Keywords: Réactions radicalaires multi-composants, Carbo-alcénylation d'alcènes, Eucophylline, lactame ponté, réaction de Friedländer Multi-component radical reactions (MCR), carbo-alkenylation reactions, Eucophylline alkaloid, bridgehead lactam, Friedländer reaction Acetyl MeCN: Acetonitrile atm: Atmospheric pressure AIBN: Azobis(isobutyronitrile) ACCN 1, 1 0]undec-7-ene DCM: Dichloromethane Lithium diisopropylamide LUMO: Lowest Unoccupied Molecular Orbital Milligram mmHg: Millimeter of mercury MS: Molecular sieves MW: Molecular weight NBS: N-bromosuccinimide NMR: Nuclear magnetic resonance Nu: Nucleophilic

Titre : Développement de nouveaux processus radicalaires. Application à la synthèse de l'Eucophylline.

Résumé : L'objectif de ce travail a consisté en le développement de nouveaux processus multi-composant radicalaires et leur application en synthèse organique. Des carbo-alcénylation d'oléfines ont ainsi été réalisées avec de nouveaux précurseurs de radicaux, des oléfines diverses, en présence de Z-diphénylsulfonyléthylène comme accepteur terminal. Les conditions de la réaction ont été optimisées, en introduisant notamment la diphénylsulfonylhydrazine comme amorceur de radicaux sous irradiation UV, et substitut au couteux DTBHN. Des conditions sans étain ont également été étudiées avec l'objectif de remplacer le réactif (Bu 3 Sn) 2 par des radicaux silylés. Le tris (triméthylsilyl)silylthiopropene a ainsi été testé avec succès en tant qu'agent de propagation des chaînes radicalaires. A l'issue de ce travail méthodologique, nous avons développé une stratégie de synthèse de l'Eucophylline, un alcaloïde isolé de Leuconotis griffithii, dont le squelette tétracyclique a été élaboré sur la base d'une réaction de carbo-oximation radicalaire d'oléfine. Ce processus multicomposant, suivi d'une réduction de la fonction oxime et d'une lactamisation offre une voie d'accès rapide au motif bicyclo[3.3.1]lactame, intermédiaire-clé de la synthèse. Une réaction de type Friedländer entre ce lactame et un ortho-aminobenzonitrile a permis d'accéder au squelette tetrahydrobenzo[1,8]naphthyridine de l'Eucophylline. La synthèse du composé modèle a enfin été complétée par l'introduction du substituant vinylique par un couplage de Heck.

L'objectif premier de ce travail a donc consisté en le développement de nouveaux processus multi-composant radicalaires et leur application en synthèse organique. Des réactions à trois composants de carbo-alcénylation d'oléfines ont été réalisées. De nouveaux précurseurs de radicaux C-centrés ont ainsi été additionnés sur le système-π d'oléfines diverses, en présence d'un accepteur sulfonylé, le Z-diphénylsulfonyléthylène. Les études concernant la variation de la nature de l'oléfine ont ainsi mis en évidence que des oléfines simples conduisaient aux produits de réaction à trois composants avec des rendements satisfaisants, tandis que les oléfines bicycliques pourtant plus tendues étaient non réactives dans les mêmes conditions. Le périmètre du processus de carbo-alcénylation a ensuite été étendu à l'étude de la nature des précurseurs de radicaux, en utilisant notamment des accepteurs comportant un substituant nitrile ou deux groupements esters (radical malonyle).

Les conditions de la réaction de carbo-alcénylation ont été optimisées, en introduisant notamment la diphénylsulfonylhydrazine comme amorceur de radicaux sous irradiation UV, et utilisée comme substitut au couteux DTBHN. Les résultats dans le benzène ou le dichloroéthane sur différentes oléfines se sont avérés encourageants.

En parallèle, des conditions sans étain ont également été étudiées avec l'objectif de remplacer le réactif (Bu 3 Sn) 2 par des radicaux silylés. Le tris(triméthylsilyl)silylthiopropène a ainsi été testé avec succès en tant qu'agent de propagation des chaînes radicalaires pour des réactions de vinylation. Des rendements satisfaisants ont pu être obtenus en utilisant le bromoacétonitrile et un allylsilane, l'AIBN comme initiateur, et le tert-butylbenzène comme solvant afin de favoriser la fragmentation du radical thiyl à plus haute température. L'ajout d'un substituant méthyle sur le motif propènyle du silylthioéther a amélioré sensiblement les rendements alors que l'ajout d'un phényle s'est avéré délétère.

A l'issue de ce travail méthodologique, une stratégie de synthèse de l'eucophylline, un alcaloïde isolé de Leuconotis griffithii a été développé. Ce travail s'inscrit dans un programme de recherche sur la synthèse de la leucophyllidine, un alcaloïde hétérodimérique de la même famille dont l'eucophylline constitue le fragment sud. Au cours de cette thèse il a ainsi pu être montré que la réaction de carbo-oximation d'oléfines convenablement substituées, suivie de la réduction de la fonction oxime permettait effectivement d'obtenir avec de bons rendements le motif pipéridinone attendu. Les étapes suivantes ont été étudiées et optimisées sur des substrats modèles, permettant de consolider le schéma de synthèse.

Dans le cadre de cette thèse, les réactions de Vilsmeier et Friedländer sur des composés modèles ont ainsi été testées permettant la préparation de diverses naphthyridines à partir de la 2-pipéridinone commerciale. Cette stratégie permet l'accès au motif naphthyridine présent dans l'eucophylline en seulement 4 étapes.

Après la mise au point de la réaction de Vilsmeier, les réactions de type Friedländer ont été réalisées en présence de plusieurs bases, la LDA s'avérant la mieux adaptée.

Un composé tétracyclique modèle, ne différant du produit naturel (que l'on pourrait donc nommer nor-éthyl-eucophylline) que par un substituant éthyle, a ainsi pu être synthétisé suivant cette méthodologie. Les lactames pontés bicyliques se comportant différemment des simples pipéridinones, une mise au point de la réaction de Vilsmeier, a dû être réalisée demandant des efforts importants d'optimisation.

Sur la base de ces travaux, la synthèse de lactames pontés bicycliques présentant le squelette de l'eucophylline a été réalisé récemment au laboratoire. Les travaux préliminaires de la candidate ont ainsi permis de valider la stratégie de synthèse du motif sud de la leucophyllidine. La synthèse de l'eucophylline est ainsi en passe d'être achevée au laboratoire.

I feel greatly privileged to have been accepted into his research group, an experience that allowed me to greatly expand my knowledge in synthetic organic chemistry. On a more personal note, I greatly respect him for the continuous support during my Ph.D. study and research, for his patience, motivation, enthusiasm and immense knowledge. His guidance helped me in all the time of research and writing of this thesis. I could not have imagined having better advisor and mentor for my Ph.D. study.

Beside my advisor, I would like to express my deep appreciation and gratitude to Dr. Frederic ROBERT, for this keen interest, valuable advices, continuous guidance and encouragement as well as helpful discussion during the progress of this dissertation.

My sincere thanks also go to Dr. Valerie DESVERGNES for her kindness, valuable advices and encouragement.

I would like to specially thank Virginie for her help, support and excellent advices in radical chemistry. I would also like to sincerely thank all the members of the LANDAIS research group (Redouane, Alexandre, Benjamin, Clément, Haitham, Paul, Jessica, Ignacio, Simon and Ahmed) whom I had the pleasure of working with throughout my doctoral studies. They have created a stimulating research environment where the mutual exchange of ideas was always welcome. I would like to extend my thanks to the past members of the group including Nachiket, Emeline, Anthony and Jerome who set very high standards to follow and were also very supportive during my early training.

I would like of course to thank the technical team of the "Groupe Synthèse": Muriel, Clothilde, Jonathan, Marie Hélène and Dimitri for their availability and good mood.

Of course, I would also like to thank Jean-Michel and Noël for their availability and assistance in the NMR analytical part of this thesis.

I would like to acknowledge The Kurdistan Government and the HCDP Program for the very helpful financial support offered during my doctoral studies. I would like to thank my family who have supported me financially and morally as well as encouraged me to excel throughout my studies. My final thanks go to my husband Dr. Ammar, for having the strength to endure what has been a very busy and often stressful four years. The realization of this dream would not have been possible without his companionship, his tolerance of my grueling work schedule and his love.

Introduction I. Multi-Component Radical Reactions (MCRs).

The growing demand for large libraries of compounds, readily available for high throughput screening and the discovery of new drugs is pushing for further development of new and faster elaboration of novel chemical entities.

Nowadays, the main issue in synthesis is how a molecule can be made in a practical fashion as close as possible to an "ideal" one. In this context, Multi-Component Reactions (MCRs) play a key role as they are known to be efficient (providing good yields), selective (reducing the number of byproducts), time saving (limited number of reaction steps), atom economic and using readily available starting materials. 1 Multi-component reactions are defined as reactions in which three or more starting materials react together in a one pot operation, providing a final product where most, if not all atoms of the initial components are incorporated. 2 A MCR is thus a domino process by definition. 3 MCRs allow the installation of several bonds in a single operation, without purifications of the intermediates, modification of the reaction conditions and / or further addition of reagents. These advantages are obvious when the multistep synthesis complexity increases in proportion to the number of steps. The concept of bond forming efficiency has been introduced by Tietze 4 as the number of bonds formed in one process. This number can be an important measure to define the quality of MCRs.

The first part of my thesis thus consisted in the development of a free-radical carbo-alkenylation of olefins. During the radical addition of carbon fragments across the -bond of various olefins, we have studied the effect of the nature of electrophilic precursors and that of the olefins on the whole process. The nature of the initiator has also been an issue. Finally, we have examined the development of a "tin-free" approach using new silylthioether precursors. bicyclic[3.3.1] skeleton of Eucophylline has also been prepared based on the strategy devised on model compounds. The bicyclic core, including the generation of a quaternary center, is elaborated relying on a free-radical multicomponent olefin carbo-oximation process. The latter reaction is mechanistically closely related to the carbo-alkenylation of olefins studied in the first part of the thesis.

This work thus demonstrates that multicomponent free-radical functionalization of olefins can serve as to elaborate small building blocks useful in total synthesis of natural alkaloids.

reactions were poorly selective and could be hardly controllable was very strong, because of the high reactivity that distinguishes them.

Nevertheless, the huge amount of kinetic work carried out during the 1970s and the 1980s, mainly as a consequence of the development of electronic spin/paramagnetic resonance (ESR or EPR) and other spectroscopic techniques, has demonstrated that the reputed lack of selectivity so often attributed to radical reactions, was by no means universal and such prejudice disappeared. In this context, the synthetic chemistry governed by radicals, built upon solid grounds due to long and hard-working experiments during the course of time, started growing, rushing, and expanding very quickly.

Indeed, Giese's reductive additions to carbon-carbon double bonds unequivocally showed that the addition of radicals to alkenes does not necessarily degenerate in polymerizations. 17 New methods to produce carbon-and heteroatom-centered radicals were proposed by Barton,18 while Hart prepared some pyrrolizidines with methodologies that used a radical reaction as the key step. 19 Simultaneously, Pereyre then Keck recognized the importance of the radical allylation: their suggested strategy still remains of fundamental importance. 20 Radical species were employed by Stork as pivotal intermediates in some regio-and stereoselective reactions in order to generate new carbon-carbon bonds. Curran realized bright syntheses of natural products through tandem radical cyclizations, underlining the great peculiarity and selectivity of the radical reactions conducted in sequence. 21 Nowadays the chemistry of radicals has become of fundamental importance. In everyday life, radical reactions are playing a vital role, being exploited in the production of many modern materials, plastics and other polymers, in the chemistry of paints and foodstuffs, in the oxidative degradation of lubricants, as well as in a broad spectrum of biochemical processes occurring in living organisms.

Over the time, the important and advantageous features of the radical chemistry-selectivity, generality, reactivity and predictability -have contributed to make it a widely recognized and essential synthetic tool, destined to be used more and more for the development of complex synthetic strategies. 17 Giese, B. Angew. Chem. 1985, 97, 555. 18 Barton, D. H. R.; Parekh, S. I. Half a Century of Radical Chemistry; Cambridge University Press: Cambridge, 1993, pp 164. 19 Stork, G. Bull. Chem. Soc. Jpn. 1988, 61, 149. 20 (a) Grignon, J.; Pereyre, M. J. Organomet. Chem. 1973, 61, C33; (b) Grignon, J.; Servens, C.; Pereyre, M. J. Organomet. Chem. 1975, 96, 225; (c) Keck, G. E.; Yates, J. B J. Organomet. Chem. 1983, 248, C21; (d) Keck, G. E. E. J. Enholm, Yates, M. R. Wiley, Tetrahedron 1985, 41, 4079. 21 Curran, D. P.; Pakiewicz, D. M. Tetrahedron 1985, 41, 3943. -12-Noteworthy, stability of free radicals decreases as the % of s-character in the orbital increases, so this make the alkyl radical more stable than a vinyl radical itself more stable than an alkynyl radical (Scheme 4).

The stability of free radicals decreases when located onto atoms such as fluorine, oxygen and nitrogen which have higher electronegativity than carbon. Going down the periodic table, one observes an increasing stability in free radicals, going from F < Cl < Br < I. While this can likewise be thought of as resulting from a decrease in electronegativity, another way to look at it is that going down the periodic table an increase in the size of the atom occurs allowing for the electrondeficient orbital to be spread out over a greater volume (Scheme 5). 25 Finally free radicals adjacent to an electron-withdrawing group (for instance CF 3 and CN groups) are less stable, the electron-density being taken away from what is already an electron deficient species. 26

І.3. Different types of Free Radicals.

Generally, there are three kinds of organic radicals having different reactivity and stability, neutral 1 and charged (cation and anion) radicals 2 and 3 (Scheme 6). 25 (a) Dolbier Jr., W. R., Chem. Rev. 1996, 96, 1557; (b) Smith, M. B.; March J. Advanced Organic Chemistry; Reactions, Mechanism and structure", 6 th edition, John Wiley and Sons, Inc., New Jersey, 2007, pp.949. 26 Hay, J. M. Reactive Free Radicals, Academic Press London and New York, 1974, pp. 47.

І.4.2. Reactions between Radicals and non-Radical species.

These kinds of reaction are useful for synthetic purposes, due to many attractive features: 32



The radical species is not lost during the reaction, so that a catalytic amount of radical initiators may be used,



In most cases, the reactions are not diffusion controlled and the selectivities can be controlled by variation of the substituents nature,



The concentration of non-radical species may be easily controlled.

In order to develop successful reactions between radicals and non-radicals species, two basic conditions must be met:

 The reaction between radicals and non-radical species should be faster than radical recombination processes.

 The reactivity of the different radical species involved in the radical chain should vary from one another.

To illustrate this concept, one can describe the successful application of the tin method in the radical chain between alkyl halides A and alkenes 10 in presence of tributyltin hydride which gives product 12 (Figure 1, Giese reaction). 36 The alkyl radical A attacks alkene 10 to give the adduct radical 11, which is then trapped by tributyltin hydride leading to the product 12, regenerating in the meantime the tin radical, which sustains the radical chain and gives back the radical A. This method is useful for synthetic purposes, providing that these different steps are faster than all other possible reactions of radicals A, 11 and 13. The specific reactivity and selectivity of each radical species involved in the chain is the most important feature of these reactions.

36 Giese, B. Angew. Chem. Int. Ed. Engl. 1985, 24, 553.

І.4.2.a. Addition Reactions.

Addition reactions are particularly useful for carbon-carbon bond formation, involving the addition of alkyl radicals to the double bond of an olefin. The rate of the addition depends on the nature of substituents on the alkene. For instance, electron withdrawing groups on the olefin backbone increase the addition rate by reducing the energy level differences between the SOMO and the olefin LUMO. 37 In the presence of a peroxide initiator, hydrogen halide (HX) thus adds to alkenes via an anti-Markovnikov, free-radical mechanism (Scheme 12). The radical product, issued from the first propagation step will be more stable if the carbon with the unpaired electron is highly substituted.

Consequently, the halogen atom finally binds to the less substituted carbon, to afford the anti-Markovnikov addition product. In substitution processes an atom is replaced by another atom or group of atoms. Free radical substitution reactions involve breaking carbon-hydrogen bond in alkanes such as methane, ethane and propane. It also happens in acids like acetic acid (CH 3 COOH), which contains a methyl group and can undergo carbon-hydrogen bond abstraction in the methyl group behaving like methane. 39 Electrophilic alkoxy radicals are particularly efficient for hydrogen-abstraction from C-H bonds which exhibit high HOMO energies, for instance in the α C-H bond of amines, ethers and alkyl C-H bond of esters. In contrast, nucleophilic alkyl radicals abstract hydrogen atoms from C-H bond with lower LUMO energies as for example acyl group of esters (Scheme 13).

This is well illustrated below with the regioselective hydrogen abstraction in propionic acid which depends on the nature of the abstracting agent (Scheme 14). For example the electrophilic chlorine atom radical abstracts the β-hydrogen, while the nucleophilic methyl radical leads to α-hydrogen abstraction. 39b The halogenation of alkanes with Br 2 or NBS (N-bromosuccinimide) is probably the best known example of abstraction-halogenation process based on this radical reaction. This chain reaction is initiated by homolytic cleavage of Br 2 using light or heating. The propagation step consists of two atom abstractions (Scheme 15). 40 40 Smith, M.; March, J. Advanced Organic Chemistry; Reactions, Mechanism and structure, 6 th edition, John Wiley and Sons, Inc., New Jersey, 2007, pp. 942.

І.4.2.c. Elimination (Fragmentation) Reactions.

These reactions take place when two molecules are formed from one and are determined by activation entropies, so the free energy gain increases with increasing the reaction temperature.

Therefore, alkoxy radicals undergo β-elimination reactions although there is a small enthalpy difference between π-CO and -C-C bonds. 41 The C-OR bond αto the radical center is cleaved very slowly, due to the less stable π-CC bond that is formed (Scheme 16). There are other weak bonds, such as C-Br, C-SR and C-SnR 3 , which undergo fast β-elimination reactions. 42

41 Brun, P.; Waegell, B. in Reactive Intermediates, Abramovitch, R. A. Ed., Vol. 3, Plenum Press, New York, 1983, p. 392. 42 (a) Kerr, J. A.; Lioyd, A. C. Quart. Rev. (London), 1968, 22, 549; (b) Boothe, T. E.; Greene, J. L.; Shevlin, P.B. J. Am. Chem. Soc. 1976, 98, 951; (c) Keck, G. E.; Enholm, E. J.; Yates, J. B.; Wiley, M. R. Tetrahedron, 1985, 41, 4079. Then the rearrangement of the bromine substituted isobutyl radical in the photochemical reactions (Scheme 21) was characterized by Skell 47 and co-workers, which led to a 1,2 shift of the halogen via an isomerization event.

І.4.2.e. Electron Transfer Reactions.

Electron transfer processes involving metal ions are common. Addition to or removal of one electron from a diamagnetic organic molecule using metal salts constitutes a powerful manner to generate a radical species. For this purpose, many transition metal ions, including copper or iron have more than one stable oxidation state (Scheme 22). 48 The difference in reduction potentials between adducts and products determines the rate of the electron transfer reactions, 49 for instance alkyl radicals 45 with high SOMO energies undergo fast electron transfer reactions with many metal salts including Cu metal (Scheme 23). 50 This radical generates another radical 47 by addition to acrylonitrile 46. The benzyl radical formed 49 is then -22-this will interact with both π * -antibonding orbital (the LUMO) and the π-orbital (the HOMO) of the olefin. Both the SOMO-HOMO and SOMO-LUMO interactions lead to a net drop in energy. The dominant interaction and the reaction rates depend on the relative energies of these orbitals. Most radicals have high energy SOMO ' s and the SOMO-LUMO interaction is likely to be the most important.

To explain these interactions, let us consider for example the interactions between radicals (CH 3 ) 3 C• and (C 2 H 5 O 2 C) 2 CH• with olefins (Figure 2). (CH 3 ) 3 C• is an electron-rich radical species due to the inductive effects that result from the electron-donating groups of three methyl groups. Its SOMO has a high energy level and thus the tert-butyl radical exhibits a nucleophilic character, leading to favored interactions with the low-energy LUMO of electron-poor olefins, such as phenylvinylsulfone. In contrast, the electron-deficient (C 2 H 5 O 2 C) 2 CH• radical (due to the resonance effect with the two ester groups) possesses a low energy SOMO which thus possesses an electrophilic character. One can then expect strong interactions with electron-rich olefins (high HOMO energy) such as ethylvinyl ether and thus good SOMO-HOMO overlapping.

In summary, the small energy differences in SOMO-HOMO or SOMO-LUMO interactions are crucial to rationalize, for example the relative reactivity, during addition reactions, of nucleophilic cyclohexyl radical and electrophilic malonyl radical towards a range of substituted alkenes (Figure 3 . Chem., Int. Ed. 2010, 49, 262. 57 Giese, B.;Groninger, K. Tetrahedron Lett. 1984, 25, 2743.

Angew

І.6.2. Regioselectivity.

Regioselectivity in radical reactions relies on a subtle combination of steric and electronic effects, and depends on the nature of the radical species. For example, during radical additions to the carbonyl groups, nucleophilic radicals will prefer to add on the carbon atom, while electrophilic radical will prefer the addition onto the oxygen atom.

When nucleophilic acyl radical is reacted with diolefinic precursors (Scheme 27), only the attack onto the less accessible α-substituted electron-deficient olefin will be observed. 59 The regioselectivity is also remarkable in the case of intramolecular cyclizations of 1-hexyl radicals, which afford five-membered rings instead of the more stable six-membered rings (Scheme 28). This follows the rules proposed by Baldwin. 60 Beckwith rationalized this behavior invoking the ring 58 Stork, G.; Baine, N. H. J. Am. Chem. Soc. 1982, 104, 2321. 59 Gottschalk, P.; Neckers, D. C. J. Org. Chem. 1985, 50, 3498. 60 Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734. -25-strain effects, at the origin of a faster cyclization in the favor of the five-membered ring relative to the six-membered ring system through an unsymmetrical transition state. 61 Such transition state models are better known now as Beckwith-Houk models and serve to explain the stereocontrol in many radical cyclizations. 62 Regioselectivity in radical processes is appreciated in the construction of complex natural products such as terpenes. Polycyclization is thus possible through regioselective elemental radical processes as illustrated with the synthesis of hirsutene by Curran and co-workers starting with a tin-mediated iodine abstraction and two 5-exo cyclization reactions (Scheme 29). 63 61 (a) Fujimoto, H.; Yamabe, S.; Minato, T.; Fukui, K. J. Am. Chem. Soc. 1972, 94, 9205; (b) Dewar, M. J. S.; Olivella, S. J. Am. Chem. Soc. 1978, 100, 5290. 62 Three different modes of radical addition are found, which include syn-addition, both new bonds being formed from the same side (face) of the double bond, anti-addition, where the two new bonds are formed from opposite faces of the double bond, and finally non-stereoselective addition leading to syn-and anti-addition products. For example, at -80°C, the radical addition of HBr to Z-or Ealkenes yields anti-addition products, due to the bridging of the bromine atom in β-position (Scheme 30). The stereoselectivity was also shown to decrease when the temperature rose. 64 The stereoselectivity is also quite high with cyclic radicals. For example, cyclopentyl radicals give exclusively anti-adducts if the neighboring substituent is an amide group (Scheme 31). 65 The stereoselectivity decreases with less shielding, CH 3 or OR, groups, but it rises again if alkenes have low reactivity. 66 The selectivity of cyclohexyl radicals can be comparatively high. 64 Skell, P. S.; Shea, K. J. in Free Radicals, J. K. Kochi Ed., Vol. 2, New York 1973, p. 809. 65 Henning, R.;Urbach, H. Tetrahedron Lett. 1983, 24, 5343. 66 (a) Giese, B.; Heuck, H.; Lenhardt, H.; Luning, U. Chem. Ber. 1984, 117, 2132; (b) Giese, B.; Harnisch, H.; Luning, U. Chem. Ber. 1985, 118, 1345. Carbohydrate radicals also exhibit selectivity higher than that of cyclohexyl radicals (Scheme 32). 67

І.7. Radicals in Natural Product Syntheses.

Radical chemistry provides a powerful tool for the selective formation of carbon-carbon and carbon-heteroatom bonds. The mild, neutral conditions and functional group compatibility of Ccentered radicals, is particularly attractive for the use in the context of the synthesis of complex systems including natural products. Kilburn et al. reported the use of samarium iodide as a mild and selective reductant in a cascade cyclization reaction during the synthesis of paeonilactone B (Scheme 33). 68 Zard and co-workers have developed 69 a synthesis of Lycopodium alkaloids (1,3-deoxyserratine) using a mild method for generation of nitrogen-centered amidyl radicals from O-acylhydroxamic acids (Scheme 34).

67 Giese, B.; Gonzalez-Gomez, J. A.; Witzel, T. Angew. Chem. Int. Ed. Engl. 1984, 23, 69. 68 (a) Boffey, R. J.; Santagostino, M.; Whittingham, W. G.; Kilburn, J. D. Chem. Commun. 1998, 1875; (b) Boffey, R. J.; Whittingham, W. G.; Kilburn, J. D. J. Chem. Soc. Perkin Trans. 2001, 1, 487. 69 Cassayre, J.;Gagosz, F.;Zard, S. Z. Angew. Chem. 2002, 114, 1861;Angew. Chem. Int. Ed. 2002, 41, 1783. Pattenden et al. used imaginative radical cascade to enable the diastereoselective formation of three rings and four stereocenters in a single operation to complete a short synthesis of (±) estrone (Scheme 35). 70 Parker and co-workers 71 prepared (-)-morphine using a remarkable radical cascade process installing the all-carbon quaternary stereocenter and the tricyclic system of the alkaloid in a single step (Scheme 36). 70 (a) Pattenden, G.; Reddy, L. K.; Walter, A. Tetrahedron Lett. 2004, 45, 4027;(b) Pattenden, G.;Gonzalez, M. A.;McCulloch, S.;Walter, A.;Woodhead, S. J. Proc. Natl. Acad. Sci. USA 2004, 101, 12024. 71 (a) Parker, K. A.; Fokas, D. J. Am. Chem. Soc.1992, 114, 9688; (b) Parker, K. A.; Fokas, D. J. Org. Chem. 2006, 71, 449. Chapter ІІ: Free-Radical Multicomponent Processes.

The concept of multicomponent reactions (MCRs) 72 has been around in organic chemistry since the beginning of the 90's. 73 They are based on the previous development of selective methods for carbon-carbon and carbon-heteroatom bond formation. Such strategies allow a fast building up of functionalized molecules in a one-pot process. 32,74 A MCR is a reaction where more than two starting materials are involved and where most of the atoms contained in these compounds are found in the reaction product. The first MCR was the Strecker synthesis of α-aminonitriles, 75 which was followed by the preparation of dihydropyridines by Hantzsch 76 and the development of the Mannich reaction. 77 Today the rational design of MCRs is based on a mechanistic approach and the concept of structure-reactivity that led to new methods such as the replacement of one of the components (Single Reactant Replacement-SRR). Thus, the first SRR case reported in the literature related to a four components synthesis to access Ugi peptide structures. 78 This assembly is similar to the Passerini reaction including O-acylated α-hydroxamides synthesized according a three-component process (Scheme 37).

Polar effects are particularly important in radical chemistry and consequently in MCRs, polarity of radical species strongly influencing the overall kinetic of the reaction. 32,79 Radicals have been divided into three different types and classified as electrophilic, nucleophilic and borderline (Figure 5). 80 It is worthy of note that in contrast to ionic processes, a reaction between an electron-poor species and an electron-poor alkene can take place although it will be much slower than a reaction between the same electron-poor species and an electron-rich alkene.

Multicomponent reactions were also classified according to the number of substrates involved, so that the radical and radical-ionic MCRs follow the nomenclature: 3-CR, 4-CR and 5-CR corresponding respectively to three-, four-and five-component reactions. Letters A (Acceptor) and D (Donor) has also been added, referring to the polarity of the radical species involved in the multicomponent process. 80 The discussion will focus on multicomponent reactions based on radical mechanisms and will not be limited to processes which assemble three, four and even five components by one-pot process, but will also describe processes involving radical and ionic steps.

ІІ.1. Bibliography of Three-Component Radical Reactions.

ІІ.1.1. Carbonylation Reactions.

The first example of this type of reaction was reported by Lipscomb and co-workers, 81 using high pressure of carbon monoxide (CO) as a radical acceptor (A). The reaction process (Scheme 38) involved the addition of a sulfanyl radical (A) 104i onto propene (D) 105, the resulting radical 105i then reacting with CO 106 to give the acyl radical (105ii). The latter then reacts with electron-poor 79 (a) DeVleeschouwer, F.; VanSpeybroeck, V.; Waroquier, M.; Geerlings, P.; DeProft, F. Org. Lett. 2007, 9, 2721; (b) Arthur, N. L., Potzinger, P. Organometallics, 2002, 21, 2874; (c) Am. Chem. Soc. 1956, 78, 5606. substrates or via group transfer processes such as S H 2 to produce 3-CR product 108 in low yield due to the formation of the sulfide 107 as a side product. Later, use of [Co(CO) 8 ] as a catalyst by Tsuji led to an increase of the yield of the product. 82

ІІ.1.2. Carbo-allylation Reactions.

This class of reaction was the first multicomponent process studied and developed by the group of Mizuno, Otsuji and co-workers in 1988. 83 This involved the 1,4-addition of electron-rich radical species onto an electron-deficient alkenes such as α,β-unsaturated carbonyl compounds (Michael acceptor), followed by the trapping of the enolate by an electrophile, which led to the formation of two new carbon-carbon bonds. A nucleophilic radical (D) 109i generated from the corresponding iodide 109 adds to the electron-poor olefin (A) 110 through a SOMO-LUMO interaction (Scheme 39). The new electron-deficient radical intermediate 110i is trapped with an allyltin (D) 111 through SOMO-HOMO interaction, affording the product 112 in excellent yield, the tributyltin radical being regenerated, sustaining the radical chain.

82 Susuki, T.; Tsuji, J. J. Org. Chem. 1970, 35, 2982. 83 Mizuno, K.; Ikeda, M.; Toda, S.; Otsuji, Y. J. Am. Chem. Soc. 1988, 110, 1288.

ІІ.1.3 Carbo-hydroxylation Reactions.

This class of reactions involves the cascade addition of a carbon fragment onto an olefin, followed by the trapping of the resulting radical enolate with persistent TEMPO. 84 The reaction between organoborane 113 and one equivalent of TEMPO generates a nucleophilic cyclohexyl radical 113i (Scheme 40), which then adds to maleimide 114 to produce an enoyl radical 114i, which is finally trapped by a second molecule of TEMPO 115 to afford the product 116.

Alternative radical-mediated alkene carbooxygenations have been developed recently by Alexanian and co-workers. 85 Alkene oxyallylation, oxycyanation and oxyacylation processes using N-aryl hydroxamic acids 117 have thus been described. These reactions proceed through the in situ generation of amidoxyl radical 117i from 117 (Scheme 41), then intramolecular addition of the Noxyl radical onto the alkene, leading to a new C-centered radical which is finally trapped with various sulfonyl acceptors, including allyl sulfones 118, tosylcyanide 120 or sulfonyloxime 122, to afford products 119, 121 and 123 respectively. 84 (a) Cadot, C.; Dalko, P. I.; Cossy, J.; Ollivier, C.; Chuard, R; Renaud, P. J. Org. Chem. 2002, 67, 7193; (b) Schaffner, A.-P.; Renaud, P. Eur. J. Org. Chem. 2004, 2004, 2291. 85 Quinn, R. K.; Schmidt, V. A.; Alexanian, E. J. Chem. Sci. 2013, 4, 4030.

ІІ.1.4. Carbo-sulfenylation Reactions.

The strategy of this reaction relies on the trapping of the radical intermediate 125i by the Barton reagent N-methoxycarbonyloxypyridine-2-thione (PTOC-OMe). 86 Enantioselective hydroboration of norbornene with catecholborane (Scheme 42) in the presence of a chiral rhodium catalyst furnished borane 124, which upon irradiation in the presence of PTOC-OMe led to the C-centered radical 124i. The nucleophilic norbornyl radical 124i then added to the olefin 125 producing intermediate 125i, which was finally trapped with Barton carbonate 126 to afford thioether 127 in a good yield. 86 Renaud, P.; Ollivier, C.; Weber, V. J. Org. Chem. 2003, 68, 5769. ІІ.1.5. Carbo-phosphorylation Reactions.

Multicomponent reactions under free-radical conditions using phosphorus compounds have been described. Alkyl and aryl radicals undergo addition through π-system of an activated olefin to produce electrophilic radical species which was shown to react with Me 3 SnPPh 2 130. For example, the reaction of t-butyl iodide 128 in the presence of 1,1 ' -azobis(cyclohexane-1-carbonitrile) (V-40) produced the corresponding radical 128i (Scheme 43), which then adds onto acrylonitrile 129, leading to electrophilic radical 129i. 87 The latter then reacts with Me 3 SnPPh 2 130 through homolytic substitution, affording, after oxidation, the phosphine oxide 131 in very good yield.

ІІ.1.6. Multicomponent Radical-Ionic Reactions.

The addition of a radical species onto an olefin gives a new radical which undergoes reduction (stabilized by electron-poor system) or oxidation (stabilized by electron-rich system) reactions to generate a nucleophile (carbanion), or an electrophile (carbocation) respectively, able to react with a third partner in the reaction medium under ionic conditions (Figure 6). Many tandem radical-anion processes have been described over the last twenty years. The first involved metals such as Cr 89 , Co 90 , Pd, Zn, Cu and Sm, 91 which exhibit reductive properties. But a wide variety of sequences were developed around elements such as boron (Et 3 B) as well as zinc 92 (Et 2 Zn) which are commercial, inexpensive and harmless. Chemla and co-workers 93 have developed a radical carbocyclization process (Scheme 44), in which a butyl radical (D), generated from dibutylzinc 132 in the presence of oxygen, was shown to add onto α,β-unsaturated esters (A) (Michael acceptors) such as 133 leading to a stable radical 133i that can then undergo a 5-exo trig cyclization 94 to yield primary radical 133ii. Homolytic substitution on dibutylzinc generates a butyl radical which propagates the reaction chain, leaving an alkyl-zinc species 133iii that can be trapped with allyl bromide (A) 134 in the presence of CuCN to produce 135 in good yield.

Hydroxysulfenylation of α,β-unsaturated imines using Et 3 B, in the presence of oxygen, has also been reported recently. 95 The process involved addition of a sulfanyl radical 136i, generated from PhSH 136 and an Et radical to afford an alkoxyaminyl radical (Scheme 45), then formation of a boryl enamine and Et radical through homolytic substitution (S H ) onto the boron center of Et 3 B. This boryl enamine then reacts with oxygen 138, producing a peroxy radical which is trapped with 89 Takai, K.; Matsukawa, N.; Takahashi, A.; Fujii, T. Angew. Chem. Int. Ed. 1998, 37, 152. 90 Mizutani, K.;Shinokubo, H.;Oshima, K. Org. Lett. 2003, 5, 3959. 91 (a) Murakami, M.; Kawano, T.; Ito, H.; Ito, Y. J. Org. Chem. 1993, 58, 1458; (b) Murakami, M.; Kawano, T.; Ito, Y. J. Am. Chem. Soc. 1990, 112, 2437. 92 Yamamoto, Y.;Nakano, S.;Maekawa, H.;Nishiguchi, I. Org. Lett. 2004, 6, 799. 93 (a) Denes, F.;Chemla, F.;Normant, J. F. Angew. Chem. 2003, 115, 4177;(b) Denes, F.; Chemla, F.; Normant, J. F. . Chem. Int. Ed. 2003, 42, 4043;(c) Denes, F.;Cutri, S.;Perez-Luna, A.;Chemla, F. Chem. Eur. J. 2006, 12, 6506. 94 Addition followed by 5-exo-trig cyclization onto alkynes: (a) Giboulot, S.; Perez-Luna, A. P.; Botuha, C.;Ferreira, F.;Chemla, F. Tetrahedron Lett. 2008, 49, 5322;(b) Perez-Luna, A.;Botuha, C.;Ferreira, F.;Chemla, F. Chem. Eur. J. 2008, 14, 8784. 95 Ueda, M.; Miyabe, H.; Shimizu, H.; Sugino, H.; Miyata, O.; Naito, T. Angew. Chem. Int. Ed. 2008, 47, 5600. PhSH to give an hydroperoxide. The latter is finally reduced into the hydroxysulfenylation product 139 and disulfide.

