1035cm -1 (Z)-4- (3,3,3-trifluoro-2-(2-(p-tolyl) , 3171, 3026, 2973, 2859, 2834, 1606, 1525, 1456, 1376, 1346, 1273, 1251, 1174, 1118,1053 7.40-7.32 (m, 4H, H-f,g), 7.20 -7.05 (m, 4H, H-b,c), 4.16 (s, 1H, H-3), 3.76 (bs, 4H, H-5), 2.47 (bs, 4H, H-4), 2.34 (s, 3H, H-6). , 3170, 2971, 2856, 1604, 1524, 1493, 1455, 1364, 1287, 1244, 1205, 1164, 1096, 1035cm -1 (Z)-4- (3,3,3-trifluoro-2-(2-(pyridin-2-yl) to a solution of morpholine (0.5 mmol, 44 mg, 1.0 eq) and formaldehyde (0.5 mmol, 41 mg, 37 %, 1.0 eq) in 3 ml toluene. The stirred mixture was heated to reflux under Ar for 12 h.

After completion of present reaction, the reaction mixture was concentrated under vacuum.

The residue was purified by column chromatography on silica gel (eluent: EA:PE = 50:50) to afford the desired product III-19 (81 %, 116 mg).

Aspect: yellow oil

Rf: 0.54 (EA:PE = 50:50)

I.R.(thin film)

: 3172, 2972, 2899, 2863, 2830, 1597, 1577, 1515, 1444, 1375, 1345, 1296, 1268, 1178, 1146, 1058cm -1 (Z)-4- (1-(4-chlorophenyl)-3,3,3-trifluoro-2-(2-(pyridin-2-yl) to a solution of morpholine (0.5 mmol, 44 mg, 1.0 eq) and p-chlorobenzaldehyde (0.5 mmol, 70 mg, 1.0 eq) in 3 ml toluene. The stirred mixture was heated to reflux under Ar for 15 h.

After completion of present reaction, the reaction mixture was concentrated under vacuum.

The residue was purified by column chromatography on silica gel (eluent: EA:PE = 40:60) to afford the desired product III-20 (47 %, 93 mg).

Aspect: yellow oil

Rf: 0.63(EA:PE = 40:60)

1 H NMR (400 MHz, CDCl 3 ) δ 12.11 (s, 1H, H-NH), 1H,7.63 (t,J = 7.8 Hz,1H,7.41 (d,J = 8.2 Hz,2H,3H,d),6.89 (dd,J = 8.1,4.0 Hz,1H,4.16 (s,1H,4H,2.45 (bs,4H,.

I.R.(thin film)

: 3173,2970,2860,2828,1596,1575,1510,1493,1443,1362,1297,1269,1169,1146,1120,1094 Trifluoroacetaldehyde phenylhydrazone (0.5 mmol, 94 mg, 1.0 eq) was added to a solution of piperidine (0.5 mmol, 43 mg, 1.0 eq) and p-chlorobenzaldehyde (0.5 mmol, 70 mg, 1.0 eq) in 7.3 Hz,2H,1H,4.14 (d,J = 4.4 Hz,1H,2.42 (bs,4H,, 1.78 -1.42 (m, 6H, H-5,6). to a solution of pyrrolidine (0.5 mmol, 36 mg, 1.0 eq) and p-chlorobenzaldehyde (0.5 mmol, 70 mg, 1.0 eq) in 3 ml toluene. The stirred mixture was heated to reflux under Ar for 15 h.

After completion of present reaction, the reaction mixture was concentrated under vacuum.

The residue was purified by column chromatography on silica gel (eluent: Et 1H,7.67 (td,J = 8.2,1.8 Hz,1H,2H,3H,d),6.92 (ddd,J = 7.2,5.0,0.9 Hz,1H,4.21 (s,1H,2.55 (bs,4H,4H,. , 2976, 2817, 1597, 1575, 1511, 1492, 1442, 1359, 1295, 1268, 1169, 1124, 1093, 1016cm Trifluoroacetaldehyde 4-nitrophenylhydrazone (0.5 mmol, 117 mg, 1.0 eq) was added to a solution of aqueous formaldehyde (1 mmol, 82 mg, 37 %, 2.0 eq) and allylamine (0.5 mmol, 57 mg, 1.0 eq) in 3 ml toluene. The stirred mixture was heated to reflux under Ar for 12 h.

After completion of present reaction, the reaction mixture was concentrated under vacuum. 3086, 2928, 2846, 1593, 1506, 1422, 1405, 1337, 1281, 1222, 1205, 1179, 1132, 1132, 1068, 1022cm Trifluoroacetaldehyde 4-nitrophenylhydrazone (0.5 mmol, 117 mg, 1.0 eq) was added to a solution of aqueous formaldehyde (1 mmol, 82 mg, 37 %, 2.0 eq) and tryptamine (0.5 mmol, 80 mg, 1.0 eq) in 3 ml toluene. The stirred mixture was heated to reflux under Ar for 12 h.

After completion of present reaction, the reaction mixture was concentrated under vacuum. , 1592, 1513, 1336, 1284, 1259, 1205, 1175, 11131, 1111, 1067, 1021cm , 1668, 1595, 1522, 1491, 1387, 1346, 1257, 1214, 1189, 1113, 1095, 1016cm

I.R.(thin film)

: 1674,1595,1526,1492,1349,1310,1292,1221,1198,1142, 1039, 1015cm 1, 127.6, 126.0, 125.9, 125.0, 124.8, 122.3, 120.9(q, J = 273 Hz, C-1), 120.0, 118. 9, 114.2, 113.3, 112.9, 109.8, 33.0 (C-9), 30.1 (C-6), 29.6 (C-3), 18.9 (C-8). , 1672, 1595, 1524, 1495, 1348, 1310, 1293, 1221, 1197, 1139, 1111, 1040cm 121.0(q, J = 273 Hz, C-1), 100.9 (C-4), 51.8 (C-6), 36.5 (C-3), 17.8 (C-8).

HRMS

HRMS: calculated for C

I.R.(thin film)

: 3063, 3014, 1671, 1581, 1490, 1470, 1439, 1381, 1360, 1317, 1292, 1222, 1199, 1140, 1093, 1041cm HRMS: calculated for C 15 H 15 F 3 N 2 O: 296.1136, found:296.1122.

I.R.(thin film)

: 3039,2924,1664,1562,1512,1420,1393,1381,1360,1319,1243,1219,1190,1111, 1039, 1018cm , 1667, 1637, 1592, 1557, 1489, 1382, 1350, 1243, 1214, 1189, 1122, 1091, 1037, 1024, 1013cm

I.R.(thin film)

: 3043, 2933, 2904, 2887, 2834, 1674, 1607, 1593, 1490, 1386, 1315, 1265, 1216, 1179, 1149, 1115, 1105, 1074, 1032, 1015, 1002cm HRMS: calculated for C 20 H 16 ClF 3 N 2 : 376.0954, found:376.0941.

I.R.(thin film)

: 3042, 2956, 2850, 1679, 1594, 1584, 1496, 1489, 1379, 1329, 1294, 1225, 1186, 1160, 1117, 1090, 1077, 1014cm -1 Experimental part: chapter IV 1 General procedure

Synthesis of nitroalkanes

In a round-bottomed flask fitted with a Dean and Stark trap was added ketone (100 mmol, 14.6 g, 100 mol%), nitromethane (1 mol, 61 g, 10 eq), N,N-dimethylethane-1,2-diamine ( 30mmol, 2.6 g, 30 mol%), and toluene (50 ml), the mixture was refluxed for 96 h. After evaporation of solvent under reduced pressure, the residue crude was purified by column chromatography on silica gel to afford the desired product.

Synthesis of double Michael addition adducts

To a solution of nitroalkanes (0.5 mmol, 100 mol%) in acetonitrile (1.5 ml) was added Michael acceptors (2.5 mmol, 5 eq) and DBU (38 mg, 50 mol%), the mixture was stirred for 3 h at r.t. under Ar. After evaporation of solvent under reduced pressure, the residue crude was purified by column chromatography on silica gel to afford the desired product.

Synthesis of mono Michael addition adducts

To a solution of nitroalkanes (0.5 mmol, 100 mol%) in acetonitrile (1.5 ml) was added Michael acceptors (1.5 mmol, 3 eq) and DBU(15 mg, 10 mol%), the mixture was stirred for 2 h at r.t. under Ar. After evaporation of solvent under reduced pressure, the residue crude was purified by column chromatography on silica gel to afford the desired product.

Synthesis of naphthalene

To a solution of mono or double Michael addition adducts (0.5 mmol, 100 mol%) in DMF (1.5 ml) was added Cs 2 CO 3 (0.5 mmol, 163 mg, 100 mol%), Pd(OAc) 2 (5 mol%), and dppe (5 mol%), the mixture was stirred for 30 min at 120 o C under Ar. After evaporation of solvent under reduced pressure (vacuum, 80 o C), the residue crude was purified by column chromatography on silica gel to afford the desired product. 3066, 3001, 2954, 2893, 2837, 1737, 1542, 1487, 1452, 1439, 1379, 1348, 1293, 1202, 1179cm -1 . 3047, 3001, 2953, 2848, 1731, 1597, 1511, 1457, 1438, 1419, 1396, 1368, 1326, 1259, 1202, 1174, 1014 cm -1 . 4-(3,4- , 2953, 1731, 1597, 1511, 1438, 1395, 1367, 1251, 1220, 1168, 1147, 1011cm -1 . 5-(3,4- 3064, 3024, 2944, 2893, 2836, 1717, 1551, 1489, 1451, 1437, 1428, 1366, 1167, 1023cm -1 . 3044, 2941, 1710, 1595, 1509, 1396, 1354, 1262, 1218, 1180, 1162, 2986, 2938, 2852, 1542, 1485, 1445, 1370, 1223, 1200, 1155, 1080, methyl 4-(naphthalen-1-yl) ,2989, 2949, 1734, 1638, 1590, 1506, 1435, 1361, 1252, 1194, 1156, 1062, 1024 cm -1 .

Characterization Data

5-(naphthalen

4-(nitromethyl)-6,7-dihydro-1H-indole , 2941, 1572, 1546, 1503, 1459, 1413, 1329, 1301, 1240, 1182, 1139, 1100,1018cm -1 . 4-(6,7-dihydro-1H-indol-4-

La 4 -

 4 nitrophényl hydrazone, obtenue avec un rendement de 90% à partir de 4-nitrophényl hydrazine et de trifluoroacétaldéhyde, a été initialement choisie pour maximiser nos chances d'observer un couplage en raison de son acidité plus élevée et de l'effet bénéfique d'un substituant nitro observé dans nos études précédentes sur les couplages de Mannich des hydrazones. Ce choix nous a permis d'obtenir un couplage efficace dans des conditions proches de celles mise au point pour les produits non fluorés. Ensuite, nous avons préparé une bibliothèque de produits d'addition de Mannich en faisant varier les 3 composants de la réaction, et dans le toluène comme solvant. Les nouvelles NH-arylhydrazones C-fonctionnalisées ont été obtenues avec d'excellents rendements dans la plupart des exemples (schéma 7).

  2009, Sorensen et al. synthesized 3-aminoindoles from aldimines, isocyanides in presence of a strong Brønsted acid. A aldimine was traped by an isocyanide to form a α-amino nitrilium ion, after Houben-Hoesch cyclization and tautomerization, desired 3-aminoindole analogue was obtained (scheme 1This reaction was first discovered by Passerini in 1921. It's the first isocyanide based multicomponent reaction. It involves the condensation between a carbonyl substrate(aldehyde or ketone), a carboxylic acid and an isocyanide. And it gives a direct access to α-acyloxycarboxamides in a one-pot reaction (scheme1-35). 48 This reaction is usually carried out in nonpolar aprotic solvents (toluene or dichloromethane) at room temperature in a relatively high concentration. Several examples are conducted as well without solvent. Based on the reactivity differences observed when changing the 48 (a) M.Passerini, G. Simone, Chim. Ital. 1921, 51, 126. (b) M.Passerini, Chim. Ital. 1921, 51,181. (c) L.

  108 a) D.Koszelewski, W. Szymanski, J. Krysiak, R. Ostaszewski, Synth. Commun. 2008, 38, 1120-1127; b) T. Bousquet, M.. Jida, M. Soueidan, R. Deprez-Poulain, F.Agbossou-Niedercorn, L. Pelinski, Tetrahedron Lett. 2012, 53, 306-308.

  ) didn't change a behavior consistent with the relatively sensitive ester moieties of Passerini adducts as already observed in our recent conversion of Passerini adducts of cinnamaldehyde into α-ketoamides (scheme 2-31). 109

  114 A.Domling, Chem Rev. 2006, 106, 17-89. 115 a) K. Ma, C. Zhang, M. Liu, Tetrahedron Lett. 2010,51,1870-1872. b) M. Heravi, V. Zadsirjan, B. Savadjani, Curr Org Chem. 2014,18,2857-2891. 116 a) Z. Sun, B. Chen, S. Zhang, C. Hu,

  123 a) L. Gall, C. Haurena, S. Sengmany, T. Martens, M. Troupel, J. Org Chem. 2010, 75, 2645. b) L. Gall, C. Haurena, S. Sengmany, T. Martens, M. Troupel, J. Org Chem. 2009, 74, 7970. 124 R. Ramachandran, S. Jayanthi, T. Jeong, Tetrahedron. 2012, 68, 363.

  2011, Peng et al. described an anti-Mannich reaction where simple aldehydes react with preformed N-Boc and N-Cbz imines in presence of 5 mol% catalyst to give the corresponding products in excellent yields (up to 95 %), diastereoselectivities (up to 96:4 dr) and enantioselectivities (up to >99 % ee) 128 (scheme 3-11). Recently, An et al. developed the asymmetric three-component Mannich reactions of cyclohexanone, anilines and aromatic aldehydes in the presence of water mediated by Isosteviol-proline as highly efficient amphiphilic organocatalysts, and afforded syn-Mannich products with excellent diastereoselectivities (syn/anti up to 98:2) and enantioselectivities (up 128 M. Chuan, H. Chen, Z. Gao, H. Zhang, and G. Peng, Chem. Commun. 2011, 47, 3260-3262 to>99% ee) (Scheme 3-12). 129 In 2008, Blanchet and coworkers described an anti-selective direct and three-component Mannich reaction catalysed by 3-trifluoromethanesulfonamido-pyrrolidine. High yields and selectivities for various substrates ranging from linear and branched aldehydes to ketones were obtained. It was indicated that the acidity of the trifluoromethylsulfonamide group was critical to achieve high stereoselectivity, and C-2 symmetry of catalyst was not a key structural feature for a high stereoselectivity(scheme 3-13

  . The use of chiral N, N-dialkylhydrazones has allowed the development of diastereoselective additions. 143 The Enders SAMP/RAMP hydrazone alkylation reaction is an asymmetric carbon-carbon bond formation reaction facilitated by pyrrolidine chiral auxiliaries. It was first discovered by E. J. Corey and D. Enders in 1976 144 , and was further developed by D. Enders and his group 145 . The preparation of the hydrazines SAMP ((S) -1 -amino -2methoxymethylpyrrolidine) and RAMP (the enantiomer (R)) is made in a few steps from (S)proline and (R) -glutamic acid. The addition of hydrazine to an aldehyde makes it possible to obtain chiral hydrazones, which can react with different organometallic reagents, such as organolithium, organocerium, 146 and Grignard reagents 147 to give N-substituted secondary amine with the simultaneous generation of a new chiral center. A chiral primary amine was obtained after reduction (scheme 3-22). In 2002, Kobayashi et al. proposed a synthesis of homoallyl α, α -disubstituted amines by a diastereospecific allylation of benzoylhydrazones. The stereoselectivities are always excellent,

competitive Pictet -

 Pictet Spengler type reaction occurring simultaneously. A tryptamine could undergo ring closure after condensation with an aldehyde while the reaction mixture was heated forming thus a lot of side products (scheme 3-52). 183 183 a)A. Pictet, T. Spengler, Berichte der deutschen chemischenGesellschaft. 1911. 44 (3) 2030-2036.b) M.Whaley, R. Govindachari, Org. React. 1951, 6, 74.

