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Le manuscrit porte sur l'étude de la combinaison entre les complexes des métaux du groupe 4 et les lanthanides métalliques.La première partie s'intéresse à la réduction des dichlorométallocènes du groupe 4 par les lanthanides. En fonction du lanthanide choisi, il est possible d'accéder à différents degrés d'oxydation du titane. La présence d'un excès de lanthanides permet la réduction des métallacyclopentadiènes issus de la dimérisation réductrice d'alcynes comportant des groupements aryles. La seconde partie concerne l'adaptation du système d'oléfination de groupements carbonyles mis au point par Takeda. Le choix du système Cp2TiCl2/Dy, sans phosphite, permet la conversion de nombreux composés carbonylés en alcènes avec pour certains une bonne sélectivité. Un des atouts de ce nouveau système est la possibilité de réaliser une procédure « tout-en-un ». La troisième partie porte sur la synthèse de nouveaux hétérocycles phosphorés. Suite à la dimérisation réductrice d'alcynes vrais avec le système Cp2ZrCl2/La, une sélectivité est observée pour la formation de phospholes substitués en position 1, 2 et 4. Ces nouveaux composés sont oxydés par du soufre pour obtenir des thiooxophospholes qui peuvent, dans certains cas, subir une dimérisation [2+2]. La dernière partie présente la mise au point d'une méthodologie de synthèse de cyclopropylamines secondaires utilisant le système Ti(OiPr)4/RMgBr. / This thesis deals with the study of the combination of group 4 metal complexes with lanthanides.The first part of this work presents the reduction of dichlorometallocenes with lanthanides. Depending on the lanthanide, different oxidation states of titanium can be accessed. With an excess of lanthanide metal, it is possible to reduce the metallacyclopentadienes formed during the reductive dimerization of alkynes carrying one aryl group.The second part concerns the modification of the Takeda carbonyl olefination system. The system Cp2TiCl2/Dy, without phosphite, allows the conversion of many carbonyl compounds into alkenes with a good selectivity in certain cases. One of the advantages of this new system is the possibility to perform an “all-in-one” procedure.The third part is about the synthesis of new phosphorous heterocycles. Following the reductive dimerization of terminal alkynes using the Cp2ZrCl2/La system, the selective transformation of the reaction intermediates into 2,4-disubstituted phospholes is observed. These new compounds can be converted into thiooxophospholes with sulfur, which in some cases undergo a [2+2] dimerisation.The last part presents a new methodology for the synthesis of secondary cyclopropylamines with the Ti(OiPr)4/RMgBr system.

The thesis entitled “Regioselective Functionalization of Indoles using Directing Group Strategy: An Efficient Transition Metal Catalysis” is divided into two sections. Section A, which is presented in three chapters, describes the regioselective alkenylation of indoles using directing group strategy. Whereas, Section B, which is divided in to two chapters, narrates the synthesis of 4-amino indoles using directing group strategy and site selective addition of maleimide to indole at C2-position. Section A Chapter 1. C2-Alkenylation of indoles The indole ring system is one of the most abundant heterocycles present in nature. The synthesis and functionalization of indoles is one of the major areas of focus for synthetic organic chemists.1 Alkenylation of indole at C2-position is a challenging task due to the electrophilic nature of the reaction. For this reason, the functionalization of indole at C2-position is less addressed. In this chapter, a highly regioselective alkenylation of indole at the C2-position has been described by using the Ru(II) catalyst and employing a directing group (DG) strategy.2 This directing group strategy offers rare selectivity for the alkenylation of N-benzoylindole at the C2-position in the presence of the more reactive C3-position. A variety of N-benzoylindole derivatives are shown to undergo alkenylation at C2-positon. Deprotection of the benzoyl group has also been demonstrated, and the resulting products serve as a useful synthon for synthesizing a variety of natural products. A few representative examples are highlighted in Scheme 1.3 1 (a) Cacchi, S.; Fabrizi, G. Chem. Rev. 2005, 105, 2873. (b) Karamyan, K. A. J.; Hamann, M. T. Chem. Rev. 2010, 110, 4489. 2 (a) Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147. (b) Engle, K. M.; Mei, T.