Angew

ІІ.1.6.b. Multicomponent Radical-Cationic Reactions.

In parallel with multicomponent radical-anionic reactions, various radical-cationic processes have also been described involving metals. The conversion of a radical into a cationic species relies on the ability of an organometallic species to selectively oxidize a certain type of radicals. Ryu and Alper were the first to observe that the electron transfer from an acyl group to the metal (Mn ІІІ ) was faster than transfer from alkyl radicals. 96 An illustration of the utility of this observation is given below (Scheme 46). The reaction starts by the generation of the electrophilic malonyl radical (A) 140i from Mn(OAc) 3 (Scheme 46), then addition onto olefin 141 to form the nucleophilic radical 141i, which can undergo another addition to CO 103. 97 An acyl radical 141ii is thus formed, which is then oxidized by Mn(OAc) 3 into an acylium cation 141iii that is immediately trapped by H 2 O (D) 142 as a fourth component to yield the desired product 143. 96 (a) Ryu, I.; Alper, H. J. Am. Chem. Soc. 1993, 115, 7543; (b) Okuro, K.; Alper, H. J. Org. Chem.1996, 61, 5312. 97 Carbonyl-substituted radicals are known to have ambiphilic character, see: a) Giese, B.; He, J.; Mehl, W. Chem. Ber. 1988, 121, 2063; b)

II.2.1. Carbo-allylation Reactions.

Renaud 101 and co-workers have developed radical conjugated addition to electron-deficient olefins such as vinyl sulfones, maleimides and fumarates, followed by reaction with allyl sulfone acceptors. 102 The reaction sequence (Scheme 47) is achieved by hydroboration of cyclohexene 144 with catecholborane (CatBH), then conjugated addition to the activated vinyl phenyl sulfone 146 and allylation of the radical adduct 145i with the allyl sulfone 146, affording the product 147 with generation of the phenylsulfonyl radical which sustains the reaction chain.

Furthermore, Zard and co-workers 103 have reported radical additions onto the double bond of ethylallylsulfones. Generally, this tin-free reaction proceeds with high yields and can be applied to both iodides and xanthates. The radical reaction is initiated with AIBN, which reacts with 149, forming the ethyl radical 149i, after SO2 extrusion, able to abstract an iodide or a xanthate group 101 Schaffner, A. P.; Sarkunam, K.; Renaud, P. Helv. Chim. Acta 2006, 89, 2450. 102 (a) Chatgilialoglu, C.; Ballestri, M.; Vecchi, D.; Curran, D. P. Tetrahedron Lett. 1996, 37, 6383; (b) from 148 to generate the C-centered radical 148i (Scheme 48). The latter then adds onto ethylallylsulfone 149 affording the product 150 with elimination of an ethylsulfony radical (149i), which upon α-scission releases SO 2 and 149ii that can propagate the reaction chain.

The unique reactivity of phenyl-and alkylsulfonyl radicals has led to the development of several useful multicomponent processes that encompass the successive formation of C-C and C-N bonds.

These include carbo-azidation, carbo-alkynylation and alkenylation of olefins, which are described below.

ІІ.2.2. Carbo-azidation Reactions.

The radical carboazidation of terminal alkenes has recently been developed by Renaud and coworkers. 104 The reaction involves the addition of an electrophilic ethyl acetate radical 151i to the olefin 152, affording a nucleophilic radical 152i which reacts with strongly electrophilic sulfonyl azide 153 to produce the desired product 154 in good yield (Scheme 49). As mentioned above, the 104 (a) Ollivier, C.; Renaud, P. J. Am. Chem. Soc. 2001, 123, 4717; (b) Renaud, P.; Ollivier, C.; Panchaud, P. Angew Chem. 2002, 114, 3610; (c) Ollivier, C.; Renaud, P. Angew. Chem. Int. Ed. 2002, 41, 3460; (d) success of such a multicomponent reaction relies on matched polar effects between the various constituents. Based on these premises, the carboazidation process may be carried out by simply premixing the reagents together, considering that PhSO 2 N 3 153 will only react with nucleophilic alkyl radical 152i in presence of electrophilic alkyl radical 151i, which will react faster with electron-rich olefins.

The addition mechanism of nucleophilic radical 152i onto the electrophilic sulfonyl azide 153 (Scheme 50) can proceed through two ways and the structure of radical 153 can be represented in two forms 153i and 153ii, that undergo elimination of phenylsulfonyl radical and produce the same product 154.

In 2002, Landais and co-workers applied the carboazidation process to chiral allylsilanes 156, which provided the desired β-silyl azides 157 in good yield and satisfying diastereocontrol (Scheme 51).

ІІ.2.3. Carbo-oximation Reactions.

Kim and co-workers showed that sulfonyl oximes are also excellent radical acceptors, allowing the installation of an oxime onto a carbon framework. 106 The approach involved the addition of an alkyl radical such as 158i onto the C=N bond of the sulfonyl oxime ether 159, which then undergoes a βelimination to afford the oxime ether 160 (Scheme 52).

Addition of functionalized carbon fragments and sulfonyl oximes across the olefinic π-system has been developed recently in our group and was shown to be a general strategy for the carbon-carbon bonds formation. For instance, a sequential carbo-formylation protocol involving a one-pot 3component radical carbo-oximation, under mild conditions, has been developed. This multicomponent free radical process may be regarded as a formal [2+2+2] process using (benzyl and SEM) sulfonyl oximes substitution as electrophilic traps. 107 The process is carried out by generation of a tin radical using DTBHN as an initiator, which abstracts the xanthate or iodide 161 to form an electrophilic alkyl radical. Addition of the latter onto olefin 162 produced the nucleophilic radical which was finally trapped by sulfonyl oxime 163, yielding the three-component products 164 (Scheme 53).

106 (a) Kim, S.; Lee, I. Y.; Yoon, J. Y.; Oh, D. H. J. Am. Chem. Soc. 1996, 118, 5138; (b) Kim, S.; Yoon, J.-Y. J. Am. Chem. Soc. 1997, 119, 5982; (c)

ІІ.2.4. Carbo-alkynylation and alkenylation Reactions.

The carbo-alkynylation of olefins through free-radical multicomponent reactions has similarly been developed. Fuchs and co-workers have thus shown that trifluoromethylsulfonylalkyne derivatives were effective for this process. 108 The reaction proceeds through a radical C-H abstraction by the electrophilic trifluoromethyl radical in a process involving addition of alkyl radical 165i to the acetylenic triflone 166, to form vinyl radical 166i leading to the product 167 and trifluoromethylsulfonyl radical. The latter undergoes a β-fragmentation into sulfur dioxide and the trifluoromethyl radical which propagates the chain (Scheme 54).

Renaud et al. reported alkenylation and alkynylation of olefins, through the corresponding alkylcatecholborane intermediate. 109 The reaction here starts with hydroboration of the olefin 168, which produces the corresponding alkylcatecholborane. Decomposition of DTBHN generates a t-BuO radical which adds to boron producing a nucleophilic alkyl, which adds to alkenylsulfone 169, sulfonyloxime 122 or alkynylphenylsulfone 172, affording products 170, 171 and 173 in good yields (Scheme 55). 108 (a) Gong, J.; Fuchs, P. L. J. Am. Chem. Soc. 1996, 118, 4486; (b) Xiang, J. S.; Fuchs, P. L. Tetrahedron Lett. 1996, 37, 5269; (c) Xiang, J.; Jiang, W. L.; Fuchs, P. L. Tetrahedron Lett. 1997, 38, 6635. 109 Schaffner, A. P.; Darmency, V.; Renaud, P. Angew. Chem. Int. Ed. 2006, 45, 5847. -45-More recently, a three-component free-radical carbo-alkynylation and alkenylation of olefins has been developed by Landais and co-workers, 110 starting from readily available xanthates or bromides such as 174, (ester, amide, ketone, etc.), olefins and sulfone acceptors. This method is closely related to the carboazidation described above (Scheme 56). It proceeds through the generation of a radical species by abstraction of a xanthate or bromide group by tin. The alkyl radical thus generated then adds onto the less hindered end of an olefin 175, producing a nucleophilic radical which is trapped by the electrophilic vinyl 111 or alkynyl sulfonyl acceptor 176, yielding products 177 in good yield along with the phenylsulfonyl radical, which propagates the radical chain.

110 Liautard, V.; Robert, F.; Landais, Y. Org. Lett. 2011Lett. , 13, 2658. 111 . 111 (a) Russell, G. A.; Tashtoush, H.; Ngoviwatchai, P. J. Am. Chem. Soc. 1984, 106, 4622; (b) Russell, G. A.; Ngoviwatchai, P. J. Org. Chem. 1989, 54, 1836; (c) Russell, G. A.; Ngoviwatchai, P.; Tashtoush, H. L.; Pla-Dalmau, A.; Khanna, R. J. J. Am. Chem. Soc. 1988, 110, 3530; (d) Bertrand, F.; Quiclet-Sire, B.; Zard, S. Z. Angew. Chem., Int. Ed. 1999, 38, 1943; (e) Schaffner, A.-P.; Darmency, V.; Renaud, P. Angew. Chem., Int. Ed. 2006, 45, 5847. This study has recently been extended to the free-radical carbo-alkenylation of enamides and enecarbamates (Scheme 57), 112 providing the three-component products with a high level of diastereocontrol in cyclic systems, but a much lower in acyclic analogues, due to the absence of allylic strain in this case.

112 Poittevin, C.; Liautard, V.; Beniazza, R.; Robert, F.; Landais, Y. Org. Lett. 2013, 15, 2814.

II.3. Our Objectives.

In this project, we proposed to improve new multicomponent radical functionalization of olefins via the addition of two functionalized carbon-fragments across an olefinic π-system that would lead to the creation of two new carbon-carbon bonds. Our plan involved first, the preparation of different Due to the important role of vinylbisphenylsulfone in free-radical multicomponent processes described above, we started our study with the synthesis of the Z-isomer of the vinylbisphenyl sulfone, in order to compare its reactivity with that of the commercially available E-isomer. The synthetic pathway is summarized in Scheme 59 below. First, we used dichloroethane 180 as a starting material that underwent successfully a double substitution reaction with thiophenol under basic conditions to afford 181. Chlorination of the latter with NCS led as expected to 182.

Unfortunately, we were unable to obtain bis-sulfone 183 through oxidation reaction. 113 113 Houk, K. H.; Li,Y.; Mcallister, M. A.; Odoherty, G.; Paquette, L. A.; Siebrand, W.; Smedarchina, Z. K. J. Am. Chem. Soc. 1994, 116, 10895. An alternative route starting from the Z-dichloroethene substrate 184 was thus proposed. This synthesis required two steps (Scheme 60). The first is a substitution of the chlorine atoms in 184 with thiophenol, which successfully led to 185 in good yield. 114 The second step is an oxidation of the sulfide groups in 185 into the corresponding sulfones using H 2 O 2 as an oxidizing agent in refluxing glacial acetic acid, which led to the desired product 169 in high yield. 115 The isomerization of 185 (Z) to 186 (E) was done by the U.V. irradiation process with diphenyl disulfide as a catalyst 116 (Scheme 61). This could be a good way for preparing the sulfide E-isomer which can later undergo an oxidation and yield the E-isomer of 169. Unfortunately, both 1 H NMR analysis and chromatography indicated only the presence of starting material.

Vinylsulfoxides are also known as reactive acceptors in radical reactions. 117 Therefore, we envisioned the synthesis of the vinyldisulfoxide 187 from 185. Oxidation of disulfide compound 185 into disulfoxide 187 using sodium periodate as an oxidizing agent (Scheme 62) in methanol was attempted. Unfortunately, this led essentially to recovered starting material 185.

114 Bauld, N. L.; Aplin, J. T.; Yueh, W.; Loinaz, A. J. Am. Chem. Soc. 1997, 119, 11381. 115 Paquette, L. A.; Kunzer, H. J. Am. Chem. 1986, 108, 7431. 116 Harrowven, D. C.;Hannan, J. C. Tetrahedron 1999, 55, 9341. 117 Miyamoto, N.;Fukuoka, D.;Utimoto, K.;Nozaki, H. Bull. Chem. Soc. 1974, 47, 503. Sequentially, the isomer Z-disulfone 169 was tested in multicomponent reaction (Scheme 63), using xanthate 155, allylsilane 188 in the presence of tin and DTBHN in refluxing DCE. This reaction led to the desired product as the E-isomer that matched with the product obtained previously using the E-disulfone. This demonstrated and proved that we can equally use the E or Z-isomer with no problems in these radical reactions.

Therefore, starting from the Z-isomer 169 leads to the E-isomer in the final product, indicating that isomerization has to occur at some point during the reaction. This can be explained invoking a slow β-elimination of the sulfonyl radical from radical intermediate 169i, allowing a rotation around the central C-C bond and thus the formation of the thermodynamic product 190ii from conformation 169iii (Scheme 64). Elimination from conformation 169ii is likely disfavoured due to gauche interactions between R and SO 2 Ph substituents.

ІІ.4.1.b. Preparation of the Phenylsulfonylthiophene acceptor.

In parallel, we also envisioned the preparation of arenesulfonyl acceptors for their incorporation into our multicomponent approaches. The phenylsulfonylthiophene 193 was thus designed as a potent acceptor, accessible through a Suzuki coupling between 2-thienylboronic acid 191 and benzenesulfonyl chloride 192 in the presence of palladium chloride as a catalyst (Scheme 65). 118 This process did not lead to the desired product 193 but instead to a complex mixture of products ( 1 H NMR), in which 193 was absent.

We found another way, which involved a substitution reaction between sodium benzenesulfonate 195 and bromothiophene 194 using copper iodide as a catalyst under basic conditions. An acceptable yield of the desired product 193 was obtained after purification on silica gel (Scheme 66). 119 Sulfone acceptor 193 was then tested in free-radical three-component processes in the presence of xanthate 120 155 and allylsilane 121 188 (Scheme 67). The reaction should start with the addition of ethylacetate radical species onto olefin 188 producing a nucleophilic radical which should be trapped by sulfonylthiophene acceptor 193. Several attempts were carried out but all failed to get the desired product 196. Degradation of all starting materials (as shown by 1 H NMR), including precursor 193 was observed under the reaction conditions.

118 Bandgar, B. P.; Bettigeri, S. V.; Phopase, J. Org. Lett. 2004Lett. , 6, 2105. 119 . 119 Zhu, W.; Ma, D. J. Org. Chem. 2005, 70, 2696. 120 Kapat, A.; Nyfeler, E.; Giuffredi, G. T.; Renaud, P. J. Am. Chem. Soc. 2009, 131, 17746. 121 Soderquist, J. A.;Hassner, A. J. Org. Chem. 1983, 48, 1801. ІІ.4.2. Attempts to use indole and bicyclic olefins in MCRs.

ІІ.4.2.a. Preparation of Boc-indole olefin and application in MCRs.

Amongst the many olefins that were tested in our laboratory such as enamides and enecarbamates, 115 which provides access to the corresponding three-component adducts with a high level of diastereocontrol in cyclic compounds, we were interested in the reactivity of indoles as potent "olefinic" partners in multicomponent reactions. Previous studies by Miranda 122 effectively showed that the addition of radical species onto indoles and pyrroles is possible. For this purpose, we first protected the amino group of indole 197 with a Boc group, as previously reported, 123 to form the desired product 198 in excellent yield (Scheme 68).

Protected indole 198 was then incorporated in the multi-component carbo-alkenylation reaction using xanthate 155 and Z-vinylbisphenylsulfone 169 as partners (Scheme 69). The regioselectivity issue of the reaction was of particular interest as the addition of the ethyl acetate radical can occur both at C2 and C3 in indole 198. Unfortunately and despite many attempts the reaction did not afford the desired product, and only degradation was observed. We next investigated the reactivity of several bicyclic olefins in our multicomponent processes. The 2,3-diethyl-2,3-diazobicyclo[2.2.1]hept-5-ene was designed as our first target and prepared following a literature procedure through a Diels-Alder cycloaddition. Freshly distilled cyclopentadiene 200 was heated in the presence of DEAD 201, affording the desired adduct 202 in excellent yield (Scheme 70). 124 202 was then submitted to the standard carbo-alkenylation conditions (Scheme 71), leading to the formation of the desired product 203, seen by NMR, but isolated in very low yield and with some impurities due to a difficult purification.

We then turned our attention to another bicycle, i.e. the 1,4-dihydro-1,4-methanonaphthalene 205, which is known to react under radical conditions. 125 The latter was obtained, albeit in low yield, through a Diels-Alder reaction between 1,2-dibromobenzene 204 and cyclopentadiene 200 (Scheme 72). 126 124 John, J.; Indu, U.; Suresh, E.; Radhakrishnan, K. V. J. Am. Chem. Soc. 2009, 131, 5042. 125 (a) Hodgson, D. M.; Bebbington, M. W. P.; Willis, P. Org. Biomol. Chem. 2003, 1, 3787; (b) Cristol, S. J.; Nachtigall, G. W. J. Org. Chem. 1967, 32, 3727; (c) Cristol, S. J; Sullivan, J. M. J. Am. Chem. Soc. 1971, 93, 1967; (d) Sonawane, H. R. Nanjundiah, Kelkar, R. G. Tetrahedron 1986, 42, 6673. 126 Coe, J. W.; Wirtz, M. C.; Bashore, C. G.; Candler, J. Org. Lett. 2004, 6, 1589. -53-205 was then tested in the multicomponent reaction by addition of the radical issued from xanthate 155 (Scheme 73). Unfortunately, only traces of the desired product 206 were present according to 1 H NMR analysis. Purification of the crude reaction mixture did not allow the isolation of the desired product.

ІІ.4.3. New MCRs using Bromoacetonitrile Substrate.

Based on previous results on multi-component carbo-alkenylation reaction obtained in our laboratory, we envisioned varying also the nature of the electrophilic radical precursor. We have described so far xanthate 155 having an ester function; we then extended the process to other simple precursors such as bromoacetonitrile or bromomalonate. The best conditions developed previously 110 in our three-multicomponent syntheses involved 1 equiv. of bromoacetonitrile 207 as an electrophilic precursor, 4 equiv. of allylsilane 188 as an electron-rich olefin and 1.2 equiv. of Evinylsulfone acceptor 169 in presence of 1.5 equiv. of (Bu 3 Sn) 2 and 0.15 equiv. of DTBHN in refluxing DCE as a solvent (Scheme 74).

Such conditions using Z-disulfone isomer were applied varying the nature of olefins as summarized in Table 1. The first attempt was carried out using 1-octene 209 as the olefin, which produced the desired 3-component adduct 215 in acceptable yield (entry 1). Using olefins 210 and 211, compounds 216 and 217 bearing a quaternary center were isolated, albeit in lower yield (entry 2 and 3). The process was also compatible with electron-rich olefins such as 3,4-dihydro-2H-pyran 212 and N-Boc-3,4-dihydro-2H-pyridine 178 which afforded the desired products 218 and 219 in reasonable yields (entry 4 and 5). The study was then extended to vinyl- andallylethers 213 and214 leading respectively to 220 (entry 6) and221 (entry 7) in satisfying yields.

ІІ.4.4. New MCRs using Dimethyl bromomalonate Substrate.

The nature of the radical precursor was also varied, for instance by using another electrophilic substrate such as dimethylbromomalonate, which includes two electron-withdrawing groups and should thus be more electrophilic and efficient in the three-multicomponent reactions. Refluxing The reactions with 223 were carried out applying the same conditions than above using similar olefins (Table 2). The first reaction was tested with 1-octene 209, which was shown to be moderately reactive toward the addition of 223 leading to 225 with yields close to that obtained with bromoacetonitrile above (entry 1). This reaction was also examined with olefin 224 bearing an aliphatic chain and a chlorine atom. The expected product 226 was obtained in moderate yield, but interestingly the chlorine atom was found compatible with the presence of the tin reagent present in the medium (entry 2). Dihydropyran 212 led to the addition product 227 in relatively low yield, as compared to similar reactions with related xanthates (entry 3), indicating that as expected 1,2disubstituted olefins are less reactive even when they are electron-rich. The quaternary center in product 228 could also be generated using 1,1-disubstituted olefin 211, albeit in very low yield, again emphasizing on the importance of steric effects in these processes (entry 4).

ІІ.5. Conclusion.

In this chapter, we have described the addition of carbon-radical species across the π-system of electron-rich olefins, using a Z-sulfonyl acceptor as a terminal trap, resulting in a useful carboalkenylation process. These reactions were tested on bicylic (strained) olefins that were either unreactive or produced complex mixtures. Better results were obtained with monosubstituted olefins. Various radical precursors including nitrile or malonate functional groups allowed the easy introduction of useful functionalities on the olefinic backbone.

The generally proposed mechanism is depicted in Scheme 76 below and includes the generation of an electrophilic radical Ii through abstraction of the bromine atom by the tin radical. Precursor Ii then adds onto olefin II to produce a nucleophilic radical IIi, which is enventually trapped by the electron-poor vinylbisphenylsulfone III, yielding the desired product, after an addition-elimination process.

Chapter III: Radical Initiators and Tin-Free Alternative.

III.1. Radical Initiators.

ІІІ.1.1. Introduction.

In chemistry, radical initiators are substances that can produce radical species under mild conditions and promote radical reactions. 128 These substances generally possess weak covalent bonds (having small bond dissociation energies (BDE)), which can be cleaved homolytically by a sufficient energy intake in the form of heat or light irradiation. These radical initiators should be stable at room temperature and decompose under mild conditions to produce radicals, ready to initiate free radical chain reactions.

ІІІ.1.2. Classification of Radicals Based on Energy Supplied.

ІІІ.1.2.a. Radical Production by Thermolysis.

This method is used most often with organic peroxides, azo compounds, nitrite ester or N-hydroxy-2-thiopyridine that possess weak bonds in their structures. Heating causes these bonds to cleave and dissociate at T < 150°C into free radicals. A commonly used azo compound is α,α ' -azobisisobutyronitrile (AIBN) 229, which decomposes into two cyanopropyl radicals 229i and a molecule of dinitrogen (Scheme 77). 129

ІІІ.1.2.b. Radical Production by Photolysis.

A photolysis reaction involves the homolytic cleavage of a covalent bond by absorption of light. For instance, under such conditions, azo compounds 229 (AIBN) produces two radicals 229i through the unstable Z-isomer (Scheme 78). Similarly, peroxides (ROOR) produce alkoxy (RO Azo compounds are organo-nitrogen derivatives with the characteristic -N=N-functionality and general formula R-N=N-R ' , where R and R ' can be the same or different organic groups. Azo compounds are often used as initiators in organic synthesis due to their stability but yet high decomposition ability. 231 thus undergoes decomposition into the corresponding alkyl radicals and 131 Fossey, J.; Lefort, D.; Sorba, J. Free Radicals in Organic Chemistry, Wiley, Masson, Paris, 1995, p. 105. 132 Lindsay, A. S.; Jaskey, H. Chem. Rev. 1957, 57, 583. nitrogen by heating or through light absorbtion (Scheme 81). It has been shown that azo compounds can decompose below room temperature and may be useful in the stereoselective construction of carbon-carbon bonds. 133 Furthermore, azo compounds act as effective initiators in aqueous media when they possess hydrophilic functional groups .134

The half-life and advantages of some azo initiators at different temperatures is summarized below (Table 3). 135

ІІІ.1.3.b. Peroxide.

Peroxides have a weak O-O bond, so their decomposition upon heating produces alkoxy radicals and acyloxy radicals by cleavage of the peroxide bond. 136 The nature of the radicals produced is generally electrophilic and depends on the structure of the radical species. The half-life of some peroxide initiators at different temperatures is summarized below (Table 4). 137

ІІІ.1.3.c. Organometallic Compounds.

Organometallic compounds have also been used as initiators in many stereoselective syntheses, due to the fact that they can be handled effectively at -78 o C.

ІІІ.1.3.c.1. Triethylborane (Et 3 B).

Et 3 B is a colourless liquid, which self-ignite in air and is readily oxidized by oxygen via a radical mechanism, producing ethyl radicals (Scheme 82). This reactivity led to one of its most common application, as an initiator in radical reactions. 138 The ability of Et 3 B to participate as an initiator in free radical reactions has been identified since the earliest investigations of its chemistry, 139 which showed that it was effective even at low temperatures. The Et 3 B is one of the most widely used initiator at -78 • C and is thus particularly useful in stereoselective radical synthesis (Scheme 83). 140 138 (a) Ryu, I.; Araki, F.; Minakata, S.; Komatsu, M. Tetrahedron Lett. 1998, 39, 6335; (b) Zinc chloride can also act as a radical initiator as well as a chelating agent at low temperature in certain radical reactions of allylstannanes to produce the corresponding allylated products (Scheme 85). 142 141 Perchyonok, V. T.; Schiesser, C. H. Tetrahedron Lett. 1998, 39, 5437. 142 Yamamoto, Y.; Onuki, S.; Yumoto, M.; Asao, N. J. Am. Chem. Soc. 1994, 116, 421.

ІІІ.1.3.4.b. Samarium iodide (SmI 2 ).

Samarium iodide acts as a radical initiator by reaction with alkyl halides or ketones through electron transfer. The ketyl radical can then undergo a 5-exo-trig cyclization onto unactivated alkene. The diastereoselectivity generally varies with the nature of the substituent next to the ketone (Scheme 86).143

III.1.4. Our strategy.

Free-radical three-component carbo-alkenylation of olefins in the presence of tin and DTBHN as an initiator has been developed previously in the group (Scheme 87). In this chapter, our plan involved first the preparation of some new initiators, including sulfonyl hydrazine and diphenylsulfone compounds that can replace DTBHN iniator which is potentially dangerous, expensive and prepared through a low-yielding procedure. We figured that sulfonyl hydrazine and diphenylsulfone, which are easily prepared and stable at room temperature, could undergo homolytic cleavage to release the PhSO 2 radical that could then react with the Sn-Sn bond to produce the required Sn radical.

Furthermore, we envisioned that the PhSO 2 radical formed through this approach could be exploited in the 3-CR carbo-alkenylation process above (scheme 87). In this case, there are two ways for the production of the PhSO 2 radical and this is more than enough to propagate the radical chain.

ІІІ.1.5. Results.

Our plan here was to prepare some new initiators based on disulfonylated hydrazines that contain 2 aliphatic residues as in 247 or a mixture of aliphatic and aromatic substituents. Compounds like 250 could play an efficient role in multi-component reactions by generating a MeSO 2 radical which would then react with Sn-Sn bond to produce the required tin radical.

ІІІ.1.5.a. Preparation of some sulfonylhydrazine derivatives.

We tried first to prepare alkylsulfonyl hydrazine initiator including substrates having a methyl group. The substitution reaction carried out between methanesulfonyl chloride 245 and hydrazine hydrate 246 in pyridine as a base produced the desired product 247, as a white solid in low yield, after recrystallization from ethanol (Scheme 88).

Preparation of 250 was carried out in two steps (Scheme 89). In the first step, reaction between benzenesulfonyl chloride 248 and hydrazine hydrate 246 produced sulfonylhydrazine 249, which was treated directly without purification with methanesulfonyl chloride 245 to yield the desired product 250 after recrystallization as a white solid in low overall yield.

Using a similar approach, we then prepared bis-phenylsulfonyl hydrazine 251. The reaction involved an addition of phenylsulfonyl chloride 248 onto hydrazine hydrate 246 in the presence of pyridine as a base, which gave the product 251 in a moderate yield (Scheme 90). 144 144 Shyam, K.; Cosby, L. A.; Sartorelli, A. C. J. Med. Chem. 1985, 28, 525. Applying the same conditions and starting from 252, we tried to prepare hydrazine 253 having Nmethyl substituents, figuring that the methyl donating groups could accelerate the β-scission step.

But unfortunately, the reaction did not produce the expected product 253 and the crude 1 H NMR gave complex mixture (Scheme 91).

Diphenylsulfone 254 may be considered as a convenient source of phenylsulfonyl radical through homolysis of the S-S bond. 145 Compound 254 was formed under acidic condition by mixing the bisphenylsulfonyl hydrazine 251 with nitric acid (Scheme 92). 146 The mechanism of this reaction proceeds through oxidation of 251 into PhSO 2 N=NSO 2 Ph using HNO 3 , followed by decomposition of the diazene into phenylsulfonyl radicals, which then recombine to provide 254, and dinitrogen.

ІІІ.1.5.b. Methodology using diphenyl disulfone as radical initiator.

Our preliminary investigations were carried out using bis-phenylsulfonyl hydrazine 251 as a precursor of phenylsulfonyl radicals. Previous studies by Scaiano et al. 147 effectively showed that under irradiation, 251 was able to produce the desired sulfonyl radical. The mechanism proceeds through an homolytic cleavage of the S-N bond, under irradiation, to produce a phenylsulfonyl radical and a nitrogen-centered radical. The latter then proceeds through β-scission to yield diimine in addition to the sulfonyl radical that can sustain the radical carbo-alkenylation chain reaction (Scheme 93).

145 Karasch, N.; Khodair, A. I. A. Chem. Commun. 1967, 98. 146 Bartman, E. A. Synthesis 1993, 5, 490. 147 Coenjarts, C.; Ortica, F.; Cameron, J.; Pohlers, G.; Zampini, A.; Desilets, D.; Liu, H.; Scaiano, J. C. Chem. Mater.

2001, 13, 2305.

Chapter ІІІ: Radical Initiators & Tin-free alternative.

-67-251 was tested in our three-component carbo-alkenylation reaction, using 1 equiv. of xanthate 155 as an electrophilic precursor, 4 equiv. of allylsilane 188 as an electron-rich olefin and 1.2 equiv. of sulfone 169 as an acceptor in the presence of various amounts of (Bu 3 Sn) 2 and 251 in DCE or benzene under reflux. A 300W tungsten lamp was used for irradiation. Results are summarized in Table 5. No product was formed in the absence of irradiation (entry 1), even with an increase of the amount of 251 (up to 0.2 equiv.). When the U.V. irradiation process (300W tungsten lamp) was applied, we were pleased to find that the carboalkenylation product was obtained in excellent yield (entry 2). A similar yield was obtained by increasing the amount of tin to 1.5 equiv. (entry 3).

Literature reports showed that xanthates but also Bu 3 SnSnBu 3 may be cleaved under irradiation, thus generating in situ, respectively the corresponding C-centered and Sn-centered radicals.

Therefore, in order to study the real influence of hydrazine 251, the reaction was repeated in the absence of 251. To our surprise, the reaction led to a reasonable but lower yield than in the presence of 251 (entry 4). Without Bu 3 SnSnBu 3 and 251, the reaction still produced the desired compound, albeit in low yield (entry 5). When the tungsten lamp was replaced by a mercury lamp with and without 251, only traces of the desired compound were obtained (entries 6 and 7). The yield increased slightly by allowing the light source to be closer to the reactor (entry 8) (Figure 8). With 251, but without ditin, we observed a yield increase in the reaction, demonstrating the role of 251 in the initiation process (entry 9). The last two experiments showed that the presence of Bu 3 SnSnBu 3 is crucial. However, excess of ditin is also detrimental to the final yield and traces of tin residue are found in the final product. Efforts where thus directed toward the decrease of the amount of ditin. 0.5 then 0.2 equivalents were thus used (entries 10-11) to afford useful yields of product in the former case but lower in the latter. Using only 0.5 equiv. of ditin led to 62% yield of the desired product (entry 12), but still slightly lower than in the presence of 251. As a conclusion, the use of 0.05 equiv. of 251 in the presence of 1 equiv. of ditin appears as the optimal conditions. When benzene instead of DCE was used, yields were shown to be lower (entries 13 and 14).

Bromide and iodide precursors were also studied but led to much lower yields than the corresponding xanthate (entries 15-16).

Then the optimized conditions were applied to various olefins as summarized in Table 6.

Surprisingly, with olefin 210, we were surprised to find that the reaction was more efficient in benzene than in DCE (compare entry 1 vs 2) in contrast with results obtained previously (Table 5).

Experiments were thus systematically performed in various solvents. Reaction in the absence of hydrazine 251 (entry 3) or with reduced amount of tin (entry 4) led to lower yields. With olefin 255, benzene was again the best solvent (entry 5), while tert-butyl benzene having a higher boiling point at 140 o C, and DCE led to lower efficiency (entries 6 and 7). Similar observations were made with olefins 209 (entries 8 and 9) and 213 (entries 10 and 11). Reducing the amount of tin led to a reduced yield (entry 12). When the reaction was carried out in the absence of hydrazine initiator and 0.5 equiv. of tin, low yield of the desired product was observed (entry 13). Finally, no product formation takes place when benzene is substituted for DMF (entry 14). Under the optimal conditions and benzene as a solvent, olefins 224 and 178 led to the desired products in satisfying yields (entry 15 and 16), while no product was obtained with vinyltrifluoroborate 256 (entry 17).

The three-component process was also carried out using as a radical precursor aryl iodide 263 (Scheme 94). The reaction was carried out first in the absence of tin and initiator (entry 1), then in the absence of tin and 0.05 equiv. of initiator (entry 2). Unfortunately, the reaction did not give any conversion. Under the optimal conditions above, the product 295 was produced in trace amount and was found difficult to purify (entry 3).

Following the mechanism proposed by Scaiano et al, PhSO 2 radical should be produced during irradiation of 251, which would then react with ditin. In order to show that the sulfonyl radical was effectively produced upon irradiation, we carried out the series of experiments below. We first reacted 251 directly with allylsilane 188 under U.V. irradiation in order to trap the phenylsulfonyl radical. It was expected that under such conditions, addition of the electrophilic PhSO 2 radical onto the electron-rich allylsilane would be followed by a β-fragmentation of the silyl group producing allylsulfone 265 (Scheme 95). Unfortunately, no conversion of the starting material 251 into 265 was observed.

We then carried out the three-component process described above using disulfone 254 known to generate the PhSO 2 radical upon irradiation. 148 254 was used as an initiator in the three-component reaction above, with different solvents, using 155 as an electrophilic precursor (Scheme 96). When the reaction was carried out in refluxing DCE (80°C) and tert-butylbenzene (140°C), without irradiation, modest yields were obtained even when the equivalent number of 254 and the time were increased (entry 1 and 2). In contrast, upon U.V. irradiation with only 0.05 equiv. of initiator 254, the product 189 was formed in excellent yield (entry 3).

III.I.6. Conclusion.

We have described above the preparation and the use of new-hydrazine initiators in multicomponent carbo-alkenylation reactions. Diphenylsulfonylhydrazine 251 was thus found to be a rather efficient radical initiator under U.V. irradiation. Three-component products were usually formed in good to excellent yields in DCE or benzene as solvents. The bis-phenylsulfone 254 was also examined in carbo-alkenylation reaction and proved its efficiency in this process. Although we were unable to trap the phenylsulfonyl radical intermediate generated upon the UV-mediated decomposition of 251 and 254, we are confident that the radical process is sustained by the phenylsulfonyl radical which ultimately reacts with Bu 3 Sn-SnBu 3 . The presence of the latter in at least equimolar amount was thus found to be critical to the success of the whole process.

III.2. A tin-Free Alternative.

III.2.1. Bibliography.