(

  A, B, C, D, E), or the new group (Nu 2 ) inserted in the Michael additions (F, G, H, I). On the other hand, the electrophiles involved can be the hydrazone C=N bond (F, G), the electron-withdrawing group (R 2 ) in the 4-position of the azo-ene systems (C, H, I) or a new group (E) inserted in the Michael additions (B, E) (scheme 3-64). 193

  4, entry 6) substituents. The formation of III-27 in a low 34% yield may be probably explained by the required shorter reaction time associated with the use of microwave conditions. The examples obtained with cyclopentanone and cyclohexanone (Table3-4, entries 9 and 10) are indicative of the efficiency of the process and further support our initial mechanistic hypotheses: thermal elimination of morpholine allows the formation of an enamine intermediate which is engaged in a Michael addition with the azoalkene. Cyclization and elimination of morpholine finally afford 4-Hydropyridazine. (Scheme 3-68).

  present study demonstrates the interest in trifluoroacetaldehyde NH-aryl hydrazones as the carbon centered nucleophile in Mannich reactions. The electron-withdrawing properties of the trifluoromethyl group are strongly associated with the success of the couplings allowing various NH-aryl hydrazone derivatives to react with formaldehydes as well as different aromatic aldehydes. The resulting Mannich adducts are valuable starting materials for the generation of azoalkene intermediates and the preparation of trifluoromethyl substituted heterocycles. Considering the potential of azoalkene intermediates in the construction of five-and six-membered hetero ring systems, we can probably extent this work to [4+1] cycloaddition reaction with isocyanide as we published for non fluorinated system 198 (scheme 3-69). 198 V. Atlan, L. Elkaïm, C. Buron, Synlett 2000, 489.

  203 N. Mishra, S. Sharma, J. Park, S. Han, and I.Kim, ACS Catal., 2017, 7 (4), pp 2821-2847 204 M. Trost, T.Zhang, D. Sieber, Chem. Sci. 2010, 1, 427-440.

  reduced. In 1982, Hegedus et al. reported a palladium (0) catalyzed allylic alkylation (scheme 4-23). 247 In 1986, Tamura et al. demonstrated that primary, secondary, and tertiary allylic nitro compounds could undergo Pd(0)-catalyzed allylic substitution by stabilized carbanions, secondary amines, and benzenesulfinate ion (PhSO 2 -). The regiochemistry of these substitutions was related to the structure of the allylic nitro compound and the steric bulk of the nucleophile. Generally, substitution occurred at the less hindered or least substituted site (scheme 4-24). 248 247 T. Rui, L. Hegedus, J. Am.Chem. Soc., 1982, 104, 3727-3729 248 R. Tamura, Y. Kai, M. Kakihana, K. Hayashi, M.Tsuji, T. Nakamura, and D. Oda, J. Org. Chem. 1986, 51, 4375-4385 Stimulated by our interest in Tsuji-Trost reactions, we envisioned that in the absence of a potential nucleophlic group, the π-allyl intermediate derived from nitro compounds could afford under basic conditions an interesting access to diene, and my colleague Mansour Dolè Kerim discovered a base triggered Tsuji-Trost elimination leading to cyclic diene analogues from nitrocyclohexene derivatives (scheme 4-25).

13 C

 13 NMR (101 MHz, CDCl 3 ) δ 169.1 (C-2), 167.9 (C-4), 149.2 (C-i), 147.9 (C-h), 135.0 (C-d), 134.1 (C-a), 130.9 (C-e), 129.0 (C-c), 128.8 (C-b), 120.8 (C-f), 112.0 (C-j), 111.3 (C-g), 74.8 (C-3), 56.0 (C-7), 56.0 (C-8), 40.6 (C-5), 35.1 (C-6), 21.0 (C-1).

  calculated for C 16 H 21 NO 3 : 275.1521, found: 275.1530 I.R.(thin film):

  c), 123.5(C-b), 122.2 (C-d), 75.7 (C-3), 48.4 (C-5), 32.7 (C-6), 25.5(C-8), 24.7 (C-7), 21.0 (C-1). HRMS: calculated for C 15 H 20 N 2 O 3 : 276.1474, found: 276.1471 I.R.(thin film): 3690

9 (

 9 b), 110.7(C-c), 68.8 (C-3), 48.4 (C-5), 32.9 (C-6), 32.8 (C-6), 25.5(C-8), 24.8 (C-7), 20.

3 )

 3 δ 7.40(d, J = 7.4 Hz, 2H), 3H), 6.74 (d, J = 16.0 Hz, 1H), 6.28 (dd, J = 16.0, 6.9 Hz, 1H), 5.91 (d, J = 7.6 Hz, 1H), 5.72 (d, J = 6.9 Hz, 1H),3.86 -3.77 (m, 1H), 2.22 (s, 3H), 1.96 -1.93 (m, 2H), 1.74 -1.62 (m, 3H), 1.43 -1.33 (m, 2H), 1.23 -1.16 (m, 3H).

13 C

 13 NMR (101 MHz, CDCl 3 ) δ 169.4 (C-2), 167.2 (C-4), 135.8 (C-9), 134.9 (C-d), 128.8 (C-b), 128.5 (C-a), 127.0 (C-c), 122.8 (C-10), 74.6 (C-3), 48.4 (C-5), 33.1 (C-6), 25.6 (C-8), 24.9 (C-7), 21.3 (C-1).

  ),1.70 -1.59 (m, 3H, H-cy), 1.38 -1.29 (m, 2H, H-cy), 1.19 -1.11 (m, 3H, H-cy).

  d), 114.2 (C-b), 75.2 (C-3), 55.4 (C-9), 48.3 (C-5), 33.0 (C-6), 33.0 (C-6), 25.5 (C-8), 24.8 (C-7), 21.2 (C-1).

13 C 8 (

 138 NMR (101 MHz, CDCl 3 ) δ 171.2 (C-5), 139.7 (C-d), 134.5 (C-a), 129.0 (C-c), 126.7 (C-b), 119.8 (C-1), 77.5 (C-4), 48.8 (C-6), 35.1 (C-3), 33.0 (C-7), 32.8 (C-7), 25.5 (C-9), 24.

  b), 119.8(C-1), 77.6 (C-4), 51.8(C-6), 35.1 (C-3), 28.6 (C-7), 12.3 (C-2). HRMS: calculated for C 15 H 19 ClN 2 O 2 :294.1135, found: 294.1139 I.R.(thin film): 3691

13 C

 13 NMR (101 MHz, CDCl 3 ) δ 172.5 (C-5), 159.1 (C-h), 139.6 (C-d), 134.3 (C-a), 129.4 (C-e), 128.8 (C-f), 128.7 (C-c), 126.7 (C-b), 119.7 (C-1), 114.2 (C-g), 77.5 (C-4), 55.3

13 C

 13 NMR (101 MHz, CDCl 3 ) δ 172.1 (C-5), 149.1 (C-i), 147.9 (C-h), 139.4 (C-d), 134.5 (C-a), 130.7 (C-e), 129.0 (C-c), 126.7 (C-b), 120.8 (C-f), 119.7 (C-1), 111.8 (C-j), 111.4

  c), 119.9(C-1), 115.8 (C-b), 77.5(C-4), 48.7 (C-6), 35.1 (C-3), 33.0 (C-7), 32.8 (C-7), 25.5(C-9), 24.8(C-8), 12.3 (C-2).

13 C

 13 NMR (101 MHz, CDCl 3 ) δ 170.4(C-5), 148.4 (C-a), 147.8(C-d), 126.4 (C-c), 123.8(C-b), 119.6 (C-1), 77.9(C-4), 48.9 (C-6), 35.2 (C-3), 33.0 (C-7), 32.7(C-7), 25.4 (C-9), 24.8(C-8), 24.7(C-8), 12.3 (C-2).

13 C

 13 NMR (101 MHz, CDCl 3 ) δ 171.1 (C-5), 157.4 (C-e), 147.2 (C-a), 138.0 (C-c), 123.7 (C-b), 121.4 (C-d), 119.5 (C-1), 76.6 (C-4), 48.6 (C-6), 36.7 (C-3), 33.0 (C-7), 32.8 (C-7), 25.5 (C-9), 24.8 (C-8), 12.2 (C-2). HRMS: calculated for C 16 H 21 N 3 O 2 :287.1634,not found, fragment: 161.0707 I.R.(thin film): 3405

  108.1(C-b), 74.0(C-c), 49.2 (C-4), 34.7 (C-6), 32.9 (C-3), 32.8 (C-7), 25.5(C-9), 24.7(C-8), 12.0 (C-2).HRMS: calculated for C 15 H 20 N 2 O 3 : 276.1474, found: 276.1473 I.R.(thin film): 3691

13 CIFollowing

 13 NMR (101 MHz, CDCl 3 ) δ 171.2(C-5), 135.7(C-d), 130.8 (C-10), 129.7 (C-11), 128.9(C-b), 128.5(C-a), 126.9 (C-c), 119.9 (C-1), 48.8(C-6), 35.2 (C-3), 33.2 (C-7), 33.0 (C-7), 25.5(C-9), 24.9 (C-8), 12.1(C-2).HRMS: calculated for C 19 H 24 N 2 O 2 : 312.1838, not found, fragment (-C 6 H 11 CONH): 186.0914 general procedure C with 2-(4-chlorophenyl)-4-cyano-N-cyclohexyl-2-hydroxybutanamide II-3a (120 mg, 0.375 mmol, 100 mol%), the mixture was purified by column chromatography on silica gel (eluent: PE:EA = 90:10) to afford II-4a (90 mg, 0.281 mmol,

13 C

 13 NMR (101 MHz, CDCl 3 ) δ 175.0 (C-1), 169.1(C-5), 137.5(C-d), 134.8 (C-a), 128.9(C-c), 126.2 (C-b), 87.5(C-4), 48.9 (C-6), 33.6 (C-2), 33.0 (C-7), 32.7 (C-7), 28.3 (C-3), 25.4(C-9), 24.9(C-8), 24.8 (C-8).HRMS: calculated forC 17 H 20 ClNO 3 : 321.1132, not found, fragment: 295.0970 I.R.(thin film): 3422

  calculated for C 15 H 18 ClNO 3 : 295.0975, found: 295.0980 I.R.(thin film): 3691

13 C

 13 NMR (101 MHz, CDCl 3 ) δ 174.8 (C-1), 169.9 (C-5), 159.3 (C-h), 137.3 (C-d), 134.9 (C-a), 129.2 (C-e), 129.1 (C-f), 129.0 (C-c), 126.2 (C-b), 114.3 (C-g), 87.5 (C-4), 55.4

  chlorophenyl)-4-cyano-N-(3,4dimethoxyphenethyl)-2-hydroxybutanamide II-3d (151 mg, 0.375 mmol, 100 mol%), the mixture was purified by column chromatography on silica gel (eluent: PE:EA = 70:30) to afford II-4d (130 mg, 0.323 mmol, 86 %). Aspect: white solid, m.p. 101.1-102.4 o C Rf: 0.50 (EA:PE = 4:6) 1 H NMR (400 MHz, CDCl 3 ) δ 7.42 (d, J = 8.7 Hz, 2H, H-b), 7.32 (d, J = 8.7 Hz, 2H, H-c), 6.71 (d, J = 8.1 Hz, 1H, H-g), 6.59 (d, J = 1.8

Following

  general procedure C with 4-cyano-N-cyclohexyl-2-(4-fluorophenyl)-2hydroxybutanemide II-3e (114 mg, 0.375 mmol, 100 mol%), the mixture was purified by column chromatography on silica gel (eluent: PE:Et 2 O = 50:50) to afford II-4e (99 mg, 0

13 C

 13 NMR (101 MHz, CDCl 3 ) δ 175.1 (C-1), 169.3 (C-5), 162.9(d, J = 246 Hz, C-a), 134.8 (C-d), 126.7 (C-c), 115.8 (C-b), 115.6 (C-b), 87.6 (C-4), 48.8 (C-6), 33.7 (C-2), 33.1 (C-7), 32.7 (C-7), 28.3 (C-3), 25.4 (C-9), 24.9 (C-8), 24.8 (C-8). HRMS: calculated for C 17 H 20 FNO 3 :305.1427, found: 305.1426 I.R.(thin film):

Following

  general procedure C with 4-cyano-N-cyclohexyl-2-hydroxy-2-phenylbutanamide II-3g (107 mg, 0.375 mmol, 100 mol%), the mixture was purified by column chromatography on silica gel (eluent: PE:EA = 80:20) to afford II-4g(78 mg, 0.27 mmol, 88 (m, 1H, H-cy), 1.74 -1.56 (m, 4H, H-cy), 1.35 -1.02 (m, 5H, H-cy).

  a), 124.7(C-b), 88.1(C-4), 48.8 (C-6), 33.5 (C-2), 33.1 (C-7), 32.7 (C-7), 28.4 (C-3), 25.5(C-9), 24.9 (C-8), 24.8(C-8).HRMS: calculated forC 17 H 21 NO 3 :287.1521, found: 287.1522 I.R.(thin film): 3349

Following

  -cyclohexyl-5-oxo-2-(pyridin-2-yl)tetrahydrofuran-2-carboxamide (II-4h) general procedure C with 4-cyano-N-cyclohexyl-2-hydroxy-2-(pyridin-2-yl)butanamide II-3h (108 mg, 0.375 mmol, 100 mol%), the mixture was purified by column chromatography on silica gel (eluent: PE:EA = 50:50) to afford II-4h (54 mg, 0.188 mmol, 57 (m, 3H, H-cy), 1.39 -1.28 (m, 2H, H-cy),1.20 -1.11 (m, 3H, H-cy).