-S.; Wasa, M.; J.-Q. Yu, Acc. Chem. Res. 2012, 45, 788. (c) Neufeldt, S. R.; Sanford, M. S. Acc. Chem. Res. 2012, 45, 936. (d) Arockiam, P. B.; Bruneau, C.; Dixneuf, P. H. Chem. Rev. 2012, 112, 5879. 3 Lanke, V.; Prabhu, K. R. Org. Lett. 2013, 15, 2818. Scheme 1: C2- Alkenylation of indoles Chapter 2 describes a highly regioselective alkenylation of indoles at the C4-position by employing aldehyde functional group as a directing group, and Ru as a catalyst, under a mild reaction conditions. This approach leads to a short synthetic route for C4-alkenylated indoles, which serve as precursors for ergot alkaloids and related heterocyclic compounds.4 Further The potential of the present strategy has been demonstrated by performing (i) scale up reaction, (ii) selective reduction of olefin double bond and (iii) synthesizing substituted 1,3,4,5-tetrahydrobenzo[cd] in two steps with an overall yield of 68%. 1,3,4,5-Tetrahydrobenzo[cd] is one of the key intermediates for synthesizing ergot alkaloids. A few examples are highlighted in Scheme 2.5 4 (a) Horwell, D. C. Tetrahedron 1980, 36, 3123. (b) Kozikowski, A. P.; Ishida, H. J. Am. Chem. Soc. 1980, 102, 4265. (c) Oppolzer, W.; Grayson, J. I.; Wegmann, H.; Urrea, M. Tetrahedron 1983, 39, 3695. (d) Hatanaka, N.; Ozaki, O.; Matsumoto, M. Tetrahedron Lett. 1986, 27, 3169. (e) Horwell, D. C.; Verge, J. P. Phytochemistry 1979, 18, 519. 5 anke, V.; Prabhu, K. R. Org. Lett. 2013, 15, 6262. Scheme 2: C4- Alkenylation of indoles Chapter 3 of Section A, presents a novel mode of selective alkenylation of indoles using Ru and Rh catalyst. In these alkenylation reactions, selectivity between C2- and C4-positions of indole framework has been achieved by altering the property of directing group. Methyl ketone, as directing group, furnishes exclusively C2-alkenylated product, whereas trifluoromethyl ketone as a directing group changes the selectivity to C4, indicating that electronic nature of the directing group controls the choice between a 5-membered and 6-membered metallacycle. Developing such divergent and selective C-H functionalizations, between C2- and C4-positions, on the indole framework can lead to easy and short synthetic routes for natural, unnatural and biologically-active compounds.6 Further screening of other carbonyl derived directing groups revealed that strong and weak directing groups exhibit opposite selectivity. Experimental 6 (a) Bronner, S. M.; Goetz, A. E.; Garg, N. K. J. Am. Chem. Soc. 2011, 133, 3832. (b) Nathel, N. F. F.; Shah, T. K.; Bronner, S. M.; Garg, N. K. Chem. Sci., 2014, 5, 2184. (c) A Beilstein/Crossfire search shows that more than 600 C4- substituted indole-containing natural products exist and nearly 10,000 bioactive C4-substituted indoles have been reported. controls, deuteration experiments and preliminary DFT calculations lend support to the proposed mechanism. A few representative examples are highlighted in Scheme 3.7 Scheme 3: C4- vs C2-Alkenylation of ndoles Deuterium Labeling studies were carried out to shed light on the site of metallacycle formation and hence the origin of selectivity. Both COCF3 and COCH3 substrates were independently subjected to both standard conditions A and B, along with either D2O or AcOD as deuterium sources (Scheme 4). 7 Lanke, V.; Bettadapur, K. R.; Prabhu, K. R. Manuscript submitted. Scheme 4: Deuterium labeling studies The Section B is divided into 2 chapters. Chapter 1 presents a method for synthesizing of 3-(indol-2-yl) succinimide derivatives by using a directing group strategy. Selective functionalization at C2-position of indole in the presence of highly reactive C3-position has been achieved. A conjugate addition, instead of Heck-type reaction, has been achieved by careful selection of the alkene partner (maleimides and maleate esters). This selectivity has been achieved by avoiding β-hydride elimination. Succinimide derivatives are structural motifs that are found in many natural products and drug molecules. Moreover, succinimides can be easily reduced into 5-membered pyrrolidine rings, γ-lactams and lactims, which are part of structural scaffolds of useful natural products.8 Further the application of the protocol has been showcased by performing reduction to obtain pyrrolidine and 1,4 diols. A few representative examples are highlighted in Scheme5.9 8 (a)Crider, A. M.; Kolczynski, T. M.; Yates, K. M. J. Med. Chem. 1980, 23, 324. (b) Isaka, M.; Rugseree, N.; Maithip, P.; Kongsaeree, P.; Prabpai, S.; Thebtaranonth, Y. Tetrahedron 2005, 61, 5577. (c) Uddin, J.; Ueda, K.; Siwu, E. R. O.; Kita, M.; Uemura, D. Bioorg. Med. Chem. 2006, 14, 6954. (d) Hubert, J. C.; Wijnberg, J. B. P. A.; Speckamp, W. N. Tetrahedron 1975, 31, 1437. (e) Wijnberg, J. B. P. A.; Schoemaker, H. E.; Speckamp, W. N. Tetrahedron 1978, 34, 179. 