Tin derivatives are considered important radical chain carriers during C-C bonds formation.

However, the perceived toxicity and the difficulties to get rid of tin residues during purification led the chemists to look for alternative methods, including the use of silicon derivatives as both tin and silicon share electronic properties.

Several silanes have been examined as a replacement for triorganostannanes. Tris(trimethylsilyl) silane (TTMSH) is likely the most often used and was introduced as an alternative to tin hydride in the late 1980s. TTMSH has quickly proven to be an effective alternative to tin hydride for a majority of radical chain reactions. 149 (TMS) 3 SiH is a good reducing agent and a mediator for 149 Barton, D. H. R.; Parekh, S. I.; Tse, C. L. Tetrahedron Lett. 1992, 34, 2733. sequential radical reactions, 150 including the removal of a variety of functional groups (Cl, Br and I) in addition to reductive removal of chalcogen groups (SR and SeR). 151 Scheme 97 below shows an example of debromination starting from bromide 266 in the presence of AIBN initiator in refluxing toluene. 152 (TMS) 3 SiH is useful in deoxygenation of secondary alcohols such as 268 through thiono esters 153 (A) and deamination of primary amines via isocyanides 270 (B) (Scheme 98). 154 The reaction mechanism of these reductions is similar to that described for tin hydride, which includes attack of a silyl radical on the C=S and C=N groups to form radical species that undergo a β-scission to produce alkyl radicals which abstract the hydrogen from (TMS) 3 SiH. The latter releases a silyl radical which sustains the radical chain. The efficiency of these reactions in addition to easier purifications, absence of toxicity of the silyl hydride reagent and its by-products, have rendered this reducing agent a popular alternative to Bu 3 SnH in stoichiometric reactions.

ІІІ.2.2. Allylsilanes in Tin-free 3-Component Carbo-alkenylation reactions.

Allyltrialkylsilanes have played an important role as radical allyl transfer reagents under tin-free reaction conditions. An early example, published by Saito in 1985, involves the allylation of the uracil derivative (Scheme 99) under photolytic conditions with allyltrimethylsilane. 156 It should be added that in this case, a silyl radical is probably not released during the reaction. An iodine-atom transfer process is more likely giving rise to a β-silyliodide which then β-eliminates to afford 274.

Guindon and the workers 157 have reported the diastereoselctive allylation reactions of alkyl iodide 275 using allyltrimethylsilane 273 in the presence of magnesium bromide-diethyl etherate, using triethylborane as an initiator (Scheme 100). As mentioned above, this group demonstrated that the reaction does not proceed through a fragmentation reaction, but via an atom transfer process followed by an ionic elimination of Me 3 SiI to form the final allylated product 276.

Chatgilialoglu and Curran 158 have described allyl transfer processes using a variety of allyl tris(trimethylsilyl)silanes bearing substituents at the 2-position (Scheme 101). These underwent reactions with alkyl halides when heated with a radical initiator. These reactions were relatively sensitive to the electronic effects, which mean that the electrophilic radical reacted well with electron-rich allylsilanes. In contrast with above allylation, this allyl transfer process proceeds through the intermediacy of a silyl radical, similarly to allylation using allyltin reagents.

Very recently, our group 159 has described novel tin-free oximation, vinylation and allylation reactions of alkyl halides (iodide and bromide) using allylsilanes or allylthioethers as a radical chain carriers (Scheme 102).

Curran 160 and Yoo have described allylation reactions using 3-tris(trimethylsilyl)silylthiopropene 286, which proceeds through the easier β-fragmentation of a C-S bond. Based on this precedent, our group has developed carbo-oximation and vinylation using allylthioethers such as 286 (Scheme 103). 159 Addition of electrophilic PhSO 2 radical onto 286 produces the (Me 3 Si) 3 SiS radical species 286ii that can undergo a fast rearrangement, via a [1,2]-silyl shift, into a silyl radical 286iii, which acts as a radical chain carrier. Addition of carbon radicals onto 286 is known to be slow, 161 so addition of electrophilic PhSO 2 radical can be fast enough to propagate the chain.

III.2.3. Our strategy.

Due to increased concerns regarding hazards, toxicity and environmental impacts of tin, in addition to the difficulties with product purifications, we envisioned developing a tin-free approach of our three-component radical process. Based on the pioneering studies of Chatgilialoglu, Curran 158 and our laboratory 159 , we decided to study the effect of allylthiosilanes and their different substituents with (methyl, phenyl and cyano group) in tin-free radical carbo-alkenylation processes. It was envisioned that the electrophilic radical precursor 292i could be generated through addition of the The synthesis of allyltris(trimethylsilyl)silanes is usually carried out via hydrosilylation of allylsulfones or allylthioethers using (Me 3 Si) 3 SiH 298. So our initial work was to prepare the expensive silane 298 via a two steps protocol (Scheme 107). The sequence involves first a coupling reaction between freshly distilled chlorosilanes 295 and 296 in the presence of lithium metal, to produce the tetrakis(trimethylsilyl)silane 297 as a white solid after recrystallization from acetone. 164 This is then followed by the generation of the silylpotassium via treatment with t-BuOK, and hydrolysis of the latter under acid conditions. Unfortunately, in our hands, the reaction did not produce the desired product 298, but only recovered starting material 297.

Therefore, we turned our attention toward the synthesis of 301 through a coupling reaction between methylallyl chloride 299 and the corresponding tris(trimethylsilyl)silyl potassium as an intermediate. This process led to the desired product 301 in excellent yield (Scheme 108).

III.2.4.b. Allyltris(trimethylsilyl)silane in Vinylation Reaction.

As explained above, the addition of the electrophilic PhSO 2 radical onto 301 should allow the chain propagation. So the feasibility of the approach was first established with the vinylation of adamantyl bromide 280 using styrylsulfone 281 in the presence of allylsilane 301 under U.V. irradiation (Scheme 109). Among the initiators that were examined, sulfonylhydrazine 251 in DCE produced the desired product, albeit in modest yield (entry 1). Replacing DCE by benzene led only to traces of allylated adamantane (entry 2). 164 Gilman, H.; Lichtenwalter, G. D.; Wittenberg, D. J. Am. Chem. Soc. 1959, 81, 5320. Examination of the reactivity of 286 was first carried out in the vinylation process in the presence of the initiator 254 using adamantyl bromide as a substrate in refluxing tert-butylbenzene (Scheme 112). The reaction afforded the desired product, albeit in lower yield than that observed above with allylsilane 286. As a comparison, the same reaction performed with AIBN as an initiator led to 284 in lower yield. 159 We then applied allylthioether 286 in a three-component carbo-alkenylation process using various alkyl bromides as a potent source of electrophilic precursors. We started the study by using 304 as an electrophilic radical precursor with an α-bromo substituent, various olefins and vinylsulfone 169 as a final acceptor in the presence of 2 equiv. of 286 and 0.2 equiv. of AIBN as an initiator (Scheme 113). The first reaction proceeds smoothly by using olefin 188, which afforded the desired product 189 along with the corresponding allylsulfone 265 as a side product (entry 1). The olefin 210 was tested in this reaction, but led to the desired product 257 in low yield with allylsulfone as a side product (entry 2). Using the electron-rich enol ether 213, the desired product was obtained albeit in very low yield, which contrasts with yields obtained using ditin 114 (entry 3). In this case, the initiator V-40 (instead of AIBN) was also tested leading to a similar yield (20%). The same conditions were applied with olefin 212 but no product was detected through 1 H NMR (entry 4). The low yields observed previously prompted us to test different electrophilic precursors. So we first started with Weinreb amide 308 that can be prepared in very good yield following the procedure below (Scheme 114). 166 Amide 308 was then applied in the three-component carbo-alkenylation with allylsilane 188. The expected product 309 was obtained albeit in modest yield along with recovered 286. The yield was not better when larger amount of 286 was used (Scheme 115).

Consequently, we replaced the electrophilic precursor 308 by another substrate 223 having two electron-withdrawing groups which we thought could be more efficient in this process. We observed that the reaction with the olefin 188 effectively led to the expected product 310 with acceptable yields. Surprisingly, when using olefin 210 no product could be observed (Scheme 116).

166 Donohoe, T. J.; Fishlock, L. P.; Basutto, J. A.; Bower, J. F.; Procopiou, P. A.; Thomposon, A. L. Chem. Commun. 2009, 21, 3008. To test the efficiency of the olefin 210, we applied the reaction conditions using bromoacetonitrile 207 as an electrophilic radical precursor, vinylsulfone 169 in the presence of 2 equiv. of 286 and 0.2 equiv. of AIBN in refluxing benzene (Scheme 117). But again, the same result was observed, the allylthioether 286 and starting materials were recovered unchanged.

Bromoacetonitrile was also reacted with 4 equiv. of allylsilane 188, 1.2 equiv. of Z-vinylsulfone 169 as an acceptor in the presence of 2 equiv. of allylthiosilane 286 and (4 x 0.05) equiv. of AIBN in refluxing benzene (Table 7). This produced the desired product in moderate yield (entry 1).

When replacing the Z-vinylsulfone 169 by the E-isomer (entry 2) a slightly lower yield in compound 208 having the E-stereochemistry was obtained, indicating that the Z-isomer is more reactive than the E. Reducing the amount of 286 using the Z-169 led to an increase in product yield (entry 3), while under similar conditions, a decrease was observed with the E-isomer (entry 4).

Replacing benzene solvent with DCE made the reaction less efficient (entry 5). Concentration of the benzene solution altered the reaction efficiency (entry 6). The slow addition of AIBN initiator (1 mL) over 6 hours by syringe pump was also tested in order to allow a slow release of the silyl radical. However, this did not increase the yield (entry 7). Raising the temperature above 80 • C, did not have a positive effect on the product yield (entry 8 and 9). The best conditions were finally obtained using AIBN added in one portion at 90 o C, thus totally consuming the starting material 207 (entry 10). Finally, we decided to add AIBN at 90 • C in two portions over 4 hours, but the yield was only 50% (entry 11).

The carbo-alkenylation process using compound 286, was finally extended to xanthate 155 as an electrophilic precursor in the presence of cyclic and heterocyclic olefins (Scheme 118). The first cyclic olefin 210 gave the desired product in modest yield, with allylsulfone as a side-product (entry 1). The other heterocyclic olefins 212 and 178 led only to degradation products (entries 2 and 3).

The best conditions above were also tested on the three-component carbo-oximation process using oxime 122 (Scheme 119). The reaction led to degradation products in which the desired product was absent.

III.2.4.d. Preparation and application of (tris(trimethylsilyl)silylthiopropene derivatives in MCRs.

This project involved also the preparation of new allyl(tris(trimethylsilyl)silylthiopropenes, varying the nature of the substituents at the 2-position (Scheme 120), including methyl, phenyl and cyano groups that could be more efficient in the carbo-alkenylation process due to a putative faster βfragmentation process.

We first prepared phenyl(tris(trimethylsilyl)silylthio)propene through a three-steps sequence. After the bromination of α-methyl styrene 315 with NBS, in the presence of ytterbium triflate as a catalyst, allylbromide 316 was detected by 1 H-NMR of the crude reaction mixture, but the purification proved to be difficult and produced 316 containing impurities (Scheme 121). 167 167 Yamanaka, M.; Arisawa, M.; Nishida, A.; Nakagawa, M. Tetrahedron Lett. 2002, 43, 2403. We then followed another procedure, which afforded the desired product 316 in good yield after distillation (Scheme 122). 168 The next step involved the reaction of bromide 316 or chloride 317 with thiourea 318 (as a source of thiol group) in aqueous basic conditions under reflux. The desired products 319 and 320 were obtained with modest yields after chromatography and distillation (Scheme 123). 169 Another protocol was tested to increase the yield of 319 and 320, involving thioacetic acid 321 as a sulfur source. Stirring 321 with 316 or 317 with a base led to allylthiol 319 in poor yield and only to degradation products with methallyl chloride 320 (Scheme 124).

Finally the preparation of silylthioethers 322 and 323 was completed through the coupling between phenyl-and methylallylthiols 319 and 320 and tris(trimethylsilyl)silyl chloride 302 using triethylamine as a base. 322 and 323 were obtained respectively in moderate and low yields (Scheme 125).

168 Ohmura, T.; Mosuda, K.; Takase, I.; Suginome, M. J. Am. Chem. Soc. 2009, 131, 16624. 169 Mordini, A.;Pecchi, S.;Capozzi, G. Tetrahedron 1994, 50, 6029. We also attempted to prepare an allylthiosilane having a cyano-substituent through the four-steps sequence depicted in Scheme 126. This started with the Wittig reaction between formaldehyde 325 and phosphonium ylide 324 in aqueous basic conditions, which produced the desired allylic alcohol 326 in modest yield. The latter was reacted with phosphorous tribromide leading to the allyl bromide 327 in low yield. 170 However, applying the same conditions than in Scheme 123, we were not able to convert 327 into the allylic thiol 328, the reaction producing only degradation products.

Considering the difficult synthesis of the precursor, it was decided to give up the study of such allylthiosilane.

Having in hand allylthioethers 322 and 323, the best conditions developed previously (Scheme 127) were extended to these silyl radical precursors. As before, the addition of the initiator AIBN was performed in one portion at 90°C. Surprisingly, with 323 the yield in product 208 was lower than above, producing the methyl allylsulfone as a side product (entry 1). Increasing the amount of initiator and adding it in two portions, did not have a positive effect on the yield (entry 2).

With allythioether 322 having a phenyl substituent, the carbo-alkenylation reaction under the same conditions than above led to the desired product in low yield (entry 1) (Scheme 128). Addition of the initiator AIBN in one or two portions over two hours had no effect on the yield of the process (entry 2). These last two results are surprising as it was expected that addition of the PhSO 2 radical onto 322 and 323 would be favored leading to stabilized radicals ready for a fast β-fragmentation.

These observations are in contrast with previous experiments in oximation and vinylation of alkyl halides, 159 where the introduction of a methyl group on the allylsilane moiety led to improved yields.

III.2.5. Conclusion.

In the second part of this chapter, we have described the use of new allyl(tris(trimethylsilyl))silanes and tris(trimethylsilyl)thiopropenes in vinylation reactions in the presence of some initiators such as 251 and 254. The tris(trimethylsilyl)thiopropene was also examined in carbo-alkenylation reactions in the presence of AIBN, and was found to be more efficient in these reactions. Various electrophilic precursors were then tested in benzene and produced the expected adducts in moderate yields in the presence of E-or Z-vinyldiphenylsulfone, depending on the nature of the substituents.

Finally, new methyl-and phenyl-allylthiosilane compounds were prepared and examined in the carbo-alkenylation reactions under the same conditions. In this process, the methyl-substituted allylthiosilane was shown to be more efficient than the phenyl-substituted one.

Discovering new biologically dimeric indole alkaloids should be worth considering for future clinical application. Dimeric indole alkaloid Leucophyllidine 334, the structure of which was established through X-ray crystallographic analysis, shows potent antitumor activity against drugresistant cells (Scheme 130). Cytotoxic Leucophyllidine has been isolated as a minor alkaloid (yield, ca. 710 mg/kg) from the ethanol extract of the stem-bark of Leuconotis griffithii, -92-

The coupling of type I, II and III monomeric alkaloids leads to quite common heterodimeric indole alkaloids and more rarely to homodimeric indole alkaloids. Scheme 132 summarizes the chemotaxonomic network between different monomeric indole alkaloids in plant.

Biogenetic hypothesis have been proposed to justify the formation of these dimers. Vinblastine biogenetic synthesis was proposed very early involving a direct coupling between vindoline and catharanthine, possessing respectively a plumeran and ibogane-type skeletons (Scheme 133). This hypothesis, verified in vivo, has been used since by several synthetic chemists in their total synthesis plans (vide infra).

While the method of coupling has led to many important studies for Vinca alkaloids, such is not the case for other dimers. Kam and also Morita 178 and co-workers have however recently proposed a -93-Mannich-type coupling as a biogenetic hypothesis for the formation of Bisleuconothine A (Scheme 134) in Leuconotis griffithii (an Apocynaceae).

A similar hypothesis was proposed for Leucophyllidine (Scheme 135), which can then be disconnected into two fragments of similar size which we called the "North Fragment A" 341 for the eburnamine type motif, and the "South Fragment B" 335 for the aminoquinolone motif. This will constitute the basis of our synthesis.

As mentioned above, Morita and co-workers 179 Through this chapter, we will discuss our approach to the synthesis of Eucophylline alkaloid 335, using as main intermediate a bridgehead lactam scaffold (azabicyclo[3.3.1]nonane) (Scheme 140).

A survey of the literature on the chemistry of structurally intriguing azabicyclo[3.3.1]nonane systems is provided below.

IV.3. Distorted Amide Bonds.

The amide bond is one of the most important functional groups in chemistry and biology fields (Scheme 137). The properties of amides result from the intervention of two major canonical structures, showing the partial double bond character of the N-C(O) bond and preserving the planarity of the amide bond. 180 However, not all amide bonds are perfectly planar. Deviation from planarity, as in 342b (distorted amide bonds), is accompanied by hybridization and geometry changes at nitrogen that lead to modifications in chemical reactivity of amide bonds. 181 The potential flexibility of amide bonds leads to a number of essential and intriguing questions:

What is the distortion energy barrier that marks the amide and the keto-amine-like reactivity of amide bonds ? 182 Could the distorted amides be affected in their properties ? And how many types Bredt's rule by formation of a zwitterionic resonance structure. 183 But he was not able to prepare the three bridged amides through cyclizations into 347, 349 and 351 (Scheme 139), and concluded that these amides are too strained and thus impossible to prepare. 184 The bridgehead amides 352 (derivatives of 1-azabicyclo[2.2.2]-octan-2-one) and 353 (related to the bicyclo[3.3.1]non-1-ene systems in Eucophylline) (Scheme 140) were shown to have significant differences while belonging to the same class. This is exemplified by the fact that the compound 352 is strained enough to follow the anti-Bredt's rule and behaves as an "amino-ketone", while the compound 353 could behave similarly to unstrained amides. 185 Between 1980 and 1990s, many syntheses of amides of different sizes have been reported. We will restrict our discussion to the synthesis of compounds bearing the bicyclo[3.3.1] system found in Eucophylline 335. Most of these syntheses focused on amine condensations with acyl chlorides (Scheme 141). Steliou 186 introduced Bu 2 SnO as an efficient promoter for difficult lactamizations, 183 Lukes, R. Collect. Czech. Chem. Commun. 1938, 10, 148. 184 Fawcett, F. S. Chem. Rev. 1950, 47, 219. 185 Hall Jr, H. K.; Shaw Jr, R. G.; Deutschmann, A. J. Org. Chem. 1980, 45, 3722. 186 Steliou, K.; Poupart, M. A. J. Am. Chem. Soc. 1983, 105, 7130. Finally, in 2006, Tani andStoltz 194 reported the synthesis of the ionic twisted amide 374, e.g. 2quinuclidone (isolated as its tetrafluoroborate salt) through an intramolecular Schmidt ring expansion reaction (Scheme 144). This method differs from the classical amide bond formation and required anhydrous conditions for the isolation of the product. The X-ray indicated a fully orthogonal amide bond for the protonated amide (τ = 90.9° and χ N = 59.5°). As expected, 2quinuclidone was found to be unstable under hydrolysis conditions (in water t 1/2 < 15s) and led to fast decomposition with other nucleophilic solvents such as DMSO and MeOH. Reasoning that the Vilsmeier reaction with a bridgehead lactam and an aniline might not be so straightforward, preliminary studies were carried out with simpler monocyclic and bicyclic models 379 and 355 respectively (Scheme 146). Several approaches are discussed using these model substrates. Model 355 is closely related to the bicyclo[3.3.1] occurring in the natural product and will afford useful informations on the reactivity of these bridgehead lactam in Vilsmeier reactions.

IV

IV.5.2. Synthesis of a simple naphthyridine model.

In these preliminary studies, we will focus our effort on the construction of the naphthyridine In the meantime, the required amino-benzonitrile was prepared through reduction of the nitro-group of 388 into aniline 389, using tin dichloride in a mixture of DME and ethanol under slightly acidic conditions (acetic acid). 196 Unfortunately, this method led only to degradation (Scheme 149).

Hydrogenation in the presence of palladium on charcoal, proved to be a better way for reduction of 388. As expected, this method afforded 389 in a good yield (Scheme 150). 197 Formation of a quinoline through coupling between an ortho-amino benzoic ester and an enolizable ketone is known as the Friedländer reaction. 198 While this reaction can be carried out in one pot starting from a ketone, such is not the case with amides having less acidic α-protons. To achieve a Friedländer reaction process with amides, we developed a two-step sequence involving an amidine intermediate. We thus turned our attention first to the synthesis of amidines 390, 391 and 392 that should afford the key target to then perform the connection between both rings. N-Methyl and Nbenzyl piperidinones were designed as precursors for the synthesis of the corresponding amidines, 199 finally obtained in high yield (Scheme 151). Following some literature reports, SnCl 4 was used concomitantly with POCl 3 . In order to understand the exact role and effect of SnCl 4 on this reaction, we carried out the preparation of 390 and 392 in absence of tin chloride. Observed yields were similar to those recorded in Scheme 151, indicating that tin chloride did not improve the efficiency of such coupling, in contrast with precedents in the literature. 199 196 Pletnev, A. A.; Tian, Q.; Larock, R. C. J. Org. Chem. 2002, 67, 9276. 197 Arenediazonium salts such as 397 are effectively functionalized through palladium-catalyzed coupling processes after elimination of nitrogen from 397 (Scheme 155). 201 Counter-anions with low nucleophilicity (tetrafluoroborate, hexafluoroborate, among others) are often used as they can be isolated and manipulated even though they contain an excellent leaving group such as nitrogen. We thus prepared the arenediazonium salt 400 by reaction of 393 with tetrafluoroboric acid 399, 202 which gave the desired product as a red solid isolated in good yield and used directly in the next step after filtration and washing by ether/pentane (Scheme 156). Other conditions including NaNO 2 and HCl 203 or (t-butylnitrite t-BuONO) in the presence of BF 3 .OEt 2 204 were used for the preparation of diazonium salts, but all these procedures failed.

Applying the conditions described by Genet, 205 the coupling process was performed between arenediazonium tetrafluoroborate 400 and vinylboronic acid 401 using Pd(OAc) 2 as a catalyst in 1,4-dioxane at room temperature, producing the product 402, albeit in low yield (Table 8, entry 1).

Addition of the ligand PPh 3 (10 mol%) and a base led to a reduced yield (entries 2 and 3). When we tried to replace the catalyst Pd(OAc) 2 by Pd(PPh 3 ) 4 , no product was formed (entry 4). Using BINAP as a catalyst slightly increased the yield (entry 5). Finally, when the reaction was performed in methanol, the yield was not satisfying (entry 6). Reasoning that the low yield above might be due to the instability of the diazonium salt during filtration, it was decided to add the coupling reagents in situ after the diazonium salt formation (red color). Unfortunately, no product was formed under these conditions and only degradation was observed. Subsequently, we proposed to prepare the more stable iodide from the diazonium salt in the presence of potassium iodide. 207 This could then undergo coupling reaction in the presence of a palladium catalyst. The desired product 403 was thus obtained in moderate yield through a substitution on the diazonium salt 400 with KI 404 in hot toluene (Scheme 157).

Several coupling conditions involving iodoarene 403 were then tested to obtain the coupling product 402 (Table 9). Pd(OAc) 2 in methanol (entry 1), 208 DMF (entry 2), 209 dioxane (entry 3) 210 and acetonitrile (entry 4) 211 were tested, but none of them provided satisfying results. In the meantime we tested a free-radical mediated vinylation, using aryl diazonium salt 400 as a source of aryl radical in the presence of iron (II)-sulfate heptahydrate (Scheme 158). 212 This reaction would provide a vinyl chloride 406, which could then be dechlorinated 213 to afford the desired vinyl product. Unfortunately, this reaction led only to a mixture of degradation products.

IV.6. Conclusion.

In conclusion, we have prepared successfully the vinyltricyclic model 402 in only three steps albeit in low overall yield (17% overall yield in 4 steps from the comercially available 2-piperidinone compound 379). The general approach includes an access, in high yields, to new aromatic amidine intermediates 390, 391 and 392, via the corresponding Vilsmeier reagent, followed by an efficient synthesis of amino-arenes 393, 394 and 395 via a cyclization process using LDA as a base. We have also described the preparation of the corresponding diazonium salts, in very good yields, using NaNO 2 and HBF 4 , which were then submitted to Pd-mediated Suzuki and Stille reactions albeit, with limited success. 210

IV.7.1. Construction of the hydroxyquinoline moiety of 409 (Route 1).

Route 1 involves the formation of the ketone 407, as a key precursor in the synthesis of 409, which simple retrosynthetic analysis is illustrated in Scheme 160 below. Coupling under basic conditions of 413 and amide 355 should provide 407, which upon heating should cyclize and give 409 through aromatization by tautomerization.

Mono-or bisprotection of the aniline moiety (with Boc groups) were also tried, but were found inefficient to provide the desired 1,3-diketonic compound. 217 Replacement of the amino group in 418 would both avoid amine protections and increase the electrophilicity of the ester functional group. Couplings between 355 and nitro derivative 422, using several bases such as t-BuOK, DBU, sodium ethoxide or KHMDS were thus tested, but were not able to initiate the formation of the amide enolate and its reaction with the ester of 422, only starting material being recovered (Scheme 164).

We also tested the same protocol using an aromatic compound devoid of any substitution ortho to the ester group. Treatment of phenyl benzoate 424 in the presence of NaH in refluxing toluene unfortunately led to no conversion of the starting material (Scheme 165). In conclusion, the development of a Friedländer-type annulation strategy using a bridged lactam substrate did not provide an entry toward quinoline synthesis. Different bases have been tested, but without success. This route was thus abandoned and our efforts were then directed toward Route 2 and the formation of amidine intermediates.

IV.7.2. Amidine Synthesis through cyclization (Route 2).

Two different strategies were adopted to generate the required amidines. The first approach relies on a preparation of an amide, which could then be cyclized into the amidine. The amide was prepared by coupling carboxylic acid 426 and aniline 418. We thus protected first the amino-group of piperidine precursor 354, using a Boc-group under basic aqueous conditions. This provided the desired acid 426 pure enough to be used in the next step without further purification (Scheme 166). 219 The desired amide was prepared through the coupling between acid 426 and aniline 418 under various conditions (Table 10). Four different methods were tested, using either the coupling reagent DCC (entry 1), 220 thionyl chloride (entry 2), 221 oxalyl chloride 222 in chloroform (entry 3) and HOBT in the presence of the Hünig's base (entry 4). 223 Unfortunately, none of them afforded amide 427.

However, using Mukaiyama's reagent 224 427 was finally obtained in a satisfying yield (entry 5). Conversion of the carbonyl group of 427 into an imino-triflate (an analogue of the Vilsmeier reagent 379iii prepared above with POCl 3 ) was carried out using triflic anhydride and pyridine, 225 followed by the deprotection of the Boc group under acidic conditions. This one-pot process and subsequent cyclization was supposed to provide amidine 420, but resulted instead in the degradation of the starting material (Scheme 167).

In conclusion, the synthesis of amidine 420 through the coupling reaction between an acid and an aniline using Mukaiyama reagent, followed by a cyclization process after activation of the amide functional group was not successful and did not provide the expected amidine. We thus turned our attention toward the method developed above for the synthesis of the tricyclic system 393-395 using a Vilsmeier reagent as an intermediate. 225 Charette, A. B.; Mathieu, S.; Martel, J. Org. Lett. 2005, 7, 5401.

IV.7.3. Amidine Synthesis through Vilsmeier Intermediate (Route 3).

To achieve the alternative approach based on a Friedländer-type process, we turned our attention to the same method that we have described for the preparation of compounds 390-392. Coupling between the bicyclic amide 355 and aniline 429 and 418 in the presence of POCl 3 was carried out to produce the corresponding amidines 420 and 430 (Scheme 168). Surprisingly, while both reactions did proceed under the reaction conditions, yields were relatively poor, illustrating the unique reactivity of the bridged lactam 355.

The structure of amidine 430 was unambiguously assigned through X-ray diffraction studies (Figure 9). The amidine was shown to possess a E-configuration and the bicyclic system (A-B) to adopt a boat-chair conformation.

In order to improve yields of formation of amidine, we carried out the coupling between amide 355 and aniline 429 using various Lewis and Brönsted acids (Table 11). 199 The first test was performed in the presence of tin tetrachloride in refluxing toluene under dry conditions. The reaction led only to recovered starting material (entry 1 and 2). The same negative result was obtained using ptoluene sulfonic acid in different solvents such as toluene and p-xylene (entry 3 and 4). A low yield in 430 was finally observed when using triflic anhydride in DCM with and without additional amine (entry 5 and 6). An alternative approach was devised for the preparation of amidine starting from an iminophosphorane generated from aniline 429. Aryliminophosphorane 431 was thus prepared treating aromatic amine 429 with triphenylphosphine in the presence of DEAD or DIAD (Scheme 169). This mixture underwent smooth formation of the azaphosphorane at ambient temperature in dry DCM to give 431. 227 Subsequently, 431 was reacted with bicyclic amide 355 to initiate the formation of amidine through an aza-Wittig process. 228 This reaction is a very powerful tool for the construction of C=N bond, and proceeds via the intermediacy of a phosphonium ylide. Unfortunately, this reaction in refluxing pyridine 228 did not produce the desired product 430 and only recovered starting materials were observed (Scheme 170). When the same reaction was carried out under reflux in higher boiling point solvents such as toluene 229 In addition to the previous works, we turned our attention toward thioamide intermediate known for their higher reactivity as compared to amides. In order to test this approach, the thioamide model 432 was prepared using Lawesson's reagent in refluxing toluene (Scheme 171). 231 Then, we applied this substrate in amidine preparation via the coupling between 432 and cyano-aniline 429 in the presence of mercury (II) acetate in toluene under reflux. Unfortunately, the mercury activation of the thioamide proved inefficient to produce amidine 430.

An alternative strategy was to use the more reactive thioiminium salts 433 or 434, 232 available through simple treatment of the thioamide with reactive alkyl halides or triflates. But again all our efforts to generate 433 or 434 failed, likely as a result of the reluctance of bridged lactam 432 to lead to highly energetic anti-bredt iminiums (Scheme 172).

Reasoning that the bridged lactam 355 could behave as an amino-ketone, thus explaining failures above, we tested its reactivity in the presence of a Wittig reagent (Scheme 173). In line with precedent in the literature, 185

IV.7.4. Optimization of Amidine Synthesis using Vilsmeier intermediate.

Considering the failures above, we looked more carefully at results obtained above and summarized in Table 12. Although these were not satisfying, it was decided to optimize such conditions, varying for instance the quantity of POCl 3 , the nature of the solvent and the temperature of the reaction.

First attempts were made by reacting 355 and aminobenzonitrile 429 in a mixture of DCM/THF through slow addition of POCl 3 (2 equiv.). This produced the amidine 430 in the same yield as above (entries 1 and 2). Increasing the amount of POCl 3 to 5 equiv. did not improve the yield (entry 3). However, an encouraging result was obtained when 5 equiv. of POCl 3 was added by syringe pump over 2h (entry 4).

The best conditions established above (Table 12) were applied to amino-ester 418 leading to the amidine 420 in a modest 57% yield, in addition with two unknown side products (Table 13, entry 1). We also observed that the way the work-up of the reaction was performed, influenced the outcome of the process. We thus tested different conditions, including concentrated basic aqueous conditions such Na 2 CO 3 and NaOH and we concluded that addition of 30% of NaOH at the end of the reaction to reach pH 9 at 0 o C was the best conditions. The influence of the nature of the solvent was also tested as literature shows that such reactions with POCl 3 are efficient in many solvents. Low yields were however observed when the preparation of the amidine was carried out in benzene, 233 performed with excess of thionyl-, oxalyl-chloride or PCl 5236 only starting materials being recovered (entries 5, 6 and 7).

In order to approach more closely the Eucophylline 335 skeleton, we extended our work to the synthesis of new amidine compounds bearing a methoxy-substituent on the aromatic moiety (hydroxyl group in Eucophylline 335) (Scheme 136). Surprisingly, applying the best conditions as in Table 13 (POCl 3 (5 equiv., DCM/THF, 40°C, 12 h)), the corresponding amidine 436 was not observed, despite the disappearance of 355 (monitored by TLC) (Scheme 174).

The failure of the reaction above is likely due to the presence of both ester-and methoxy groups and the excess of POCl 3 in the reaction medium. We therefore decided to perform another optimization of the reaction using a substrate containing a methoxy group such as 389 (Table 13). The first attempt was made using amide 355, 1 equiv. of POCl 3 in DCM/THF and heating at 60 o C until all 355 was consumed (3h as monitored by TLC), followed by addition of 389 and further heating for 12h. This produced the desired product 437, albeit in low yield (entry 1). Replacing the DCM/THF mixture by benzene did not improve the yield (entry 2). Some improvements were observed using MeCN, DCM and a mixture of MeCN/DCM as solvents (entry 3, 4 and 5). Based on these results, we finally observed the best yields when using 1 equiv. of POCl 3 in DCM and 1.5 equiv. of 437 at 60 o C for 12h, indicating that subtle solvent effects operate in this reaction (entry 6).

To get some insights into the mechanism of this reaction and the nature of the Vilsmeier intermediate, we performed NMR studies on a reaction mixture containing 1 equiv. of 355 and 1 equiv. of POCl 3 previously refluxed in CD 2 Cl 2 for 3h at 60 o C (Table 15). With amidines 420, 430 and 437 in our hand both compounds, the cyclization process to form the required aminoquinoline was then studied. These cyclization reactions should also install the amino-and hydroxyl-groups on the tetracyclic skeleton. We thus carried out first these reactions with LDA (Table 16) which proved successful during the construction of the tricyclic model (Scheme 160). Surprisingly, only recovered starting material was observed, whatever the temperature (entry 1). Similarly, KHMDS led to recovered starting material (entry 2). Finally, we were pleased to find that treatment of amidine 430 with t-BuOK led to the desired product in high yield (entry 3).

Furthermore, the cyclization process (Scheme 179) was applied to amidine compounds 420 and 437, which on treatment with t-BuOK led to the desired products 439 and 440 in high yields.

We then turned our attention to the Comins' reagent, often used to access vinyl triflates from the corresponding ketone enolates or dienolates. 243 Vinyl triflates 447 and 448, prepared above, are useful substrates in the Suzuki reaction. 245 For instance, palladium-catalyzed cross-coupling between these triflates and vinyltrifluoroborate 401 led to the desired vinyl quinolines 451 and 452 in good yields, using either Et 3 N 246 or K 2 CO 3 247 as bases at high temperature (Scheme 185).

IV.8. Conclusion.

In summary, we have developed an efficient approach toward the tetracyclic core of Eucophylline 335, based on the formation of an amidine key building block prepared through the intermediacy of IV.9. Approach to "South fragment" B -Elaboration of the piperidinone core.

IV.9.1. Our strategy.

We have developed above an efficient access to the eucophylline 335 core using the bridgehead IV.9.2. Construction of piperidinone core.

Preparation of oxime 454 through the free-radical multicomponent carbo-oximation process requiring the sulfonyloxime 122, the latter was prepared according to a literature procedure, 251 albeit in higher yields (Scheme 187).