13 C

 13 NMR (101 MHz, CDCl 3 ) δ 175.9(C-1), 168.6 (C-5), 157.3 (C-e), 149.5(C-a), 137.3(C-c), 123.8 (C-b), 120.6(C-d), 88.0(C-4), 48.6 (C-6), 32.9 (C-2), 31.9 (C-7), 28.7 (C-3), 25.5(C-9), 24.8(C-8).HRMS: calculated for C 16 H 20 N 2 O 3 : 288.1474, not found, fragment: 288.1476 I.R.(thin film): 3691

13 C

 13 NMR (101 MHz, CDCl 3 ) δ 175.2 (C-1), 167.4 (C-5), 150.5 (C-d), 143.8 (C-a), 110.8 (C-b), 109.5 (C-c), 83.7 (C

  (380 mg, 2.5 mmol) in water (10 ml) containing concentrated hydrochloric acid(d = 1.18, 0.2 ml); Trifluoroacetaldehyde (0.4 ml, 5 mmol) was added and the solution was heated at 45 o C for 10 min, it was then kept at room temperature for 1.5 h during which time trifluoroacetaldehyde 4-nitrophenylhydrazone separated as fine yellow solid (525 mg, 90 %, 210.1 o C-212.5 o C). The spectra data are in agreement with the literature report. 251 1 H NMR (400 MHz,DMSO) δ 11.80(s, 1H, H-NH), 8.19 (d, J = 9.2 Hz, 2H, H-b),7.54 (q, J =4.3Hz, 1H, H-2), 7.19 (d, J = 9.2 Hz, 2H, H-c) 13 C NMR (101 MHz, DMSO) δ 149.2 (C-d), 140.5 (C-a), 126.8(q, J = 37 Hz, C-2), 126.1 (C-b), 121.2(q, J = 267 Hz, C-1), 112.5 (C-c). 251 Wojciechowska, Agata; Jasiński, Marcin; Kaszyński, Piotr ,Tetrahedron, 2015 , 71, ,2349 -2356. prepared by dissolving phenylhydrazine (271 mg, 2.5 mmol) in water (10 ml) containing concentrated hydrochloric acid (d = 1.18, 0.2 ml); Trifluoroacetaldehyde (0.4 ml, 5 mmol) was added and the solution was heated at 45 o C for 10 min, it was then kept at room temperature for 1.5 h during which time trifluoroacetaldehyde phenylhydrazone separated as fine yellow solid (385 mg, 82 %, 68.2 o C-69.8 o C). The spectra data are in agreement with the literature report.[1] 1 H NMR (400 MHz, CDCl 3 ) δ 7.83 (s, 1H, H-NH),7.24-7.20 (m, 2H, H-b), 7.01-6.98 (m, 2H, H-c), 6.94 -6.87 (m, 1H, H-a), 6.87 -6.79 (m, 1H, H-2).

1 1H

 1 (306 mg, 2.5 mmol) in water (10 ml) containing concentrated hydrochloric acid (d = 1.18, 0.2 ml); Trifluoroacetaldehyde (0.4 ml, 5 mmol) was added and the solution was heated at 45 o C for 10 min, it was then kept at room temperature for 1.5 h during which time trifluoroacetaldehyde 4-methylphenylhydrazone separated as fine yellow solid (355 mg, 70 %, 89.7 o C-90.6 o C). The spectra data are in agreement with the literature report. NMR (400 MHz, CDCl 3 ) δ 7.90 (s, 1H, H-NH),7.15-7.13 (m, 2H, H-b), 7.04-6.98 (m,

  2 O:PE = 50:50) to afford the desired product III-1 (94 %, 156 mg). Aspect: light yellow solid, m. p. 118.5-119.7 o C. Rf: 0.43 (Et 2 O:PE = 50:50) 1 H NMR (400 MHz, CDCl 3 ) δ 11.72 (s, 1H, H-NH), 8.18 (d, J = 9.2 Hz, 2H, H-b), 7.12 (d, J = 9.2 Hz, 2H, H-c),3.76 (bs, 4H, H-5),3.52 (s, 2H, H-3), 2.55 (bs, 4H, H-4).

13 C

 13 NMR (101 MHz, CDCl 3 ) δ 148.7 (C-d), 141.9 (C-a), 130.8(q, J = 34 Hz, C-2), 126.1(C-b), 121.2(q, J = 271 Hz, C-1), 112.8(C-c), 67.0(C-5), 54.8(C-3), 52.8(C-4). HRMS: calculated for C 13 H 15 F 3 N 4 O 3 : 332.1096, found: 332.1081 I.R.(thin film): 3689

  2 O:PE = 60:40) to afford the desired product III-2 (99 %, 220 mg). Aspect: light yellow solid, m. p. 88.2-90.1 o C. Rf: 0.50 (Et 2 O:PE = 60:40) 1 H NMR (400 MHz, CDCl 3 ) δ 12.61 (s, 1H, H-NH), 8.22(d, J = 9.2 Hz, 2H, 4H,g), 7.20 (d, J = 9.1 Hz, 2H, 4.22 (s, 1H, 3.74 (bs, 4H, 2.47 (bs, 4H,.

  residue was purified by column chromatography on silica gel (eluent: EA:PE = 40:60) to afford the desired product III-3 (99 %, 225 mg). Aspect: yellow solid, m. p. 155.1-156.6 o C. Rf: 0.47 (EA:PE = 40:60) 1 H NMR (400 MHz, CDCl 3 ) δ 12.46 (s, 1H, H-NH), 4H,h,i), 7.76 (d, J = 7.8 Hz, 1H, 7.61 (t, J = 8.0 Hz, 1H, 2H, 4.39 (s, 1H, 4H, 4H,.

  calculated for C 19 H 18 F 3 N 5 O 5 : 453.1260, found: 453.1252.

  residue was purified by column chromatography on silica gel (eluent: EA:PE = 20:80) to afford the desired product III-4 (99 %, 224 mg). Aspect: yellow solid m.p. 123.5-124.6 o C Rf: 0.20 (EA:PE = 20:80) 1 H NMR (400 MHz, CDCl 3 ) δ 12.51 (s, 1H, H-NH), 4H,g), 7.61 (d, J = 8.7 Hz, 2H, 7.22 (d, J = 9.1 Hz, 2H, 4.38 (s, 1H, 4H, 4H,.

  calculated for C 20 H 21 F 3 N 4 O 4 : 438.1515, found: 438.1499.

  2 O:PE = 50:50) to afford the desired product III-6 (82 %, 179 mg). Aspect: light yellow solid, m. p. 189.9-192.1 o C. Rf: 0.35 (Et 2 O:PE = 50:50) 1 H NMR (400 MHz, CDCl 3 ) δ 12.75 (s, 1H, H-NH), 8.22(d, J = 9.2 Hz, 2H, 4H,c), 6.88 (d, J = 8.8 Hz, 2H, 4.19 (s, 1H, 3.79 (s, 3H, 3.75(bs, 4H, 2.47 (bs, 4H,.

  calculated for C 20 H 21 F 3 N 4 O 4 : 438.1515, found: 438.1520.

  2 O:PE = 50:50) to afford the desired product III-7 (48 %, 100 mg). Aspect: black solid, m. p. 135.1-137.2 o C. Rf: 0.5 (Et 2 O:PE = 50:50) 1 H NMR (400 MHz, CDCl 3 ) δ 12.14 (s, 1H, H-NH), 8.26 -8.19 (m, 2H, H-b), 7.30 (dd, J =

13 C

 13 NMR (101 MHz, CDCl 3 ) δ 148.2(C-d), 142.1(C-a), 136.2(C-e), 131.8(q, J = 33 Hz, nitrophenylhydrazone (0.5 mmol, 117 mg, 1.0 eq) was added to a solution of morpholine (0.5 mmol, 44 mg, 1.0 eq) and nicotinaldehyde (0.5 mmol, 54 mg, 1.0 eq) in 3 ml toluene. The stirred mixture was heated to reflux under Ar for 15 h. After completion of present reaction, the reaction mixture was concentrated under vacuum. The residue was purified by column chromatography on silica gel (eluent: Et 2 O:PE = 50:50) to afford the desired product III-8 (99 %, 201 mg). Aspect: white solid, m. p. 182.6-183.4 o C. Rf: 0.45 (Et 2 O:PE = 50:50) 1 H NMR (400 MHz, CDCl 3 ) δ 12.52 (s, 1H, H-NH),

  calculated for C 18 H 18 F 3 N 5 O 3 : 409.1362, found: 409.1373.

  trifluoro-1-(1-methyl-1H-indol-3-yl)-2-(2-(4-nitrophenyl)hydrazono)propyl)monitrophenylhydrazone (0.5 mmol, 117 mg, 1.0 eq) was added to a solution of morpholine (0.5 mmol, 44 mg, 1.0 eq) and 1-methyl-1H-indole-3-carbaldehyde (0.5 mmol, 80 mg, 1.0 eq) in 3ml toluene. The stirred mixture was heated to reflux under Ar for 15 h. After completion of present reaction, the reaction mixture was concentrated under vacuum. The residue was purified by column chromatography on silica gel (eluent: Et 2 O:PE = 50:50) to afford the desired product III-9 (58 %, 133 mg). Aspect: gray solid, m. p. 178.1-180.0 o C. Rf: 0.42 (Et 2 O:PE = 50:50) 1 H NMR (400 MHz, CDCl 3 ) δ 12.75 (s, 1H, H-NH), 8.24 (d, J = 9.0 Hz, 2H, H-b), 7.63 (d, J

  nitrophenylhydrazone (0.5 mmol, 117 mg, 1.0 eq) was added to a solution of morpholine (0.5 mmol, 44 mg, 1.0 eq) and trifluoroacetaldehyde (0.5 mmol, 65 mg, 1.0 eq) in 3 ml toluene. The stirred mixture was heated to reflux under Ar for 12 h. After completion of present reaction, the reaction mixture was concentrated under vacuum. The residue was purified by column chromatography on silica gel (eluent: Et 2 O:PE = 50:50) to afford the desired product III-10 (79 %, 158 mg). Aspect: brown solid, m. p. 198.6-199.5 o C. Rf: 0.44 (Et 2 O:PE = 50:50) 1 H NMR (400 MHz, MeOD) δ 8.15 (d, J = 9.1 Hz, 2H, H-b), 7.28 (d, J = 4.2 Hz, 1H, H-3), 7.15 (d, J = 9.1 Hz, 2H, H-c),3.68 -3.59 (m, 4H, H-5), 2.78 (2.82-2.73, m, 4H, H-4).

13 C 1 (

 131 NMR (101 MHz, MeOD) δ 150.7(C-d), 142.6(C-a), 127.4(q, J = 39 Hz, C-2), 126.9 (q, J = 291 Hz, C-6), 126.8(C-b), 122.5(q, J = 267 Hz, C-1), 113.4 (C-c), 84.2(q, J = 27 Hz, C-3), 68.3(C-5), 51.0(C-4).HRMS: calculated for C 14 H 14 F 6 N 4 O 3 : 400.0970, not found, fragment 234.0365I.R.(thin film):3691, 2968, 2860, 1596, 1454, 1339, 1273, 1251, 1161, 1117, 1021cm -nitrophenylhydrazone (0.5 mmol, 117 mg, 1.0 eq) was added to a solution of pyrrolidine (0.5 mmol, 36 mg, 1.0 eq) and p-chlorobenzaldehyde (0.5 mmol, 70 mg, 1.0 eq) in 3 ml toluene. The stirred mixture was heated to reflux under Ar for 12 h. After completion of present reaction, the reaction mixture was concentrated under vacuum. The residue was purified by column chromatography on silica gel (eluent: CH 2 Cl 2 :PE = 50:50) to afford the desired product III-11(82 %, 175 mg).Aspect: yellow oilRf: 0.47 (CH 2 Cl 2 :PE = 50:50) 1 H NMR (400 MHz, CDCl 3 ) δ 12.63 (s, 1H, H-NH), 8.08 (d, J = 9.2 Hz, 2H, H-b), 7.25 -

  nitrophenylhydrazone (0.5 mmol, 117 mg, 1.0 eq) was added to a solution of piperidine (0.5 mmol, 43 mg, 1.0 eq) and p-chlorobenzaldehyde (0.5 mmol, 70 mg, 1.0 eq) in 3 ml toluene. The stirred mixture was heated to reflux under Ar for 12 h. After completion of present reaction, the reaction mixture was concentrated under vacuum. The residue was purified by column chromatography on silica gel (eluent: CH 2 Cl 2 :PE = 40:60)to afford the desired product III-12 (87 %, 191 mg). Aspect: light yellow solid, m.p. 192.9-194.4 o C Rf: 0.50 (DCM:PE = 40:60) 1 H NMR (400 MHz, CDCl 3 ) δ 13.03 (s, 1H, H-NH), 8.21 (d, J = 9.2 Hz, 2H, H-b), 7.32 (s,

  nitrophenylhydrazone (0.5 mmol, 117 mg, 1.0 eq) was added to a solution of 1-benzylpiperazine (0.5 mmol, 88 mg, 1.0 eq) and p-chlorobenzaldehyde (0.5 mmol, 70 mg, 1.0 eq) in 3 ml toluene. The stirred mixture was heated to reflux under Ar for 12 h. After completion of present reaction, the reaction mixture was concentrated under vacuum. The residue was purified by column chromatography on silica gel (eluent: Et 2 O:PE = 70:30) to afford the desired product III-13 (81 %, 215 mg). Aspect: white solid, m. p. 84.1-85.9 o C. Rf: 0.40 (Et 2 O:PE = 70:30) 1 H NMR (400 MHz, CDCl 3 ) δ 12.81 (s, 1H, H-NH), 8.23 (d, J = 9.1 Hz, 2H, H-b), 7.39 -

  δ (ppm) = 12.32 (s, 1H, H-NH), 8.16 (d, J = 9.0 Hz, 2H, H-b), 7.07 (d, J = 9.0 Hz, 2H, H-c), 3.56 (s, 2H, H-3), 2.60 (q, J = 7.1 Hz, 4H, H-4), 1.12 (t, J = 7.1 Hz, 6H, H-5).

13 C

 13 NMR (101 MHz, CDCl 3 ): δ (ppm) = 149.0 (C-d), 141.5 (C-a), 132.4(q, J = 33 Hz, C-2), 126.1 (C-b), 121.3(q, J = 271 Hz, C-1), 112.5 (C-c), 50.6 (C-3), 46.7 (C-4), 11.5 (C-5). HRMS: calculated for C 13 H 17 F 3 N 4 O 2 : 318.1304, found: 318.1305 I.R.(thin film): 3691

13 C

 13 NMR (101 MHz, CDCl 3 ) δ 143.7(C-d), 129.5(C-b), 126.3(q, J = 34 Hz, C-2), 121.9(q, J = 270 Hz, C-1), 121.8(C-a), 113.4 (C-c), 67.1(C-5), 54.4 (C-3), 52.7(C-4).HRMS: calculated for C 13 H 16 F 3 N 3 O: 287.1245, found: 287.1247.

  The residue was purified by column chromatography on silica gel (eluent: Et 2 O:PE = 40:60) to afford the desired product III-16 (85 %, 169 mg). Aspect: white solid, m. p. 135.8-136.7 o C. Rf: 0.51 (Et 2 O:PE = 40:60) 1 H NMR (400 MHz, CDCl 3 ) δ 11.94 (s, 1H, H-NH),

13 C 3 (

 133 NMR (101 MHz, CDCl 3 ) δ 143.4 (C-d), 134.9 (C-h), 134.6 (C-e), 130.3 (C-f), 129.6 (C-b), 129.5(C-h), 127.7(q, J = 32 Hz, C-2), 121.9 (C-a), 121.9(q, J = 272 Hz, C-1), 113.