9 Lanke, V.; Bettadapur, K. R.; Prabhu, K. R. Org. Lett. 2015, 17, 4662. Scheme 5: Addition of Maleimide to Indole at C2-position Chapter 2 describes a highly regioselective amidation of unprotected indoles at the C4-position by employing aldehyde functional group as a directing group. This reaction has been performed using Ir(III) catalyst, under mild reaction conditions. Thus, an efficient, simple, short synthetic route for C4-amido indoles has been achieved. C4-Amido indoles are privileged molecules, which serve as precursors for indolactum V,10 teleocidin and related heterocyclic compounds.11 To the best our knowledge, this is the first report of using aldehyde as a directing group for amidation reactions. The potential of the present strategy has been demonstrated by performing scaling up reaction, and deprotection of tosyl group to obtain corresponding amines. A few representative examples are highlighted in Scheme 6.12 10 Garg, N. K. et al., J. Am. Chem. Soc. 2011, 133, 3832 11 Kehler, J. J. Med. Chem. 2014, 57, 5823 12 Lanke, V.; Prabhu, K. R. (Manuscript submitted). Scheme 6: C4- amidation of indoles 7

L’objectif de ces travaux de thèse a consisté en le développement de nouveaux accepteurs radicalaires de type vinylsulfoxydes et vinylsulfoximines pour la mise en œuvre de processus multicomposants radicalaires. Ces réactions de carbo-alcénylation d’oléfines permettent l’accès à des substrats comportant plusieurs fonctionnalités utiles en synthèse organique et la formation de plusieurs liaisons carbone-carbone en un seul pot. L’absence de contrôle de la stéréochimie du centre asymétrique créé lors de la dernière étape élémentaire du processus multi-composants constitue l’un des derniers problèmes à résoudre dans cette méthodologie. Nous avons, étudié le développement de réactions multicomposants radicalaires impliquant des précurseurs vinylsulfoxydes et sulfoximines. Lors de ces processus, les produits de carboalcénylations d’oléfines ont été obtenus avec des rendements moyens à bons. Nous avons développé en parallèle une méthode efficace pour l’alcénylation directe photocatalysée d’hétérocycles oxygénés par activation de liaisons Csp3 -H à l’aide d’une quantité catalytique de diarylcétone sous irradiation UV. Ce processus permet notamment un accès aisé aux dioxanes substitués par un groupement alcényle, avec un rendement élevé. Une approche énantiosélective de ce processus a également été réalisée. Dans une derniére partie, nous avons développé une stratégie sans étain qui utilise le diphenyliodonium hexafluorophosphate pour réaliser la vinylation des halogénures d'alkyle dans des conditions radicalaires. Le diphenyliodonium hexafluorophosphate est donc considéré comme un substitut efficace de l'étain dans ce processus de radical libre. / The aim of this thesis was to develop new radical acceptors including vinylsulfoxides and vinylsulfoximines for the implementation of radical multicomponent processes. These carbo- alkenylation reactions of olefins allow access to substrates having several functionalities, which are useful in organic synthesis and the formation of several carbon-carbon bonds in a single pot. The lack of control of the stereochemistry of the stereogenic center, created during the last elementary stage of the multi-component process, is one of the key problems to be solved in this methodology. We have studied the development of radical multicomponent reactions involving vinylsulfoxide and sulfoximine precursors. In these processes, the olefin carbo-alkenylation products were obtained in moderate to good yields. We have developed in parallel an efficient method for the direct photocatalyzed alkenylation of oxygenated heterocycles through the activation of a Csp3 –H bond, using a catalytic amount of a diarylketone under UV irradiation. This process provides an easy access to alkenyl-substituted dioxanes in high yield. An enantioselective version of this process was also studied. In the final part, we developed a tin-free strategy that uses diphenyliodonium hexafluorophosphate tovinylate alkyl halides under free radical conditions. Diphenyliodonium hexafluorophosphate is thereforeconsidered as an efficient tin surrogate in this free-radical process.