In parallel, diester olefin 453 was prepared in high yield through a Wittig olefination on commercially available ketone 462 using triphenyl phosphonium ylide (Scheme 188). 252 Our study on the carbo-oximation process started by reacting 1 equiv. of xanthate 155, 2 equiv. of olefin 453 and 1.2 equiv. of oxime 122 in the presence of 1.5 equiv. of (Bu 3 Sn) 2 and DTBHN in refluxing benzene for 6 h at 65 • C (Table 17). Our first attempt led to the desired product 454, albeit in low yield (entry 1). Anticipating that the olefin 453 was not reactive enough, due to steric hindrance, we increased the number of equivalent of olefin 453 to 4, which effectively led to better yield (entry 2). The yield was also slightly increased when increasing the number of equivalent of oxime 122 to 2 (entry 3). But the best result was obtained when both olefin 453 and oxime 122 were increased to 4 and 2 equiv. respectively, leading to 454 in a very satisfying 79% yield (entry 4). We finally returned to a hydrogenation process using the more reactive Raney-Nickel under 50 atmosphere of hydrogen for 3 days. This relatively slow reduction however offered a direct access to lactam 457 in a good yield after N-O bond breaking, reduction of the C=N bond and lactamization (Scheme 191).

With diester 457 in hand, we envisaged a selective saponification of one ester functional group (possibly using enzymes to perform the reaction in an enantioselective manner), followed by a Barton-McCombie decarboxylation. This would leave an ester function which could be reduced into an alcohol that could then cyclized into the bridgehead lactam 375.

Two different saponification conditions were thus tested on the compound 457 (Scheme 192).

Initially, a mono-saponification reaction was attempted using NaOH in ethanol under reflux. 255 The desired hemiester 464 was effectively formed, albeit in low yield, along with degradations. No trace of diacid could be observed under these conditions (entry 1). We then tried the saponification using Baker's yeast in the presence of glucose. 256 In this case the hemiester was not formed and only starting material was recovered (entry 2). was obtained with a chemoselective reduction using a silane in the presence of a zinc catalyst under mild conditions (entry 2). 257 Finally, our attempts at reducing a Vilsmeier intermediate prepared from amide 457 and POCl 3 also failed, leading to several non-identified compounds and degradation products (entry 3).

In the meantime we tried to reduce selectively a single ester group into an alcohol, using LiBH 4 , freshly prepared in situ from NaBH 4 and LiCl (Scheme 194). 258 This method led only to recovered starting material (entry 1). The use of a commercially available LiBH 4 also led to starting material (entry 2). Finally, treatment of 457 with an excess of sodium trimethoxyborohydride in refluxing dimethoxyethane, 259 led to a similar result (entry 3).

Following the retrosynthetic analysis described before, we also envisioned the formation of the symmetrical imide 467 through the cyclization of the amide group of 457 onto one of the ester 257 (a) Daniele, S.-D.; Addis, D.; Zhou, S.; Junge, K.; Beller, M. J. Am. Chem. Soc. 2010, 132, 1770; (b) Konstanze, S.-D.; Moller, K.; Junge, K.; Beller, M. Chem. Eur. J. 2011, 17, 7414. 258 Hamada, Y.; Shibata, M.; Sugiura, T.; Kato, S.; Shioiri, T. J. Org. Chem. 1987, 52, 1252. 259 Gravestock, M. B.;Bell, R. A. Can. J. Chem. 1969, 47, 2099. group. Our efforts in this direction were not rewarding, as heating 457 in ethanol with pyridine 260 (entry 1) or in the presence of NaH in DME (entry 2) never produced the expected imide, but led only to recovered starting material (Scheme 195).

Due to the low yields observed during mono-saponification of 457, it was decided to prepare the amidine 468 using the procedure developed previously for bicyclic amide 430 and 438 above. This reaction was efficient, producing the expected amidine 468 in reasonable yield (Scheme 196).

With diester 468 in hand, several approaches were investigated to access the bicyclic system found in the natural product. Initially, treatment of 468 as before for compound 457, with t-BuOK in refluxing THF, was expected to provide a cyclized product (Scheme 197). This process, intead, gave the mono-saponified product 469, albeit in low yield, which was treated, without further purification, in the presence of tin oxide and refluxing toluene. Again the lactamization did not occur and only degradation products were observed. In parallel, we carried out the carbo-oximation process with α-bromosulfone 477 (Scheme 201). It was reasoned that removal of the sulfonyl group later (using Al(Hg) amalgam 265 ) in the sequence would also allow the introduction of the required ethyl substituent on the piperidinone quaternary center. The multicomponent reaction was thus carried out using 477 as an electrophilic precursor, olefin 453 and oxime 122 in presence of tin and DTBHN. The product 478 was formed with acceptable yield. However, we also observed the formation, as above, of the reduced side product

479.

Several hydrogenations under Raney-Nickel catalysis were tested on the compound 478 to achieve the cyclization into product 480 (Scheme 202). Unfortunately, none of our attempts produced the expected product, probably due to the too low pressure used in our experiments (1 atm in entry 1 and H-Cube apparatus in entry 2). 264 Togo, H. in Advanced in Free Radical Reactions for Organic Synthesis, 1 st edditions, Elsevirer Ltd., 2004, p. 171. 265 Kajiwara, Y.;Scott, A. I. Tetrahedron Lett. 2002, 43, 8795. In conclusion, all of our attempts to construct the bicyclic lactam skeleton met with failure, whatever the strategy. We thus turned our attention to the carbo-oximation of olefins having the requisite substitution pattern, thus avoiding further tedious functionalization of the diester moiety.

Our results in this context are described below.

IV.9.3. Carbo-oximation reaction of olefins having methyl and ethyl substituents.

As mentioned above, our next objective was the development of a carbo-oximation of olefins having the required substituents already in place, as to avoid the time-consuming functionalization of the diester moiety. As the olefins required for the carbo-oximation are not commercially available, our first task was to devise a straightforward approach to these precursors from readily available starting material. Olefin 486 was designed as our first model target as the starting olefin 482 is readily available. Synthesis of 486 involved first a Johnson-Claisen rearrangement starting from allylic alcohol 482 in the presence of triethyl-orthoacetate and an acid at high temperature.

This gave the corresponding ester 484, which was reduced with LiAlH 4 , to provide the alcohol 485. 267 The latter was then benzylated under basic conditions to afford the desired product 486 in good overall yield (Scheme 205). 268 267 (a) Green, J. C.; Brown, E. R.; Pettus, T. R. R. Org. Lett. 2012, 14, 2929; (b) Cai, Z.; Yongpruksa, N.; Harmata, M.;

Org. Lett. 2012Lett. , 14, 1661. 268 . 268 Bonder, D.; Liu, J.; Muller, T.; Paquette, L. A. Org. Lett. 2005, 7, 1813. In parallel, we prepared olefin 492 bearing an ethyl group, as that found in the natural product. The synthesis started from commercially available ethylacrolein 487 (Scheme 206) which underwent reduction into the corresponding alcohol 488 in the presence of NaBH 4 , followed by a bromination of the alcohol using PBr 3 leading to the bromide 489, 269 albeit in low yield, due to the high volatility of the product. Coupling between the latter and dimethyl malonate under basic conditions, led to 491, albeit in very poor yield, preventing the formation of the desired olefin 492. 270 Other methods have been described to prepare olefin 492. For instance, it was used in the synthesis of alkaloid aspidospermidine and (±)-Mersicarpine by Magnus and Zard respectively, 271 starting from ethyl hydroxymethyl propanediol 493 (Scheme 207). The latter undergoes a chlorination reaction using thionyl chloride to afford the corresponding trichloride 494 as a white solid, after recrystallization from methanol, followed by a rearrangement process using flame-dried Mg. 272 Dry CO 2 gas is then bubbled through the reaction mixture to generate olefin 495. This reaction was repeated several times, but in all cases, product 495 was obtained in low yield.

269 Cheng, B.; Sunderhaus, J. D.; Martin, S. F. Org. Lett. 2010, 12, 3622. 270 Ma, S.; Jiao, N.; Zhao, S.; Hau, H. J. Org. Chem. 2002, 67, 2837. 271 (a) Exon, C.; Gallagher, T.; Magnus, P. J. Am. Chem. Soc. 1983, 105, 4739;(b) Biechy, A.;Zard, S, Z. Org. Lett. 2009, 11, 2800. 272 McCaffery, E. L.; Shalaby, S. W. J. Organomet. Chem. 1967, 8, 17. With acid 495 in hand, several methods were tested for the formation of the corresponding ester 496 (Scheme 208). Acid 495 was stirred with thionyl chloride in ethanol (entry 1), treated using ethyl iodide under basic medium (entry 2), 273 and finally treated with a TMSCHN 2 solution in methanol (entry 3). In all cases, no product was formed but several non-identified compounds and degradation products were observed.

Finally, we have been able to prepare the ester 496 through a two steps sequence (Scheme 209), involving first the reaction of propargyl alcohol 497 with ethyl magnesium bromide in the presence of copper iodide as a catalyst, 274 followed by a Johnson-Claisen rearrangement through reaction of the allylic alcohol 488 with triethyl-orthoacetate in the presence of an acid in toluene. This gave the desired ester 496 in satisfying yield, notably when the reaction was carried out in toluene at higher temperature (entry 2).

273 Kim, S. S. PCT Int, Appl., WO 2008/087560 A2, 2008. 274 Barile, F.; Bassetti, M.; D'Annibale, A.; Gerometta, R.; Palazzi, M. Eur. J. Org. Chem. 2011, 32, 6519. Compounds 498 was thus subjected to the high pressure of hydrogen in the presence of Raney-Nickel catalyst in ethyl acetate. The reaction (Scheme 212) gave the desired products 499 in high yield.

IV.10. Conclusion.

In conclusion we have described in this chapter the approach toward the piperidinone skeleton starting from a multicomponent carbo-oximation process. This work was followed by a reduction and cyclization of the diester 454 into the corresponding lactam 457 in one pot under high pressure of hydrogen and Raney-nickel catalysis. Various further elaborations were then tested, such as mono-saponification of the diester, reduction of amide into amine, reduction of the ester into the corresponding alcohol followed by a second cyclization. But most of these attempts failed to produce the expected products, while others gave too low yields. Then we described the amidine reaction of lactam 457 through a Vilsmeier intermediate in good yields. On the other side, we have also extended our approach toward piperidinone synthesis by preparation of olefin 496 having the required ethyl substituent. Carbo-oximation of the latter led to encouraging yields of the desired oxime 498, opening a viable avenue to the formation of the final bicyclic lactam. The lack of time and little quantity of material unfortunately did not allow us to perform several attempts to afford the second cyclization. The success of this cyclization is crucial as it would provide us with a short total synthesis of Eucophylline 335.

General Conclusion and Perspectives

In the course of this PhD thesis, we have first described carbo-alkenylation reactions through addition of C-centered radicals across the π-system of electron-deficient olefins using a Z-sulfonyl acceptor as a terminal trap (Scheme 213). In that context, we have also described the variation of the nature of the olefin, which showed that simple olefins were able to produce reasonable to good yields of three-component products, while the strained bicyclic olefins were unreactive under similar conditions. We have also extended the scope of the carbo-alkenylation process by varying the nature of the radical precursors, including those having a nitrile or a malonate functional group.

During the second part of our project, we have described the preparation of some new sulfonylhydrazine initiators. The carbo-alkenylation reaction using diphenylsulfonyl hydrazine 251 as a radical initiator under U.V. irradiation has been tested with an allylsilane, a xanthate, and the diphenylsulfonylalkene as an acceptor, which afforded the expected product in good yield in DCE. This methodology has then been extended with success to several olefins in benzene. The initiator 251 has also been tested with other electrophilic precursors such as 263, but the results were not encouraging.

In parallel, we have described radical vinylation reactions using tris(trimethylsilyl)silylthiopropene 282 in the presence of some initiators such as 251. The different attempts afforded the desired product in low yields, while moderate yields were obtained using the initiator 254 in tertbutylbenzene. In the other hand, we have prepared then tested allylthiosilanes 322-323 in the presence of various electrophilic radical precursors in carbo-alkenylation reactions. We have shown that bromoacetonitrile 207 and allylsilane 188 were suitable candidates for this purpose in the presence of AIBN as an initiator. The methyl substituted allylsilylthioether 323 was more efficient in these reactions than the phenyl substituted one 322.

In the third part of the PhD thesis, we have developed several approaches towards Eucophylline, a natural fragment present in cytotoxic alkaloid Leucophyllidine. In this context, we have prepared corresponding lactam 454. Unfortunately, all attempts to complete the synthesis of the piperidinone core 375 from 454 have been unsuccessful. Lack of time and little quantity of material did not allow us to perform several attempts for the second cyclization. The success of this cyclization through three steps is crucial as it would provide us with a straightforward total synthesis of Eucophylline 335.

To date, the synthesis of Eucophylline alkaloid 335 using our methodology has not been totally successful. A ready access to the piperidinone 375 having an ethyl substituent on the quaternary center is under scrutiny in the laboratory (Scheme 216). However, our investigations have opened new avenues toward the synthesis of strained bicyclo[3.3.1]amides, key intermediates in the total synthesis of Eucophylline 335.

An optimized version of the approach above is currently investigated and involves a threecomponent carbo-oximation involving an iodo-thioester as the radical precursor (Scheme 217). This would lead to an adduct having orthogonal carbonyl functional groups which should be easier to functionalize later. One could for instance envision the selective reduction of the more reactive thioester function into an alcohol, followed by the reduction of the oxime group, which would trigger the final lactamization. Activation of the primary alcohol (as a mesylate) followed by a cyclization would afford the required bicyclo[3.3.1]amide.

EXPERIMENTAL PART

General remarks

All reactions were carried out under argon atmosphere with dry solvents under anhydrous conditions, unless otherwise noted. Yields refer to chromatographically and spectroscopically ( 1 H NMR) homogeneous materials. Commercial reagents were used without purification, unless otherwise stated. Benzene was distilled over sodium and benzophenone. Et 3 N, (i-Pr) 2 NH and 1,2-Dichloroethane were distilled over CaH 2 . Merck silica gel 60 (70-230 mesh) and (230-400 mesh ASTM) was used for flash chromatography. 1 H NMR and 13 C NMR were recorded on Bruker DPX-200 FT ( 1 H: 200 MHz, 13 C: 50.3 MHz), Bruker Advance-300FT ( 1 H: 300 MHz, 13 C: 75.5 MHz), Bruker DPX-400 FT ( 1 H: 400 MHz, 13 C: 100.2 MHz) and Bruker AC-600 FT ( 1 H: 600 MHz, 13 C: 150.13 MHz) using CDCl 3 as internal reference unless otherwise indicated. The chemical shifts (δ) and coupling constants (J) are expressed in ppm and Hz respectively. Highresolution mass spectra (HRMS) were recorded with a Q-TOF 2 spectrometer in the electrospray ionisation (ESI) mode at the Centre Régional de Mesures Physiques de l'Ouest (Université de Rennes). Infrared (IR) spectra were recorded on Perkin-Elmer Paragon 1000 FT-IR spectrophotometer. Melting point were not corrected and determined by using a Buchi-Totolli apparatus. Et 3 N, pyridine and (i-Pr) 2 NH were distilled from CaH 2 . PhH was distilled from sodium and benzophenone.

EXPERIMENTAL PART CHAPTER ΙІ

2-(Phenylsulfonyl)thiophene (193).

To a solution of 2-bromothiophene 194 (0.5 ml, 5.1 mmol, 1 equiv.) in DMSO (2 mL) were added sodium benzenesulfonate 195 (1.08 g, 5.9 mmol, 1.1 eq.), copper iodide (0.1 g, 0.5 mmol, 0.1 eq.), L-proline (0.115 g, 1 mmol, 0.2 eq.), NaOH (4 mg, 1 mmol, 0.2 eq.). The solution was stirred and heated at 90 o C for 48h under argon. The reaction mixture was cooled down to room temperature and water was added. The mixture was extracted three times with ethyl acetate. The organic layers were combined and washed with brine, dried over MgSO 4 and concentrated under vacuum to give a deep green compound. The crude product was purified by silica gel chromatography (petroleum ether/ ethyl acetate 80/20) affording 193 (614 mg, 2.74 mmol, 54%). NMR spectral data were identical to those previously reported. 119 R f = 0.4 (petroleum ether/ ethyl acetate 80/20). IR (ATR) ν max (cm -1 ) = 3095, 1446, 1399, 1317, 1151, 1104, 724. 1 H NMR (CDCl 3 , 300 MHz): δ (ppm) = 7.96-7.88 (m, 2H, CH ar ), 7.62 (dd, 1H, J = 1.2 and 3.6 Hz, H3), 7.58 (dd, 1H, J = 1.2 and 5.1 Hz, H1), 7.41-735 (m, 3H, CH ar ), 7.00 (dd, 1H, J = 3.9 and 5.1 Hz, H2). 13 C NMR (CDCl 3 , 75.5 MHz): δ (ppm) = 143.2 (C q or C4), 142.2 (C q or C4), 134.0 (C ar ), 133.5 (C3), 133.4 (C2), 129 (C ar ), 128 (C3), 127.4 (C ar ).

General Procedure for the Carbo-alkenylation (A).

To a solution of bromoacetonitrile 207 (105 mg, 0.5 mmol, 1 eq.) in dry degassed benzene (2.5 mL) were added olefin 209-214 or 178 (2 mmol, 4 eq.), bissulfone 169 (1.2 eq.) and di(tributyltin) (253 μL, 0.5 mmol, 1 eq.). The reaction mixture was stirred at 65°C. Then 15 mol% of DTBHN (13 mg) were added and the reaction mixture was stirred for 1.5 h. The reaction progress was monitored by TLC and further addition of DTBHN (15 mol%) was carried out (up to 3 more times) depending on the quantity of bromide remaining. The reaction mixture was then concentrated under reduced pressure and purified by chromatography on silica gel.

4-(2-(Phenylsulfonyl)vinyl)decanenitrile (215).

Synthesized according to the general procedure for carboalkenylation (A) above, bromo acetonitrile 207 (60 mg, 0.5 mmol, 1 eq.), 1-octene 209 (0.314 ml, 2 mmol, 4 eq.) and bissulfone 169 (185 mg, 0.6 mmol, 1.2 eq.) were heated for 6h at 65°C. The crude reaction mixture was purified by silica gel chromatography (petroleum ether/ ethyl acetate 70:30) then (toluene/ ethyl acetate 80:20) to provide 215 (83 mg, 0.26 mmol, 52%) as a colorless oil. R f = 0.3 (petroleum ether/ ethyl acetate 70/30). IR (ATR) ν max (cm -1 ) = 2927, 1446, 1318, 1306, 1180, 1085, 820, 752, 716, 687. 1 H NMR (CDCl 3 , 300 MHz): δ (ppm) = 7.95 -7.81 (m, 2H, CH ar ), 7.67 -7.47 (m, 3H, CH ar ), 6.97 (dd, 1H, J = 9.6 and 15.3 Hz, H5), 6.39 (d, 1H, J = 15 Hz, H6), 2.44 -2.11 (m, 3H, H2 and H4), 1.92 -1.56 (m, 1H, H3), 1.54 -1.04 (m, 10H, H7, H8, H9, H10 and H11), 0.83 (appearant t, 3H, J = 6.9 and 6 Hz, H12). 13 C NMR (CDCl 3 , 75.5 MHz): δ (ppm) = 147.9 (C5), 140.5 (C ar ), 133.6 (C6), 132.5 (C ar ), 129.5 (C ar ), 127.6 (C ar ), 118.9 (CN), 41.0 (C4), 33.9 (C3), 31.6 (C7), 29.5 (C8), 29.0 (C9), 26.9 (C10), 22.5 (C11), 15.2 (C2), 14.1 (C12). HRMS (ESI): [M+Na] + C 18 H 25 NO 2 NaS: calcd. 342.15037, found 342.1502.

3-(1-(2-(Phenylsulfonyl)vinyl)cyclohexyl)propanenitrile (216).

Synthesized according to the general procedure for carboalkenylation (A) above, bromoacetonitrile 207 (60 mg, 0.5 mmol, 1 eq.), methylenecyclohexene 210 (0.24 ml, 2 mmol, 4 eq.) and bissulfone 169 (185 mg, 0.6 mmol, 1.2 eq.) were heated for 6h at 65°C. The crude reaction mixture was purified by silica gel chromatography (petroleum ether/ ethyl acetate 85:15) then (toluene/ ethyl acetate 95:5) to provide 216 (16 mg, 0.053 mmol, 10%) as a colorless oil. R f = 0.34 (petroleum ether/ ethyl acetate 85/15). IR (ATR) ν max (cm -1 ) = 2927, 1446, 1305, 1150, 1085, 749, 736,687. 1 H NMR (CDCl 3 , 300 MHz): δ (ppm) = 7.95-7.83 (m, 2H, CH ar ), 7.75 -7.49 (m, 3H, CH ar ), 6.76 (d, 1H, J = 15.6 Hz, ,H5), 6.28 (d, 1H, J = 15.6 Hz, H6), 2.11 (appearant t, 2H, J = 7.5 and 8.7 Hz, H2), 1.80 (apparent t, 2H, J = 7.5 and 8.7 Hz, H3), 1.68 -1.23 (m, 10H, H7, H8, H9, H10 and H11).

(E)-4-Methoxy-4-methyl-6-(phenylsulfonyl)hex-5-enenitrile (217).

Synthesized according to general procedure for carbo-alkenylation (A), bromoacetonitrile 207 (60 mg, 0.5 mmol, 1 eq.), 2-methyl propene 211 (0.19 ml, 2 mmol, 4 eq.) and bissulfone 169 (185 mg, 0.6 mmol, 1.2 eq.) were heated for 6h at 65°C. The crude reaction mixture was purified by silica gel chromatography (petroleum ether/ ethyl acetate 75:25) then (toluene/ ethyl acetate 90:10) to provide 217 (42 mg, 0.150 mmol, 30%) as a colorless oil. R f = 0.35 (petroleum ether/ ethyl acetate 75/25). IR (ATR) ν max (cm -1 ) = 2934, 1447, 1307, 1289, 1182, 1085, 1066, 830, 753, 717, 688. 1 H NMR (CDCl 3 , 600 MHz): δ (ppm) = 7.96 -7.82 (m, 2H, CH ar ), 7.74 -7.52 (m, 3H, CH ar ), 6.78 (d, 1H, J = 15 Hz, H5), 6.52 (d, 1H, J = 15 Hz, H6), 3.17 (s, 3H, CH 3 methoxy), 2.37 -2.15 (m, 2H, H2), 2.09 -1.99 (m, H, H3a), 1.92 -1.82 (m, 1H, H3b), 1.34 (s, 3H, H7). 13 C NMR (CDCl 3 , 150.13 MHz): δ (ppm) = 147.5 (C5), 140.1(C ar ), 133.9 (C6), 132.1 (C ar ), 129.6 (C ar ), 127.8 (C ar ), 119.5 (CN), 50.7 (methoxy C), 49.6 (C4), 34.24 (C3), 22.1 (C 7), 11.6 (C2). HRMS (ESI): [M+Na] + C 14 H 17 NO 3 NaS: calcd. 302.08269, found 302.0826.

2-(2-(2-(Phenylsulfonyl)vinyl)tetrahydro-2H-pyran-3-yl)acetonitrile (218).

Synthesized according to the general procedure for carbo-alkenylation (A), bromoacetonitrile 207 (60 mg, 0.5 mmol, 1 eq.), 3,4-dihydro-2Hpyran 212 (0.18 ml, 2 mmol, 4 eq.) and Z-1,2-bis(phenyl sulfonyl)ethylene 169 (185 mg, 0.6 mmol, 1.2 eq.) were heated for 6h at 65°C. The crude reaction mixture was purified by silica gel chromatography (petroleum ether/ ethyl acetate 75:25) then (toluene/ ethyl acetate 90:10) to provide 218 (58 mg, 0.2 mmol, 40%) as a colorless oil. R f = 0.30 (petroleum ether/ ethyl acetate 75/25). IR (ATR) ν max (cm -1 ) = 2929, 2856, 1447, 1306, 1182, 1083, 753, 719, 687. 1 H NMR (CDCl 3 , 600 MHz): δ (ppm) = 7.88 (d, 2H, J = 7.8 H Z , CH ar ), 7.67-7.52 (m, 3H, CH ar ), 6.95 (dd, 1H, J = 4.8 and 15 Hz, ,H5), 6.67 (d, 1H, J = 15 Hz, H6), 3.99 (d, 1H, J = 12 Hz, H9a), 3.85 (dd, 1H, J = 4.8 and 9.6 Hz. H9b), 3.46 -3.37 (m, 1H, H4), 2.49 -2.31 (m, 2H, H2), 2.04 (d, 1H, J = 10.8 Hz, H3), 1.78-1.51 (m, 4H, H7 and H8). 13 C NMR (CDCl 3 , 150.13 MHz): δ (ppm) = 141.6(C5), 139.9 (C ar ), 133.8 (C6), 132.8 (C ar ), 129.5 (C ar ), 128.0 (C ar ), 117.1 (CN), 78.2 (C4), 67.9 (C9), 37.2 (C3), 29.2 (C2), 25.4 (C7 or C8), 20.6 (C7 or C8). HRMS (ESI): [M+Na] + C 15 H 17 NO 3 NaS: calcd. 314.08269, found 314.0826.

tert-Butyl 3-(cyanomethyl)-2-(2-(phenylsulfonyl)vinyl)piperidine-1-carboxylate (219).

Synthesized according to the general procedure for carboalkenylation (A), bromoacetonitrile 207 (60 mg, 0.5 mmol, 1 eq.), N-Boc-3,4-dihydro-2H-pyridine 178 (0.37 ml, 2 mmol, 4 eq.) and bissulfone 169 (185 mg, 0.6 mmol, 1.2 eq.) were heated for 6h at 65°C. The crude reaction mixture was purified by silica gel chromatography (petroleum ether/ ethyl acetate 70:30) then (toluene/ ethyl acetate 80:20) to provide 219 (121 mg, 0.310 mmol, 62%) as a colorless oil. R f = 0.35 (petroleum ether/ ethyl acetate 70/30). IR (ATR) ν max (cm -1 ) = 2978, 2937, 1688, 1408, 1318, 1308, 1273, 1163, 1150, 1085, 753, 732. 1 H NMR (CDCl 3 , 300 MHz): δ (ppm) = 7.91-7.84 (m, 2H, CH ar ), 7.68 -7.51 (m, 3H, CH ar ), 6.90 (dd, 1H, J = 4.2 and 15.3 Hz, ,H5), 6.37 (dd, 1H, J = 2.1 and 15.3 Hz, H6), 4.88 (br, 1H, H4), 4.49 (d, 1H, J = 13.8 Hz, H9a),2.85-2.70 (m, 2H, H9b), 2.66 -2.38 (m, 2H, H2), 2.37 -2.23 (m, 1H, H3), 1.79-1.69 (m, 2H, H7 or H8), 1.58-148 (m, 2H, H7 or H8), 1.37 (s, 9H, H12, H13 and H14).

4-(tert-Butoxy)-6-(phenylsulfonyl)hex-5-enenitrile (220).

Synthesized according to the general procedure for carboalkenylation (A), bromoacetonitrile 207 (60 mg, 0.5 mmol, 1 eq.), tert-butylvinylether 213 (0.18 ml, 2 mmol, 4 eqiuv.) and Z-1,2bis(phenyl sulfonyl)ethylene 169 (185 mg, 0.6 mmol, 1.2 eq.) were heated for 6h at 65°C. The crude reaction mixture was purified by silica gel chromatography (petroleum ether/ ethyl acetate and KF 80:20) to provide 220 (87.6 mg, 0.29 mmol, 57%) as a colorless oil. R f = 0.36 (petroleum ether/ ethyl acetate 80/20). IR (ATR) ν max (cm -1 ) = 2975, 1447, 1306, 1182, 1084, 754, 735, 717, 688.

1 H NMR (CDCl 3 , 300 MHz): δ (ppm) = 7.90-7.81 (m, 2H, CH ar ), 7.67-7.49 (m, 3H, CH ar ), 6.92 (dd, 1H, J = 15 and 3 Hz, ,H5), 6.55 (dd, 1H, J = 1.5 and 15 Hz, H6), 4.35 -4.24 (m, 1H, H4), 2.50-2.23 (m, 2H, H2), 1.94 -1.67 (m, 2H, H3 ), 1.12 (s, 9H, H8, H9 and H10).

4-(Ethoxymethyl)-6-(phenylsulfonyl)hex-5-enenitrile (221).

Synthesized according to the general procedure for carbo-alkenylation (A), bromoacetonitrile 207 (60 mg, 0.5 mmol, 1 eq.), allyl ethylether 214 (0.18 ml, 2 mmol, 4 eq.) and bissulfone 169 (185 mg, 0.6 mmol, 1.2 eq.) were heated for 6h at 65°C. The crude reaction mixture was purified by silica gel chromatography (petroleum ether/ ethyl acetate 80:20) then (toluene/ ethyl acetate 90:10) to provide 221 (59 mg, 0.20 mmol, 40%) as a colorless oil. R f = 0.35 (petroleum ether/ ethyl acetate 80/20). IR (ATR) ν max (cm -1 ) = 2974, 1287, 1447, 1306, 1185, 1112, 1085, 822, 753, 717, 688. 1 H NMR (CDCl 3 , 600 MHz): δ (ppm) = 7.87 (d, 2H, J = 8.4 Hz, CH ar ), 7.67 -7.50 (m, 3H, CH ar ), 6.85 (dd, 1H, J = 9 and 15 Hz, H5), 6.45 (d, 1H, J = 15 Hz, H6), 3.47 -3.39 (m, 4H, H7 and H8), 2.68 -2.60 (m, 1H, H4), 2. 43 -2.35 (m, 1H, H2a), 2.34 -2.25 (m, 1H, H2b), 2.00 -1.90 (m, 1H, H3a), 1.81 -1.73 (m, 1H, H3b), 1.12 (appearant t, 3H, J = 6.6 and 7.2 H Z ,) H9).

General Procedure for Carbo-alkenylation (B).

To a solution of dimethylbromoacetate 223 (105 mg, 0.5 mmol, 1 eq.) in dry degassed benzene (2.5 mL) were added olefin (2 mmol, 4 eq.), Z-1,2-bis(phenyl sulfonyl)ethylene 169 (1.2 eq.) and di(tributyltin) (253 μL, 0.5 mmol, 1 eq.). The reaction mixture was stirred at 65°C. Then 15 mol% of DTBHN (13 mg) were added and the reaction mixture was stirred for 1.5 h. The reaction progress was monitored by TLC and further addition of DTBHN (15 mol%) was carried out (up to 3 more times) depending on the quantity of bromide remaining. The reaction mixture was then concentrated under reduced pressure and purified by chromatography on silica gel.

Dimethyl 2-(2-(2-(phenylsulfonyl)vinyl)octyl)malonate (225).

Synthesized according to the general procedure for carboalkenylation (B), dimethylbromoacetate 223 (105 mg, 0.5 mmol, 1 eq.), 1-octene 209 (0.314 ml, 2 mmol, 4 eq.) and bissulfone 169 (185 mg, 0.6 mmol, 1.2 eq.) were heated for 6h at 65°C. The crude reaction mixture was purified by silica gel chromatography (petroleum ether/ ethyl acetate 80:20) then (toluene/ ethyl acetate 90:10) to provide 225 (404 mg, 0.984 mmol, 48%) as a colorless oil. R f = 0.30 (petroleum ether/ ethyl acetate 80/20). IR (ATR) ν max (cm -1 ) = 2955, 2927, 1750, 1733, 1446, 1307, 1180, 1086, 821, 752, 688. 1 H NMR (CDCl 3 , 300 MHz): δ (ppm) = 7.86 -7.74 (m, 2H, CH ar ), 7.43 -7.26 (m, 3H, CH ar ), 6.61 (dd, 1H, J = 9.6 and 9.3 Hz, H5), 6.20 (d, 1H, J = 15 Hz, H6), 3.60 (d, 6H, J = 9.9 Hz, CH methoxy), 3.17 (dd, 1H, J = 6.3 and 9 Hz, H2), 2.21-1.75 (m, 3H, H3 and H4), 1.47-0.98 (m, 12H, H7, H8, H9, H10, H11), 0.75 (appearant t, 3H, J = 6.3 and 7.2 Hz, H12). 13 C NMR (CDCl 3 , 50.3 MHz): δ (ppm) = 169.4 (2 C=O ester), 148.9 (C5), 140.7 (C ar ), 133.5 (C ar ), 131.6 (C6), 129.4 (C ar ), 128.4 (C ar ), 127.7 (C ar ), 52.8 (C methoxy), 52.7 (C methoxy), 49.5 (C2), 40.2 (C7), 34.4 (C4), 33.0 (C3), 31.7 (C8), 29.1 (C9), 26.9 (C10), 22.6 (C11), 14.1 (C12). HRMS (ESI): [M+Na] + C 21 H 30 O 6 NaS: calcd. 433.16608, found 433.1664.

Dimethyl 2-(2-(2-(phenylsulfonyl)vinyl) chlorohexyl)malonate (226).

Synthesized according to the general procedure for carboalkenylation (B), dimethylbromoacetate 223 (105 mg, 0.5 mmol, 1 eq.), 5-chloro-1-pentene 224 (416 mg, 2 mmol, 4 eq.) and bissulfone 169 (185 mg, 0.6 mmol, 1.2 eq.) were heated for 6h at 65°C. The crude reaction mixture was purified by silica gel chromatography (petroleum ether/ ethyl acetate 70:30) then (toluene/ ethyl acetate 80:20) to provide 226 (87 mg, 0.216 mmol, 43%) as a colorless oil. R f = 0.32 (petroleum ether/ ethyl acetate 70/30). IR (ATR) ν max (cm -1 ) = 2955, 2926, 1749, 1731, 1446, 1436, 1306, 1306, 1143, 1085, 821, 753. 1 H NMR (CDCl 3 , 300 MHz): δ (ppm) = 7.90-7.81 (m, 2H, CH ar ), 7.66-7.48 (m, 3H, CH ar ), 6.68 (dd, 1H, J = 9.6 and 15 Hz, H5), 6.31 (d, 1H, J = 15.3 Hz, H6 ), 3.67 (d, 6H, J = 10.5 Hz, CH methoxy), 3.44 (appearant t, 2H, J = 6.3 and 5.7 Hz, H9), 3.25 (dd, 1H, J = 6 and 9 Hz, H2), 2.34-1.85 (m, 3H, H3 and H4), 1.74 -1.45 (m, 4H, H7 and H8). 13 C NMR (CDCl 3 , 75.5 MHz): δ (ppm) = 169.2 (C=O ester), 147.7 (C5), 140.4 (C ar ), 133.6 (C6), 132.4 (C ar ), 129.5 (C ar ), 127.7 (C ar ), 52.9 (C methoxy), 52.8 (C methoxy), 49.3 (C2), 44.4 (C9 ), 39.5 (C4), 39.5 (C4), 32.8 (C3), 31.5 (C7 or C8), 29.8 (C7 or C8). HRMS (ESI): [M+Na] + C 18 H 23 O 6 ClNaS: calcd. 425.08016, found 425.0799.

Dimethyl 2-(2-(2-(phenylsulfonyl)vinyl)tetrahydro-2H-pyran-3-yl)malonate (227).

Synthesized according to the general procedure for carbo-alkenylation (B), dimethylbromoacetate 223 (105 mg, 0.5 mmol, 1 eq.), 3,4dihydro-2H-pyran 212 (0.182 mg, 2 mmol, 4 eq.) and bissulfone 169 (185 mg, 0.6 mmol, 1.2 eq.) were heated for 6h at 65°C. (cm -1 ) = 2955, 1750, 1733, 1446, 1436, 1307, 1285, 1750, 1085, 829, 754, 688. 1 H NMR (CDCl 3 , 600 MHz): δ (ppm) = 7.88 (d, 1H, J = 7.2 Hz, CH ar ), 7.62 (t, 1H, J = 7.2 Hz, CH ar ), 7.55 (appearant t, 2H, J = 7.2 and 8.4 Hz, CH ar ), 6.77 (d, 6H, J = 15 Hz, H5), 6.50 (d, 1H, J = 15 Hz, H6), 3.70 (d, 6H, J = 13.8 Hz, CH 3 ester), 3.40 (t, 1H, J = 3 Hz, H2), 3.11 (s, 3H, H7), 2.38 (dd, 1H, J = 6 and 14.4 Hz, H3a), 2.20 (dd, 1H, J = 6.6 and 14.4 Hz), 1.30 (s, 3H, H7). 13 C NMR (CDCl 3 , 150.13 MHz): δ (ppm) = 169.9 (C=O ester), 169.7 (C=O ester), 148.3 (C5), 140.3 (C ar ), 133.6 (C6), 131.1(C ar ), 129.5 (C ar ), 127.8 (C ar ), 75.9 (C4), 53.0 (C methoxy), 52.9 (C methoxy), 50.6 (C ether), 46.9 (C2), 36.9 (C3), 22.4 (C7). HRMS (ESI): [M+Na] + C 17 H 22 O 7 NaS: calcd. 393.09839, found 393.0985.