13 C

 13 NMR (101 MHz, CDCl 3 ) δ 141.5(C-d), 131.2 (C-a), 129.9(C-b), 125.5(q, J = 34 Hz, C-2), 121.9(q, J = 270 Hz, C-1), 113.4 (C-c), 67.1(C-5), 54.3 (C-3), 52.7(C-4), 20.8 (C-6).HRMS: calculated forC 14 H 18 F 3 N 3 O:301.1402, found: 301.1404 I.R.(thin film): 3691

  methylphenylhydrazone (0.5 mmol, 101 mg, 1.0 eq) was added to a solution of morpholine (0.5 mmol, 44 mg, 1.0 eq) and p-chlorobenzaldehyde (0.5 mmol, 70 mg, 1.0 eq) in 3 ml toluene. The stirred mixture was heated to reflux under Ar for 12 h. After completion of present reaction, the reaction mixture was concentrated under vacuum. The residue was purified by column chromatography on silica gel (eluent: CH 2 Cl 2 :PE = 50:50) to afford the desired product III-18 (68 %, 140 mg).Aspect: yellow oilRf: 0.34 (DCM:PE = 50:50) 1 H NMR (400 MHz, CDCl 3 ) δ 11.85 (s, 1H, H-NH),

13 C 3 (

 133 NMR (101 MHz, CDCl 3 ) δ 141.2 (C-d), 134.9 (C-h), 134.7 (C-e), 131.4 (C-a), 130.3 (C-b), 130.1 (C-f), 129.5(C-g), 127.0(q, J = 32 Hz, C-2), 122.0(q, J = 272 Hz, C-1), 113.

13 C

 13 NMR (101 MHz, CDCl 3 ) δ 156.1(C-e), 147.9 (C-a), 138.2 (C-c), 128.4(q, J = 34 Hz, C-2), 121.4(q, J = 271 Hz, C-1), 117.4 (C-b), 107.6 (C-d), 66.8 (C-5), 54.3 (C-3), 52.8 (C-4). HRMS: calculated for C 12 H 15 F 3 N 4 O:288.1198, found: 288.1200.

  calculated for C 18 H 18 ClF 3 N 4 O:398.1121, found: 398.1131.

3

  ml toluene. The stirred mixture was heated to reflux under Ar for 12 h. After completion of present reaction, the reaction mixture was concentrated under vacuum. The residue was purified by column chromatography on silica gel (eluent: CH 2 Cl 2 :PE = 10:90) to afford the desired product III-21 (75 %, 148 mg).Aspect: yellow oilRf: 0.78 (DCM:PE = 10:90) 1 H NMR (400 MHz, CDCl 3 ) δ 12.29 (s, 1H, H-NH),7.39-7.33 (m, 6H, H-b,f,g), 7.21 (d, J =

13 C 2 (

 132 NMR (101 MHz, CDCl 3 ) δ 143.8 (C-d), 135.9 (C-e), 134.5 (C-h), 130.2 (C-f), 129.5 (C-b), 129.3 (C-g), 128.8(q, J = 32 Hz, C-2), 122.0(q, J = 271 Hz, C-1),121.5 (C-a),113.-2-(2-(2,2,2-trifluoroethylidene)hydrazinyl)pyridine (0.5 mmol, 90 mg, 1.0 eq) was added

  2 O:PE = 30:70) to afford the desired product III-22 (58 %, 111 mg). Aspect: yellow oil Rf: 0.56 (Et 2 O:PE = 30:70) 1 H NMR (400 MHz, CDCl 3 )δ 12.24 (s, 1H, H-NH),

  The residue was purified by column chromatography on silica gel (eluent: PE:Et 2 O = 60:40)to afford the desired product III-23 (98 %, 154 mg). Aspect: white solid m.p. 86.3 o C-87.5 o C Rf: 0.39 (PE:Et 2 O = 60:40) 1 H NMR (400 MHz, CDCl 3 ) δ 8.16 (d, J = 9.4 Hz, 2H, H-b), 7.23 (d, J = 9.4 Hz, 2H, H-c),5.86 (ddt, J = 16.8, 10.1, 6.6 Hz, 1H, 2H,, 4.62 (s, 2H, H-7), 3.57 (s, 2H, H-3), 3.17(d, J = 6.6 Hz, 2H,.

13 C

 13 NMR (101 MHz, CDCl 3 ) δ 149.7 (C-d), 141.8 (C-a), 133.4 (C-5), 133.0(q, J = 35 Hz, C-2), 125.6 (C-b), 120.6(q, J = 271 Hz, C-1), 120.3 (C-6), 113.1 (C-c), 63.0 (C-7), 56.7

13 C 1 (

 131 NMR (101 MHz, CDCl 3 ) δ 159.6 (C-h), 149.7 (C-d), 141.8 (C-a), 132.9(q, J = 35 Hz, C-2), 130.5 (C-f), 128.1 (C-e), 125.6 (C-b), 120.6(q, J = 272 Hz, C-1), 114.2 (C-c), 113.

13 C

 13 NMR (101 MHz, CDCl 3 ) δ 197.0(C-5), 147.3(C-d), 145.7(C-a), 144.8(C-7), 137.7(q, J = 36 Hz, C-2), 124.9(C-b), 124.7 (C-c), 120.5(q, J = 272 Hz, C-1), 106.9 (C-4), 30.2 , 221 mg) was dissolved in 2.5 mL acetone, and the stirred mixture was heated to 130 o C under microwave for 1 h. After completion of present reaction, the reaction mixture was concentrated under vacuum. The residue was purified by column chromatography on silica gel (eluent: Et 2 O:PE = 50:50) to afford the desired product III-27(34 %, 67 mg).Aspect: yellow oilRf: 0.7(Et 2 O:PE = 50:50) 1 H NMR (400 MHz, CDCl 3 ) δ 8.27(d, J = 9.2 Hz, 2H, 7.47 (d, J = 9.1 Hz, 2H, 7.30 (d, J = 8.5 Hz, 2H, 7.12 (d, J = 8.4 Hz, 2H, 5.11 (dd, J = 6.3, 1.1 Hz, 1H, 4.41 (d, J = 6.2 Hz, 1H, 1.93 (s, 3H,.

  calculated for C 20 H 15 ClF 3 N 3 O 3 :437.0754, found: 437.0734.

  calculated for C 19 H 15 ClF 3 N 3 O:393.0856, found: 393.0847.

13 C

 13 NMR (101 MHz, CDCl 3 ) δ 197.0 (C-5), 147.1 (C-7), 140.1 (C-d), 137.8 (C-a), 135.0(q, J = 35 Hz, C-2), 130.0 (C-b), 126.1 (C-c), 120.9(q, J = 271 Hz, C-1), 102.8(C-4), 30.3 (C-6), 22.4 (C-3), 21.2 (C-9), 18.0(C-8).

  calculated for C 21 H 18 ClF 3 N 2 : 390.1111, found:390.1120.

13 C 1 (

 131 NMR (101 MHz, CDCl 3 ) δ 136.1 (C-e), 136.0 (C-c), 132.0 (C-f), 128.2 (C-d), 128.

13 C

 13 NMR (101 MHz, CDCl 3 ) δ 172.4 (C-8), 137.3 (C-e), 133.4 (C-f), 131.8 (C-c), 131.3 (C-2), 128.4 (C-d), 127.6 (C-b), 126.7 (C-a), 122.5 (C-3), 94.1 (C-1), 52.0 (C-9), 51.9 (C-9), 29.8 (C-6), 29.1 (C-7), 28.1 (C-5), 23.3 (C-4). HRMS: calculated for C 19 H 23 NO 6 : 361.1525, not found, fragment (-HNO 2 ): 314.1518 I.R.(thin film):

3 )

 3 of dimethyl 4-(3,4-dihydronaphthalen-1-yl)-4-nitroheptanedioate (0.5 mmol, 181 mg, 100 mol%) in DMF (1.5 ml) was added Cs 2 CO 3 (0.5 mmol, 163 mg, 100 mol%), Pd(OAc) 2 (5 mol%), and dppe (5 mol%), the mixture was stirred for 30 min at 120 o C under Ar. After evaporation of solvent under reduced pressure (vacuum, 80 o C), the residue crude (384 mg) was purified by column chromatography on silica gel (eluent: Et 2 O:PE = 20:80) to afford the desired product (87 %, 137 mg), δ 8.09(d, J = 8.2 Hz, 1H, 1H, 7.73 (d, J = 8.1 Hz, 1H, 3H,c,j), 7.38 (d, J = 6.6 Hz, 1H,,3.56 (s, 6H, H-1,5), 2.26 -1.96 (m, 8H, H-3,2).

13 C

 13 NMR (101 MHz, CDCl 3 ) δ173.8(C-4), 139.6 (C-g), 133.9 (C-e), 132.6 (C-f), 129.0(C-d), 126.9 (C-i), 125.9(C-j), 125.6 (C-b), 125.5(C-c), 122.8 (C-a), 51.4(C-5), 36.7

13 CI 3 )

 133 NMR (101 MHz, CDCl 3 ) δ137.5(C-2), 133.2(C-e), 131.8(C-f), 130.4 (C-c), 129.0(C-d), 128.5 (C-b), 127.1(C-a), 122.1(C-3), 118.0 (C-8), 93.5 (C-1), 30.9(C-5), 27.9(C-6), 23.4 (C-4),13.2 (C-7).HRMS: calculated for C 17 H 17 N 3 O 2 : 295.1321, not found, fragment: 249.1386 dihydronaphthalen-1-yl)-4-nitroheptanedinitrile (0.5 mmol, 148 mg, 100 mol%) in DMF (1.5 ml) was added Cs 2 CO 3 (0.5 mmol, 163 mg, 100 mol%), Pd(OAc) 2 (5mol%), and dppe (5 mol%), the mixture was stirred for 30 min at 120 o C under Ar. After evaporation of solvent under reduced pressure (vacuum, 80 o C), the residue crude (357 mg) was purified by column chromatography on silica gel (eluent: Et 2 O:PE = 70:30) to afford the desired product (71 %, 88 mg). δ 8.18(d, J = 7.8 Hz, 1H, 1H, 7.82 (d, J = 8.2 Hz, 1H, 3H,i,b), 7.36 (d, J = 7.1 Hz, 1H, 3.87 (s, 1H, 8H,3).

13 C

 13 NMR (101 MHz, CDCl 3 ) δ 136.7(C-g), 134.1(C-e), 132.6 (C-f), 129.3 (C-d), 128.1(C-i), 126.9(C-j), 126.2 (C-b), 125.7 (C-c), 122.7 (C-a), 122.3 (C-h), 119.4 (C-4), 36.4 of 4-(nitromethyl)-1,2-dihydronaphthalene (0.5 mmol, 90 mg, 100 mol%) in acetonitrile (1.5 ml) was added methyl acrylate (1.5 mmol, 129 mg, 3 eq) and DBU (15 mg, 10 mol%), the mixture was stirred for 2 h at r.t. under Ar. After evaporation of solvent under reduced pressure, the residue crude (267 mg) was purified by column chromatography on silica gel (eluent: DCM:PE = 40:60) to afford the desired product (71 %, 98 mg).

13 CI 3 )

 133 NMR (101 MHz, CDCl 3 ) δ172.5(C-8), 136.4(C-2), 132.2(C-e), 131.8(C-f), 130.6(C-c), 128.2 (C-d), 127.9(C-b), 126.9(C-a), 122.2(C-3), 86.2 (C-1), 52.0(C-9), 30.3 (C-7), 27.8(C-5), 27.6 (C-6), 23.1 (C-4).HRMS: calculated for C 15 H 17 NO 4 : 275.1158, found: 275.1161 of methyl 4-(3,4-dihydronaphthalen-1-yl)-4-nitrobutanoate (0.5 mmol, 138 mg, 100 mol%) in DMF (1.5 ml) was added Cs 2 CO 3 (0.5 mmol, 163 mg, 100 mol%), Pd(OAc) 2 (5 mol%), and dppe (5 mol%), the mixture was stirred for 30 min at 120 o C under Ar. After evaporation of solvent under reduced pressure (vacuum, 80 o C), the residue crude (361 mg) was purified by column chromatography on silica gel (eluent: Et 2 O:PE = 10:90) to afford the desired product (66 %, 75 mg), δ 8.09(d, J = 8.3 Hz, 1H,, 7.87(d, J = 7.9 Hz, 1H, 7.74 (d, J = 8.1 Hz, 1H, 2H,i), 7.41 (t, J = 7.6 Hz, 1H, H-b), 7.33 (d, J = 6.9 Hz, 1H, H-h), 3.70 (s, 3H, H-5), 3.13 (t, J = 7.7 Hz, 2H, H-1), 2.44 (t, J = 7.3 Hz, 2H, 2.11 (p, J = 7.4 Hz, 2H,.

13 C

 13 NMR (101 MHz, CDCl 3 ) δ 174.1 (C-4), 137.6 (C-g), 134.0 (C-f), 131.9 (C-a), 128.9 (C-d), 127.0 (C-i), 126.3 (C-j), 126.0 (C-e), 125.6 (C-b), 125.6 (C-c), 123.9 (C-h), 51.7

  of 4-(nitromethyl)-1,2-dihydronaphthalene (0.5 mmol, 90 mg, 100 mol%) in acetonitrile (1.5 ml) was added but-3-en-2-one (1.5 mmol, 105 mg, 3 eq) and DBU(15 mg, 10 mol%), the mixture was stirred for 3 h at r.t. under Ar. After evaporation of solvent under reduced pressure, the residue crude (229 mg) was purified by column chromatography on silica gel (eluent: Et 2 O:PE = 30:70) to afford the desired product (84 %, 109 mg).

13 C

 13 NMR (101 MHz, CDCl 3 ) δ 206.7 (C-8), 136.2 (C-2), 132.2 (C-e), 131.8 (C-f), 130.4 (C-c), 128.1 (C-d), 127.8 (C-b), 126.8 (C-a), 122.1 (C-3), 86.2 (C-1), 39.3 (C-7), 30.0 (C-9), 27.5 (C-5), 26.4 (C-6), 23.0 (C-4). HRMS: calculated for C 15 H 17 NO 3 :259.1208, found 259.1201 I.R.(thin film):

3 )

 3 dihydronaphthalen-1-yl)-5-nitropentan-2-one (0.5 mmol, 130 mg, 100 mol%) in DMF (1.5 ml) was added Cs 2 CO 3 (0.5 mmol, 163 mg, 100 mol%), Pd(OAc) 2 (5 mol%), and dppe (5 mol%), the mixture was stirred for 30 min at 120 o C under Ar. After evaporation of solvent under reduced pressure (vacuum, 80 o C), the residue crude (300 mg) was purified by column chromatography on silica gel (eluent: Et 2 O:PE = 20:80) to afford the desired product (71 %, 75 mg), δ 8.11(d, J = 8.4 Hz, 1H, 1H, 7.74 (d, J = 8.2 Hz, 1H, 2H,i), 1H, 7.32 (d, J = 6.8 Hz, 1H, H-h), 3.10(t, J = 8.0 Hz, 2H, H-1), 2.52 (t, J = 7.2 Hz, 2H, H-3), 2.14 (s, 3H, H-5), 2.06 (p, J = 8.0 Hz, 2H, H-2).