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This dissertation summarizes research efforts focused on the use of boron and transition metal halides to form new carbon-carbon and carbon-halide bonds. The boron halide mediated alkyne-aldehyde coupling reaction to generate 1,3,5-triaryl-1,5-dihalo-1,4-dienes was reinvestigated in an attempt to explain the stereochemistry observed during changing of both the mode of addition and the reaction temperature. Either (Z,Z)-1,4-dienes or (Z,E)-1,4-dienes can be the predominant product depending on reaction conditions used. This mechanistic investigation also led to the discovery of several novel reactions. These include the stereoselective preparation of (Z)-3-chloroallylic ethers from the reaction of alkenylboron dichlorides with aryl aldehydes in the presence of an amine; the titanium(IV) halide coupling of alkoxides and alkynes; the haloallylation of aryl aldehydes with boron trihalide using different allylmetals; and the base induced elimination of the haloallylated products to form 1,3-dienes. The results of these studies strongly imply a cationic mechanism. The new reactions described herein can be characterized as atom-efficient, environmentally friendly, and capable of generating the desired products in good to excellent yields.

Les imidazolones sont des molécules étudiées de longue date, soit en tant que molécules bioactives, soit pour leurs propriétés de fluorescence, l'exemple le plus connu étant la GFP. De nombreuses synthèses étaient déjà décrites, en particulier la condensation d'une amine avec une oxazolone (méthode d'Erlenmeyer). Au cours de ce travail, nous avons non seulement amélioré le protocole d'Erlenmeyer, mais surtout développé une synthèse originale consistant à utiliser l'arylation C-H de 2-H imidazolones. Dans cet objectif, il a fallu tout d'abord mettre au point un protocole de synthèse des 2-H imidazolones, jusqu'alors très peu décrites, puis mettre au point les conditions d'arylation et de vinylation directe de ces molécules. Deux séries d'imidazolones ont été étudiées et publiées séparément : en premier lieu, les 4,4'-dialkyl-imidazolones, fréquemment employées pour leurs propriétés biologiques, puis, au cours du travail qui a suivi, l'arylation et la vinylation des 4- arylidène-2-H imidazolones. / Imidazolones have been studied for a long time, either as bioactive molecules or for their fluorescence properties, the best known example being the Green Fluorescent Protein or GFP. Numerous syntheses are already described, in particular the condensation of an amine with an oxazolone (Erlenmeyer method). In this work, we not only improved the condensation protocol but also developed an original synthesis consisting in using 2-H imidazolones CH arylation. To this end, it was first necessary to develop a protocol for the synthesis of 2-H imidazolones, hitherto very little described, and then to develop the conditions for arylation and direct vinylation of these molecules. Two sets of imidazolones have been studied and published separately: first, the 4,4'- dialkylimidazolones, frequently used for their biological properties, followed by arylation and vinylation of 4-arylidene-2-H imidazolones.

京都大学 / 新制・課程博士 / 博士(理学) / 甲第23734号 / 理博第4824号 / 新制||理||1690(附属図書館) / 京都大学大学院理学研究科化学専攻 / (主査)教授 依光 英樹, 教授 若宮 淳志, 教授 時任 宣博 / 学位規則第4条第1項該当 / Doctor of Science / Kyoto University / DGAM

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