1.5 h at room temperature. The reaction mixture was then concentrated under reduced pressure and purified by chromatography on silica gel.

(E)-Ethyl 3-(1-(2-(phenylsulfonyl)vinyl)cyclohexyl)propanoate (257).

Synthesized according to the general procedure for (A) above, xanthate 155 (104 mg, 0.5 mmol, 1 eq.), methylene cyclohexane 210 (0.24 mL, 2 mmol, 4 eq.), bissulfone 169 (185 mg, 0.6 mmol, 1.2 eq.) and 251 (8 mg, 0.026 mmol, 5 mol %). The crude reaction mixture was purified by silica gel chromatography (petroleum ether/ ethyl acetate 90:10) to provide 257 (122 mg, 0.348 mmol, 70%) as a colorless oil. NMR spectral data were identical to those previously reported. 110 R f = 0.4 (petroleum ether/ ethyl acetate 90/10). 1 H NMR (CDCl 3 , 300 MHz): δ (ppm) = 7.92-7.82 (m, 2H, CH ar ), 7.69-7.45 (m, 3H, CH ar ), 6.81 (d, 1H, J = 15.6 Hz, H7), 6.22 (d, 1H, J = 15.6 Hz, H8), 4.08 (q, 2H, J = 7.2 Hz, H2), 2.16-2.01 (m, 2H, H4), 1.84-1.63 (m, 2H, H5), 1.63-1.14 (m, 10H, H9, H10, H11, H12, H13), 1.22 (t, 3H, J = 7.2 Hz, H1).

(E)-Ethyl-4-(((tert-butyldimethylsilyl)oxy)methyl)-4-methyl-6-(phenylsulfonyl)hex-5-enoate (258).

Synthesized according to the general procedure (A) above, xanthate 155 (104 mg, 0.5 mmol, 1 eq.), tertbutyldimethylsilane 255 (0.65 g, 2 mmol, 4 eq.), bissulfone 169 (185 mg, 0.6 mmol, 1.2 eq.) and 251 (8 mg, 0.026 mmol, 5 mol %). The crude reaction mixture was purified by silica gel chromatography (petroleum ether/ ethyl acetate 80:20) to provide 258 (145 mg, 0.319 mmol, 64%) as a colorless oil. NMR spectral data were identical to those previously reported. 110 R f = 0.43 (petroleum ether/ ethyl acetate 80/20). 1 H NMR (CDCl 3 , 300 MHz): δ (ppm) = 7. 85-7.71 (m, 2H, CH ar ), 7.68-7.52 (m, 5H, CH ar ), 7.51-7.31 (m, 8H, CH ar ), 6.84 (d, 1H, J = 15.4 Hz, H7), 6.15 (d, 1H, J = 15.4 Hz, H8), 4.10 (q, 2H, J = 7.1 Hz, H2), 3. 64-3.47 (m, 2H, H10), 2.21-2.08 (m, 2H, H2), 1.76-1.54 (m, 4H, H5 and H9), 1.24 (t, 3H, J = 7.1 Hz, H1), 1.01 (s, 9H, H12, H13 and H14), 0.98 (s, 3H, H15).

(E)-Ethyl 4-(2-(phenylsulfonyl)vinyl)decanoate (259).

Synthesized according to the general procedure (A) above, xanthate 155 (104 mg, 0.5 mmol, 1 eq.), octene 209 (0.314 ml, 2 mmol, 4 eq.), Z-1,2-bis(phenyl sulfonyl)ethylene 169 (185 mg, 0.6 mmol, 1.2 eq.) and 251 (8 mg, 0.026 mmol, 5 mol %). The crude reaction mixture was purified by silica gel chromatography (petroleum ether/ ethyl acetate 90:10) to provide 259 (95.2 mg, 0.297 mmol, 52%) as a colorless oil. NMR spectral data were identical to those previously reported. 110 R f = 0.2 (petroleum ether/ ethyl acetate 90/10). 1 H NMR (CDCl 3 , 300 MHz): δ (ppm) = 7.92-7.83 (m, 2H, CH ar ), 7.68-7.50 (m, 3H, CH ar ), 6.75 (dd, 1H, J = 15 and 9.4 Hz, H7), 6.29 (dd, 1H, J = 15 and 0.6 Hz, H8), 4.09 (q, 2H, J = 7.2 Hz, H2), (q, 2H, J = 7.2 Hz, H2), 4. 04-3.88 (m, 1H, H11a), 2.81-2.64 (m, 1H, H11b), 2.60-2.44 (m, 1H, H5), 2.44-2.18 (m, 2H, H4), 1.68-1.30 (m, 4H, H9 and H10), 1.33 (s, 9H, H14, H15 and H16).

(E)-Ethyl 4-((dimethyl(phenyl)silyl)methyl)-6-(phenylsulfonyl)hex-5-enoate (189).

To a solution of xanthate 155 (104 mg, 0.5 mmol, 1 eq.) in dry degassed DCE (2.5 mL), allylsilane 188 (0.34 ml, 2 mmol, 4 eq.), bissulfone 169 (185 mg, 0.6 mmol, 1.2 eq.) and 254 (7 mg, 0.026 mmol, 5 mol %) were added. The reaction mixture was irradiated using a tungsten lamp (3000W) during 1.5 h at room temperature. The crude reaction mixture was concentrated and purified by silica gel chromatography (petroleum ether/ ethyl acetate 90:10) to provide 189 (185 mg, 0.430 mmol, 86%) as a colorless oil. NMR spectral data were identical to those previously reported. 110 1 H NMR (CDCl 3 , 300 MHz): δ (ppm) = 7.89-7.78 (m, 2H, CH ar ), 7.66-7.48 (m, 3H, CH ar ), 7.42-7.23 (m, 5H, CH ar ), 6.23 (d, 1H, J = 15.8 Hz, H7), 6.71 (dd, 1H, J = 15.3 and 9.3 Hz, H7), 6.11 (d, 1H, J = 15.8 Hz, H8), 4.06 (m, 2H, J = 3.9 Hz, H2), 2.41-2.19 (m, 3H, H4 and H6), 1.92-1.57 (m, 2H, H5), 1.20 (t, 3H, J = 7.1 Hz, H1), 1.05 (dd, 1H, J = 15 and 5.1 Hz), 0.97 (dd, 1H, J = 15 and 9 Hz), 0.31 (s, 3H, H10), 0.29 (s, 3H, H11).

1-((E)-Styryl)adamantane (284).

Method 1: To a solution of adamantyl bromide 280 (43 mg, 0.2 mmol, 1 eq.) in dry degassed DCE (2.5 mL) were added styrylsulfone 281 (73 mg, 0.3 mmol, 1.5 eq.), allylsilane 301 (302 mg, 1 mmol, 5 eq.) and 251 (6 mg, 0.02 mmol, 0.1 eq.). The reaction mixture was irradiated using a tungsten lamp (3000W) during 3h at RT, then concentrated under reduced pressure. Purification using silica gel (petroleum ether) afforded the product 284 contaminated by silicon impurities which was recrystallized from methanol (17 mg, 0.071 mmol, 36%). Method 2: To a solution of adamantyl bromide 280 (43 mg, 0.2 mmol, 1 eq.) in dry degassed tertbutylbenzene (2.5 mL) were added styrylsulfone 281 (73 mg, 0.3 mmol, 1.5 eq.), allylsilane 301 (302 mg, 1 mmol, 5 eq.), and 254 (6 mg, 0.02 mmol, 0.1 eq.). The reaction mixture was then heated for 1.5 h at 140°C. The reaction progress was monitored by TLC and further addition of 254 (10 mol%) was carried out (up to 3 times). After purification, as above, 284 was further recrystallized from methanol (24 mg, 0.10 mmol, 50%). Method 3: To a solution of adamantyl bromide 280 (43 mg, 0.2 mmol, 1 eq.) in dry degassed benzene (2.5 mL) were added styrylsulfone 281 (73 mg, 0.3 mmol, 1.5 eq.), allylsilane 301 (302 mg, 1 mmol, 5 eq.) and 254 (6 mg, 0.02 mmol, 0.1 eq.). The reaction mixture was heated for 1.5h at 80°C. The reaction progress was monitored by TLC and further addition of 254 (10 mol%) was carried out (up to 3 times). After purification, as above, 284 was further recrystallized from methanol (16.5 mg, 0.07 mmol, 35%). Method 4: To a solution of adamantyl bromide 280 (43 mg, 0.2 mmol, 1 eq.) in dry degassed tertbutylbenzene (2.5 mL) were added styrylsulfone 281 (73 mg, 0.3 mmol, 1.5 eq.), allylthiosilane 286 (320 mg, 1 mmol, 5 eq.), and 254 (6 mg, 0.02 mmol, 0.1 eq.). The reaction mixture was then heated for 1.5h at 140°C. The reaction progress was monitored by TLC and further addition of 254 (10 mol%) was carried out (up to 3 times). After purification, as above, 284 was further recrystallized from methanol (14.3 mg, 0.06 mmol, 30%). NMR spectral data were identical to those previously reported. 159 R f = 0.85 (petroleum ether). M.p = 69 -70 o C. 1 H NMR (CDCl 3 , 200 MHz): δ (ppm) = 7.40-7.14 (m, 5H, CH ar ), 6.26 (d, 1H, J = 16.3 Hz, H2), 6.11 (d, 1H, J = 16.3 Hz, H1), 2.03 (br s, 3H, H5, H7 and H9), 1.81-1.69 (m, 12H, H2, H4, H6, H8 and H10).

General Procedure for Carbo-alkenylation (B).

To a solution of ethyl bromoacetate 304 (84 mg, 0.5 mmol, 1 eq.) in dry degassed benzene (2.5 mL) were added olefin (2 mmol, 4 eq.), bissulfone 169 (1.2 eq.), allylthiosilane 286 (307 mg, 1 mmol, 2 eq.) and AIBN (16 mg, 0.1 mmol, 0.2 eq.). The reaction mixture was stirred for 1.5 h at 80°C. The reaction progress was monitored by TLC and further addition of AIBN (20 mol%) was carried out (up to 3 times) depending on the quantity of bromide remaining. The reaction mixture was then concentrated in vacuo and purified by chromatography on silica gel.

(E)-Ethyl 3-(1-(2-(phenylsulfonyl)vinyl)cyclohexyl)propanoate (257).

Synthesized according to the general procedure for (B) above, ethyl bromoacetate 304 (84 mg, 0.5 mmol, 1 eq.), methylene cyclohexane 210 (0.24 mL, 2 mmol, 4 eq.), bissulfone 169 (185 g, 0.6 mmol, 1.2 eq.) and AIBN (16 mg, 0.1 mmol, 0.2 eq.) were heated for 6 h at 80 o C. The crude reaction mixture was purified by silica gel chromatography (petroleum ether / ethyl acetate 90:10) to provide 257 (51 mg, 0.15 mmol, 29%) as a colorless oil. NMR spectral data were identical to those previously reported. 114

(E)-Ethyl 4-(tert-butoxy)-6-(phenylsulfonyl)hex-5-enoate (260).

Synthesized according to the general procedure (C), ethyl bromoacetate 304 (84 mg, 0.5 mmol, 1 eq.), tert-butylvinylether 213 (0.26 mL, 2 mmol, 4 eq.), bissulfone 169 (185 g, 0.6 mmol, 1.2 eq.) and AIBN (16 mg, 0.1 mmol, 0.2 eq.) were heated for 6 h at 80 o C. The crude reaction mixture was purified by silica gel chromatography (petroleum ether / ethyl acetate 90:10) to provide 260 (3 mg, 0.008 mmol, 18%) as a colorless oil. NMR spectral data were identical to those previously reported. 114 (E)-4-((Dimethyl(phenyl)silyl)methyl)-N-methoxy-N-methyl-6-(phenylsulfonyl)hex-5-enamide (309).

To a solution of bromomethyl acetamide 308 (91 mg, 0.5 mmol, 1 eq.) in dry degassed benzene (2.5 mL) were added allylsilane 188 (0.34 mL, 2 mmol, 4 eq.), bissulfone 169 (185 mg, 0.6 mmol, 1.2 eq.) and allylthiosilane 286 (307 mg, 1 mmol, 2 eq.) and AIBN (16 mg, 0.1 mmol, 0.2 eq.).The reaction mixture was stirred for 1.5 h at 80°C. 2.35-2.16 (m, 1H4a), 2.11-2.01 (m, 1H, H5), 1.96-1.79 (m, 1H, H4b), 1.48-1.29 (m, 1H, H6), 0.71 (dd, 1H, J = 14.7 and 6.3 Hz, H9a), 0.58 (dd, 1H, J = 14.7 and 7.8 Hz, H9b), 0.17 (s, 3H, H10 or H11), 0.14 (s, 3H, H10 or H11). To a solution of dimethylbromomalonate 223 (105 mg, 0.5 mmol, 1 eq.) in dry degassed benzene (2.5 mL) were added allylsilane 188 (0.34 ml, 2 mmol, 4 eq.), Z-1,2-bis(phenyl sulfonyl)ethylene 169 (185 mg, 0.6 mmol, 1.2 eq.), allylthiosilane 286 (307 mg, 1 mmol, 2 eq.) and AIBN (16 mg, 0.1 mmol, 0.2 eq.). The reaction mixture was stirred for 1.5 h at 80°C. The reaction progress was monitored by TLC and further addition of AIBN (20 mol%) was carried out (up to 3 times). The crude reaction mixture was concentrated under vacuum and purified by silica gel chromatography (petroleum ether / ethyl acetate 80:20) to provide 310 (133 mg, 0.280 mmol, 56%) as a colorless oil. NMR spectral data were identical to those previously reported. 110 R f = 0.17 (petroleum ether/ ethyl acetate 80/20). 1 H NMR (C 6 D 6 , 300 MHz): δ (ppm) = 7.90-7.79 (m, 2H, CH ar ), 7.30-7.26 (m, 2H, CH ar ), 7.23-7.12 (m, 3H, CH ar ), 6.97-6.88 (m, 3H, CH ar ), 6.72 (dd, 1H, J = 15 and 9.6 Hz, H5), 5.98 (d, 1H, J = 15 Hz, H6), 3.30 (s, 3H, CH methoxy), 3.22 (s, 3H, CH methoxy), 3.26-3.13 (m, 1H, H2), 2.19-2.04 (m, 2H, H3), 1.90-1.84 (m, 1H, H4), 0.64 (dd, 1H, J = 14.7 and 5.7 Hz, H7a), 0.50 (dd, 1H, J = 14.7 and 8.1 Hz, H7b), 0.12 (s, 3H, H8), 0.10 (s, 3H, H9).

(E)-4-((Dimethyl(phenyl)silyl)methyl)-6-(phenylsulfonyl)hex-5-enenitrile (208).

To a solution of bromoacetonitrile 207 (60 mg, 0.5 mmol, 1 eq.) in dry degassed benzene (2.5 mL) were added allylsilane 188 (0.34 ml, 2 mmol, 4 eq.), bissulfone 169 (185 mg, 0.6 mmol, 1.2 eq.), allylthiosilane 286 (153 mg, 0.5 mmol, 1 eq.) and AIBN (16 mg, 0.1 mmol, 0.2 eq.). The reaction mixture was stirred for 2 h at 90°C. The crude reaction mixture was concentrated under vacuum and purified by silica gel chromatography (petroleum ether / ethyl acetate 85:15) to provide 2082 (128 mg, 0.334 mmol, 67%) as a colorless oil. NMR spectral data were identical to those previously reported. 110 R f = 0.46 (petroleum ether/ ethyl acetate 80/20). 1 H NMR (CDCl 3 , 300 MHz): δ (ppm) = 7.88-7.80 (m, 2H, CH ar ), 7.69-7.50 (m, 3H, CH ar ), 7.41-7.27 (m, 5H, CH ar ), 6.65 (dd, 1H, J = 15 and 9.6 Hz, H5), 6.21 (dd, 1H, J = 15 and 0.5 Hz, H6), 2.51-2.02 (m, 3H, H3 and H4), 1.86-1.53 (m, 2H, H3), 1.00 (dd, 1H, J = 14.9 and 5.8 Hz, H7a), 0.90 (dd, 1H, J = 14.9 and 8.4 Hz, H 7b), 0.24 (s, 3H, H8), 0.23 (s, 3H, H9). To a solution of 2-phenylallylthiol 319 (450 mg, 3 mmol, 1 eq.) and triethylamine (0.41 mL, 3.6 mmol, 1.2 eq.) in a 1:1 ether/THF mixture (25 mL), was added chlorotris(trimethyl)silyl silane 302 (92 mg, 3 mmol, 1 eq.) in one portion. The reaction mixture was stirred at room temperature overnight, then quenched with (1N) HCl and extracted three times with ether. The organic layer was washed with brine, dried over MgSO 4 , and the solvent concentrated under vacuum to give a residue, which was purified by silica gel chromatography (petroleum ether) to provide 322 (643 mg, 1.62 mmol, 54%) as a colorless oil. R f = 0.6 (petroleum ether). IR (ATR) ν max (cm -1 ) = 2958, 1251, 1043, 839, 755, 691. To a solution of 2-methylallylthiol 320 (500 mg, 5.67 mmol, 1 eq.) and triethyl amine (0.77 ml, 6.8 mmol, 1.2 eq.) in a 1:1 ether/THF mixture (50 mL), was added chlorotris(trimethyl) silane 302 (1.73 g, 5.67 mmol, 1 eq.) in one portion. The reaction mixture was stirred at room temperature overnight, then quenched with (1N) HCl and extracted three times with ether. The organic layer was washed with brine, dried over MgSO 4 , and the solvent concentrated under vacuum to give a residue, which was purified by silica gel chromatography (petroleum ether) to provide 323 (474 mg, 1.42 mmol, 25%) as a colorless oil. R f = 0.5 (petroleum ether). IR (ATR) ν max (cm -1 ) = 2958, 1251, 1044, 835, 754, 689. Method 1: To a solution of bromoacetonitrile 207 (60 mg, 0.5 mmol, 1 eq.) in dry degassed benzene (2.5 mL) were added allylsilane 188 (0.34 ml, 2 mmol, 4 eq.), Z-1,2-bis(phenyl sulfonyl)ethylene 169 (185 mg, 0.6 mmol, 1.2 eq.), allylmethylthiosilane 323 (167 mg, 0.5 mmol, 1 eq.) and AIBN (16 mg, 0.1 mmol, 0.2 eq.). The reaction mixture was stirred for 2 h at 90°C. The crude reaction mixture was then concentrated under vacuum and purified by silica gel chromatography (petroleum ether / ethyl acetate 85:15) to provide two products 208 (112 mg, 0.318 mmol, 58%) as a colorless oil and 329 (81 mg, 0.413 mmol, 42%). NMR spectral data were identical to those previously reported. 110

Method 2: To a solution of bromoacetonitrile 207 (60 mg, 0.5 mmol, 1 eq.) in dry degassed benzene (2.5 mL) were added allylsilane 188 (0.34 ml, 2 mmol, 4 eq.), Z-1,2-bis(phenyl sulfonyl)ethylene 169 (185 mg, 0.6 mmol, 1.2 eq.), allylphenylthiosilane 322 (198 mg, 0.5 mmol, 1 eq.) and AIBN (16 mg, 0.1 mmol, 0.2 eq.). The reaction mixture was stirred for 2 h at 90°C. The crude reaction mixture was concentrated under vacuum and purified by silica gel chromatography (petroleum ether / ethyl acetate 85:15) to provide 208 (38 mg, 0.1 mmol, 20%) as a colorless oil. NMR spectral data were identical to those previously reported.

EXPERIMENTAL PART CHAPTER IV

Compound 355 186 has been published following puplished procedure.

(E)-2-((1-Methylpiperidin-2-ylidene)amino)benzonitrile (390).

To a solution of methyl piperidinone 379 (6 g, 53.02 mmol, 1 eq.) in dry THF/DCM (1:1, 60 mL), POCl 3 (9.9 mL, 109 mmol, 2.05 eq.) and SnCl 4 (1.25 mL, 10.60 mmol, 0.2 eq.) were added. The reaction mixture was stirred for 1.5h at room temperature. A solution of aminobenzonitrile 429 (6.61 g, 53.55 mmol, 1.05 eq.) in DCM (20 mL) was added dropwise to the reaction. The reaction was heated to 40 o C overnight. Ice-cold water was then added followed by a 30% NaOH solution to alkaline pH. The organic solvents were concentrated under vacuum, the extracted with DCM, brine and dried over MgSO 4 . The solvent was evaporated in vacuum and the crude purified by chromatography on silica gel using (petroleum ether/ethyl acetate 70:30). The desired compound 390 was obtained as a yellow solid (9.49 g, 44.52 mmol, 84%). Mp = 84-85 o C. R f = 0.4 (petroleum ether/ethyl acetate 70:30). IR (ATR) ν max (cm -1 ) = 2940, 2222, 1588, 1358, 781. 1 H NMR (CDCl 3 , 300 MHz): δ (ppm) = 7.45 (dd, 1H, J = 1.2 and 7.5 Hz, CH ar ), 7.42-7.31 (m, 1H, CH ar ), 6.97-6.85 (m, 1H, J = 1.2 and 7.8 Hz, CH ar ), 6.79 (dd, 1H, J = 0.6 and 8.1 Hz, CH ar ), 3.29 (t, 2H, J = 6 Hz, H1), 3.05 (s, 3H. H12), 2.22 (t, 2H, J = 6.6 Hz, H4), 1.88-1.61 (m, 4H, H2 and H3).

(E)-2-((1-Benzylpiperidin-2-ylidene)amino)benzonitrile (391).

To a solution of benzyl piperidinone 380 (100 mg, 0.528 mmol, 1 eq.) in dry THF/DCM (1:1, 6 mL), POCl 3 (99 µmL, 1.082 mmol, 2.05 eq.) and SnCl 4 (12 µL, 0.106 mmol, 0.2 eq.) were added. The reaction mixture was stirred for 1.5h at room temperature. A solution of aminobenzonitrile 429 (62 mg, 0.528 mmol, 1.05 eq.) in DCM was added dropwise to the reaction. The reaction was heated to 40 o C overnight. Ice-cold water was added then a 30% NaOH solution to alkaline pH. The organic solvents were concentrated under vacuum, then extracted with DCM, brine and drying over MgSO 4 . The solvent was evaporated in vacuum and the crude mixture purified by chromatography on silica gel using (petroleum ether/ethyl acetate 80:20). The desired compound 391 was obtained as colorless oil (119.2 mg, 0.412 mmol, 78%). R f = 0.4 (petroleum ether/ ethyl acetate 80:20). IR (ATR) ν max (cm -1 ) = 2947, 2220, 1602, 1589, 1557, 1438, 1358, 1293, 1177, 707. 1H NMR (CDCl 3 , 300 MHz): δ (ppm) = 7.62-7.24 (m, 7H, CH ar ), 6.98 (appearant t, 1H, J = 7.5 and 7.2 Hz, CH ar ), 6.86 (d, 1H, J = 8.1 Hz, CH ar ), 4.86 (s, 2H, H12), 3.27 (appearant t, 2H, J = 5.4 and 6.3 Hz, H1), 2.38 (appearant t, 2H, J = 6.6 and 6.3 Hz, H4), 1. 92-1.68 (m, 4H, H2 and H3)

(E)-4-Methoxy-2-((1-methylpiperidin-2-ylidene)amino)benzonitrile (392).

To a solution of piperidinone 379 (121 mg, 1.07 mmol, 1 eq.) in dry 1:1 mixture of THF/DCM (10 mL), POCl 3 (0.2 mL, 2.20 mmol, 2.05 eq.) and SnCl 4 (25 µmL, 0.214 mmol, 0.2 eq.) were added. The reaction mixture was stirred for 1.5h at RT. A solution of aminobenzonitrile 389 (166 mg, 1.124 mmol 1.05 eq.) in DCM was added dropwise to the reaction. The reaction was heated to 40 o C overnight. Ice-cold water was added then a 30% NaOH solution to alkaline pH. The organic solvents were concentrated under vacuum, extracted with DCM, brine and dried over MgSO 4 . The solvent was evaporated and the crude purified by chromatography on silica gel (petroleum ether / EtOAc 70:30). The compound 392 was obtained as a white solid (145 mg, 0.596 mmol, 71%). Mp = 68-69 o C. R f = 0.3 (petroleum ether/ethyl acetate 70:30). IR (ATR) ν max (cm -1 ) = 2945, 2215, 1591, 1559, 1355, 1239. 1 H NMR (CDCl 3 , 300 MHz): δ (ppm) = 7.37 (d, 1H, J = 8.4 Hz, CH ar ), 6.48 (dd, 1H, J = 2.4 and 8.7 Hz, CH ar ), 6.30 (d, 1H, J = 2.4 Hz, CH ar ), 3.77 (s, 3H, 1H, CH methoxy), 3.28 (t, 2H, J = 6 Hz, H1), 3.03 (s, 3H, H12), 2.25 (t, 2H, J = 6.3 Hz, H4), 1.89-1.62 (m, 4H, H2 and H3). To a solution of n-BuLi (4.68 mL, 5.85 mmol, 2.5 eq.) in dry THF (60 mL), diisopropyl amine (0.87 mL, 6.20 mmol, 2.65 eq.) was added with stirring at -78 o C for 30 min, then a solution of amidine 390 (500 mg, 2.34 mmol, 1 eq.) in THF (2 mL) was added and the mixture was stirred at -70 °C for 2 h. During this time the color of the solution went from red to yellow orange. The reaction mixture was quenched with NH 4 Cl, then the mixture was concentrated under reduced pressure and extracted with DCM, brine and dried over MgSO 4 . The solvent was evaporated under vacuum to give a red oil, which was purified by chromatography on silica gel (DCM/MeOH/NH 4 Cl 95:4:1). The desired compound 393 was obtained as a red solid (490 mg, 2.3 mmol, 98%). Mp = 180-181 o C R f = 0.3 (DCM/MeOH/NH 4 Cl 95:4:1). IR (ATR) ν max (cm -1 ) = 2945, 1615, 1591, 1503, 1366, 760. 1 H NMR (CDCl 3 , 300 MHz): δ (ppm) = 7.63 (dd, 1H, J = 0.6 and 8.4 Hz, CH ar ), 7.50-7.37 (m, 2H, CH ar ), 7.14-7.04 (m, 1H, CH ar ), 4.28 (br, 2H, NH 2 ), 3.33 (appearant t, 2H, J = 5.7 and 5.4 Hz, H1), 3.25 (s, 3H, H13), 2.54 (t, 2H, J = 6.6 Hz, H3), ), 2.08-1.93 (m, 2H, H2

Preparation of diazonium salt (400).

To a solution of naphthyridine amine 393 (150 mg, 0.704 mmol, 1 eq.) in water (2 ml) and HBF 4 (1 ml, 15 mmol, 11.22 eq.) at -20 o C, was added a solution of sodium nitrite (0.97 g, 14 mmol, 10 eq.) in water (1 ml). The red colored reaction mixture was stirred 3h at -20 o C, followed by filtration and washing with cold pentane and ether to give the crude product 400 as a red color solid (175 mg, 0.560 mmol, 80%) which was used directly in the next step.

1-Methyl-5-vinyl-1,2,3,4-tetrahydrobenzo[b][1,8]naphthyridine (402).

Method A: To a solution of diazonium salt 400 (29 mg, 0.94 mmol, 1 eq.) in dry dioxane (6 mL), vinyl potassium borane 401 (176 mg, 0.316 mmol, 1.4 eq.), BINAP (47 mg, 0.075 mmol, 0.08 eq.), K 3 PO 4 (239 mg, 1.128 mmol, 1.2 eq.) were added. The reaction mixture was degassed for 30 min then palladium acetate catalyst (11 mg, 0.05 mmol, 0.053 eq.) was added and the mixture was heated at 70 °C for 12h. After completion of the reaction, H 2 O was added followed by an extraction with ether. The aqueous layers were combined, basified with 10% NaOH and extracted again with ethyl acetate then brine and dried over MgSO 4 . The solvents were evaporated under vacuum. The crude product was purified by chromatography on silica gel (petroleum ether/ ethyl acetate 96:4) to give the desired product 402 as a yellow oil (52 mg, 0.235 mmol, 25%). Method B: To a solution of iodoarene 403 (50 mg, 0.154 mmol, 1 eq.) in dry DMF (10 mL), vinyl potassium trifluoroborane 401 (29 mg, 0.216 mmol, 1.4 eq.) and Na 2 CO 3 (33 mg, 0.31 mmol, 2 eq.) were added. The reaction mixture was degassed for 30 min then Pd(PPh 3 ) 4 (1 mg, 0.008 mmol, 0.05 eq.) was added, followed by heating at 120 o C for 9h. The mixture was cooled down to room temperature and water was added followed by an extraction with ethyl acetate, brine and evaporated the solvent under vacuum. The crude product was purified by chromatography on silica gel (petroleum ether/ethyl acetate 96:4) to give the desired product 402 as a yellow oil (2.4 mg, 0.106 mmol, 7%). R f = 0.3 (petroleum ether/ethyl acetate 96:4). IR (ATR) ν max (cm -1 ) = 2971, 1582, 1556, 1509, 1496, 1447, 1399, 1351, 1326, 1076, 756. 1 H NMR (CDCl 3 , 300 MHz): δ (ppm) = 7.75 (dd, 1H, J = 1.2 and 8.4 Hz, CH ar ), 7.65 (dd, 1H, J = 0.6 and 8.4 Hz, CH ar ), 7.49-7.38 (m, 1H, CH ar ), 7.18-7.06 (m, 1H, CH ar ), 6.84 (dd, 1H, J = 11.7 and 18 Hz, H13), 5.77 (dd, 1H, J = 1.8 and 11.4 Hz, H14a), 5.42 (dd, 1H, J = 1.8 and 17.7 Hz, H14b), 3.46 (t, 2H, J = 5.7 Hz, H1), 3.29 (s, 3H, H15), 2.87 (t, 2H, J = 5.7 Hz, H3), 2.02-1.90 (m, 2H, H2). To a solution of diazonium salt 400 (29 mg, 0.94 mmol, 1 eq.) in dry dioxane (6 mL) at

3-(1-(tert-Butoxycarbonyl)piperidin-3-yl)propanoic acid (426).

To a solution of the acid 354 (100 mg, 0.636 mmol, 1 eq.) and NaOH (50 mg, 1.272 mmol, 2 eq.) in H 2 O (4 mL) and THF (3 mL), Bocanhydride (139 mg, 0.636 mmol, 1 eq.) was added. The reaction mixture was stirred 10h at room temperature. The solvent was evaporated under vacuum then the aqueous layer was washed with ether then acidified with 85% H 3 PO 4 to pH 1-2. Another extraction was done with ethyl acetate, brine and dried over MgSO 4 . Evaporation of the solvent gave the product (121 mg, 0.471 mmol, 74%). The product 426 was used in the next step without purification. IR (ATR) ν max (cm -1 ) = 2937, 1691, 1666, 1432, 1367, 1271, 1243, 1169, 1152.

tert-Butyl-3-(3-((2-(methoxycarbonyl)phenyl)amino)-3-oxopropyl)piperidine-1-carboxylate (427).

To a solution of Boc-N acid 426 (100 mg, 0.363 mmol, 1 eq.) and ester aniline 418 (65 mg, 0.436 mmol, 1.2 eq.) in dry DCM (10 mL), Mukaiyama reagent (111 mg, 0.436 mmol, 1.2 eq.) and triethyl amine (0.1 ml, 0.726 mmol, 2 eq.) were added. The reaction mixture was refluxed for 12h then cooled down to room temperature and water was added. The reaction was heated to 40 o C overnight. Ice-cold water was added then a 30% NaOH solution to alkaline pH. The organic solvents were concentrated under vacuum then the extraction was done with DCM, brine, dried over MgSO 4 and the solvent was concentrated under reduced pressure and the crude product purified by chromatography on silica gel (DCM/ethyl acetate 90:10) .The desired compound 430 was obtained as white solid (66 mg, 0.276 mmol, 21%). Method B: To a solution of bicyclic piperidone 355 (182 mg, 1.307 mmol, 1 eq.) in dry DCM (10 mL), Tf 2 O (70 µmL, 1.44 mmol, 1.1 eq.) was added dropwise at 0 o C. The reaction mixture was stirred for 1.5h at RT, then a solution of aminobenzonitrile 429 (162 mg, 1.373 mmol, 1.05 eq.) in DCM was added dropwise to the reaction mixture. The reaction was heated to 40 o C overnight. Icecold water was added then a 30% NaOH solution to alkaline pH. The organic solvents were concentrated under vacuum then the extraction was done with DCM, brine, dried over MgSO 4 and the solvent was concentrated under reduced pressure and the crude product purified by chromatography on silica gel (DCM/ethyl acetate 90:10). The desired compound 430 was obtained as white solid (53 mg, 0.221 mmol, 14%). Method C: To a solution of bicyclic piperidone 355 (182 mg, 1.307 mmol, 1 eq.) in THF/DCM 10 mL (1:1), POCl 3 (0.6 mL, 6.53 mmol, 5 eq.) was added by syringe pump over 2h, then a solution of aminobenzonitrile 429 (162 mg, 1.373 mmol, 1.05 eq.) in DCM was added dropwise to the reaction mixture. The reaction was heated to 40 o C overnight. Ice-cold water was added then a 30% NaOH solution to alkaline pH. The organic solvents were concentrated under vacuum then the extraction was done with DCM, brine, dried over MgSO 4 and the solvent was concentrated under reduced pressure and the crude product purified by chromatography on silica gel (DCM/ethyl acetate 90:10). The desired compound 430 was obtained as white solid (156 mg, 0.652 mmol, 50%). Mp = 93-94 o C. R f = 0.4 (DCM/ethyl acetate 96:4). IR (ATR) ν max (cm -1 ) = 2933, 2222, 1620, 1591, 1380, 1251, 1018 (s), 765, 751. 7.00 (appearant t, 1H, J = 7.5 and 7.8 Hz, CH ar ), 7.79 (d, 1H, J = 7.8 Hz, CH ar ),4.31 (d, 1H, J = 13.2 Hz, CH6a), 3.31 (d, 1H, J = 13.2 Hz, H6b), 3.12-2.85 (m, 2H, H5), 2.43-2.03 (m, 5H, H2, H3 and H4), 1.92-1.68 (m, 1H, H7a), 1.65-1.48 (m, 1H, H7b), 1.45-1.19 (m, 2H, H8). 13 C NMR (CDCl 3 , 75.5 MHz): δ (ppm) = 170.5 (C1), 154.5 (C9), 133.4 (C ar ), 133.0 (C ar ), 122.7 (C ar ), 122.3 (C ar ), 118.4 (C14), 105.4 (CN), 54.1 (C6), 52.2 (C5), 31.1 (C7), 28.9 (C3), 25.8 (C2), 24.9 (C4) 19.6 (C8). HRMS (ESI): [M+Na] + C 15 H 17 N 3 Na : calcd. 262.13147, found 262.1316.

2-((Triphenylphosphoranylidene)amino)benzonitrile (431).