13 C 8 (

 138 NMR (101 MHz, CDCl 3 ) δ 208.9(C-4), 137.8 (C-g), 133.9 (C-e), 131.9 (C-f), 128.

3 )I

 3 of 4-(nitromethyl)-1,2-dihydronaphthalene (0.5 mmol, 90 mg, 100 mol%) in DMF(1.5 ml) was added Cs 2 CO 3 (0.5 mmol, 163 mg, 100 mol%), Pd(OAc) 2 (5 mol%), and dppe (5 mol%), the mixture was stirred for 30 min at 120 o C under Ar. After evaporation of solvent under reduced pressure (vacuum, 80 o C), the residue crude (297 mg) was purified by column chromatography on silica gel (eluent: PE) to afford the desired product (35 %δ 8.04(d, J = 8.1 Hz, 1H,, 7.89 (d, J = 7.4 Hz, 1H, H-a), 7.75 (d, J = 8.1 Hz, 1H, H-j), 7.59 -7.48 (m, 2H, H-c,i), 7.41 (t, J = 7.5 Hz, 1H, H-b), 7.36 (d, J = 6.9 Hz, 1H, H-h), 2.74 (s, 3H, H-1).13 C NMR (101 MHz, CDCl 3 ) δ 134.4 (C-g), 133.7 (C-e), 132.7 (C-f), 128.7 (C-d), 126.7 (C-i), 126.5 (C-h), 125.8 (C-j), 125.7 (C-b), 125.7 (C-c), 124.2 (C-a), 19.5 (C-1).HRMS: calculated for C 11 H 10 :142.0783, found 142.0784 of 4-(nitromethyl)-1,2-dihydronaphthalene (0.5 mmol, 90 mg, 100 mol%) in 1.5 ml CH 3 CN was added formaldehyde solution (2.5 mmol, 5 eq) and DBU (50 mol%), the mixture was stirred at r.t. for 2 h under Ar. After evaporation of solvent under reduced pressure, the residue crude was purified by column chromatography on silica gel (EA:PE = 4:6) to afford the 2-(3,4-dihydronaphthalen-1-yl)-2-nitropropane-1,3-diol (66 %, 82 mg, colourless oil).In a round-bottomed flask was added 2-(3,4-dihydronaphthalen-1-yl)-2-nitropropane-1,3-diol (0.5 mmol, 125 mg, 100 mol%), p-toluenesulfonic acid (8 mg, 10 mol%),excess MgSO4(1 g) and 1.5 ml acetone. The mixture was heated to reflux for 15 h, after evaporation of solvent under reduced pressure, the residue crude was purified by column chromatography on silica gel(Et 2 O:PE = 30:70) to afford the desired product( 45 %,65 mg)

  C-8), 23.4(C-9), 21.6(C-4).HRMS: calculated for C 16 H 19 NO 4 : 289.1314, not found, fragment: 246.1380. I.R.(thin film):3413,

3 )

 3 mg, 100 mol%) in DMF(1.5 ml) was added Cs 2 CO 3 (0.5 mmol, 163 mg, 100 mol%), Pd(OAc) 2 (5 mol%), and dppe (5 mol%), the mixture was stirred for 30 min at 120 o C under Ar. After evaporation of solvent under reduced pressure (vacuum, 80 o C), the residue crude (400 mg) was purified by column chromatography on silica gel (eluent: DCM:PE = 30:70) to afford the desired product (50 %, 120 mg), δ 7.95 -7.86(m, 2H, H-j,d), 7.76 -7.74 (m, 1H, H-a), 7.67(d, J = 8.2 Hz, 2H,b), 1H, 7.18 (d, J = 7.0 Hz, 1H,, 5.34 (s, 1H, H-1), 5.03 (s, 1H, H-1),3.53 (s, 3H, 2.76 (t, J = 7.6 Hz, 2H, 2.36 (t, J = 7.7 Hz, 2H,.

3 )

 3 -bottomed flask fitted with a Dean and Stark trap was added1,5,6,7-tetrahydro-4H-indol-4-one (5 mmol, 676 mg, 100 mol%), nitromethane (50 mmol, 1.53 g, 10 eq), N,N-dimethylethane-1,2-diamine (1.5 mmol, 132 mg, 30 mol%), and toluene (25 ml), the mixture was refluxed for 72 h. After evaporation of solvent under reduced pressure, the residue crude was purified by column chromatography on silica gel (eluent: EA:PE = 30:70) to afford the desired product 4-(nitromethyl)-6,7-dihydro-1H-indole (δ 8.54 (s, 1H, H-NH), 7.41 (t, J = 1.6 Hz, 1H, H-a), 6.76 -6.68(m, 1H, 6.31 (dd, J = 3.2, 2.4 Hz, 1H, 2H,, 2.74 (t, J = 6.3 Hz, 2H, 2H,.

13 C

 13 NMR (101 MHz, CDCl 3 ) δ 149.3 (C-d), 139.0 (C-2), 127.7 (C-3), 119.4 (C-a), 115.2 (C-c), 104.3 (C-b), 26.5 (C-1), 23.1 (C-5), 22.7 (C-4). HRMS: calculated for C 9 H 10 N 2 O 2 :178.0742, found: 178.0740 I.R.(thin film): 3270

  of 4-(nitromethyl)-6,7-dihydro-1H-indole (0.5 mmol, 89 mg, 100 mol%) in acetonitrile (1.5 ml) was added acetonitrile (2.5 mmol, 265 mg, 5 eq) and DBU(38 mg, 50 mol%), the mixture was stirred for 3 h at r.t. under Ar. After evaporation of solvent under reduced pressure, the residue crude (410 mg) was purified by column chromatography on silica gel (eluent: EA:PE = 30:70) to afford the desired product (83 %, 118 mg),

13 CI 3 )

 133 NMR (101 MHz, CDCl 3 ) δ 130.4(C-2), 129.5(C-d), 119.7(C-a), 118.4(C-8), 116.8 (C-3), 112.9 (C-c), 103.4 (C-b), 94.1 (C-1),30.8 (C-5), 24.2(C-6), 20.6 (C-4),13.1 (C-7).HRMS: calculated for C 15 H 16 N 4 O 2 : 284.1273, found: 284.1267 of methyl 4-(6,7-dihydro-1H-indol-4-yl)-4-nitroheptanedinitrile (0.5 mmol, 142 mg, 100 mol%) in DMF (1.5 ml) was added Cs 2 CO 3 (0.5 mmol, 163 mg, 100 mol%), Pd(OAc) 2 (5 mol%), and dppe (5 mol%), the mixture was stirred for 30 min at 120 o C under Ar. After evaporation of solvent under reduced pressure (vacuum, 80 o C), the residue crude (410 mg) was purified by column chromatography on silica gel (eluent: EA:PE = 30:70) to afford the desired product (67 %, 80 mg). δ 8.44 (s, 1H, H-NH), 7.34(d, J = 8.2 Hz, 1H, 1H, 7.17 (t, J = 7.7 Hz, 1H, H-f), 6.91 (d, J = 7.2 Hz, 1H, H-a), 6.61 -6.60(m, 1H, H-b), 3.26 -3.20 (m, 1H,H-1), 2.22 -2.05 (m, 8H, H-2,3).

13 CI

 13 NMR (101 MHz, CDCl 3 ) δ 136.2(C-d), 131.6 (C-h), 127.1(C-a), 124.7(C-c), 122.5(C-f), 119.7(C-4), 117.9(C-g), 110.6 (C-e), 100.5(C-b), 42.0 (C-1),31.6 (C-2), 15.6(C-3).HRMS: calculated forC 15 H 15 N 3 :237.1266, found: 237.1269 Route de l'Orme aux Merisiers RD 128 / 91190 Saint-Aubin, France Titre : Hétérocycles par Réactions multicomposants et réaction de Tsuji-Trost des dérivés nitrés allyliques. Mots clés : réactions multicomposants, hétérocycles, hydrazones, réactions de Tsuji-Trost, naphtalène Résumé : Les réactions multicomposants jouent un rôle important en chimie organique. Elles permettent de coupler au moins trois produits de départ ensemble fournissant des adduits qui ont été largement utilisés pour la synthèse de molécules complexes et de composés bioactifs. Les réactions multicomposants à base d'isonitriles ont été plus particulièrement développées pour la préparation de bibliothèques de structures organiques exploitées dans la recherche pharmaceutique. La réaction de Passerini, combinée à des additions de Michael suivies de cyclisation, a permis un accès rapide aux γ-butyrolactones avec de bons rendements. Les adduits de Passerini des aldéhydes aromatiques agissent comme des nucléophiles dans les additions de Michael avec l'acrylonitrile. La réaction se déroule conjointement avec l'hydrolyse de l'ester. Le γ-hydroxynitrile résultant peut être cyclisé dans des conditions acides pour donner des γêtre impliquées dans des réactions de type Mannich avec le formaldéhyde ou des aldéhydes aromatiques. Nous avons démontrés que cette réaction à trois composants peut être utilisée pour la formation d'hétérocycles substitutés par des groupes CF3. Ainsi le chauffage des hydrazones adduits de Mannich avec des β-cetoesters conduit à l'élimination de l'amine avce formation de 1,2diazine. La réaction fait probablement intervenir des azoalcènes intermédiaires. Nous avons dans une troisième partie préparé de nouveaux dérivés du naphtalène en travaillant sur des élimination de type Tsuji-Trost de composés nitrés allyliques. Couplée à la chimie des dérivés nitrés, cette synthèse de diène fournit un outil synthétique puissant pour la formation de naphtalènes 1-substitués. Title : Multicomponent Reactions toward Heterocycles and Tsuji-Trost Reaction of Allylic Nitro Derivatives Keywords : multicomponent reactions, heterocycles, hydrazones, Tsuji-Trost reactions, naphthalene Multicomponent reactions play an important role in organic chemistry. They make it possible to couple at least three starting materials together providing adducts that have been widely used for the synthesis of complex molecules and bioactive compounds. The multicomponent reactions based on isonitriles have been developed more particularly for the preparation of libraries of organic structures used in pharmaceutical research. The Passerini reaction, combined with Michael additions followed by cyclization, allowed rapid access to γ-butyrolactones in good yields. Passerini adducts of aromatic aldehydes act as nucleophiles in Michael additions with acrylonitrile. The reaction proceeds in conjunction with the hydrolysis of the ester. The resulting γ-hydroxynitrile can be cyclized under acidic conditions to give γ-butyrolactones. NH-aryl hydrazones derived from trifluoroacetaldehyde hemiacetal can be involved in Mannich reactions with formaldehyde or aromatic aldehydes. We have demonstrated that this threecomponent reaction can be used for the formation of CF3-substituted heterocycles. Thus, heating hydrazone Mannich adducts with β-ketoesters leads to the elimination of the amine with the formation of 1,2-diazines. The reaction probably involves intermediate azoalkenes. In a third part, we have prepared new naphthalene derivatives by working on Tsuji-Trost elimination of allylic nitro compounds. Coupled with the chemistry of nitro compounds, this diene synthesis provides a powerful synthetic tool for the formation of 1-substituted naphthalenes.

  ). 11 large number of MCRs have been reported in the literature, among which Mannich reactions are very important. IMCRs allow for the synthesis of the largest number of different scaffolds. Before discussing the IMCRs in details, an introduction about isocyanides will be presented.

8

(a) P.

Biginelli, Ber. Dtsch. Chem. Ges. 1891, 24, 2962. (b)

P.

Biginelli, Ber. Dtsch. Chem. Ges. 1893, 26, 447. 9 C. Mannich, A. Krösche, Pharm. (Weinheim, Ger.) 1912, 250, 647. 10

(a) G. Passerini, G.Simone, Chim. Ital. 1921, 51, 126. (b) G. Passerini, Chim. Ital. 1921, 51, 181. (c) G. Passerini, Chim. Ital. 1922, 52, 432. Reviews: (a) L. Banfi, R. Riva, Org. React. 2005, 65, 1. 11 (a) I. Ugi, R. Meyr, U. Fetzer, C. Steinbrückner, Angew. Chem. 1959, 71, 386. (b) I. Ugi, C. Steinbrückner, Angew. Chem. 1960, 72, 267.

A

  36

35

(a) D.

Bachi, A. Balanov, N. Bar-Ner, J. Org. Chem. 1994, 59, 7752. (b)

B.

Bachi, N. Bar-Ner, A. Melman, J. Org. Chem. 1996, 61, 7116. (c)

L. Benati, R. Leardini, M. Minozzi, D. Nanni, R. Scialpi, P. Spagnolo, S. Stazzari, G. Zanardi, Angew. Chem.

Int. Ed. 2004, 43, 3598. (d)

P.

Curran, H. Liu, J. Am. Chem. Soc. 1991, 113, 2127. 36

H. Josien, S. Ko, D. Bom, P.

Curran, Chem. Eur. J. 1998, 4, 67. (b) D. Curran, H. Liu, H. Josien, S. Ko, Tetrahedron 1996, 52, 11385

  45

43

V.

Hoang and G. Bruce, org. lett. 2011 ,13, 2584-2585 44

U.

Nef, Justus Liebigs Ann. Chem. 1892, 210, 269. 45 D. Coffinier, L. Elkaïm, L. Grimaud, Org. Lett. 2009, 11, 1825.

  Ugi proposed a mechanism for this coupling.49 It's assumed that the mechanism was non-ionic. Hydrogen bonding plays a crucial role in the formation of the presumed cyclic intermediate in which the isocyanide inserts. A Mumm type rearrangement underwent to give the final adduct (scheme 1-36).

	In 2011, Maeda et al. proposed a mechanism through a theoretical method, which was close
	to that suggested by Ugi. It involves the addition of the isocyanide onto the aldehyde, which
	is activated by the acid. After Mumm rearrangement, the final product was delivered (scheme
	1-38). 50

Banfi, R. Riva, Org. React. 2005, 65, 1 reaction solvent, in 1961, The Mumm rearrangement was first documented in 1910. It is a 1,3 (O,N) acyl transfer of an acyl imidate or isoimide group to an imide (scheme 1-37).

49 I.

Ugi, R. Meyr, Chem. Ber. 1961, 94, 2229. 50

S. Maeda, S. Komagawa, M. Uchiyama, K. Morokuma, Angew. Chem.

Int. Ed. 2011, 50, 644.

  ).

	63 I. Ugi, C. Steinbrücker, Chem. Ber. 1961, 94, 2802.
	64 (a) D. Floyd, A. Harnett, A. Miller, S. Patel, L. Saroglou, M. Whittaker, Synlett 1998, 637. (b) U. Kazmaier, C. Hebach,
	Synlett 2003, 1591. (c) R. Pick, M. Bauer, U. Kazmaier, C.Hebach, Synlett 2005, 757. (d) J. Thompson, B. Chen, J. Org.
	Chem. 2009, 74, 7084.

.3 Scope of the isocyanides

	cascade reaction to prepare tetrazoylisoindolinones (Scheme 1-56). 72 "universal" isocyanides. Cyclohexenyl isocyanide as a convertible isocyanide in Ugi reaction
	was introduced by Armstrong. This isocyanide provides an Ugi adduct, which in acidic
	medium, generates a münchnone in situ. This dipolar species can react with different
	nucleophiles especially with dienophiles in 1,3-dipolar cycloadditions (scheme 1-58). 74
	In 2005, our lab developed a new Ugi-type coupling. Some electron-deficient phenols could
	successfully be employed as the acid component. In this case, a final Smiles rearrangement
	takes place instead of a Mumm acyl transfer (scheme 1-57). 73
	Ugi et al. described an Ugi/TMSN 3 3.4A facile method for achieving greater functional diversity is the use of convertible
	69 S. Heck, A. Dömling, Synlett. 2000, 3, 424
	70 I. Ugi, C. Steinbrückner, Angew. Chem. 1960, 72, 267. 72 I. Ugi, C. Steinbrückner, Chem. Ber. 1961, 94, 734.
	71 E. Haslinger, Chem. 1978, 109, 747. 73 L. Elkaïm, L. Grimaud, J. Oble, Angew. Chem. Int. Ed. 2005, 44, 7961.

Chapter II A Passerini/Michael pathway towards butyrolactones

  2004, the Dömling et al. synthesized various substituted pyrrolidinones through an

	99%). No competitive CH activation was observed during their course of study. 1 Introduction
	The work described in this chapter has been published on Eur. J. Org. Chem:
	75 H. Spatz, M. Umkehrer, C. Kalinski, G. Ross, C. Burdack, J. Kolb, T. Bach, Tetrahedron Lett. 2007, 48, 8060. Shuanglong JIA, Laurent EL Kaïm. Eur. J. Org. Chem. 10.1002/ejoc.201800958
	76 R. Bossio,S. Marcaccini, R. Pepino, T. Torroba, Heterocycles 1999, 50, 463

1.1.5 Synthesis of macrocycles

	Passerini reaction of carboxylic acid with allyl isocyanide and glyoxal and the subsequent
	ring closure to the oxazole led to a long-chain bis allyl compound. RCM of the terminal
	bisolefin resulted in the formation of a 17-membered oxazole containing macrocycle (scheme
	2-13). 93
	The Passerini reaction of α-chloroketones, isocyanides, and carboxylic acids led to
	α-acyloxy-β-chlorocarboxamides. The reaction of carboxamides with CsF afforded the
	The multicomponent reaction of isocyanides, arylglyoxals, and carboxylic acids led to the 3-acyloxy-2-azetidinones. The treatment of carboxamides with KOH in tetrahydrofuran, led
	Passerini product. The cyclization of the Passerini intermediate, using a Knoevenagel to O-deacylation followed by a Darzens-type O-alkylation to give the functionalized oxiranes
	condensation reaction with Et 3 N and followed by acidification resulted in the butenolides. A (scheme 2-9). 89
	subsequent methylation of these compounds afforded the desired furan derivatives (scheme
	2-7). 87
	1
	Synthesis N-substituted 2-acyloxy-3-aryl-3-oxopropionamides were reported by the Passerini
	The condensation of 2-furancarboxaldehyde, acetylenic acids and isocyanides gave the reaction between arylglyoxals, carboxylic acids and isocyanides, followed by the reaction
	Passerini reaction followed by a strong base triggered Dieckmann condensation to achieve Passerini adduct, which underwent Diels-Alder intramolecular cycloaddition upon treatment with ammonium acetate led to trisubstituted oxazole-5-carboxamides via Davidson
	the ring closure (scheme 2-6). 86 with Me 2 AlCl to give highly functionalized oxabicyclo[2.2.1]heptadiene derivatives (Scheme cyclization (scheme 2-10). 90
	2-8). 88
	85 B. Beck, M. Magnin-Lachaux, E. Herdtweck, A. Dömling, Org. Lett., 2001, 3, 2875-2878.
	86 M. Yehia, W. Antuch, B. Beck, S. Hess, M. Almstetter, P. Furer, E. Herdtweck, A. Dömling, Bioorg. Med. Chem. Lett., 87 R. Bossio, S. Marcaccini, R. Pepino, Liebigs Ann. Chem., 1994, 527-528. 89 S. Sebti, A. Foucaud, Synthesis, 1983, 546-549.
	2004, 14, 3121-3125. 88 L. Wright, V. Robotham, K. Aboud, Tetrahedron Lett., 2002, 43, 943-946. 90 R. Bossio, S. Marcaccini, R. Pepino, Liebigs Ann. Chem., 1991, 1107-1108.

.2 γ-Butyrolactones 1.2.1 A brief presentation of γ-butyrolactones

	agents. 95 Some representative members of this family are depicted in Figure 2-1.
	γ-Butyrolactones serve as an outstanding class of chiral building skeletons for the synthesis
	of diverse biological active compounds and complex molecules. Various transformations
	could be performed to access a range of chiral products due to the presence of a highly
	versatile functional group.
	Considering the varying biological activity profiles and wide-ranging structural diversity of
	the optically active γ-butyrolactone structure, the development of synthetic strategies for
	assembling such interesting scaffolds has attracted enormous attention from synthetic
	γ-Butyrolactones are a very common structure in organic compounds, present in about 10% chemists, 96 and a number of approaches have been well documented.
	of all natural products. 94 A wide variety of mono-, di-and trisubstituted monocyclic
	γ-butyrolactones are well known, but they are also found as part of more complex
	frameworks, especially in bicyclic and tricyclic ring systems. γ-Butyrolactones and
	derivatives, especially in enantiomerically pure form, display an impressive range of
	biological activities which are important for the development of physiological and therapeutic
	93 B. Beck, G. Larbig, B. Mejat, M. Magnin-Lachaux, A. Picard, E. Herdtweck, A. Dömling, Org. Lett., 2003, 5, 1047-1050.
	94 a)Hoffmann HMR, J. Rabe, Angew Chem Int Ed Engl 1985, 24, 94-110. b) C. Koch, Chamberlin AR., Studies in Natural
	Products Chemistry, Edited by Attaur Rahman. Elsevier Science; 1995, Vol. 16, 687-725.

1.2.2 Synthesis of γ-butyrolactones 1.2.2.1 Reductive lactonization

	In 2016, Sakai et al. developed a gallium (III)-catalyzed lactonization of γ-keto acids in the
	presence of PhSiH 3 , which led to the production of γ-lactone derivatives with a variety of
	substituents. This reducing system involving GaCl 3 and PhSiH 3 in benzene retained the
	formed ester moiety (scheme 2-14). 97

1.2.2.2 Oxidative lactonization

	In 2015, Canney group described a synthesis of β,β-disubstituted γ-butyrolactones from
	readily prepared substituted 1,4-diols and γ-hydroxy olefins treated with the RuCl 3 /NaIO 4
	oxidation system in modest to good yields (scheme 2-15). 98
	97 S. Norio, H. Shuhei and O. Yohei, RSC Adv., 2016, 6, 81763-81766
	98 G. Rong, F. Rong, C. Daniel, Synlett. 2015, 26, 661-665

1.2.2.3 Oxidation

	In 1980, Magnus and co-workers demonstrated that the epoxysilanes treated with methanol in
	the presence of boron trifluoride etherate could give the lactol methyl ethers. After Jones
	oxidation, γ-butyrolactones can be obtained (scheme 2-16). 99
	1

.2.2.4 Radical reaction

	In 2013, Yang et al. developed an efficient method for direct preparation of aryl-substituted
	lactones from corresponding aryl carboxylic acids promoted by ammonium iodide, which
	may involve a radical intramolecular cyclization. It has some advantages such as mild
	reaction conditions, simple procedure, and moderate to good yields (scheme 2-17). 100
	99 E. Ehlinger and M. Philip, J. Am. Chem. SOC., 1980, 102, 5005
	100 B. Zhang, L. Han, T. Li, J. Yan, and Z.Yang, Synthetic Communications, 2014 ,11, 1608-1613

1.2.2.5 Enantioselective halolactonization

	In 1995, Taguchi et al. described the first example of the catalytic desymmetrizing
	enantioselective iodolactonization of malonate derivatives with iodine in the presence of
	chiral titanium taddolate to afford the corresponding fused γ-butyrolactone with 96-99% ee
	(scheme 2-18). 101 The iodocarbocyclization proceeded in a highly enantiofacial selective
	manner benefited from strong coordination between the chiral titanium taddolate and
	malonate.
	101 a) T. Inoue, O. Kitagawa, O. Ochiai, M. Shiro, T. Taguchi, Tetrahedron Lett. 1995, 36, 9333-9336. b) T. Inoue, O.
	Kitagawa, A. Saito, T. Taguchi, J. Org. Chem. 1997, 62, 7384-7389.

Table 2 -

 2 2).The first Passerini step has the wider scope and gives high yields for most aldedydes and isocyanides tested (table 2-2, entry 1-12). The synthetic sequence is limited to aromatic aldehydes in agreement with the need of a relatively acidic position for the Michael step to proceed (table 2-2, entry 1-10). Indeed, when Passerini adduct II-1l (Table2-2, entry 12)

	entry aldehydes isocyanides	Passerini adducts	Michael adducts
	1
		II-1a 99 %	II-3a 90 %
	2
		II-1b 98 %	II-3b 90 %
	3
		II-1c 80 %	II-3c 95 %
	4
		II-1d 84 %	II-3d 79 %

Table 2

 2

	-4.

  119

117 K. Yang, H. Chen, P.

Wang, Tetrahedron, 2011, 67, 4192-4195 118

F, Chen, L. Chen, H. Chen, P. Wang, J Nat Prod. 2009, 72, 18-23 119 B. Dongare, V. Chavan, S. Bhale, B. Mule, S. Kotmale, P. Bandgar. Chin Chem

Lett. 2016, 27, 99-103

  127

125 P.

Loh, L. Chen, Org Lett. 2002, 4, 3647. 126

V. Sathesh, M. Sathishkumar, G. Ramachandran, S. Rathore, I. Sathiyanarayanan, RSC Adv. 2013, 3, 23035. 127 K.

Behbahani, P. Ziaei, Chin J Chem. 2012, 30, 65.

3 Extension of the Mannich reaction to other nucleophiles

  Due to the very attractive nature of Mannich bases, numerous methods have been developed for the indirect synthesis of β-amino aldehydes and ketones, 131 as well as β-amino carboxylic acid derivatives 132 . Modern versions of the Mannich reaction usually allow a distinctly simpler route into β-aminocarbonyl compounds through the use of preformed nucleophiles (enolates, enol ethers, and enamines). The level of performance and the versatility of these methods have already been powerfully demonstrated in the synthesis of β-amino acid derivatives and β-lactams.133 Recently, several notable advances have been made in these areas.

). 130 129 J.

An, C. Wang, P. Liu, and C. Tao, Helv. Chim. Acta 2012, 95, 43. 130

M. Pouliquen, J. Blanchet,C. Lasne, and Rouden, J. Org.

Lett. 2008Lett. , 10, 1029

1.

In 1979, N. Holy et al. reported sterically hindered ketones such as camphor can be aminomethylated via converted into enolates (scheme 3-14).

134

In 1993, Petasis et al. demonstrated that boronic acids could act as nucleophiles in the Mannich reaction. Vinyl boronic acids react with adducts of secondary amines and 131 a) J.

Barluenga, F. Fernandez-Mari, E. Aguilar, B. Olano, J. Org. Chem. 1996, 61, 5659, and

references therein; b) G. Molander, P. Stengel, ibid. 1995, 60, 6660; c) S. Davies, T. McCarthy, Synlett 1995, 701; d) C. Louis, S. Mill, V. Mancuso, C. Hootele, Can. J. Chem. 1994, 72,1347; e) C. Camiletti, D. Dhavale, L. Gentilucci, C. Trombini, J. Chem. Soc. Perkin Trans. 1 1993, 3157; f) A. Dondoni, D. Perrone, Synthesis 1993, 1162; g) J. Baldwin, R. Adlington, A. Russel, Synlett 1993, 51; h) C. Palomo, J. Aizpurua, J. Odriozola, J. Org. Chem. 1994, 59, 5184. 132 a) Enantioselective Synthesis of β-Amino Acids (Ed.: E. Juaristi), VCH, New York, 1997; b) G. Cardillo, C. Tomasini,

Chem. Soc. Rev. 1996, 25, 117; c)

Y. Hayashi, J. Rohde, E.

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Davies, G. Bhalay, Tetrahedron: Asymmetry 1996, 7, 1595; e)

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; g) D. Enders, J. Wiedemann, W. Bettray, Synlett 1995, 369; h) M.

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S.

Davies, D. Fenwick, J. Chem. Soc. Chem. Commun. 1995, 1109; j)

N.

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133 a) N.

Risch, M. Arend, Methoden Org. Chem. 1952,21, 1908; b) D. Cole, Tetrahedron 1994, 50, 9517; c)

E.

Kleinman in Comprehensive Organic Synthesis, 1991, 2 ,p. 893; d) D. Hart, D. Ha, Chem. Rev. 1989, 89, 1447; e)

M.

Brown, Heterocycles 1989, 29, 2225. 134 N. Holy, R. Fowler, E. Burnett, R. Lorenz, Tetrahedron 1979, 35, 613.

  141

140 L.

Henry, Bull. Acad. R. Belg. 1896, 32, 33. 141

X. Cui, Z. Vlahakis, E. randall, A. Szarek, Bioorg. Med.

  150

	In 1988, Kamitori et al. developped trifluoroacetylations of hydrazones using trifluoroacetic
	anhydride (scheme 3-25).

148

C. Ogawa, M. Sugiura, S.

Kobayashi, J. Org. Chem. 2002 , 67 , 5359 -5364. 149 E. Abdel-Zaher, D. Hicham, A. Nouria and E. Mohammad, ARKIVOC 2007, 2, 272-315 150 R. Brehme, Tetrahedron lett. 1982, 23, 1131 -1134. 151

In addition, asymmetric induction was achieved using chiral pyrrolidines. Elegant asymmetric additions to enones, 152 α,β-unsaturated esters, 153 nitroalkenes, 154 α-amino and αalkoxy-aldehydes 155 were made using Enders SAMP and RAMP hydrazones (scheme 3-26). 156 151 Y. Kamitori, M. Hojo, R. Masuda, T. Fujitani, S. Ohara, T. Yokoyama, J.

Org. Chem. 1988 , 53,129 -135 152

M. Lassaletta, R. Fernandez, E. Martin -Zemora, E. Diez, J. Am .

Chem. Soc. 1996 , 118, 7002 -7003. 153 D. Enders, M. Lassaletta, R. Fernandez, J. Vazquez, A. Prieto, Chem. Comm. 2002, 498 -499. 154 R. Fernandez, C. Gasch, M. Lassaletta, M. Llera, Tetrahedron Lett. 1994, 35, 471. 155

M. Lassaletta, R. Fernandez, E. Martin -Zemora, C. Pareje, J.

Org. Chem., 2001, 66, 5201 -5207. 156 D. Enders, P. Fey, H. Kipphardt, Org. Synth. 1987, 65, 173 -182.

Table 3 -

 3 1, entries 1, 12, 15, 5).

	1
	III-15
	95 %
	2
	III-16

similar yields compared to their nitro analogues. When comparing the lack of reactivity of the related N-phenyl acetaldehyde hydrazone in Mannich reactions, this behavior clearly demonstrates a strong activating effect of the trifluoromethyl group.

  In a context of growing medicinal interest for new fluorinated compounds and trifluoromethylated compounds in particular, this reaction offers interesting opportunities for the preparation of new trifluoromethylated heterocycles.180 A first family of trifluorinated 1,2,4-triazines could be easily obtained when primary amines such as allylamine or 4-methoxybenzylamine were reacted with trifluoroacetaldehyde 4-nitrophenylhydrazone and a twofold excess of formaldehyde (Table3-2). 181 Before our work, this kind of reaction was already described with formaldehydes and non-fluorinated hydrazones (scheme 3-51).182

	entry	hydrazone	aldehyde		amine	Product & yield a
	1
						III-23
						98 %
	2
						III-24
						99 %
	(scheme 3-49). 178
	3
						III-25
						36 %
	In 2018, Gong et al. described a straightforward method for preparing
	3,6-disubstituted-1,2,4-triazines	through	a	redox-efficient	cyclodehydration	of
	β-keto-N-acylsulfonamides with hydrazine salts (scheme 3-50). 179

1,2,4-Triazine derivatives have been widely reported because of interesting biological In 2016, Krasavin et al. reported a practically simple, one-pot method to prepare 3,6-disubstituted 1,2,4-triazines via a zinc catalyzed hydrohydrazination-cyclodehydrationoxidation sequence involving propargylamides and BocNHNH2, in moderate to good yields 178 A. Lukin, T. Vedekhina, N. Tovpeko, M. Krasavin, RSC Advances ,2016, 6(63), 57956-57959 179 D. Matthew, W. Jiao, J. Hou, Y. Jiang, and S. Gong, J. Org. Chem. 2018, 83, 4229-4238 180 (a) V. Petrov, Fluorinated Heterocyclic Compounds: Synthesis, Chemistry, and Applications, Wiley, Hoboken, New Jersey, 2009; (b) Fluorinated Heterocycles, ed. A. Gakh and K. Kirk, ACS Symposium Series, 2009, 1003. 181 (a) N. Saldabol, L. Alekseeva, B. Brizga, L. Kruzmetra, A. Zile, A

. Popel, Pharm. Chem. J., 1968, 2, 626-629; (b)

H.