Method A: To a solution of aminobenzonitrile 429 (236 mg, 2 mmol, 1 eq.) and triphenyl phosphine (525 mg, 2 mmol, 1 eq.) in dry DCM (8 ml), a solution of DEAD (0.377 mL, 2.4 mmol, 1.2 eq.) in DCM (2 mL) was added dropwise over 10 min then stirring 2h at room temperature. The extraction was done with diethyl ether and washed with saturated solution of NaHCO 3 , dried over MgSO 4 and the solvent was concentrated under reduced pressure and the crude material purified by chromatography on silica gel (DCM/EtOAc 76:24) to give the desired product 431 (426 mg, 1.126 mmol, 56%). Method B: To a solution of aminobenzonitrile 429 (236 mg, 2 mmol, 1 eq.) and triphenyl phosphine (525 mg, 2 mmol, 1 eq.) in dry DCM (8 mL), a solution of DIAD (0.473 mL, 2.4 mmol, 1.2 eq.) in DCM (2 mL) was added dropwise over 10 min then stirring 2h at room temperature. The extraction was done with Et 2 O and washed with saturated solution of NaHCO 3 , dried over MgSO4 and the solvent was concentrated under reduced pressure and the crude material purified by chromatography on silica gel (DCM/ethyl acetate 76:24) to give the desired product 431 (363 mg, 1.105 mmol, 48%). R f = 0.35 (DCM/ethyl acetate 80:20). IR (ATR) ν max (cm -1 ) = 1437, 1192, 1120, 754, 721, 695.

1-Azabicyclo[3.3.1]nonane-2-thione (432).

To a solution of bicyclic piperidone 355 (322 mg, 2.313 mmol, 1 eq.) in dry toluene, Lawesson's reagent (701.7 mg, 1.735 mmol, 0.75 eq.) was added. The reaction mixture was refluxed 4h, and then cooled down to room temperature. The solvent was concentrated under reduced pressure and purified by chromatography on silica gel (petroleum ether/ethyl acetate 90:10). The desired product 432 was obtained as a white solid (255 mg, 1.642 mmol, 71%). Mp = 65-66 o C. R f = 0.4 (petroleum ether/ethyl acetate 90:10). IR (ATR) ν max (cm -1 ) = 2929, 1457, 1398, 1238, 1065, 1012.

1 H NMR (CDCl 3 , 300 MHz): δ (ppm) = 4.83 (dd, 1H, J = 6 and 12.6 Hz, H6a), 3. 46 -3.18 (m, 3H, H6b and H5), 3.07 (dd, 1H, J = 4.5 and 14.7 Hz, H2a), 2.77-2.58 (m, 1H, H2b), 2.51-2.39 (m, 1H, H4), 2.25-2.02 (m, 2H, H3), 1.89-1.69 (m, 1H, H7a), 1.50-1.14 (m, 3H, H7b and H8). 13 C NMR (CDCl 3 , 75.5 MHz): δ (ppm) = 216.9 (C=S), 59. To a solution of bicyclic piperidone 355 (21 mg, 0.151 mmol, 1 eq.) in dry DCM (1 ml), POCl 3 (14 µmL, 0.151 mmol, 1 eq.) was added.

The mixture was heating under reflux at 60 o C for 3h then cooled down to room temperature. A solution of methoxyaminobenzonitrile 389 (33.5 mg, 0.226 mmol, 1.5 eq.) in DCM was added dropwise. The reaction mixture was heated at 60 o C for 12h. Ice-cold water was added then a 30% NaOH solution to alkaline pH. The extraction was done with DCM, brine, drying over MgSO 4 and the solvent was concentrated under reduced pressure and the crude product purified by chromatography on silica gel (DCM/ethyl acetate 96:4). The desired compound 437 was obtained as colorless oil (28.5 mg, 0.106 mmol, 70%). R f = 0.3 (DCM/ethyl acetate 96:4). IR (ATR) ν max (cm -1 ) = 2937, 2217, 1631, 1595, 1377, 1251, 1227, 1165, 1019, 941, 736. 1 H NMR (CDCl 3 , 300 MHz): δ (ppm) = 7.43 (d, 1H, J = 8.7 Hz, CH ar ), 6.54 (dd, 1H, J = 2.1 and 8.7 Hz, CH ar ), 6.29 (s, 1H, CH ar ), 4.27 (d, 1H, J = 12 Hz, CH6a), 3.78 (s, 3H, CH methoxy), 3.28 (d, 1H, J = 13.2 Hz, H5a), 3.10-2.87 (m, 2H, H6b and H5b), 2.46-2.00 (m, 5H, H2, H3 and H4), 1.97-1.69 (m, 1H, H7a), 1.65-1.62 (m, 3H, H7b and H8). To a solution of bicyclic piperidinone 355 (20 mg, 0,144 mmol, 1 eq.) in dry CD 2 Cl 2 (1mL), POCl 3 (13 µmL, 0.144 mmol, 1 eq.) was added. The reaction mixture was refluxed for 3h at 60 o C. The crude reaction was analyzed by NMR. 1 H NMR (CDCl 3 , 600 MHz): δ (ppm) = 5.32 (t, 1H, J = 1.2 Hz, H2), 3. 65-3.30 (m, 4H, H5 and H6), 2.68 (ddd, 1H, J = 19.8, 7.2 and 3 Hz, H3a), 2.41 (br, 1H, H4), 2.41 (br, 1H, H4), 2.19 (dd, 1H, J = 7.2 and 3 Hz, H3b), 1.97-1.75 (m, 4H, H7 and H8). 13 C NMR (CDCl 3 , 150.9 MHz): δ (ppm) = 128.8 (C2), 123.9 (C1), 55.3 (C5 or C6), 50.9 (C5 or C6), 30.4 (C3), 29.3 (C4), 23.6 (C7 or C8), 16.2 (C7 or C8). To a solution of the cyano amidine 430 (100 mg, 0.418 mmol, 1 eq.) in dry THF (15 mL), was added t-BuOK (124 mg, 1.107 mmol, 2.65 eq.) in one portion at 0 o C. The reaction mixture was stirred for 5h at room temperature. The reaction mixture was quenched with NH 4 Cl solution and evaporated the solvents under vacuum. The extraction was done with DCM, brine, and drying over MgSO 4 . The solvents were concentrated under reduced pressure and the crude material purified by chromatography on silica gel (DCM/MeOH/NH 4 OH 95:4:1) to give the product 438 as a white solid (77.8 mg, 0.325 mmol, 78%). Mp = 241-243 o C. R f = 0.4 (DCM / MeOH / NH 4 OH 95:4:1). IR (ATR) ν max (cm -1 ) = 3184, 2931, 1670, 1571, 1501, 1448, 1376, 1072, 1019, 763. 1 H NMR (CDCl 3 , 300 MHz): δ (ppm) = 7.87 (d, 1H, J = 8.4 Hz, CH ar ), 7.70 (d, 1H, J = 8.4 Hz, CH ar ), 7.54 (appearant t, 1H, J = 7.2 and 7.5 Hz, CH ar ), 7.32 (appearant t, 1H, J = 7.2 and 7.5 Hz, CH ar ), 4.80 (br, 2H, NH 2 ), 3.79 (d, 1H, J = 13.2 Hz, H6a), 3.47-3.05 (m, 3H, H6b and H5), 2.95 (dd, 1H, J = 7.8 and 16.5 Hz, H3a), 2.42 (d, 1H, J = 16.2 Hz, H3b), 2.27 (br, 1H, H4), 2.10-1.90 (m, 1H, H7a), 1.86-1.69 (m, 1H, H7b), 1.56-1.11 (m, 2H, H8). To a solution ester amidine 420 (47 mg, 0.173 mmol, 1 eq.) in dry THF (7 mL), t-BuOK (51 mg, 0.458 mmol, 2.65 eq.) was added in one portion at 0 o C, then stirring 5h at room temperature. The reaction mixture was quenched with NH 4 Cl solution and the solvent evaporated under vacuum. The solution was then extracted with DCM, brine, and dried over MgSO 4 . The solvent was concentrated under reduced pressure and the crude purified by chromatography on silica gel (DCM/MeOH/NH 4 OH 95:4:1) to give the product 439 as a white solid (38 mg, 0.159 mmol, 91%). Mp = 256 -257 o C. R f = 0.3 (DCM/MeOH/NH 4 OH 95:4:1). IR (ATR) ν max (cm -1 ) = 2923, 1627, 1555, 1499, 1473, 1394, 1010, 762. 1 H NMR (CDCl 3 , 300 MHz): δ (ppm) = 10.63 (br, 1H, OH), 8.43 (dd, 1H, J = 0.9 and 8.1 Hz, CH ar ), 7. 61-7.43 (m, 2H, CH ar ), 7.31-7.18 (m, 1H, CH ar ), 3.42 (d, 1H, J = 13.5 Hz, H6a), 3.25-2.90 (m, 4H, H6b, H5 and H3a), 2.64 (d, 1H, J = 17.7 Hz, H3b), 2.36-2.09 (m, 1H, H4). 1.96-1.47 (m, 3H, H7 and H8a), 1.32-1.15 (m, 1H, H8b). To a solution of cyano imidine 437 (23.1 mg, 0.086 mmol, 1 eq.) in dry THF (6 mL), t-BuOK (255 mg, 2.27 mmol, 2.65 eq.) was added in one portion at 0 o C, then stirring 5h at room temperature. The reaction mixture was quenched with NH 4 Cl solution and the solvent evaporated under vacuum. The solution was then extracted with DCM, brine, and dried over MgSO 4 . The solvent was concentrated under reduced pressure and purified by chromatography on silica gel (DCM/MeOH/NH 4 OH 95:4:1) to give the product 440 as a red solid (16 mg, 0.06 mmol, 69%). Mp = 210-211 o C. R f = 0.25 (DCM/MeOH/NH 4 OH 95:4:1). IR (ATR) ν max (cm -1 ) = 3198, 2925, 1672, 1622, 1577, 1502, 1467, 1345, 1325, 1229, 1021. 1 H NMR (CDCl 3 , 300 MHz): δ (ppm) = 7.54 (d, 1H, J = 9.3 Hz, CH ar ), 7.18 (d, 1H, J = 2.7 Hz, CH ar ), 6.94 (dd, 1H, J = 2.7 and 9.3 Hz, CH ar ), 4.62 (s, 2H, NH 2 ), 3.86 (s, 3H, CH methoxy), 3.74 (dd, 1H, J = 3.9 and 13.5 Hz, H6a), 3.35 (d, 1H, J = 13.2 Hz, H5a), 3.22 (td, 1H, J = 3.3 and 13.2 Hz, H6b), 3.10 (d, 1H, J = 13.2 Hz, H5b). 2.60 (dd, 1H, J = 8.1 and 16.2 Hz, H3a), 2.36 (d, 1H, J = 16.2 Hz, H3b), 2.23 (br, 1H, H4), 2.05-1.88 (m, 1H, H7a), 1.81-1.68 (m, 1H, H7b), 1.53-1.32 (m, 1H, H8a), 1.29-1.13 (m, 1H, H8b). To a solution of the aniline 440 (53 mg, 0.197 mmol, 1 eq.) and H 2 SO 4 (52µmL, 0.984 mmol, 5 eq.), NaNO2 (679 mg, 0.984 mmol, 5 eq.) in H 2 O (2 mL) was added dropwise at 0 o C, and then stirring 12h at room temperature. A 20% NaOH solution was added dropwise at 0 o C to pH = 9. The product was extracted with ethyl acetate, brine, dried over MgSO 4 and concentrated under reduced pressure and purified by chromatography on silica gel (DCM/MeOH/NH 4 OH 96:3:1) to give the product 443 as a white solid (33.7 mg, 0.125 mmol, 70% yield). 1H, J = 2.2 Hz, CH ar ), 6.89 (dd, 1H, J = 2.2 and 8.8 Hz, CH ar ), 3.73 (s, 3H, CH methoxy), 3.52 (dd, 1H, J = 10.4 Hz, H6a), 3.28-3.15 (m, 4H, H6a, H5a, H5b and H3a), 2.62 (d, 1H, J = 17.6 Hz, H3b), 2.17 (br, 1H, H4). 1. 98-1.44 (m, 3H, H7a, H7b and H8a), 1.34-1.12 (m, 1H, H8b). To a solution of NaH (9 mg, 0.416 mmol, 2 eq.) in dry THF (5 mL), phenol 439 (50 mg, 0.208 mmol, 1 eq.) in dry DMF (1 mL) was added at 0 o C with stirring for 30 min and the color changed to yellow. The Comins' reagent (61 mg, 0.156 mmol, 0.75 eq.) was added to the reaction mixture, then stirring 12h at RT. Ammonium hydroxide solution was added to pH = 13 and the solvent evaporated under vacuum, then extracted with EtOAc, brine, and dried over MgSO 4 . After removal of the solvents, the crude was purified by chromatography on silica gel (DCM/MeOH/NH 4 OH 98:1:1) to give the desired product 447 as a white solid yield (70 mg, 0.188 mmol, 91%). Mp = 165-167 o C. R f = 0.4 (DCM/MeOH/NH 4 OH 98:1:1). IR (ATR) ν max (cm -1 ) = 3675, 2988, 2901, 1407, 1394, 1379, 1241, 1224, 1075, 1065, 1056. 1 H NMR (CDCl 3 , 300 MHz): δ (ppm) = 7.97 (t, 2H, J = 7.5 Hz, CH ar ), 7.75-7.64 (m, 1H, CH ar ), 7.59-7.47 (m, 1H, CH ar ), 3.80 (d, 1H, J = 12.9 Hz, H6a), 3.55-3.26 (m, 3H, H6b, H5a and H3a), 3.18 (d, 1H, J = 13.4 Hz, H5b), 2.94 (d, 1H, J = 18.3 Hz, H3b), 2.30 (br, 1H, H4), 2.14-1.94 (m, 1H, H7a), 1.88-1.73 (m, 1H, H7b), 1.45-1.22 (m, 2H, H8). Method A: To a solution of NaH (20 mg, 0.826 mmol, 2 eq.) in dry THF (10 ml), phenol 443 (112 mg, 0.413 mmol, 1 eq.) in dry DMF (1.5 mL) was added at 0 o C with stirring for 30 min and the color of the solution during that changed to yellow. The Comins' reagent (122 mg, 0.309 mmol, 0.75 eq.) was added to the reaction mixture, stirred then 12h at room temperature. Ammonium hydroxide solution was added to pH =13 and the solvent evaporated under vacuum, extracted with EtOAc, brine, and drying over MgSO 4 . The solvent was concentrated under reduced pressure and purified by chromatography on silica gel (DCM/MeOH/NH 4 OH 98:1:1) to give the desired product 448 as a white solid yield (156 mg, 0.388 mmol, 94%). Method B: To a solution of phenol 443 (44 mg, 0.163 mmol, 1 equiv) in dry DCM (5 mL), triethyl amine (34 µmL, 0.244 mmol, 1.5 eq.), DMAP (10 mg, 0.081 mmol, 0.5 eq.) were added at 0 o C with stirring for 30 min and the color during that changed from white to deep yellow. The Comins' reagent (96 mg, 0.244 mmol, 1.5 eq.) was added to the reaction mixture, then stirring 16h at room temperature. Ammonium hydroxide solution was added until pH = 13 and the organic solvent evaporated under vacuum. The solution was then extracted with EtOAc, saturated NaCl solution and dried over MgSO 4 . The solvent was concentrated under reduced pressure and the crude material purified by chromatography on silica gel (DCM/MeOH/NH 4 OH 98:1:1) to give the desired product 448 as a white solid yield (60 mg, 0.150 mmol, 92%). Mp = 178-179 o C. R f = 0.3 (DCM/MeOH/NH 4 OH 98:1:1). IR (ATR) ν max (cm -1 ) = 2940, 1639, 1625, 1282, 1240, 1224, 1161, 1030, 858. 1 H NMR (CDCl 3 , 300 MHz): δ (ppm) = 7.83 (d, 1H, J = 9 Hz, CH ar ), 7.33 (d, 1H, J = 2.4 Hz, CH ar ), 7.19 (dd, 1H, J = 2.4 and 9.3 Hz, CH ar ), 3.93 (s, 3H, CH methoxy), 3.82 (d, 1H, J = 12 Hz, H6a), 3.46 (d, 1H, J = 13.5 Hz, H5a), 3.41-3.24 (m, 2H, H6b and H3a), 3.17 (d, 1H, J = 13.5 Hz, H5b). 2.88 (d, 1H, J = 18 Hz, H3b), 2.29 (br, 1H, H4), 2.10-1.92 (m, 1H, H7a), 1.79 (d, 1H, J = 13.5 Hz, H7b), 1.45-1.20 (m, 2H, H8). To a solution of phenol 443 (50 mg, 0.185 mmol, 1 eq.) in freshly distillated DCM (2 mL), was added triethyl amine (19µ mL, 0.185 mmol, 1 eq.) with stirring 30 min at 0 o C. Then pnitrobenzene sulfonyl chloride 449 (41 mg, 0.185, 1 eq.) in DCM was added dropwise to the reaction mixture and stirred 10h at room temperature. The solvent was evaporated, the crude material then dissolved in EtOAc and washed with 1N HCl, 1N NaOH, saturated NaCl solution. The organic phase was dried over Na 2 SO 4 . The solvent was concentrated under reduced pressure and the crude material purified by chromatography on silica gel (DCM/MeOH 98:2) to produce the desired product 450 as yellow solid (65 mg, 0.143 mmol, 77% yield). Mp = 187-189 o C. R f = 0.5 (DCM/MeOH 98:2). IR (ATR) ν max (cm -1 ) = 2962, 1258, 1084, 1014, 791. 1 H NMR (CDCl 3 , 300 MHz): δ (ppm) = 8.49 (d, 2H, J = 8.7 Hz, CH ar ), 8.26 (d, 2H, J = 9 Hz, CH ar ), 7.29 (appearant t, 2H, J = 2.4 and 1.8 Hz, CH ar ), 6.93 (dd, 1H, J = 2.4 and 9 Hz, CH ar ), 3.92 (s, 3H, CH methoxy), 3.82 (d, 1H, J = 10.8 Hz, H6a), 3.46 (d, 1H, J = 15 Hz, H5a), 3.41-3.24 (m, 2H, H6b and H3a), 3.18 (d, 1H, J = 15 Hz, H5b). 2.83 (d, 1H, J = 16.8 Hz, H3b), 2.23 (br, 1H, H4), 2.11-1.71 (m, 2H, H7), 1.48-1.22 (m, 2H, H8). To a solution of the triflate 447 (100 mg, 0.269 mmol, 1 eq.) in dry DMF (7 mL), vinyl potassium trifluoroborate 405 (54 mg, 0.403 mmol, 1.5 eq.) was added. The reaction mixture was bubbled for 30 min then Pd(PPh 3 ) 4 (31 mg, 0.027 mmol, 0.1 eq.) was added and reflux for 12h. The mixture was cooled down to room temperature and the solvent evaporated under vacuum. The product was purified by chromatography on silica gel (ethyl acetate 100%) to give the expected product 452 as yellow oil (51.9 mg, 0.207 mmol, 77%). R f = 0.35 (ethyl acetate 100%). IR (ATR) ν max (cm -1 ) = 2927, 1561, 1494, 1397, 1368, 1344, 1168, 1015, 745. 1 H NMR (CDCl 3 , 300 MHz): δ (ppm) = 8.03 (d, 1H, J = 8.7 Hz, CH ar ), 7.92 (d, 1H, J = 8.4 Hz, CH ar ), 7.64-7.52 (m, 1H, CH ar ), 7. 44-7.33 (m, 1H, CH ar ), 6.88 (dd, 1H, J = 11.7 and 18 Hz, CH ar ), 5.87 (dd, 1H, J = 1.8 and 11.7 Hz, H17a), 5.57 (dd, 1H, J = 1.8 and 18 Hz, H17b), 3.82 (dd, 1H, J = 3.9 and 13.8 Hz, H6a), 3.51-3.09 (m, 4H, H6b, H5 and H3a). 2.69 (d, 1H, J = 18 Hz, H3b), 2.23 (br s, 1H, H4), 2.10-1.92 (m, 1H, H7a), 1.90-1.61 (m, 1H, H7b), 1.52-1.16 (m, 2H, H8). To a solution of the triflate 448 (74 mg, 0.184 mmol, 1 eq.) in freshly distillated DME (3 mL) and H 2 O (1.5 mL), vinyl potassium trifluoroborate 401 (37 mg, 0.276 mmol, 1.5 eq.) and K 2 CO 3 (25 mg, 0.184 mmol, 1 eq.) were added. The reaction mixture was bubbled for 30 min, then Pd(PPh 3 ) 4 (21 mg, 0.018 mmol, 0.1 eq.) was added and heating to 95 o C for 3h. The reaction mixture was cooled down to room temperature and the solvent evaporated under vacuum. The product was purified by chromatography on silica gel (EtOAc 100%) to produce the product 451 as yellow oil (42.3 mg, 0.151 mmol, 82% yield). R f = 0.3 (ethyl acetate 100). IR (ATR) ν max (cm -1 ) = 2927, 1619, 1565, 1498, 1449, 1368, 1344, 1224, 1163, 1030, 1015, 823. 1 H NMR (CDCl 3 , 600 MHz): δ (ppm) = 7.93 (d, 1H, J = 9 Hz, CH ar ), 7.29 (d, 1H, J = 2.4Hz, H16), 7.05 (dd, 1H, J = 2.4 and 9 Hz, CH ar ), 6.93-6.80 (m, 1H, CH ar ), 5.85 (d, 1H, J = 13.2 Hz, H17), 5.56 (d, 1H, J = 19.2 Hz, H17b), 3.93 (s, 3H, CH methoxy), 3.81 (d, 1H, J = 10.2 Hz, H6a), 3.41 (d, 1H, J = 13.2 Hz, H5a), 3.36-3.24 (m, 1H, H6b), 3.21-3.08 (m, 2H, H5b and H3a). 2.64 (d, 1H, J = 17.4Hz, H3b), 2.22 (br s, 1H, H4), 2.06 -1.94 (m, 1H, H7a), 1.85-1.75 (m, 1H, H7b), 1.48-1.34 (m, 1H, H8a), 1.31-1.19 (m, 1H, H8b). 13 C NMR (CDCl 3 , 150.9 MHz): δ (ppm) = 162.0 (C1), 160.1 (C9), 148.5 (C15), 143.9 (C13), 132.1 (C ar ), 126.1 (C ar ), 122.7 (C ar ), 121.9 (C10), 119.4 (C2), 117.6 (C16), 106.7 (C17), 56.4 (C methoxy), 55.5 (C6), 52.5 (C5), 32.

Diethyl 4-methyleneheptanedioate (453).

To a solution of methyl triphenyl phosphonium bromide (2.86 g, 8 mmol, 1.6 eq.) in dry THF (35 mL), a freshly sublimated of t-BuOK (0.84 g, 7.5 mmol, 1.5 eq.) was added at 0 o C with stirring for 30 min.

A solution of diester ketone 462 (1.15 g, 5 mmol, 1 eq.) in THF (15 mL) was then added and the reaction mixture stirred for 5h at room temperature. The reaction was quenched with NH 4 Cl solution, followed by extraction with ethyl acetate, washing with brine, drying with MgSO 4 and evaporation of the solvent gave the crude product which was purified by silica gel chromatography (petroleum ether/ethyl acetate 90:10) to give the product 453 as a colorless oil (1.02 g, 4.67 mmol, 89%). To a solution of 478 (500 mg, 0.965 mmol, 1 eq.) in EtOAc (10 mL), nickel Raney catalyst (slurry in water) was added. The reaction mixture was subjected to high pressure of hydrogen (50 atm) with stirring for 3 days at room temperature. The reaction mixture was filtered through a short pad of celite and the solvent was concentrated under reduced pressure to give the crude product which was purified by chromatography on silica gel (DCM/MeOH 96:4). The desired compound 480 was obtained as a white solid (284 mg, 0.773 mmol, 80%). R f = 0.4 (DCM/MeOH 95:4). IR (ATR) ν max (cm -1 ) = 1730, 1670, 1304, 1184, 1146, 1087, 743, 689. 1 H NMR (CDCl 3 , 300 MHz): δ (ppm) = 7.83 (d, 2H, J = 7.2 Hz, CH ar ), 7.66-7.45 (m, 3H, CH ar ), 7.08 (s, 1H, NH), 4.02 (q, 2H, J = 7.2 Hz, H9), 3. 08-2.80 (m, 4H, H5 and H12), 2.31-1.98 (m, 4H, H2 and H7), 1.84-1.37 (m, 6H, H3, H6 and H 11), 1.16 (appearant t, 3H, J = 6.9 and 7.2 Hz, H10). 13 C NMR (CDCl 3 , 75.5 MHz): δ (ppm) = 172.7 (C1), 171.7 (C8), 138.6 (C ar ), 133.9 (C ar ), 129.4 (C ar ), 127.9 (C ar ), 60.7 (C9), 50.9 (C5 or C12), 50.2 (C5 or C12), 33.3 (C4), 29.6 (C2 or C7), 28.9 (C2 or C7), 28.0 (C3 or C6), 27.4 (C3 or C6), 26.4 (C11), 14.1 (C10). HRMS (ESI): [M+Na] + C 18 H 25 NO 5 NaS : calcd. 390.1345, found 390.1345.

Ethyl 4-methylenehexanoate (496).

To a solution of allylethyl alcohol 488 (1 g, 11.61 mmol, 1 eq.), triethyl-orthoacetate (2.34 mL, 12.77 mmol, 1.1 eq.) and acetic acid (7 µmL, 1.16 mmol, 0.1 eq.) were added. The reaction mixture was refluxed at 150-170 o C for 8h using Dean-Stark. The solvent was evaporated under vacuum then the crude material was purified by chromatography on silica gel using (petroleum ether/ethyl acetate 98:2). The desired compound 496 was obtained as colorless oil (1 g, 6.40 mmol, 55%). R f = 0.3 (petroleum ether/ethyl acetate 98:2). IR (ATR) ν max (cm -1 ) = 2980, 1729, 1154, 1039. 1 H NMR (CDCl 3 , 300 MHz): δ (ppm) = 4.71 (m, 2H, H9), 4.11 (q, 2H, J = 7.2 Hz, H7), 2.52-2.52 (m, 4H, H4 and H5), 2.02 (appearant q, 2H, J =7.2 and 7.5 Hz, H2), 1.24 (appearant t, 3H, J = 6.9 and 7.2 Hz, H8), 1.02 (appearant t, 3H, J = 7.2 and 7.5 Hz, H1). To a solution of xanthate 155 (104 mg, 0.50 mmol, 1 eq.) in dry degassed benzene (2.5 mL), ester olefin 496 (313 mg, 2 mmol, 4 eq.), oxime 122 (275 mg, 1 mmol, 2 eq.), di(tributyl)tin (0.375 mL, 0.750 mmol, 1.5 eq.) and 20 mol% of DTBHN (17 mg) were added. The reaction mixture was stirred for 1.5h at 65 o C. The reaction progress was monitored by TLC and further addition of DTBHN (20 mol%) was carried out (up to 3 more times) depending on

  Il a été envisagé que le squelette tétracyclique pouvait être élaboré sur la base d'une réaction de carbo-oximation radicalaire d'oléfine. Ce processus multicomposant, suivi d'une réduction de la fonction oxime, d'une lactamisation, d'une désymétrisation (différentiation des deux groupements esters) et enfin d'une décarboxylation de Barton-McCombie, offrirait une voie d'accès rapide au motif bicyclo[3.3.1]nonane chiral, intermédiaire-clé de la synthèse. Une réaction de type Friedländer entre ce lactame et un ortho-aminobenzonitrile permettrait ensuite d'accéder au squelette tetrahydrobenzo[1,8]naphthyridine de l'Eucophylline. La synthèse de l'eucophylline serait enfin complétée par l'introduction du substituant vinylique par un couplage de Suzuki à partir de triflates ou sels de diazoniums.

  and 4).55 55Togo, H. Advanced Free Reactions of Organic Synthesis, 1st Edition, 2004, Elsevier Ltd, pp. 20-21. Chemoselective bond formations and cleavages are required for the elaboration of molecules bearing sensitive functional groups.56 An illustration of this is given by early examples of radical reactions in the field of sugar chemistry with the syntheses of carbohydrates containing several hydroxyl groups. Various glucals thus undergo radical processes with the formation of C-C bonds through homolysis of a C-Hg bond without protection of the hydroxyl groups, illustrating the mildness of the conditions in radical processes (Scheme 25). 57 56 (a) Shenvi, R. A.; Malley, O.; D. P.; Baran, D. P. Acc. Chem. Res. 2009, 42, 530; (b) Afagh, N. A.; Yudin, A. K.

  105

  105 (a) Chabaud, L.; Landais, Y.; Renaud, P. Org Lett 2002, 4, 4257; (b) Chabaud, L.; Landais, Y.; Renaud, P. Org. Lett. 2005, 7, 2587.

Z

  -and E-sulfonyl acceptors bearing a substituent that can undergo β-fragmentation to sustain the radical chain, including SO 2 Ph, SOPh, SO 2 Et and SO 2 Me which are good candidates for this purpose. These acceptors should allow the introduction in the carbon framework of a new unsaturation with new Z-and E-products. The second task was to examine indolic and bicyclic olefins that can play an efficient role in the stereocontrolled addition across the double bond, to provide an access to the corresponding new three-component adducts. The third task involved extension of the three-component carbo-alkenylation reaction by varying the nature of the electrophilic radical precursor that could contain a cyano group or two ester functional groups (Scheme 58).

  122 (a) Osornio, Y. M.; Cruz-Almanza, R.; Jimenez-Montano, Miranda, L. Chem. Commun. 2003, 2316; (b) Guerrero, M. A.; Miranda, L. D. Tetrahedron Lett. 2006, 47, 2517. 123 Xiu, S.; Yong, T.; Jiao, Z. Tetrahedron 2009, 65, 6877. ІІ.4.2.b. Preparation of bicyclic olefins and application in MCRs.

  dimethyl malonate 222 in acetonitrile in the presence of p-toluenesulfonic acid and NBS, afforded the desired precursor 223 in very good yield (Scheme 75). 127 127 Kiyoshi, M.; Takane, U.; Yoshiko, Y.; Hiroshi, T.; Morrin, A. R. Heterocycles 1985, 23, 2041.

ІІІ. 1 ІІІ

 1 .2.c. Radical Production through High-energy Radiation.These radicals are produced when a high-energy radiation such as X-rays or γ-rays is applied. This is illustrated below with bromotrichloromethane 230, which produces the trichloromethyl radical 230i via an unstable cation radical (Scheme 79). 131ІІІ.1.2.d. Radical Production by Redox Systems.These radicals are generated through oxidation or reduction reactions (redox reaction) by intermolecular electron transfer (Scheme 80).132

ІІІ

  Similarity to the triethylborane, 9-BNN acts as an initiator at -78 o C. It can be used in conjunction with stannanes and halides, as well as with other reagents that can undergo facile chain reactions (Scheme 84).141

Figure 8 :

 8 Figure 8: The close distance between the reaction and light source.

  148 Markovic, D.; Vogel, P. e-EROS Encyclopedia of Reagents for Organic Synthesis; Diphenyl Disulfone, 2005, DOI: 10.1002/047084289X.rn00631.

  The mechanism (Scheme 104), involves the generation of silyl radicals Ia and IIa from allylsilanesIor thioether II which abstract the halogen from alkyl halides 280 and generate a nucleophilic radical 280i. The latter can then add to the sulfonyl acceptors 122, 281-282, affording the desired products 283-285 and releasing the PhSO 2 radical III. The latter can then react with electron-rich allylsilane I or thioether II and regenerates the starting silyl radicals Ia or IIa that sustain the chain.Yields in the above reactions depend on the nature of R group on the allylsilane. If R is a methyl group, the allylsilane becomes more nucleophilic 162 and thus favors addition of the electrophilic PhSO 2 radical to produce a more stable tertiary radical. Steric decompression and formation of a more substituted olefin here could also explain the faster elimination of the (Me 3 Si) 3 Si substituent. 161 DFT calculations effectively showed that β-fragmentation of the TTMS group can be accelerated in presence of methyl substituent that reduces the energy barrier (Scheme 105).

  PhSO 2 radical onto tris(trimethylsilyl)silylthiopropene (Scheme 106). β-Fragmentation of the C-S bond followed by a 1,2-silicon shift would form the required silyl radical ready to abstract the halogen (or xanthate) of alkyl halides 292. The radical precursor 292i would then add onto olefin 293, leading to a nucleophilic radical 293i, finally trapped with vinylsulfone acceptor 169. Released PhSO 2 radical would propagate the reaction chain. III.2.4. Results. III.2.4.a. Preparation of Allyltris(trimethylsilyl)silane.

  Scheme 130: Structure of Leucophyllidine.

  178(a) Nugroho, A. E.; Hirasawa, Y.; Kawahara, N.; Goda, Y.; Awang, K.; Hadi, A. H.; Morita, H. J. Nat. Prod. 2009, 72, 1502; (b) Zaima, K.; Hirata, T.; Hosoya, T.; Hurasawa, Y.; Koyama, K.; Rahman, A.; Kusumawati, I.; Zaini, N. C.; Shiro, M.; Morita, H. J. Nat. Prod. 2009, 72, 1686; (c) Nugroho, A. E.; Hirasawa, Y.; Hosoya, T.; Awang, K.; Hadi, A. H.; Morita, H. Tetrahedron Lett. 2010, 51, 2589.

  reported recently the isolation of Eucophylline 335 (south-fragment B) from the bark of Leuconotis eugenifolius together with Leucophyllidine 334 (Scheme 136). Compound 335 possesses a new tetracyclic vinylquinoline moiety consisting of a naphthyridine core. The presence of both these alkaloids in the plant is consistent with the proposed biogenesis of the dimeric alkaloid 334.179 Deguchi, J.; Shoji, T.; Nugroho, A.-E.; Hirasawa, Y.; Hosoya, T.; Shirota, O.; Awang, K.; Hadi, A.H.; Morita, H. J.Nat. Prod. 2010, 73, 1727.

180

  Yamada, S. in The Amide Linkage: Structural Significance inChemistry, Biochemistry, and Materials Science, Wiley-Interscience, 2000, p. 215. 181 (a) Greenberg, A.; Venanzi, C. A. J. Am. Chem. Soc. 1993, 115, 6951; (b) Mujika, J. M.; Matxain, J. M.; Eriksson, L. A.; Lopez, X. Chem. Eur. J. 2006, 12, 7215: (c) Greenberg, A.; Moore, D. T.; Dubois, T. D. J. Am. Chem. Soc. 1996, 118, 8658. 182 (a) Greenberg, A.; Venanzi, C. A. J. Am. Chem. Soc. 1993, 115, 6951; (b) Greenberg, A.; Moore, D. T.; DuBois, T. D. J. Am. Chem. Soc. 1996, 118, 8658; (c) Wasserman, H. H. Nature 2006, 441, 699.of reactivity can be found in the distorted amides ? A better understanding of the properties of the amide bonds should provide novel synthetic tools to chemists. Moreover, answering these questions may have important biological implications.When the amide bond is substituted with relatively large groups, the geometry of the amides is affected, including deformation such as C(O)-N bond rotation and C(O)-N bond lengthening in addition to N-pyramidalization. To understand the qualitative description of distorted amides, Yamada 180 has suggested a useful classification of amide bonds into three types, based on the torsionnal angle (τ) and pyramidalization at nitrogen (χ N ) (Scheme 138).  Twisted Amide (Type A): includes amides with perpendicularly twisted N-C(O) bonds and virtually non-pyramidalized nitrogen atom such as N-pivaloylphthalimide 343 (τ = 83.2°, χ N = 14.9°).  Nonplanar Amide (Type B): includes amides with planar N-C(O) bonds and sp 3 hybridized nitrogen atom such as in N-acetylaziridine and N-acyl-7-azabicyclo[2.2.1]heptane derivatives 344 (τ = 18.9°, χ N = 39.9°).  Twisted nonplanar Amide (Type C): includes amides with perpendicular amide bonds and pyramidalized nitrogen atoms. Usually, this type is found in bicyclic bridgehead lactams such as 2-quinuclidone 345 (τ = 90.9°, χ N = 59.5°). Such systems are closely related to those studied in the synthesis of eucophylline. IV.4. Synthesis of Bridged amides. Chemists have been interested by bridgehead amides for more than 70 years. The first mention of a bridged lactam was made by Lukes in 1938, when he suggested that insertion of a nitrogen atom at a bridgehead position in bicyclic ring systems (bicyclo[2.2.1]) 346, 348 and 350 would violate

  The retrosynthetic analysis of Eucophilline below illustrates some of the key-intermediate in our synthesis (Scheme 145). Coupling of a bridgehead lactam through a Vilsmeier reaction should allow an access to an amidine intermediate, which after Friedländer-type cyclization and Suzuki coupling should provide the required south fragment B. 194 Tani, K.; Stoltz, B. M. Nature, 2006, 441, 731.

  moiety starting from the simple cyclic amides 379 and 380. This sequence is based on the condensation between piperidinone 380 and amino-benzonitrile 381 via a Vilsmeier reaction which should give amidine intermediate 382. Cyclization of the latter should produce an aromatic amine, which upon diazotation should afford a diazonium salt 383 ready for a Suzuki coupling process and the introduction of the vinyl substituent 384 (Scheme 147). Due to the acidity of the lactam N-H, we first protected the nitrogen center with a benzyl group. This reaction was carried out by metalation of 385 using NaH as a base followed by the alkylation with benzyl bromide in dry THF, leading to the desired product 387 in very good yield (Scheme 148). 195 195 Bremmer, J. B.; Perkins, D. F. Tetrahedron 2005, 61, 2659.