Moehrle and G. Keller, Z. Naturforsch., B: Chem. Sci., 2003, 58, 885-902. 182 E. Hahn, Roczniki Chemii, 1959, 33, 1245-7

a. Isolated yields after column chromatography on silica gel

  197

195 L. Wei and C.

Wang, Chem. Commun., 2015, 51, 15374-15377 196

O. Attanasi, P. Bonifazi, E. Foresti and G. Pradella, J.

Org. Chem., 1982, 47, 684-687. 197

O.

Attanasi, G. Favi, F. Mantellini, G. Moscatelli, and S. Santeusanio, J. Org. Chem. 2011, 76, 2860-2866

Table 3

 3

	-5).

a. Isolated yields after column chromatography on silica gel. b. The reaction was performed under microwave conditions at 130 °C for one hour.

  200

199 J.

Tsuji, H. Takahashi, M. Morikawa, Tetrahedron Lett. 1965, 49, 4387. 200 E. Atkins, E. Walker, M. Manyk, Tetrahedron Lett. 1970, 3821.

  reaction.214 BINAP and Trost ligands are the classically used chiral ligands in palladium-catalyzed asymmetric allylic alkylations.

214 Y. Hong, M. Stoltz, Eur. J.

Org. Chem. 2013, 19, 2745.

  222

219 (a) J. Tsuji, I. Shimizu, I. Minami, K. Ohashi, T. Sugiura, K. Takahashi, J.

Org. Chem. 1985, 50, 1523. (b)

J. Tsuji, I. Shimizu, I. Minami, Y. Ohashi, Tetrahedron Lett. 1982, 23, 4809. 220 F. Raffaella, P. Luca, Current Organic Chemistry, 2015, 19, 106-120 221 H. Thomson, Naturally Occurring Quinones IV. Recent Advances, 4th ed. Chapman & Hall: London, 1997 222 I. Meyers, J. Willemsen, Chem. Commun. 1997, 1573-1574.

2.2.4 Cyclization of aromatic enynes or enediynes

  227 In 2010, Zhou group developed a facile and efficient electrocyclization for the synthesis of naphthalene derivatives via sulfur-assisted propargyl-allenyl isomerization (scheme 4-13).

226 O. Takuya, K. Takuya and M.

Seijiro, Org. lett., 2011, 13, 5390-5393 227 A. Yamashita and A. Toy, Tetrahedron Lett., 1986, 27, 3471

.

1.2.2.3 Ring-closing metathesis (RCM)

In 2003, Otterlo et al. synthesized a number of naphthols using the Grubbs' second-generation catalyst via RCM reaction (scheme 4-12). 228 228 W. Otterlo, E. Ngidi, E. Coyanis and C. Koning, Tetrahedron Letters, 2003 , 44, 311-313 1.229 In 2012, Erker et al. discovered a modern variant of the 1,1-carboboration reaction to prepare highly substituted, very bulky borylated naphthalene derivatives from readily available bis(alkynyl)arenes. These substrates can be functionalized by transition metal catalyzed cross-coupling reactions (scheme 4-14). 230 229 H. Zhou, Y. Xing, J. Yao, and J. Chen, Org. Lett., 2010, 12, 3674-3677 230 R. Liedtke, M. Harhausen, R. Frohlich, G. Kehr, G. Erker, Org. Lett., 2012, 14, 1448-1451 1.2.

2.5 Annulations using alkynes

	In 2002, Li group developed a new synthetic strategy to generate polysubstituted naphthalene
	derivatives with complete regioselectivity through the simple coupling of alkynes and phenyl
	acetaldehydes (and ketones) catalyzed by gallium trichloride under mild conditions. However,
	the scope, mechanism, and synthetic applications of this new reaction are still under
	investigation (scheme 4-15). 231
	1.2.2.6 Rearrangements of strained rings
	In 2006, Suzuki group described a facile synthesis of substituted naphthols by successive ring
	expansion of alkenyl benzocyclobutenol derivatives. The halonium ion (X + ) induces ring
	expansion of alkenyl benzocyclobutene (four-membered ring) to indanone (five-membered
	ring), which was promoted by SmI 2 to naphthol (six-membered ring) via intramolecular
	Barbier-type reaction with concomitant elimination of ROSmI 2 (scheme 4-16). 232

231 G. Viswanathan, M.

Wang, and C. Li, Angew. Chem. Int. Ed. 2002, 41, 2138-2141 232

T. Hamura, T. Suzuki, T. Matsumoto, and K. Suzuki, Angew. Chem.

Int. Ed. 2006, 45, 6294-6296

1.2.

2.7 Lewis acid catalyzed cyclization

	In 2011, Kuninobu et al. succeeded in synthesizing naphthalene derivatives via dehydrative
	intramolecular cycloaromatization. In these transformations, generally, In(OTf) 3 showed
	higher catalytic activities (scheme 4-17). 233
	1.2.2.8 Multicomponent reaction
	In 2007, Huang et al. developed a novel three-component reaction of arynes, β-keto sulfones,
	and Michael-type acceptors for the synthesis of substituted naphthols and naphthalenes. The
	reaction may proceed via nucleophilic attack on the arynes, intramolecular nucleophilic
	substitution, Michael addition, ring closure and elimination (scheme 4-18). 234

233 Y. Kuninobu, T. Tatsuzaki, T. Matsuki, and K. Takai, J. Org. Chem. 2011, 76, 7005-7009 234 X. Huang, J. Xue, J.

Org. Chem. 2007, 72, 3965-3968

1.2.2.9 Cu(I)-Catalyzed domino reactions

In 2011, Beifuss group discovered an easy-to-perform and efficient Cu(I)-catalyzed domino processes using bromobenzyl bromides and twofold excess of β-ketoesters to yield naphthalenes (scheme 4-19). 235

235 C. Malakar, D. Schmidt, J. Conrad, U. Beifuss, Org.

chapter II 1 General Procedure General procedure A: formation of Passerini adducts

	Experimental part:
	Perkin Elmer Spectrum 65 FT-IR Spectrometer. Melting points were measured on a Stuart
	SMP3 melting point apparatus and are uncorrected. High resolution mass spectra were
	recorded on an Agilent 1100 series LC-MS (with a 6310 ion trap) under electrospray
	ionization (ESI). For compounds containing bromine, the mass of 79Br was used. Monowave

C NMR spectra were recorded at 100 MHz and residual solvent peaks were used as an internal reference (CHCl 3 δ 77.16). Data are reported as follows: chemical shift in ppm, multiplicity deduced from DEPT experiments (CH 3 , CH 2 , CH, Cq), apparent multiplicity, coupling constants and integration where relevant. Analytical TLC was performed with Merck silica gel plates, pre-coated with silica gel 60 F254 (0.2 mm). Visualisation was effected by quenching of UV fluorescence (λmax = 254 nm or 360 nm) and by staining with p-anisaldehyde, potassium permanganate or vanillin TLC stain solutions, followed by heating. Flash chromatography employed VWR (230-400 mesh) silica gel. Reactions were conducted under a positive pressure of dry nitrogen or argon in oven-dried or flame dried glassware, and at ambient room temperature, unless specified otherwise. Anhydrous solvents were either obtained from commercial sources or dried with a MBRAUN Solvent Purification System SPS-800. Petroleum ether refers to the 40-60 °C boiling fraction. Commercially available chemicals were used as purchased, or where specified, purified by standard techniques. IR spectra were recorded on a

NMR (101 MHz, CDCl 3

	1-(4-chlorophenyl)-2-((4-methoxybenzyl)amino)-2-oxoethyl acetate (II-1c) 1-(4-chlorophenyl)-2-((3,4-dimethoxyphenethyl)amino)-2-oxoethyl acetate (II-1d)
	C 20 H 22 ClNO 5
	C 18 H 18 ClNO 4 391.85 g.mol -1
	347.80 g.mol -1 Following general procedure A with para-chlorobenzaldehyde (1.4 g, 10 mmol) and
	4-(2-isocyanoethyl)-1,2-dimethoxybenzene (1.91 g, 10 mmol), the mixture was purified by
	column chromatography on silica gel (eluent: PE:EA = 80:20) to afford II-1d (3.29 g, 8.4
	mmol, 84 %).
	Rf: 0.32 (EA:PE = 3:7)
	1 H NMR (400 MHz, CDCl 3 ) δ 7.35 -7.28 (m, 4H, H-b,c), 7.11 -7.08 (m, 2H, H-f), 6.87 -6.67 -6.63 (m, 2H, H-g,j), 6.17 (s, 1H, H-NH), 5.98 (s, 1H, H-3, H-3), 3.86 (s, 3H, H-7),3.84
	HRMS: calculated for C 14 H 18 ClNO 3 :283.0975, found: 283.0987 6.79 (m, 3H, H-g), 6.00 (s, 1H, H-3), 4.31 (qd, J = 14.7, 5.8 Hz, 2H, H-5), 3.76 (s, 3H, H-6), (s, 3H, H-8), 3.55 -3.49 (m, 2H, H-5), 2.80 -2.71 (m, 2H, H-6), 2.10 (s, 3H, H-1).
	I.R.(thin film): 3433, 2971, 1748, 1685, 1521, 1492, 1456, 1369, 1218, 1093, 1037, 2.11 (s, 3H, H-1).
	1016cm -1 .
	42.8 (C-5), 20.9 (C-1).
	HRMS: calculated for C 18 H 18 ClNO 4 : 347.0924, not found, fragment: 287.0708(-HOAc)
	I.R.(thin film): 3295, 3072, 2935, 2836, 1742, 1657, 1612, 1512, 1490, 1463, 1438, 1369,
	1300, 1222, 1175, 1090, 1033, 1015 cm -1

Following general procedure A with para-chlorobenzaldehyde

(1.4 g, 10 mmol

) and 1-(isocyanomethyl)-4-methoxybenzene (1.47 g, 10 mmol), the mixture was purified by column chromatography on silica gel (eluent: PE:EA = 70:30) to afford II-1c (2.78 g, 8.0 mmol, 80 %). Aspect: white solid, m.p. 97.1-98.2 o C 13 C ) δ 169.3 (C-2), 168.0 (C-4), 159.1 (C-h), 134.9 (C-a), 134.2 (C-d), 129.7 (C-e), 129.0 (C-b), 128.9 (C-c), 128.8 (C-f), 114.1 (C-g), 74.8 (C-3), 55.2 (C-6), Aspect: white solid, m.p. 104.8-105.7 o C Rf: 0.43 (EA:PE = 4:6) 1 H NMR (400 MHz, CDCl 3 ) δ 7.32 -7.27 (m, 4H, H-b,c), 6.77 (d, J = 8.1 Hz, 1H, H-f),

Experimental part: chapter III 1 General Procedure 1.1 Synthesis of hydrazones Trifluoroacetaldehyde 4-nitrophenylhydrazone

  : calculated for C 15 H 19NO 4 : 277.1314NO 4 : 277. , found: 277.1310

	I.R.(thin film): 3361, 2931, 2855, 1757, 1710, 1663, 1529, 1451, 1347, 1259, 1185, 1154,
	1098, 1067, 1009cm -1 .

1 H NMR (400 MHz, CDCl 3

	= 8.0 Hz, 1H, H-h), 7.22 -7.15 (m, 2H, H-c), 7.00 -6.86 (m, 3H, H-f,i,j), 4.20 (s, 1H, H-3),
	3.77(s,3H, H-6), 3.75 (bs ,4H, H-5), 2.49 (bs, 4H, H-4).

) δ 12.67 (s, 1H, H-NH), 8.22

(d, J = 9.2 Hz, 2H, 7.29 (t, J

  3 ml toluene. The stirred mixture was heated to reflux under Ar for 12 h. After completion of present reaction, the reaction mixture was concentrated under vacuum. The residue was purified by column chromatography on silica gel (eluent: CH 2 Cl 2 :PE = 50:50) to afford the desired product III-15 (95 %, 136 mg).

	Aspect: colourless solid, m. p. 127.9-128.9 o C.
	Rf: 0.41 (CH 2 Cl 2 :PE = 50:50)
	1 H NMR (400 MHz, CDCl 3 ) δ 11.02 (s, 1H, H-NH), 7.36 -6.84 (m, 5H, H-a,b,c), 3.75 (bs,
	4H, H-5), 3.45 (s, 2H, H-3), 2.51 (bs, 4H, H-4).

NMR (400 MHz, CDCl 3 ) δ11

	Aspect: yellow solid m.p. 198.6 o C-199.5 o C
	Rf: 0.47 (PE:CH 2 Cl 2 = 50:50)
	.96 (s, 1H, H-NH), 8.10 (dd, J = 8.0, 2.9 Hz, 2H, H-b), 7.85
	(s, 1H, H-k), 7.53 (s, 1H, H-f), 7.41 -7.30 (m, 1H, H-h), 7.29 -7.10 (m, 2H, H-i,j), 7.09 -
	6.94 (m, 2H,H-c), 3.80 (bs, 4H, H-4,6), 3.03-2.97 (m, 4H, H-3,5).

The residue was purified by column chromatography on silica gel (eluent: PE:Et 2 O = 50:50)to afford the desired product III-25 (36 %, 75 mg).

1 H

NMR (400 MHz, CDCl 3 ) δ

	1-(5-(4-chlorophenyl)-3-methyl-2-(4-nitrophenyl)-6-(trifluoromethyl)-2,5-dihydropyridazin-4
	-yl)ethan-1-one III-28
	C 20 H 15 ClF 3 N 3 O 3
	437.80 g.mol -1
	Aspect: yellow oil
	Rf: 0.37 (Et 2 O:PE = 50:50)
	8.36 (d, J = 7.9 Hz, 2H, H-c), 7.55 (d, J = 8.0 Hz, 2H, H-b),
	7.31 (d, J = 7.2 Hz, 2H, H-g), 7.14 (d, J = 7.6 Hz, 2H, H-f), 5.14 (s, 1H, H-3), 2.42 (s, 3H,
	H-6), 2.35 (s, 3H, H-8).
	-1

Mannich adduct III-2 (0.5 mmol, 221 mg) was dissolved in 2.5 mL pentane-2,4-dione, and the stirred mixture was heated to 130 o C under Ar for 12 h. After completion of present reaction, the reaction mixture was concentrated under vacuum. The residue was purified by column chromatography on silica gel (eluent: Et 2 O:PE = 50:50) to afford the desired product 7c (80 %, 175 mg).