  Anderson, M, B. PCT Int, Appl., WO 2009/065035 A1, 2009. 198 (a) Friedländer, P. Chem.Ber. 1882, 15, 2572; (b) Freidländer, P. Gohring, C. F. Ber. 1883,16, 1833. 199 Lee, B. D.; Li, Z.; French, K. J.; Zhuang, Y.; Xia, Z.; Smith, C. D. J.Med. Chem. 2004, 47, 1413. The preparation of amidine 382 was carried out by treating a mixture of both components with POCl 3 . The mechanism of the reaction involves the preliminary attack of the amide carbonyl group onto POCl 3 to generate 379i, and a Cl anion that can re-attack the C=N bond in 379ii to afford the Vilsmeier-Haack intermediate 379iii (Scheme 152). 200 This species can then undergo nucleophilic substitution reaction with 381 to produce the product 382 after work up under basic conditions. Amidines 390-392 were then treated with LDA in dry THF at -78 o C for 30 min. Under the optimal reaction conditions, a solution of the amidine in dry THF was added in one portion to the vigorously stirred solution of LDA (2.65 equivalent) in the same solvent at -78 o C. The cyclization in all cases proceeded smoothly to afford heterocycles 393, 394 and 395 in 78-98% yield (Scheme 153). 200 Kurti, L.; Czako, B. in Strategic Application of Named Reactions in Organic Synthesis, 1 st Ed., Elsevier, 2005, 468. The proposed mechanism for the described transformation of amidines 390-392 is outlined in (Scheme 154). The initial proton abstraction by LDA forms lithioenamines 390i-392i at -78 o C. However at temperature above -70 o C, the intermediates undergoes cyclization, followed by aromatization through tautomerization.With the aminoquinoline 393-395 in hands, it was then envisioned to introduce the vinyl group through a Pd-catalyzed cross-coupling between a diazonium intermediate generated from 393-395 and various vinylic reagents. Generation of diazonium salts in organic solvents is possible by reaction of aromatic amines with nitrites (NaNO 2 ) or alkyl nitrites (t-BuONO, isoamylONO).

  201(a) Canning, P. S.J.;Maskill, H.; McCrudden, K.; Sexton, B. Bull. Chem. Soc. Jpn. 2002, 75, 789; (b) Fagnoni, M.; Albini, A. Acc. Chem. Res. 2005, 38, 713.

IV. 7 .

 7 Approach to "South fragment" B -Construction of the aminoquinoline moiety. The second part of our research program then focused on the development of a new access to a tetracyclic core model of Eucophylline 335 starting from a single synthon, e.g. the readily available bicyclic lactam 355. It was envisioned that two key intermediates 409 and 411 would be accessible through 3 different routes. Considering our limited success in the introduction of the vinyl fragment through the corresponding diazonium salt, we thus devised an additional access to hydroxyquinoline 409, itself available through 2 pathways (Routes 1 and 2). The exploration of these different pathways is described below (Scheme 159).

  226226 Gensini, M.; Altamura, M.; Dimoulas, T.; Fedi, V.; Giannotti, D.; Giuliani, S.; Guidi, A.; Harmat, N.; Meini, S.; Nannicini, R.;Pasqui, F.; Tramontana, M.; Triolo, A.; Maggi, C. A. Chem. Med. Chem. 2010, 5, 65.

  1 H NMR, 13 C NMR, 31 P NMR, as well as COSY and HSQC of the crude reaction mixture established that a compound with general structure 355(III) (X = OPOCl 2 ) or 355(IV) (X = Cl) is formed. The study of the 2D H-NMR spectrum (Figure 10) gave more information about the protons arrangement in the Vilsmeier intermediate 355(III-IV). Most obvious is that the protons H3 are splitted in two signals H3a and H3b. The proton H3a is coupled with H3b, H2 and H4 and thus appears as a (ddd) with three coupling constants. The H3b proton giving a (dd) with two coupling with H3a and H2 but no coupling with H4 implies that the diedral angle between the two C-H3b and C-H4 bond should be around 90°.

Figure 10 .

 10 Figure 10. 2D-Spectra of the bicyclic Bridgehead amide 355 with POCl 3 in CD 2 Cl 2 (600 MHz).

  It was then decided to reduce the amide group of 457 and then lactamize the amino-ester. Reduction of the amide 457 (Scheme 193) using a solution of BH 3 in dimethylsulfide was attempted but unfortunately failed to produce the expected product 465 in decent yield (entry 1). A similar result 255 Radchenko, D. S.; Pavlenko, S. O.; Grygorenko, O. O.; Volochnyuk, S. V.; Shishkin, O. V.; Komarov, I. V. J. Org. Chem. 2010, 75, 5941. 256 Wei, Z.-L.; Li, Z.-Y.; Lin, G.-Q. Tetrahedron 2001, 12, 229.

  260 Panchgelle, S. P.; Bidwai, H. B.; Chavan, S. P.; Kalkote, U. R. Tetrahedron: Asymmetry 2010, 21, 2399.65 • C (Scheme 200). The reaction afforded the expected product 475 in 41% yield, along with a side product 476. The formation of 476 may result from a 1,6-H shift 264 from the CH 2 benzyl group (CO 2 CH 2 Ph) or more likely from a reduction of the sterically hindered tertiary radical intermediate with any hydrogen source in the medium.

  13 C NMR (CDCl 3 , 75.5 MHz): δ (ppm) = 151.6 (C5), 135.0 (C ar ), 133,7 (C6), 131.7 (C ar ), 129.6 (C ar ), 127.6 (C ar ), 119.5 (CN), 40.2 (C3), 35.4 (C4), 34.8 (C7 and C11 or C8 and C10), 25.7 (C9), 21.9 (C7 and C11 or C8 and C10). HRMS (ESI): [M+Na] + C 17 H 21 NO 2 NaS: calcd. 326.11907, found 326.1193.

  13 C NMR (CDCl 3 , 75.5 MHz): δ (ppm) = 155.1 (C=O ester), 140.0 (C ar ), 133.9 (C6), 133.2 (C ar ), 129.6 (C ar ), 127.8 (C ar ), 118.2 (CN), 81.3 (C11), 54.6 (C9), 39.5 (C9), 34.7 (C3), 29.3 (C12,13 and C14), 23 (C2), 19.9 (C7 or C8), 19.2 (C7 or C8). HRMS (ESI): [M+Na] + C 20 H 26 N 2 O 4 NaS: calcd 413.1511, found 413.1511.

  13 C NMR (CDCl 3 , 75.5 MHz): δ (ppm) = 147.5 (C5), 140.2 (C ar ), 133.6 (C ar ), 131.7 (C6), 129.5 (C ar ), 127.7 (C ar ), 119.4 (CN), 75.5 (C7), 68.1 (C4), 31.6 (C3), 28.4 (C8, C9 and C10), 13.1 (C2). HRMS (ESI): [M+Na] + C 16 H 21 NO 3 NaS: calcd. 330.11399, found 330.1140.

  13 C NMR (CDCl 3 , 150.13 MHz): δ (ppm) = 145.4 (C5), 140.3 (C ar ), 133.7 (C6), 132.9 (C ar ), 129.5 (C ar ), 128.3 (C ar ), 127.7 (C ar ), 119.0 (CN), 71.5 (C8), 66.9 (C7), 41.0 (C4), 26.6 (C3), 15.2 (C2), 15.1 (C9). HRMS (ESI): [M+Na] + C 15 H 19 NO 3 NaS: calcd. 316.09834, found 316.0983.

  1 H NMR (CDCl 3 , 200 MHz): δ (ppm) = 7.53-7.43 (m, 2H, CH ar ), 7.40-7.22 (m, 3H, CH ar ), 5.41 (dd, 2H, J = 1.2 and 10.6 Hz, H1), 3.60 (s, 2H, H3), 0.25 (s, 27H, CH methyl). 13 C NMR (CDCl 3 , 50.3 MHz): δ (ppm) = 146.7 (C2), 140.0 (C ar ), 128.4 (C ar ), 127.8 (C ar ), 126.3 (C ar ), 114.0 (C1), 35.3 (C3), 1.2 (C methyl). HRMS (ESI): [M+Na] + C 18 H 36 NaSi 4 S : calcd. 419.15126, found 419.1511. 1,1,1,3,3,3-Hexamethyl-2-((2-methylallyl)thio)-2-(trimethylsilyl)trisilane (323).

  1 H NMR (CDCl 3 , 200 MHz): δ (ppm) = 4.86 (d, 2H, J = 28 Hz, H1), 3.16 (s, 2H, H3), 0.24 (s, 27H, CH methyl). 13 C NMR (CDCl 3 , 50.3 MHz): δ (ppm) = 141.3 (C2), 113.7 (C1), 38.3 (C4), 32.1 (C3), 2.1 (C methyl). HRMS (ESI): [M+Na] + C 13 H 34 NaSi 4 S : calcd. 357.13556, found 357.1354.

  13 C NMR (CDCl 3 , 75.5 MHz): δ (ppm) = 157.8 (C5), 155.7 (C6), 133.2 (C ar ), 132.8 (C ar ), 123.5 (C ar ), 121.3 (C ar ), 118.7 (C11), 106.0 (CN), 50.5 (C1), 37.5 (C12), 27.0 (C4), 23.5 (C2 or C3), 21.0 (C2 or C3). HRMS (ESI): [M+H] + C 13 H 16 N 3 : calcd. 214.13442, found 214.1345.

  13 C NMR (CDCl 3 , 75.5 MHz): δ (ppm) = 163.5 (C1), 157.8 (C8), 157.7 (C6), 134.0 (C ar ), 119.1 (C11), 108.7 (C ar ), 107.8 (C ar ), 98.1 (CN), 55.5 (C methoxy), 50.5 (C1), 37.5 (C12), 26.9 (C4), 23.5 (C2 or C3), 21.0 (C2 or C3). HRMS (ESI): [M+H] + C 14 H 18 N 3 O : calcd. 244.14499, found 244.1451.

  13 C NMR (CDCl 3 , 75.5 MHz): δ (ppm) = 155.1 (C12), 147.2 (C5), 141.3 (C11), 132.5 (C ar ), 128.3 (C ar ), 126.3 (C ar ), 124.9 (C ar ), 122.2 (C6), 122.0 (C13), 121.3 (C14), 117.6 (CN), 50.1 (C2), 37.1 (C15), 26.4 (C3), 21.7 (C2). HRMS (ESI): [M+H] + C 15 H 17 N 2 : calcd. 225.13917, found 225.1389.

  1 H NMR (CDCl 3 , 300 MHz): δ (ppm) = 4.07-3.73 (m, 2H, H1), 2.91-2.26 (m, 4H, H5 and H7), 1.91-1.28 (m, 6H, H2, H3 and H6), 1.43 (s, 9H, H11, H12 and H13), 1.20-0.97 (m, 1H, H4). 13 C NMR (CDCl 3 , 75.5 MHz): δ (ppm) = 179.2 (CO ester), 155.1 (C8), 79.7 (C10), 49.4 (C1), 44.7 (C5), 35.4 (C7), 31.6 (C2 or C3), 30.7 (C2 or C3), 28.6 (C11, C12 and C13), 28.4 (C6), 24.6 (C4). HRMS (ESI): [M+H] + C 13 H 23 NO 4 Na : calcd. 280.1519, found 280.1524.

  1 H NMR (CDCl 3 , 300 MHz): δ (ppm) = 7.74-7.60 (m, 4H, CH ar ), 7.59-7.38 (m, 8H, CH ar ). 13 C NMR (CDCl 3 , 75.5 MHz): δ (ppm) = 133.4 (C ar ), 132.28 (C ar ), 132.23 (C ar ), 132.19 (C ar ), 132.15 (C ar ), 132.15 (C ar ), 132.05 (C ar ), 132.02 (C ar ), 132.0 (C ar ), 128.7 (C ar ), 128.6 (C ar ), 128.5 (C ar ), 128.48 (C ar ). HRMS (ESI): [M+H] + C 15 H 17 N 3 Na : calcd. 401.1184, found 401.1180.

  13 C NMR (CDCl 3 , 75.5 MHz): δ (ppm) = 170.4 (C1), 163.5 (C11), 156.5 (C ar ), 134.3 (C ar ), 118.8 (C ar ), 109.3 (C ar ), 107.3 (C ar ), 97.3 (CN), 55.5 (C methoxy), 54.0 (C6), 52.1 (C5), 31.0 (C7), 28.9 (C2 or C3), 25.9 (C2 or C3) 24.8 (C4), 19.6 (C8). HRMS (ESI): [M+Na] + C 16 H 19 N 3 ONa : calcd. 292.1420, found 292.1428.

  13 C NMR (CD 3 OD, 50.2 MHz): δ (ppm) = 162.4 (C1), 151.1 (C9), 147.1 (C15), 130.0 (C ar ), 127.4 (C ar ), 124.1 (C ar ), 122.3 (C ar ), 117.7 (C10), 107.1 (C2), 56.3 (C6), 53.6 (C5), 32.7 (C7), 30.0 (C3), 27.1 (C4), 19.7 (C8). HRMS (ESI): [M+H] + C 15 H 18 N 3 : calcd. 240.15007, found 240.15000.

  13 C NMR (CDCl 3 , 75.5 MHz): δ (ppm) = 178.0 (C1), 154.3 (C9), 138.8 (C15), 131.2 (C ar ), 125.9 (C ar ), 123.7 (C10), 122.6 (C ar ), 117.5 (C ar ), 112.7 (C2), 54.7 (C6), 53.3 (C5), 31.6 (C7), 27.7 (C3), 26.1 (C4), 18.8 (C8). HRMS (ESI): [M+H] + C 15 H 17 N 2 O : calcd. 241.13409, found 241.1339. HRMS (ESI): [M+Na] + C 15 H 16 N 2 O : calcd. 263.11603, found 263.1161.

  13 C NMR (CDCl 3 , 75.5 MHz): δ (ppm) = 162.4 (C1), 160.2 (C9), 148.5 (C15), 147.1 (C13), 120.9 (C ar ), 115.8 (C ar ), 111.1 (C10), 107.1 (C ar ), 105.3 (C2), 55.4 (C methoxy), 55.3 (C6), 52.7 (C5), 31.9 (C7), 28.9 (C3), 25.8 (C4), 18.9 (C8). HRMS (ESI): [M+H] + C 16 H 20-N 3 O : calcd. 270.1600, found 270.1597.

  Mp = 230-23 o C. R f = 0.25 (DCM / MeOH / NH 4 OH 96:3:1). IR (ATR) ν max (cm -1 ) = 3335, 2974, 1381, 1088, 1046, 880, 738. 1 H NMR (CDCl 3 , 200 MHz): δ (ppm) = 11.05 (s, 1H, OH), 8.35 (d, 1H, J = 8.8 Hz, CH ar ), 7.13(d,

  13 C NMR (CD 3 OD, 100.2 MHz): δ (ppm) = 178.8 (C1), 164.1 (C9), 156.3 (C15), 141.7 (C13), 127.7 (C ar ), 118.4 (C10), 114.6 (C ar ), 112.8 (C2), 98.92 (C ar ), 56.0 (C methoxy), 55.5 (C6), 54.0 (C5), 32.9 (C7), 28.4 (C3), 27.3 (C4), 19.7 (C8). HRMS (ESI): [M+Na] + C 16 H 18 N 2 O 2 Na : calcd. 293.1260, found 293.1257.

  13 C NMR (CDCl 3 , 75.5 MHz): δ (ppm) = 160.3 (C1), 150.4 (C9), 147.6 (C15), 130.3 (C ar ), 128.5 (C ar ), 126.6 (C ar ), 121.0 (C16), 120.8 (C ar ), 119.8 (C10), 116.7 (C2), 56.8 (C6), 52.3 (C5), 31.0 (C7), 29.0 (C3), 25.1 (C4), 19.1 (C8). HRMS (ESI): [M+Na] + C 16 H 15 N 2 O 3 F 3 SNa : calcd. 395.06532, found 395.0652.

  13 C NMR (CD 3 OD, 75.5 MHz): δ (ppm) = 163.5 (C1), 161.7 (C9), 150.7 (C15), 149.2 (C13), 122.0 (C10), 120.0 (C ar ), 118.2 (C ar ), 115.6 (C2), 114.7 (CF3), 106.3 (C ar ), 56.8 (C methoxy), 55.8 (C6), 52.3 (C5), 30.9 (C7), 28.7 (C3), 25.1 (C4), 19.1 (C8). HRMS (ESI): [M+H] + C 17 H 18 N 2 O 4 SF 3 : calcd. 403.08611, found 403.08422. HRMS (ESI): [M+Na] + C 17 H 17 N 2 O 4 F 3 NaS : calcd. 425.0753, found 425.0766.

  13 C NMR (CDCl 3 , 75.5 MHz): δ (ppm) = 164.1 (C1), 161.0 (C9), 150.3 (C15), 149.5 (C13), 142.3 (C ar ), 130.0 (C ar ), 124.9 (C ar ), 124.8 (C ar ), 122.8 (C10), 118.9 (C ar ), 118.8 (C ar ), 115.2 (C2), 106.6 (C ar ), 56.6 (C methoxy), 55.6 (C6), 52.4 (C5), 31.1 (C7), 29.2 (C3), 25.2 (C4), 19.1 (C8). HRMS (ESI): [M+Na] + C 22 H 21 N 3 O 6 NaS : calcd. 478.1043, found 478.1041.

  13 C NMR (CDCl 3 , 75.5 MHz): δ (ppm) = 161.5 (C1), 146.7 (C15), 143.7 (C13), 131.8 (C16), 128.5 (C ar ), 128.4 (C ar ), 124.8 (C ar ), 124.6 (C ar ), 124.23 (C10), 124.22 (C2), 122.8 (C17), 56.2 (C6), 52.4 (C5), 32.4 (C7), 31.6 (C3), 28.2 (C4), 18.9 (C8). HRMS (ESI): [M+H] + C 17 H 19 N 2 : calcd. 251.15482, found 251.1546.

  2 (C7), 31.7 (C3), 26.3 (C4), 19.1 (C8). HRMS (ESI): [M+H] + C 18 H 21 N 2 O : calcd. 281.1648, found 281.1651.

  13 C NMR (CDCl 3 , 75.5 MHz): δ (ppm) = 173.5 (C=O ester), 149.9 (C3), 108.1 (C9), 60.4 (C7), 32.9 (C4 or C5), 31.2 (C4 or C5), 29.0 (C2), 14.3 (C8), 12.4 (C1). HRMS (ESI): [M+H] + C 9 H 16 O 2 : calcd. 157.1228 found 157.102278.

  38

37

Giese, B.; Kretzschmar, G. Chem. Ber. 1983, 116, 3267. 38

Pacaud, R. A.; Allen, C. F. H. Org. Synth. Coll. 1941, 2, 336. І.4.2.b. Substitution (Abstraction) Reactions.

І.6.3. Stereoselectivity.

2005. ІІ.1.6.a. Multicomponent Radical-Anionic Reactions.

  88

87 Lamas, M.-C.; Studer, A. Org. Lett. 2011, 13, 2236. 88 Ryu, I. Multicomponent Radical Reactions, in Multicomponent Reactions Zhu, J.; Bienayme, H. Eds. Wiley-VCH: Weinheim,

  Curran, D. P.; Kim, D.; Ziegler, C. Tetrahedron 1991, 47, 6189.

  163

162 Laub, H. A.; Yamamoto, H.; Mayr, H. Org. Lett. 2010, 12, 5206. 163 Mereau, R.; Antuono, P.; Castaldi, M.; Rouquet, G.; Robert, F.; Landais, Y. Organometallics 2010, 29, 2406.

  206

202 Lin, A. J.; Loo, T. L. J.

Med. Chem. 1978, 21, 268. 203

Chernyak, N.; Buchwald, S. L. J. Am.

Chem. Soc. 2012, 134, 12466. 204

Schmidt, B.; Berger, R.; Holter, F.; Org.

Biomol. Chem. 2010, 8, 1406. 205

Darses, S.; Michaud, G.; Genet, J.-P. Tetrahedron

Lett. 1998, 39, 5045. 206 Schmidt, B.; Berger, R. Adv. Synth. & Cat. 2013, 355, 463.

  218

217 Jabri, S. Y.; Overman, L. E. J.

Am. Chem. Soc. 2013, 135, 4231. 218

Sabbatini, F. M.; Fabio, R.; Griffante, C.; Pentassuglia, G.; Zonzini, L.; Melotto, F. M.; Alvaro, G.; Capelli, A. M.; Pippo, L.; Perdona, E.; Denis, Y.; Costa, S.; Corsi, M. Bioorg.

Med. Chem. Lett. 2010, 20, 623.

  and xylene 230 amidine 430 was not formed.

227 Adib, M.; Sheikhi, E.; Deljoush, A. Tetrahedron 2011, 67, 4137. 228 Molina, P.; Vilaplana, M. J.; Pastor, A. Synthesis 1992, 9, 827. 229 Molina, P.; Alajarin, M. Vidal, A. J. Org. Chem. 1992, 57, 6703. 230 Ungoren, S. H.; Kani, I.; Gunay, A. Tetrahedron Lett. 2012, 53, 4758.

  bicyclo[3.3.1]amides such as 355 still behave as amides and do not react with such nucleophilic reagents.

231 Zou, J.; Cho, D. W.; Mariano, P. S. Tetrahedron 2010, 66, 5955. 232 (a) Perez, M.; Arioli, F.; Rigacci, G.; Santos, M. M.; Esque, A. G.; Escolano, C.; Florindo, P.; Ramos, C.; Bosch, J.; Amat, M. Eur. J. Org. Chem. 2011, 3858; (b) Amat, M.; Lior, N.; Hidalgo, J.; Escolano, C.; Bosch, J. Org. Chem.

2003, 68, 1919.

  amide 355 as a key precursor. 355 constitutes a valuable model, closely related to amide 375, the amide required for the total synthesis of 335. It was envisioned that homochiral piperidinone 375 could be prepared through a three-component radical carbo-oximation process involving xanthate 155, diester olefin 453 and the sulfonyloxime 122 (Scheme 186). This multicomponent process provides a triester 454, which oxime will be reduced into an amine as in 455. Conversion of 455 into the corresponding imide, followed by saponification of the remaining ester group and Barton-McCombie decarboxylation 248 should afford the symmetrical bicyclic imide 456. Installation of the quaternary stereogenic center through desymmetrization of 455 will be realized using a Corey-Bakshi-Shibata (CBS) chiral borane reduction, 249 which should offer an access to homochiral 375,

after reduction of the acyliminium intermediate with Et 3 SiH. Anticipating that 455 could spontaneously cyclize into the corresponding lactam 457, this offers an opportunity to desymmetrize both ester groups using, for instance, enzymes (lipase…).

250

Further decarboxylation and cyclization would also lead to homochiral 375.

248

Barton, D. H. R.; Ferreira, J. A. Tetrahedron 1996, 52, 9367.

249

Corey, E. J.; Bakshi, R. K.; Shibata, S.; Chen, C. P.; Singh, V. K. J. Am.

Chem. Soc. 1987, 109, 7925. 250

Bornscheuer, U. T.; Kazlauskas, R. J. in Hydrolases in Organic Synthesis: Regio-and Stereoselective Biotransformations, 2 nd edition, Wiely-VCH Verlag

GmbH & Co. KGaA, Weinheim, 2006, Section 5.3-5.4.

  The reaction progress was monitored by TLC and further addition of AIBN (20 mol%) was carried out (up to 3 times). The crude reaction mixture was concentrated under vacuum and purified by silica gel chromatography (petroleum ether / ethyl acetate 70:30) to provide 309 (77 mg, 0.173 mmol, 35%) as a colorless oil. NMR spectral data were identical to those previously reported. 110 R f = 0.3 (petroleum ether/ ethyl acetate 60/40).

	1 H NMR (C 6 D 6 , 300 MHz): δ (ppm) = 7.35-7.30 (m, 2H, CH ar ), 7.20-7.13 (m, 3H. CH ar ), 6.78 (dd,
	1H, J = 15 and 5.4 Hz, H7), 5.95 (dd, 1H, J = 15 and 0.6 Hz, H8), 3.02 (s, 3H, H1), 2.83 (s, 3H,
	H2),

  Deng, K.; Chalker, J.; Yang, A.; Cohen, T. Org.Lett. 2005, 7, 3637-3640.

	110
	((2-Methylallyl)sulfonyl)benzene (329). 276
	IR (solid, KBr): ν max (cm -1 ) = 2917, 1447, 1307, 1150, 1130, 1085,
	912, 724, 689.
	1 H NMR (CDCl 3 , 300 MHz): δ (ppm) = 7.93-7.83 (m, 2H, CH ar ),
	7.71-7.46 (m, 3H, CH ar ), 5.02 (s, 1H, H1a), 4.68 (s, 1H, H1b), 3.76 (s,
	2H, H3), 1.86 (s, 3H, H4).
	13 C NMR (CDCl 3 , 75.5 MHz): δ (ppm) = 133.8 (C ar ), 133.5 (C2), 129.1 (C ar ), 128.6 (C ar ), 120.7
	(C1), 64.6 (C3), 22.8 (C4).

276

  . (C ar ), 128.5 (C ar ), 128.2 (C ar ), 127.1 (C ar ), 123.4 (C ar ), 121.2 (C ar ), 118.9 (C11), 105.8 (CN), 51.9 (C12), 47.4 (C1), 27.2 (C4), 23.3 (C2 or C3), 20.8 (C2 or C3). HRMS (ESI): [M+Na] + C 13 H 16 N 3 Na : calcd. 312.1471, found 312.1462.

  ). HRMS (ESI): [M+H] + C 14 H 18 N 3 O : calcd. 244.14499, found 244.1445.

	(C ar ), 112.1 (C ar ), 109.8 (C6), 106.2 (C ar ), 96.9 (C4), 55.4 (C methoxy), 49.7 (C1), 37.2 (C13), 22.3
	(C3), 21.6 (C2).

  0 o C, a solution of potassium iodide 404(0.388 g, 2.35 mmol, 2.5 eq.) in H 2 O was added dropwise over 15 min. The reaction mixture was covered with a layer of toluene and allowed to stand for 2h at room temperature, then warmed gently to 40 o C for 10 min then to 60 o C overnight. The reaction was cooled down to room temperature and extracted with DCM, brine, dried over MgSO 4 . The organic solvents were concentrated under reduced pressure and purified by chromatography on silica gel (DCM/ MeOH/ NH 4 OH 95:4:1). The desired compound 403 was obtained as a red oil (15.4 mg, 0.048 mmol, 48%). CDCl 3 , 75.5 MHz): δ (ppm) = 154.7 (C ar ), 147.2 (C ar ), 131.9 (C ar ), 129.3 (C ar ), 126.2 (C ar ), 125.7 (C ar ), 125.5 (C ar ), 122.7 (C ar ), 117.5 (C ar ), 50.1 (C1), 37.2 (C13), 36.2 (C3), 22.1 (C2). HRMS (ESI): [M+H] + C 13 H 15 IN 2 : calcd. 347.00210, found 347.0019.

	R f = 0.3 (DCM/ MeOH/ NH 4 Cl 95:4:1).
	IR (ATR) ν max (cm -1 ) = 2972, 2901, 1404, 1241, 1075, 1057.
	1 H NMR (CDCl 3 , 300 MHz): δ (ppm) = 7.80 (dd, 1H, J = 1.2 and 8.4 Hz, CH ar ), 7.58 (dd, 1H, J = 3
	and 9 Hz, CH ar ), 7.51-7.41 (m, 1H, CH ar ), 7.24-7.12 (m, 1H, CH ar ), 3.43 (t, 2H, J = 6 Hz, H1), 3.28
	(s, 3H, H13), 2.98 (t, 2H, J = 6 Hz, H3), 2.08-1.96 (m, 2H, H2).

13 C NMR (

  The extraction was done with DCM, brine, dried over MgSO 4 . The solvent was evaporated under vacuum to give the crude product which was purified by chromatography on silica gel (DCM/ethyl acetate 96:4). The desired product 427 was obtained as a colorless oil (97 mg, 0.248 mmol, 69%).

	R f = 0.3 (DCM/ethyl acetate 97:3).
	IR (ATR) ν max (cm -1 ) = 2933, 1688, 1589, 1528, 1449, 1245, 1163, 758.
	1 H NMR (CDCl 3 , 300 MHz): δ (ppm) = 11.06 (br, 1H, NH), 8.67 (d, 1H, J = 8.1 Hz, CH ar ), 7.97
	(dd, 1H, J = 7.5 and 1.5 Hz, CH ar ), 7.54-7.43 (m, 1H, CH ar ), 7.08-6.96 (m, 1H, CH ar ), 3.96-3.78 (m,
	2H, H5), 3.88 (s, 3H, CH methoxy), 2.85-2.68 (m, 1H, H1a), 2.62-2.35 (m, 3H, H1b and H7), 1.92-
	1.51 (m, 6H, H6, H2 and H3), 1.41 (s, 9H, H18, H19 and H20), 1.28-1.01 (m, 1H, H4).
	13 C NMR (CDCl 3 , 75.5 MHz): δ (ppm) = 171.8 (C15), 168.7 (C16), 154.9 (C8), 141.6 (C ar ), 134.7
	(C ar ), 130.8 (C ar ), 122.4 (C ar ), 120.4 (C ar ), 114.8 (C ar ), 79.3 (C17), 52.4 (C methoxy), 49.2 (C5),
	44.5 (C1), 35.9 (C7), 35.5 (C6), 30.7 (C4), 29.0 (C2 or C3), 28.9 (C2 or C3), 28.5 (C18, C19 and
	c20), 24.8 (C17).
	HRMS (ESI): [M+Na] + C 21 H 30 N 2 O 5 Na : calcd. 413.2046, found 413.2046.
	(E)-N-(1-Azabicyclo[3.3.1]nonan-2-ylidene)-2-isocyanoaniline (430).
	Method A: To a solution of bicyclic piperidone 355 (182 mg, 1.307
	mmol, 1 eq.) in THF/DCM (1:1 10 mL), POCl 3 (0.244 mL, 2.668
	mmol, 2.05 eq.) was added dropwise. The mixture was stirred for 1.5h
	at RT, then a solution of aminobenzonitrile 429 (162 mg, 1.373 mmol,
	1.05 eq.

) in dry DCM was added dropwise to the reaction mixture.

  0 (C6), 55.8 (C5), 45.2 (C2), 32.5 (C4), 30.4 (C7), 26.7 (C3 or C8), 20.7 (C3 or C8). HRMS (ESI): [M+Na] + C 8 H 13 NNaS : calcd. 178.06664, found 178.0667. HRMS (ESI): [M+H] + C 8 H 14 NS : calcd. 156.0847, found 156.0847.

(a) Kita, Y.; Gotanda, K.; Murata, K.; Suemura, M.; Sano, A.; Yamaguchi, T.; Oka, M.; Matsugi, M. Org. Proc.

(a) Molander, G. A.; Mckie, J. A. J. Org. Chem. 1995, 60, 872;(b) Molander, G. A.; McWilliams, J. C.; Noll, B. C.J. Am.Chem. Soc. 1997, 119, 1265; (c) Molander, G. A. Chem. Rev. 1992, 92, 29; (d) Kagan, H. B.; Namy, J. L. Tetrahedron 1986, 42, 6573.

(a) Gan, C.-Y.; Robinson, W. T.; Etoh, T.; Hayashi, M.; Komiyama, K.; Kam, T.-S. Org.Lett. 2009, 11, 3962;(b) Deguchi, J.; Shoji, T.; Nugroho, A. E.; Hirasawa, Y.; Hosoya, T.; Shirota, O.; Awang, K.; Hadi, A. H. A.; Morita, H. J.Nat. Prod. 2010, 73, 1727.

Szabo, L. F. Molecules, 2008, 13, 1875.

Cai, L. Tetrahedron 2000, 56, 8253.

C NMR (CDCl 3 , 75.5 MHz): δ (ppm) = 157.4 (C5), 155.6 (C9), 137.8 (C ar ), 133.2 (C ar ), 132.9

C NMR (CDCl 3 , 75.5 MHz): δ (ppm) = 160.3 (C12), 156.5 (C5),

148.9 (C11), 144.9 (C9), 120.9

H NMR (CDCl 3 , 300 MHz): δ (ppm) = 7.53(d, 1H, J = 7.8 Hz, CH ar ), 1H, CH ar ),

Acknowledgements

Foremost, I would like to express my sincere gratitude to my supervisor Prof. Yannick LANDAIS.

-24-Another example of a radical process carried out without protection of hydroxyl groups has been reported by Stork et al. in the synthesis of five-membered ring systems having two quaternary carbon centers (Scheme 26). 58 The reaction proceeds through a very reactive vinyl radical species.

Dimethylformamide DMSO: Dimethylsulfoxide DTBHN: Di-tert-butylhyponitrite DTBP: Di-tert-butyl peroxide ee: Enantiomeric excess Triethylborane EtOH: Ethanol Et 3 N: Triethylamine Et 2 O: Diethyl ether EtOAc: Ethyl acetate EWG: Electron Withdrawing Group EDG:

Electron Donating Group FMO:

Frontier Molecular Orbitals

Abbreviations

Chapter ІІ

Free-Radical Multicomponent Processes

Chapter III

Radical Initiators & Tin-Free Alternative

Allylsilane 301 was also tested with the diphenylsulfone 254 as an initiator (Scheme 110).

Proceeding as above (Scheme 109) but in refluxing tert-butylbenzene at 140 o C, a better yield in 284 was obtained when three portions of 254 were added over 4.5 h. (entry 1). In benzene, the reaction proceeded in lower yield (entry 2).

III.2.4.c. Use of (tris(trimethylsilyl)silyl)thiopropene in MCRs.

The β-fragmentation of the C-Si bond in allylsilane 301 is not a very fast process. 165 Therefore, we envisioned using, in parallel 3-tris(trimethylsilyl)silylthiopropene 286, which was used earlier by Rouquet in our group 159 for oximation and vinylation of alkyl halides.

Starting from allylthiol 303 and tris(trimethylsilyl)silyl chloride 302 as starting materials under basic conditions, we were able to prepare 286 in good yield (Scheme 111).