1 H

NMR (400 MHz, CDCl 3 ) δ8

	1-(3-methyl-5-(1-methyl-1H-indol-3-yl)-2-(4-nitrophenyl)-6-(trifluoromethyl)-2,5-dihydrop-
	yridazin-4-yl)ethan-1-one III-29
	C 23 H 19 F 3 N 4 O 3
	456.43 g.mol -1
	Aspect: yellow oil
	Rf: 0.29 (Et 2 O:PE = 50:50)
	.38 -8.29 (m, 2H, H-b), 7.62 (d, J = 8.0 Hz, 1H, H-ar), 7.59
	-7.52 (m, 2H, H-c), 7.32 -7.20 (m, 2H, H-ar), 7.17-7.13 (m, 1H, H-ar), 6.78 (s, 1H, H-ar),
	5.33 (s, 1H, H-3), 3.71 (s, 3H, H-9), 2.37 (s, 3H, H-6), 2.30 (s, 3H, H-8).
	-1

Mannich adduct III-9 (0.5 mmol, 231 mg) was dissolved in 2.5 mL pentane-2,4-dione, and the stirred mixture was heated to 130 o C under Ar for 12 h. After completion of present reaction, the reaction mixture was concentrated under vacuum. The residue was purified by column chromatography on silica gel (eluent: Et 2 O:PE = 50:50) to afford the desired product III-29

(92 %, 210 mg)

.

1 H

  : calculated for C 23 H 19 F 3 N 4 O 3 :456.1409, found: 456.1409.

I.R.(thin film): 2939

NMR (400 MHz, CDCl 3 ) δ

	Methyl-5-(4-chlorophenyl)-3-methyl-2-phenyl-6-(trifluoromethyl)-2,5-dihydropyridazine-4-
	carboxylate III-30
	C 20 H 16 ClF 3 N 2 O 2
	408.80 g.mol -1
	Aspect: yellow oil
	Rf: 0.52 (Et 2 O:PE = 40:60)
	7.50 -7.42 (m, 2H, H-b), 7.40 -7.34 (m, 1H, H-a), 7.33 -
	7.26 (m, 4H, H-c,g), 7.21 -7.15 (m, 2H, H-f), 5.04 (s, 1H, H-3), 3.76 (s, 3H, H-6), 2.26 (s,
	3H, H-8).
	-1

Mannich adduct III-16 (0.5 mmol, 199 mg) was dissolved in 2.5 mL methyl 3-oxobutanoate, and the stirred mixture was heated to 130 o C under Ar for 12 h. After completion of present reaction, the reaction mixture was concentrated under vacuum. The residue was purified by column chromatography on silica gel (eluent: Et 2 O:PE = 40:60) to afford the desired product III-30 (90 %, 184 mg).

1 H

NMR (400 MHz, CDCl 3 ) δ

  20 H 16 ClF 3 N 2 O 2 :408.0852, found: 408.0838.

	1-(5-(4-chlorophenyl)-3-methyl-2-(pyridin-2-yl)-6-(trifluoromethyl)-2,5-dihydropyridazin-4-
	yl)ethan-1-one III-31
	C 19 H 15 ClF 3 N 3 O
	393.79 g.mol -1
	Aspect: yellow oil
	Rf: 0.41 (Et 2 O:PE = 50:50)
	8.51 (ddd, J = 4.9, 1.9, 0.7 Hz, 1H, H-a), 7.87 (ddd, J = 8.2,
	7.4, 1.9 Hz, 1H, H-c), 7.66 (dd, J = 7.4, 0.8 Hz, 1H, H-d), 7.32 -7.22 (m, 5H, H-b,g,h), 5.09
	(s, 1H, H-3), 2.43 (s, 3H, H-8), 2.38 (s, 3H, H-6).
	I.R.(thin film): 2953, 1701, 1595, 1491, 1436, 1384, 1221, 1199, 1138, 1093, 1035,
	1016cm -1

Mannich adduct III-20 (0.5 mmol, 199 mg) was dissolved in 2.5mL pentane-2,4-dione, and the stirred mixture was heated to 130 o C under Ar for 12 h. After completion of present reaction, the reaction mixture was concentrated under vacuum. The residue was purified by column chromatography on silica gel (eluent: Et 2 O:PE = 50:50) to afford the desired product III-31 (56 %, 110 mg).

1 H

NMR (400 MHz, CDCl 3 ) δ

	1-(5-(4-chlorophenyl)-3-methyl-2-phenyl-6-(trifluoromethyl)-2,5-dihydropyridazin-4-yl)eth-
	an-1-one III-33
	C 20 H 16 ClF 3 N 2 O
	392.81 g.mol -1
	Aspect: yellow oil
	Rf: 0.36 (Et 2 O:PE = 30:70)
	7.48-7.44 (m, 2H, H-b), 7.40 -7.34 (m, 1H, H-a), 7.32 -7.25
	(m, 4H, H-g,c), 7.17-7.15 (m, 2H, H-f), 5.05 (s, 1H, H-3), 2.34 (s, 3H, H-6), 2.23 (s, 3H,
	H-8).
	-1

Mannich adduct III-16 (0.5 mmol, 199 mg) was dissolved in 2.5 mL pentane-2,4-dione, and the stirred mixture was heated to 130 o C under Ar for 12 h. After completion of present reaction, the reaction mixture was concentrated under vacuum. The residue was purified by column chromatography on silica gel (eluent: Et 2 O:PE = 20:80) to afford the desired product III-33 (71 %, 140 mg).

1 H

NMR (400 MHz, CDCl 3 )δ

	4-(4-chlorophenyl)-1-phenyl-3-(trifluoromethyl)-1,4,5,6,7,8-hexahydrocinnoline III-34
	C 21 H 18 ClF 3 N 2
	390.83 g.mol -1
	Mannich adduct III-16 (0.5 mmol, 199 mg) was dissolved in 2.5mL cyclohexanone and the
	stirred mixture was heated to 130 Aspect: gray oil
	Rf: 0.80 (Et 2 O:PE=40:60)
	7.40-7.36 (m, 2H, H-b), 7.32 -7.22 (m, 5H, H-a,c,g), 7.19 -
	7.12 (m, 2H, H-f), 4.11 (s, 1H, H-3), 2.27 -2.05 (m, 2H, H-5,8), 2.00 -1.87 (m, 1H, H-5),
	1.80 -1.46 (m, 5H, H-8,6,7).
	-1

o C under Ar for 12 h. After completion of present reaction, the reaction mixture was concentrated under vacuum. The residue was purified by column chromatography on silica gel (eluent: Et 2 O:PE = 20:80) to afford the desired product III-34 (68 %, 132 mg).

1 H

NMR (400 MHz, CDCl 3 ) δ

	4-(4-chlorophenyl)-1-phenyl-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-cyclopenta[c]pyridaz
	-ine III-35
	C 20 H 16 ClF 3 N 2
	376.81 g.mol -1
	Aspect: brown oil
	Rf: 0.80 (Et 2 O:PE=40:60)
	7.39-7.35 (m, 2H, H-b), 7.33 -7.25 (m, 4H, H-g,c), 7.24-7.18
	(m, 1H, H-a), 7.15 -7.13 (m, 2H, H-f), 4.48 (s, 1H, H-3), 2.79-2.72 (m, 1H, H-7), 2.38 -2.14
	(m, 3H, H-5,7), 1.98 -1.80 (m, 2H, H-6).
	-1

Mannich adduct III-16 (0.5 mmol, 199 mg) was dissolved in 2.5 mL cyclopentanone and the stirred mixture was heated to 130 o C under Ar for 12 h. After completion of present reaction, the reaction mixture was concentrated under vacuum. The residue was purified by column chromatography on silica gel (eluent: Et 2 O:PE = 20:80) to afford the desired product III-35 (90 %, 169 mg).

1 H

NMR (400 MHz, CDCl 3 )

	4-(nitromethyl)-1,2-dihydronaphthalene (IV-1a)
	C 11 H 11 NO 2
	189.21 g.mol -1
	In a round-bottomed flask fitted with a Dean and Stark trap was added α-tetralone (100 mmol,
	14.6 g, 100 mol%), nitromethane (1 mol, 61 g, 10 eq), N,N-dimethylethane-1,2-diamine (30
	mmol, 2.6 g, 30 mol%), and toluene (50 ml), the mixture was refluxed for 96 h. After

evaporation of solvent under reduced pressure, the residue crude was purified by column chromatography on silica gel (eluent: DCM:PE = 30:70) to afford the desired product 4-(nitromethyl)-1,2-dihydronaphthalene (78 %, 14.8 g), The spectra data are in agreement with the literature report. 253 Aspect: brown oil Rf: 0.56 (DCM:PE = 5:5)

1 H δ 7.24 -7.15

(m, 4H,b,c,d), 6.33 (t, J = 4.6 Hz, 1H, 5.29 (s, 2H,

, 2.84 (t, J = 8.

1 Hz, 2H, 2.43 (td, J = 8.1, 4.7 Hz, 2H,

.

  dihydronaphthalen-1-yl)-4-nitroheptanedinitrile (IV-2b) C 17 H 17 N 3 O 2 295.34 g.mol -1To a solution of 4-(nitromethyl)-1,2-dihydronaphthalene (0.5 mmol, 90 mg, 100 mol%) in acetonitrile (1.5 ml) was added acrylonitrile (2.5 mmol, 265 mg, 5 eq) and DBU (38 mg, 50 mol%), the mixture was stirred for 3 h at r.t. under Ar. After evaporation of solvent under reduced pressure, the residue crude (316 mg) was purified by column chromatography on silica gel (eluent: PE 100 % -Et 2 O 100 %) to afford the desired product (99 %, 292 mg).

	J = 7.7 Hz, 1H, H-b), 6.36 (t, J = 4.9 Hz, 1H, H-3), 2.80 -2.66 (m, 6H, H-5,6), 2.45 -2.34
	(m, 4H, H-7), 2.32-2.24 (m, 2H, H-4).

Aspect: colourless oil Rf: 0.22 (Et 2 O:PE = 7:3) 1 H NMR (400 MHz, CDCl 3 ) δ 7.24 -7.19

(m, 2H, H-c,d), 7.18 -7.13 (m, 1H,H-a)

, 6.80

(d,

A.Domling, I.Ugi, Angew. Chem., Int. Ed.

2000, 39, 3168-3210. 2 J. Ramon, M. Yus, Angew Chem Int Ed. 2005, 44, 1602-1634 3 (a) J. Zhu, Eur. J. Org. Chem. 2003, 2003, 1133. (b) J. Zhu, H. Bienaymé, Eds. Multicomponent Reactions; Wiley-VCH: Weinheim, Germany, 2005. (c)A.Dömling, Chem. Rev. 2006, 106, 17.

A. Laurent, Gerhardt CF. Ann Pharm. 1838, 28, 265.

A. Strecker, Liebigs Ann. Chem. 1850, 75, 27-51

A. Hantzsch, Justus Liebigs Ann. Chem. 1882, 215, 1.

a) H. Debus, Justus Liebigs Annalen der Chemie. 1858, 107 , 199. b) B.Radzisewski, Berichte der deutschen chemischen Gesellschaft.,1882, 15 , 2706.

I.Okada, Y. Kitano, Synthesis 2011, 3997.

V.Atlan, L. Elkaïm, C. Buron, Synlett 2000, 489.

A. Ottow, M. Brinker, T. Teichmann, E. Fritz, W. Kaiser, M. Brosche, J. Kangasjarvi, X.Jiang, A. Polle, Plant Physiol. 2005, 139, 1762-1772.

Catalytic Asymmetric Synthesis, 3rded.;I. Ojima, ,Ed.;Wiley-VCH: Hoboken, NJ, 2010.

For reviews on IMCRs, see: a) Multicomponent reactions; J. Zhu, H. Bienaymé, Eds, Wiley-VCH, Weinheim, 2005; b) A. Dömling, I. Ugi, Angew. Chem. Int. Ed. 2000, 39, 3168-3210; c) R. Orru, M. de Greef, Synthesis 2003, 1471-1499; d) C.

A. Abdessalem, R. Abderrahim, L. Elkaïm, Synlett 2015, 26, 2537-2540.

W.Ye, G. Cai, Z. Zhuang, X. Jia and H. Zhai, Org. Lett., 2005,7, 3769-3771.

G.He, a F. Wu, W. Huang, R. Zhou, L. Ouyang, and B. Han, Adv. Synth. Catal. 2014, 356, 2311-2319

A. Abdessalem, R. Abderrahim, L. Elkaïm, Synlett 2015, 26, 2537-2540.

A. Petasis, I. Akritopoulou, Tetrahedron Lett.1993, 34, 583-586.

A. Seayad, B. Ramalingam, K. Yushinaga, T. Nagata, C. Chai, Org. Lett., 2010, 12, 264-267

The A3 coupling (also known as the aldehyde-alkyne-amine reaction) is a Mannich reaction with an alkyne acting as nucleophile. It is a multicomponent reaction involving an aldehyde, an alkyne and an amine which react together to give a propargylamine.137 The reaction proceeds via direct dehydrative condensation and requires a metal catalyst, typically based on ruthenium, copper, gold or silver.138 The first example of such a process, the copper catalyzed Mannich reaction of a terminal alkyne, a secondary amine and formaldehyde (trioxane), has been discovered in the middle of the 20 th century (scheme 3-18).139 In 1896, Louis Henry reported a nitro-Mannich reaction (aza-Henry reaction) of methanolamine derived from formaldehyde and piperidine, with nitromethane to form the 137 P.Vsevolod, P. Olga and E. Erik, Chem. Soc. Rev., 2012, 41, 3790-3807 138 Name Reactions A Collection of Detailed Mechanisms and Synthetic Applications 2009 Li, Jie Jack 139 J.Guermont, Bull. Soc. Chim. Fr., 1953, 386-390

A.Gakh and K. Kirk, Fluorinated Heterocycles, 2009, 1003

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 192 For the generation of azoalkenes from aminohydrazones, see: (a) W.Ried and G. Kiel, Liebigs Ann. Chem., 1958, 616, 108-124; (b) V. Atlan, L.Elkaim, L. Grimaud and N. Jana, Synlett, 2002, 352-354; (c) V. Baillez, L.Elkaïm and V. Michaut, Synth. Commun., 2004, 34, 109-

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ACKNOWLEDGEMENTS

First I would like to thank all French people who helped me in their ways during I live in Paris.

The thesis was carried out at Ecole Nationale Supérieure de Techniques Avancées-ENSTA, under the direction of Prof. Dr. Laurent EL Kaïm.

Chapter IV A novel Tsuji-Trost reaction towards naphthalene

For the work described in this chapter, it's a part of the project; I cooperate with my colleague Mansour Dolè Kerim to finish this project. Some experiment results from him were all clearly declared in the text. This work has been published on Chem. Commun.

Mansour Dole Kerim a , Shuanglong Jia a , Chrysoula Theodorakidou a , Sebastien Prevost* and Laurent El Kaim*, Chem. Commun., 2018, 54, 10917 -10920 When we decreased the amount of Michael acceptors to 3.0 equiv., and using 0.1 equiv. of DBU, a mono Michael addition product was obtained and the following Tsuji-Trost reaction proceeded well (scheme .

However, some substituted α,β-unsaturated ketones (figure 4-3) failed to couple with IV-1a under these conditions probably due to the steric hindrance of the naphthalene moiety.

When IV-1a was directly treated under Tsuji-Trost reaction conditions, 1-methylnaphthalene was obtained in 35% yield (scheme . This was rather a surprise for us, as under basic conditions, the nitro group should form a non reactive nitronate with the palladium catalyst.