Chapter IV Approach and Synthesis of

Leucophyllidine alkaloid

We first prepared amide 355 following a known protocol. 186 The preparation of 355 involved first a reduction of 3-(3-pyridinyl)-2-propenoic acid 414 under hydrogen pressure in the presence of palladium on charcoal to form the piperidine acid 354 in excellent yield as a white solid after recrystallization from acetone (Scheme 161). 214 The second step involved the amide bond formation through a cyclization reaction in the presence of Bu 2 SnO under refluxing toluene, using a Dean-Stark apparatus. This afforded bicyclic amide 355 in good overall yield.

In the meantime, aminobenzoic ester 417 was prepared following the literature, first by esterification of the acid group using thionyl chloride in refluxing methanol (Scheme 162).

Subsequently, the reduction of the nitro-group into an amino-group was carried out under hydrogen pressure using palladium on charcoal as a catalyst. 215 Both of these reactions worked very well and gave the desired products in nearly quantitative yield.

With 355 and 418 in hand, Friedländer-type annulation conditions were tested (Scheme 163).

Coupling in the presence of HCl 216 or t-BuOK (to generate an enolate intermediate) were thus attempted to produce intermediate 419. Unfortunately, whatever the conditions, no formation of 419, nor 420 and 421 could be observed but only starting material was detected by 1 H NMR and TLC.

214 Tsui, S.-K.; Wood, J. D. Can. J. Chem. 1979Chem. , 57, 1977. 215 . 215 Again, we applied the best conditions set up above to the preparation of 436 (Scheme 176).

Surprisingly, the reaction produced the desired product, but in very low yield. This might be attributed to the possible degradation of amino-ester 417 under these acidic conditions. This is further supported by the successful preparation of the cyano-amidine 430, under the same conditions (Scheme 177).

Compound 436 not being accessible through the coupling reaction, it was decided to transform the cyano group into an ester. This was performed heating cyano-amidine 437 in a mixture of methanol and BF 3 :Et 2 O as a catalyst (Scheme 178). 237 This reaction unfortunately led to the hydrolysis of the amidine and isolation of aniline 389 through flash chromatography.

237 Jayachitra, G.; Yasmeen, N.; Srinivasa, K.; Ralte, S.; Singh, A. Synth. Comm. 2003, 33, 3461. In order to get an unambiguous proof of the structure of 440 through X-ray diffraction studies, we tried to prepare the corresponding aromatic amide having a nitro substituent. 238 Surprisingly, our attempt to prepare the desired amide 442 failed, leading only to recovered starting material, suggesting a very low nucleophilicity for the amino group (Scheme 180).

IV.7.6. Incorporation of the vinyl group through Diazonium salt intermediates.

Considering the low yields obtained during our studies on the coupling process using diazonium salts (Table 8), it was decided to modify slightly the strategy, and to perform the coupling using a triflate, starting from the corresponding hydroxy-tetracyclic product such as 443. Compounds 478 was thus subjected to the same reaction conditions than those described previously (Scheme 191), using high pressure of hydrogen in the presence of Raney-Nickel catalyst in ethyl acetate. The reaction (Scheme 203) gave the desired product 480 in high yield.

Finally, with piperidinone 480 in hand, it was envisioned to form the final bicyclic lactam through reduction of the ester function into an alcohol and final ring-closure from the intermediate mesylate.

Removal of the sulfonyl group would complete the synthesis. The reduction of the ester mediated by LiBH 4 in DME was expected to provide the desired alcohol 481 266 (Scheme 204). Unfortunately, this reaction led only to degradation products. We thought that the acidic amide proton could affect the reduction, so we first treated 480 with 1 equiv. of n-BuLi for 30 min, followed by the addition of LiBH 4 . The same result was observed with only degradation products detected in the reaction mixture.

-136-IV.9.4. Carbo-oximation reaction of olefins 486 and 496.

Subsequently, we tested the compound 486 in our three-component carbo-oximation process, using xanthate 155 and oxime 122 in the presence of tin and DTBHN as an initiator (Scheme 210).

Surprisingly, the reaction did not lead to the desired product 497, but instead to degradation products. We believe that the presence of reactive benzylic hydrogens on the protecting group likely induces undesired reaction, including hydrogen abstraction. Such hydrogen migrations have already been noticed on related processes before. 275 The carbo-oximation reaction was then performed on olefin 496, using xanthate 155, oxime 122 in the presence of tin, and DTBHN initiator in refluxing benzene for 6h. This reaction led to the expected product 498 in 43% yield, along with some degradation products. Replacing the xanthate with the corresponding iodide led to a lower yield (Scheme 211).

the vinyltricyclic model 402 (Scheme 214) in only four steps and 17% overall yield starting from the commercially available 2-piperidinone. The synthesis started with the preparation in high yields of new aromatic amidine compounds 390, 391 and 392 through Vilsmeier intermediates, followed by an efficient cyclizations with LDA. Several Pd(0)-catalyzed Suzuki couplings have been studied

to introduce the vinyl moiety from diazonium salt and iodoarenes precursors, but despite our efforts, this functionalization remained the limiting step of the sequence in terms of yields.

Following these preliminary investigations, we have described three different approaches towards the synthesis of Eucophylline 335 alkaloid. Our first approach using a Friedländer-type annulation reaction between bridged lactam 355 and aromatic substrates under different basic conditions unfortunately failed. The second strategy we have tested relied on the synthesis of amidine intermediate 428 through a coupling reaction between the N-protected acid 426 and aniline ester 418 using Mukaiyama's reagent. The successful access to 428 was followed by a N-Boc deprotection leading to an intermediate which failed to cyclized under acidic conditions. The third approach toward the tetracyclic core involved the amidine synthesis via a reaction between 355 and 431 under aza-Wittig conditions. A route to the desired amidines was finally secured through the addition of substituted anilines onto the Vilsmeier intermediate of bicyclic amide 355.

Intramolecular cyclizations of amidines 420, 430 and 437 was achieved by treatment of the latter with t-BuOK. The alcohols were then converted into the corresponding triflates using Comins'

reagent. An efficient Suzuki-vinylation process was finally set up starting from triflates 447 and 448 using a vinyltrifluoroborate. Product 452 was eventually obtained in five steps and 26% overall yield starting from the compound 355 (Scheme 215).

We have also described an approach toward the piperidinone structure using a carbo-oximation radical reaction developed in the laboratory. A one-pot reduction of the oxime followed by a lactamization under high pressure of hydrogen in the presence of Raney/nickel produced the

EXPERIMENTAL PART CHAPTER ΙІI

Compounds 251 144 , 301 158 have been prepared following published procedure.

N'-(Methylsulfonyl)methanesulfonohydrazide (247).

To a solution of hydrazine hydrate 246 (1.28 g, 20 mmol, 1 eq.) in pyridine, methanesulfonyl chloride 245 (4.582 g, 40 mmol, 2 eq.) was added dropwise at 0 o C. The reaction mixture was stirred 1h at room temperature then poured into ice / HCl (1:1) (50 mL), then extracted three times with ethyl acetate. The organic layer was washed with brine, dried over MgSO 4 and the solvents evaporated under vacuum. The desired compound 247 was obtained as a white solid (1.00 g, 26.63 mmol, 27%) after recrystallization from ethanol. M.p = 170-171 o C IR (solid, KBr): ν max (cm -1 ) = 3249, 1318, 1150, 965, 778, 666.

N'-(Methylsulfonyl)benzenesulfonohydrazide (250).

To a solution of hydrazine hydrate 246 (1.92 g, 60 mmol, 3 eq.) in benzene, phenyl sulfonyl chloride 248 (3.53 g, 20 mmol, 1 eq.) was added dropwise at 0 o C. The reaction mixture was stirred for 12h at room temperature, then filtered to give a white solid 249, which was dried under vacuum. The solid was dissolved in pyridine and cooled to 0 o C, then methanesulfonyl chloride 245 (3.207 g, 28 mmol, 1.4 eq.) was added dropwise. The reaction mixture was stirred for 9h at RT then poured into ice / HCl (1:1) (50 mL), then extracted three times with ethyl acetate. The organic layer was washed with brine, dried over MgSO 4 and the solvent evaporated under vacuum. The desired compound 250 was obtained with as a white solid (1.2 g, 4.794 mmol, 24% overall yield) after recrystallization from ethanol. M.p = 194-195 o C IR (solid, KBr): ν max (cm -1 ) 3235, 1339, 1316, 1177, 1151, 1141, 754, 730, 684.

General Procedure for Carbo-alkenylation (A).

To a solution of xanthate 155 (0.5 mmol, 1 eq.) in dry degassed benzene (2.5 mL) were added olefin (2 mmol, 4 eq.), bissulfone 169 (1.2 eq.), di(tributyltin) (253 μL, 0.5 mmol, 1eq.) and 251 (0.026 mmol, 5 mol %). The reaction mixture was irradiated using a tungsten lamp (3000W) during 2.33-2.09 (m, 3H, H4 and H6), 1.93-1.55 (m, 2H, H5), 1.52-1.02 (m, 10H, H9, H10, H11, H12, H13 and H14), 0.82 (t, 3H, J = 6.4 Hz, H1).

(E)-Ethyl 4-(tert-butoxy)-6-(phenylsulfonyl)hex-5-enoate (260).

Synthesized according to the general procedure (A) above, xanthate 155 (104 mg, 0.5 mmol, 1 eq.), tert-butylvinylether 213 (0.262 ml, 2 mmol, 4 eq.), bissulfone 169 (185 mg, 0.6 mmol, 1.2 eq.) and 251 (8 mg, 0.026 mmol, 5 mol %). The crude reaction mixture was purified by silica gel chromatography (petroleum ether/ ethyl acetate 80:20) to provide 260 (129 mg, 0.354 mmol, 71%) as a colorless oil. NMR spectral data were identical to those previously reported. 110 R f = 0.4 (petroleum ether/ ethyl acetate 80/20). 1 H NMR (CDCl 3 , 300 MHz): δ (ppm) = 7.89-7.81 (m, 2H, CH ar ), 6.97 (dd, 1H, J = 15 and 4.5 Hz, H7), 6.52 (dd, 1H, J = 15 and 1.5 Hz, H8), 4.30-4.20 (m, 1H, H6), 4.10 (q, 2H, J = 7.2 Hz, H2), 2.45-2.21 (m, 2H, H4), 1.94-1.63 (m, 2H, H5), 1.23 (t, 3H, J = 7.2 Hz, H1), 1.09 (s, 9H, H10, H11 and H12).

(E)-Ethyl 7-chloro-4-(2-(phenylsulfonyl)vinyl)heptanoate (261).

Synthesized according to the general procedure (A) above, xanthate 155 (104 mg, 0.5 mmol, 1 eq.), chloropentene 224 (0.416 g, 2 mmol, 4 eq.), bissulfone 169 (185 mg, 0.6 mmol, 1.2 eq.) and 251 (8 mg, 0.026 mmol, 5 mol %). The crude reaction mixture was purified by silica gel chromatography (petroleum ether/ ethyl acetate 70:30) then (toluene / ethyl acetate 90:10) to provide 261 (115 mg, 0.320 mmol, 64%) as a colorless oil. NMR spectral data were identical to those previously reported. 110 R f = 0.3 (toluene / ethyl acetate 95/5). 1 H NMR (C 6 D 6 , 300 MHz): δ (ppm) = 7.94-7.80 (m, 2H, CH ar ), 7.02-6.92 (m, 3H, CH ar ), 6.64 (dd, 1H, J = 15.1 and 9.5 Hz, H7), 6.01 (dd, 1H, J = 15.1 and 0.7 Hz, H8), 3.93 (q, 2H, J = 7.1 Hz, H2), 2.89 (dt, 2H, J = 6.2 and 2 Hz, H11), 1.97-1.79 (m, 2H, H4), 1.74-1.58 (m, 1H, H5a), 1.52-1.35 (m, 1H, H5b), 1.30-0.77 (m, 5H, H6, H9 and H10), 0.96 (t, 3H, J = 7.1 Hz, H1).

(E)-tert-Butyl-3-(2-ethoxy-2-oxoethyl)-2-(2-(phenylsulfonyl)vinyl)piperidine-1-carboxylate (179).

Synthesized according to the general procedure (A) above, xanthate 155 (104 mg, 0.5 mmol, 1 eq.), dihydropyridine 178 (0.37 ml, 2 mmol, 4 eq.), bissulfone 169 (185 mg, 0.6 mmol, 1.2 eq.) and 253 (8 mg, 0.026 mmol, 5 mol %).

1-Benzyl-1,2,3,4-tetrahydrobenzo[b][1,8]naphthyridin-5-amine (394).

To a solution of n-BuLi (3.25 mL, 34.55 mmol, 2.5 eq.) in dry THF (50 mL), was added diisopropyl amine (5.13 mL, 36.63 mmol, 2.65 eq.) with stirring at -78 o C for 30 min. A solution of amidine 391 (4 g, 13.82 mmol, 1 eq.) in THF (20 mL) was added and the stirring was continued at -70 o C for 2.5 h. During this time the color of the solution went from red to yellow orange. The reaction mixture was quenched with NH 4 Cl, then the solvent was concentrated under reduced pressure. The mixture was extracted with DCM and the organic layer washed with brine and dried over MgSO 4 . The solvent was evaporated in vacuum to give a red oil, which was then purified by chromatography on silica gel (DCM/MeOH/NH 4 Cl 95:4:1). The desired compound 394 was obtained as red solid (3.

8-Methoxy-1-methyl-1,2,3,4-tetrahydrobenzo[b][1,8]naphthyridin-5-amine (395).

To a solution of BuLi (2.6 ml, 5.15 mmol, 2.5 eq.) in dry THF (40 ml), diisopropyl amine (0.76 ml, 5.46 mmol, 2.65 eq.) was added with stirring at -78 o C for 30 min.A solution of methoxy imidine benzonitrile 392 (500 mg, 2.06 mmol, 1 eq.) in 2 ml of THF was then added and stirred at -70 o C for 2.5h. During this time the color of the solution went from red to yellow orange. The mixture was extracted with DCM and the organic layer washed with brine and dried over MgSO 4 . The solvent was evaporated in vacuum to give a red oil which was then purified by chromatography on silica gel (DCM/MeOH/NH 4 Cl 95:4:1). The desired compound 395 was obtained as red solid (390 mg, 1.60 mmol, 78%). To a solution of bicyclic piperidinone 355 (500 mg, 3.592 mmol, 1 eq.) in dry THF/DCM (1/1, 10 mL), POCl 3 (1.64 mL, 17.96 mmol, 5 eq.) was added. The mixture was heating under reflux at 60 o C for 3h then cooled down to room temperature. A solution of ester aniline 418 (0.488 mL, 3.77 mmol, 1.05 eq.) in DCM was added dropwise.

The reaction was heated at 60 o C for 12h. Ice-cold water was added followed by a 30% NaOH solution to alkaline pH. The extraction was done with DCM, brine, drying over MgSO 4 , the organic solvents were concentrated under vacuum and the crude material purified by chromatography on silica gel (DCM/ethyl acetate 85:15). The desired compound 420 was obtained as colorless oil (567 mg, 2.082 mmol, 58%). R f = 0.4 (DCM/ ethyl acetate 88:12). IR (ATR) ν max (cm -1 ) = 2932, 1722, 1633, 1594, 1241, 1077, 1019, 723. 1 H NMR (CDCl 3 , 300 MHz): δ (ppm) = 7.81 (dd, 1H, J = 1.6 and 7.8 Hz, CH ar ), 7.37 (td, 1H, J = 1.6 and 7.6 Hz, CH ar ), 7.10-6.91 (m, 1H, CH ar ), 6.82-6.61 (m, 1H, CH ar ), 4.38-4.02 (m, 1H, H6a), 3.83 (s, 3H, CH methoxy), 3.46-2.79 (m, 3H, H6b and H5), 2.50-1.02 (m, 9H, H2, H3, H4, H7 and H8).

(E)-Methyl 2-(1-azabicyclo[3.3.1]nonan-2-ylideneamino)-4-methoxybenzoate (436).

To a solution of piperidinone 355 (50 mg, 0.359 mmol, 1 eq.) in dry DCM (1 mL), POCl 3 (32 µmL, 0.359 mmol, 1 eq.) was added. The mixture was refluxed at 60 o C for 3h then cooled down to room temperature. A solution of aniline 417 (98 mg, 0.539 mmol, 1.5 eq.) in DCM was added dropwise. The reaction mixture was heated at 60 o C for 12h. Ice-cold water was added followed by a 30% NaOH solution to alkaline pH. The extraction was done with DCM, brine, drying over MgSO 4 , the solvents were removed and the crude material purified by chromatography on silica gel (DCM/ethyl acetate 75:25). Compound 436 was obtained as colorless oil (26 mg, 0.106 mmol, 24%). R f = 0.25 (DCM/ ethyl acetate 80:20). IR (ATR) ν max (cm -1 ) = 2925, 1717, 1644, 1597, 1252, 1078, 1034, 800, 735. 1 H NMR (CDCl 3 , 300 MHz): δ (ppm) = 7.83 (d, 1H, J = 8.7 Hz, CH ar ), 6.54 (dd, 1H, J = 2.7 and 9

Hz, CH ar ), 6.30-6.15 (m, 1H, CH ar ), 4.33-4.09 (m, 1H, H6a), 3.80 (s, 3H, CH methoxy), 3.78 (s, 3H, CH methoxy), 3.39-3.23 (m, 1H, H6b), 3.15-2.84 (m, 2H, H5), 2.49-1.12 (m, 9H, H2, H3, H4, H7 and H8). R f = 0.3 (petroleum ether/ethyl acetate 96:4). IR (ATR) ν max (cm -1 ) = 2982, 1732, 1156, 1041. 1 H NMR (CDCl 3 , 300 MHz): δ (ppm) = 4.67 (br, 2H, H12), 4.03 (qd, 4H, J = 2.6 and 5 Hz, H2 and H10), 2.45-2.13 (m, 8H, H4, H5, H7 and H8), 1.15 (td, 6H, J = 2.6 and 7.2 Hz, H1 and H11). To a solution of xanthate 155 (104 mg, 0.500 mmol, 1 eq.) in dry degassed benzene (2.5 mL), diester olefin 403 (456 mg, 2 mmol, 4 eq.), oxime 122 (275 mg, 1 mmol, 2 eq.), di(tributyl)tin (0.375 ml, 0.750 mmol, 1.5 eq.) and 20 mol% of DTBHN (17 mg) were added. The reaction mixture was stirred for 1.5h at 65 o C. The reaction progress was monitored by TLC and further addition of DTBHN (20 mol%) was carried out (up to 3 more times) depending on the quantity of xanthate remaining. The yellow reaction mixture was concentrated under reduced pressure and the crude material purified by chromatography on silica gel (petroleum ether/ethyl acetate 88:12). The desired compound 454 was obtained as colorless oil (177 mg, 0.394 mmol, 79%). R f = 0.4 (petroleum ether/ethyl acetate 85:15). IR (ATR) ν max (cm -1 ) = 2981, 1725, 1179, 1023, 699. 1 H NMR (CDCl 3 , 300 MHz): δ (ppm) = 7.42-7.22 (m, 5H, CH ar ), 7.17 (s, 1H, H17), 5.06 (s, 2H, H18), 4.12 (qd, 6H, J = 1.2 and 7.2 Hz, H2, H10 and H15), 2.22 (appearant t, 6H, J = 7.8 and 8.7 Hz, H4, H8, and H13), 1.76 (appearant t, 6H, J = 8.7 and 7.8 Hz, H5, H7 and H12), 1.26 (td, 9H, J = 1.2 and 7.2 Hz, H1, H11 and H16). 13 C NMR (CDCl 3 , 75.5 MHz): δ (ppm) = 173.2 (3C=O ester), 154.4 (C17), 137.5 (C ar ), 128.5 (C ar ), 128.4 (C ar ), 127.9 (C ar ), 75.9 (C18), 60.5 (C2, C10 and C15), 41.3 (C6), 29.5 (C5, C7 and C12), 28.6 (C4, C8 and C13), 14.2 (C1, C11 and C16). HRMS (ESI): [M+Na] + C 24 H 35 NO 7 Na : calcd. 472.23112, found 472.2311.

Diethyl 3,3'-(6-oxopiperidine-3,3-diyl)dipropanoate (457).

To a solution of 454 (200 mg, 0.445 mmol, 1 eq.) in EtOAc (10 mL), nickel Raney catalyst (slurry in water) was added. The reaction mixture was subjected to high pressure of hydrogen (50 atm) with stirring for 3 days at room temperature. The reaction mixture was filtered through a short pad of celite and the solvent was concentrated under reduced pressure to give the crude product which was purified by chromatography on silica gel (DCM/MeOH 95:5). The desired compound 457 was obtained as a white solid (97.2 mg, 0.325 mmol, 73%). Mp = 240-241 o C. R f = 0.5 (DCM/MeOH 95:5). IR (ATR) ν max (cm -1 ) = 2980, 2936, 1729, 1662, 1182, 1027. 1 H NMR (CDCl 3 , 300 MHz): δ (ppm) = 6.74 (br, 1H, NH), 4.09 (appearant q, 4H, J = 6.9 and 7. 2Hz, H9 and H14), 3.02 (s, 2H, H5), 3.32 (appearant t, 2H, J = 6.9 and 7.2 Hz, H2), 2.23 (appearant t, 4H, J = 9.6 and 7.5 Hz, H7 and H12), 1.8-1.53 (m, 6H, H3, H6 and H11), 1.23 (appearant t, 6H, J = 7.2 and 6.9 Hz, H10 and H15). 13 C NMR (CDCl 3 , 75.5 MHz): δ (ppm) = 173.2 (CO ester), 172.2 (C1), 60.8 (C9 and C14), 50.6 (C5), 33.5 (C3), 29.9 (C4), 29.0 (C7 and C12), 28.5 (C6 and C11), 27.7 (C2), 14.3 (C10 and C15). HRMS (ESI): [M+Na] + C 15 H 25 NO 5 Na : calcd. 322.16304, found 322.1631.

(E)-Diethyl 4-(3-ethoxy-3-oxopropyl)-4-((hydroxyimino)methyl)heptanedioate (463).

A suspension of oxide triester 454 (200 mg, 0.461 mmol, 1 eq.) and palladium on activated carbon Pd/C (10%) (300 mg, 2.9 mmol, 6.3 eq.) in EtOAc (15 mL) were stirred under high pressure of hydrogen (25 atm) for 24h at room temperature. The reaction mixture was filtered through a short pad of celite and the solvent evaporated under vacuum to give the desired product 463 as a colorless oil (113 mg, 0.314 mmol, 68%), pure enough to be used without purification.

IR (ATR) ν max (cm -1 ) = 2987, 1729, 1179, 1038, 1027.

1 H NMR (CDCl 3 , 200 MHz): δ (ppm) = 7. 14 (s, H17), 4.08 (appearant q, 6H, J = 7.2 and 7 Hz, H2, H10 and H15), 2.40-2.09 (m, 6H, H4, H8 and H13), 1.85-1.43 (m, 6H, H7 and H12), 1.21 (appearant t, 9H, J = 7 and 7.2 Hz, H1, H11 and H16).

3-(3-(3-Ethoxy-3-oxopropyl)-6-oxopiperidin-3-yl)propanoic acid (464).

NaOH (14 mg, 0.356 mmol, 1.2 eq.) in EtOH (2 ml) was added to the diester piperidone compound 457 (89 mg, 0.297 mmol, 1 eq.).

The resultant mixture was stirred at reflux temperature for 24h. The reaction mixture was cooled down to room temperature, the solid was filtered and washed with cold water, pH adjusted to 5-6 with 3N HCl. After an extraction with Et 2 O, the organic phase was washed with saturated NaCl solution and dried over MgSO 4 . The solvent was concentrated under reduced pressure and the crude product purified by chromatography on silica gel (DCM/MeOH 95:5). The desired compound 464 was obtained as white solid (18.5 mg, 0.068 mmol, 23%). Mp = 125-126 o C. R f = 0.35 (DCM/MeOH 95:5). IR (ATR) ν max (cm -1 ) = 2955, 1729, 1638, 1275, 750. 1 H NMR (CDCl 3 , 300 MHz): δ (ppm) = 7.62 (br, 1H, NH), 4.12 (q, 2H, J = 7.2 Hz, H12), 3.05 (s, 2H, H5), 2.45-2.17 (m, 6H, H2, H7 and H10), 1.87-1.56 (m, 6H, H3, H6 and H9), 1.26 (t, 3H, J = 7.2 Hz, H13). 13 C NMR (CDCl 3 , 50.2 MHz): δ (ppm) = 177.6 (C8), 173.9 (C1), 173.2 (C11), 60.9 (C12), 50.4 (C5), 33.5 (C2), 29.7 (C7), 29.6 (C10), 28.5 (C6 and C9), 28.3 (C3), 27.4 (C4), 14.3 (C13). HRMS (ESI): [M+Na] + C 13 H 21 NO 5 Na : calcd. 294.13174, found 294.1318.

Diethyl 3,3'-(piperidine-3,3-diyl)dipropanoate (465).

To a solution of the diester piperidinone compound 457 (100 mg, 0.30 mmol, 1 eq.) in dry THF (5 mL), then add solution of Me 2 S:BH 3 (0.103 mL, 1.2 mmol, 4 eq.) in THF. The resultant mixture was stirred at room temperature then warmed to 50 o C for 12h and the reaction mixture was quenched with NH 4 Cl saturated solution and extracted with ethyl acetate. The aqueous layer was neutralized with 1N NaOH and extracted with 30% of isopropanol/CHCl 3 . The organic phase was washed with saturated NaCl solution and dried over MgSO 4 . The solvents were concentrated under reduced pressure and the crude product purified by chromatography on silica gel (DCM/MeOH 90:10). The desired compound 465 was obtained as colorless oil (14.6 mg, 0.051 mmol, 17%). R f = 0.5 (DCM/MeOH 94:6). IR (ATR) ν max (cm -1 ) = 2930 (br.), 1727, 1183, 1024. 1 H NMR (CDCl 3 , 300 MHz): δ (ppm) = 4.09 (qd, 4H, J = 0.9 and 7.2 Hz, H9 and H14), 2.74 (br, 2H, H1), 2.51 (s, 2H, H5), 2.19 (appearant t, 4H, J = 8.1 and 8.4 Hz, H7 and H12), 1.75-1.43 (m, 6H, H3, H6 and H11), 1.41-1.30 (m, 2H, H2), 1.22 (td, 6H, J = 0.9 and 7.2 Hz, H10 and H15).

(E)-Diethyl 3,3'-(6-((2-cyanophenyl)imino)piperidine-3,3-diyl)dipropanoate (468).

To a piperidinone 457 (100 mg, 0.334 mmol, 1 eq.) in dry DCM (5 mL), was added POCl 3 (30 µmL, 0.334 mmol, 1 eq.). The mixture was heated under reflux for 3h then cooled down to RT. A solution of the cyanoaniline 429 (59 mg, 0.501 mmol, 1.5 eq.) in DCM (1mL) was added dropwise to the reaction. The reaction mixture was heated at 60 o C for 12h. Ice-cold water was added followed by a 30% NaOH solution.

The organic solvents were removed then the extraction was done with DCM, brine, drying over MgSO 4 . The solvent was concentrated under reduced pressure and the crude purified by chromatography on silica gel (DCM/MeOH 96:4). The compound 468 was obtained as an orange solid (77.4 mg, 0.194 mmol, 58%). Mp = 88-90 o C. R f = 0.3 (DCM/MeOH 96:4). IR (ATR) ν max (cm -1 ) = 3334, 2981, 1725, 1621, 1605, 1578, 1183, 771. 1 H NMR (CDCl 3 , 300 MHz): δ (ppm) = 7.77 (d, 1H, J = 8.1 Hz, CH ar ), 7.65-7.47 (m, 2H, CH ar ), 7.40-7.26 (m, 1H, CH ar ), 4.26 (q, 4H, J = 7.2 Hz, H9 and H14), 3.92 (s, 2H, H5), 2.85 (t, 2H, J = 6.9 Hz, H2), 2.45-2.22 (m, 4H, H7 and H12), 1.72 (appearant t, 6H, J = 10.5 Hz, H3, H6 and H11), 1.22 (appearant t, 6H, J = 7.2 and 6.9 Hz, H10 and H15). To a solution of xanthic salt 473 (893 mg, 4.172 mmol, 1 eq.) in acetone (10 mL), benzyl bromo acetate 472 (1 g, 4.381 mmol, 1.05 eq.) was added at 0 o C. The reaction mixture was stirred 4h at room temperature. Solvent was removed under vacuum to give the crude product which was purified by silica gel chromatography (petroleum ether/ethyl acetate 95:5) to give the desired product 474 (1.13 g, 0.271 mmol, 100%) as colorless oil. R f = 0.3 (petroleum ether/ethyl acetate 97:3). IR (ATR) ν max (cm -1 ) = 2962, 1741, 1258, 1047, 1019, 795. 1 H NMR (CDCl 3 , 300 MHz): δ (ppm) = 7.50-7.28 (m, 5H, CH ar ), 5.20 (s, 2H, 6H), 4.60 (q, 2H, J = 7.2 Hz, H2), 3.96 (s, 2H, H4), 1.37 (t, 3H, J = 7.2 Hz, H1). To a solution of xanthate 474 (100 mg, 0.437 mmol, 1 eq.) in dry degassed benzene (2.5 mL), diester olefin 453 (400 mg, 1.75 mmol, 4 eq.), oxime 122 (240 mg, 0.873 mmol, 2 eq.), di(tributyl)tin (0.33 ml, 0.655 mmol, 1.5 eq.) and 20 mol% of DTBHN (15 mg) were added. The reaction mixture was stirred for 1.5h at 65 o C. The reaction progress was monitored by TLC and further addition of DTBHN (20 mol%) was carried out (up to 3 more times) depending on the quantity of 474 remaining.

The reaction mixture was concentrated under reduced pressure and purified by chromatography on silica gel (petroleum ether/ethyl acetate 88:12 to 85:15) to provide two products, 475 (96.1 mg, 0.878 mmol, 41%) as colorless oil and 476. R f = 0.3 (petroleum ether/ ethyl acetate 90:10). IR (ATR) ν max (cm -1 ) = 2962, 1732, 1258, 1018, 793, 698. 1 H NMR (CDCl 3 , 300 MHz): δ (ppm) = 7.51-7.26 (m, 10H, CH ar ), 7.20 (s, 1H, H16), 5.14 (s, 2H, H17), 5.08 (s, 2H, H10), 4.14 (q, 4H, J = 7.2 Hz, H2 and H14), 2.41-2.17 (m, 6H, H3, H8 and H12), 1.92-1.68 (m, 6H, H5, H7 and H11), 1.28 (appearant t, 6H, J = 6.9 and 7.2 Hz, H1 and H15). The reaction progress was monitored by TLC and further addition of DTBHN (20 mol%) was carried out (up to 3 more times) depending on the quantity of 477 remaining. The reaction mixture was concentrated under reduced pressure and purified by chromatography on silica gel (petroleum ether/ethyl acetate 80:20 to 75:25) to provide two products 478 (242 mg, 0.468 mmol, 55%) as colorless oil and 507 (88.1 mg, 0.17 mmol, 20%) as colorless oil. R f = 0.3 (petroleum ether/ethyl acetate 78:22). IR (ATR) ν max (cm -1 ) = 2980, 1731, 1447, 1306, 1186, 1149, 746. 1 H NMR (CDCl 3 , 300 MHz): δ (ppm) = 7.89 (d, 2H, J = 7.5 Hz, CH ar ), 7.78-7.55 (m, 3H, CH ar ), 7.45-7.25 (m, 5H, CH ar ), 7.11 (s, 1H, H14), 5.02 (s, 2H, H15), 4.13 (appearant q, 4H, J = 7.2 and 6.9 Hz, H2 and H10), 3.09-2.97 (m, 2H, H13), 2.17 (appearant t, 4H, J = 7.5 and 9 Hz, H4 and H8), 1.92-1.81 (m, 2H, H12), 1.73 (appearant t, 4H, J = 8.7 and 7.8 Hz, H5 and H7), 1.28 (t, 6H, J = 7.2 Hz, H1 and H11). Product 507 (88.1 mg, 0.17 mmol, 20%) was isolated from the previous reaction as a colorless oil. R f = 0.2 (petroleum ether/ethyl acetate 78:22). IR (ATR) ν max (cm -1 ) = 2982, 1726, 1447, 1306, 1180, 1147, 1086, 733, 689.

1 H NMR (CDCl 3 , 300 MHz): δ (ppm) = 7.97-7.77 (m, 2H, CH ar ), 7.68-7.44 (m, 3H, CH ar ), 4.02 (q, 4H, J = 7.5 Hz, H2 and H10), 3.11-2.97 (m, 2H, H13), 2.18 (t, 4H, J = 7.5 and 7.8 Hz, H4 and H8), 1.71-1.57 (m, 2H, H12), 1.55-1.35 (m, 5H, H5, H6 and H7), 1.17 (t, 6H J = 6.9 and 7.2 Hz, H1 and H11). the quantity of xanthate remaining. The yellow reaction mixture was concentrated under reduced pressure and purified by chromatography on silica gel (petroleum ether/ethyl acetate 95:5). The desired compound 498 was obtained as colorless oil (81.2 mg, 0.215 mmol, 43%). R f = 0.5 (petroleum ether/ethyl acetate 90:10). IR (ATR) ν max (cm -1 ) = 2965, 1733, 1260, 1182, 1027, 800. 1 H NMR (CDCl 3 , 300 MHz): δ (ppm) = 7.45-7.29 (m, 5H, CH ar ), 7.21 (s, 1H, H14), 5.09 (s, 2H, H15), 4.15 (appearant q, 4H, J = 6.9 and 7.2 Hz, H2 and H10), 2.29-2.17 (m, 4H, H2, H4 and H8), 1.86-1.74 (m, 4H, H5 and H7), 2.22 (q, 2H, J = 7.5 Hz, H12), 1.29 (appearant t, 6H, J = 6.9 and 7.2 Hz, H1 and H11), 0.84 (appearant t, 3H, J = 7.2 and 7.8 Hz, H13). 13 C NMR (CDCl 3 , 75.5 MHz): δ (ppm) = 173.6 (2C=O ester), 155.5 (C14), 137.8 (C ar ), 128.5 (C ar ), 128.4 (C ar ), 127.9 (C ar ), 75.9 (C15), 60.6 (C2 and C10), 41.9 (C6), 29.4 (C4 and C8), 28.9 (C5 and C7), 27.3 (C12), 14.3 (C1 and C11), 7.7 (C13). HRMS (ESI): [M+Na] + C 21 H 31 NO 5 Na : calcd. 400.2094, found 400.2104.

Ethyl 3-(3-ethyl-6-oxopiperidin-3-yl)propanoate (499).

To a solution of 498 (200 mg, 0.960 mmol, 1 eq.) in EtOAc (10 mL), nickel Raney catalyst (slurry in water) was added. The reaction mixture was subjected to high pressure of hydrogen (50 atm) with stirring for 3 days at room temperature. The reaction mixture was filtered through a short pad of celite and the solvent was concentrated under reduced pressure to give the crude product which was purified by chromatography on silica gel (DCM/MeOH 95:5). The desired compound 499 was obtained as a white solid (157 mg, 0.691 mmol, 72%). Mp = 62-64 o C. R f = 0.4 (DCM/ MeOH 95:5). IR (ATR) ν max (cm -1 ) = 3219, 2939, 1731, 1661, 1308, 1185. 1 H NMR (CDCl 3 , 300 MHz): δ (ppm) = 7.12 (br, 1H, NH), 4.06 (appearant q, 2H, J = 10.5 and 10.8 Hz, H9), 2.96 (d, 2H, J = 0.2 Hz, H5), 2.36-2.07 (m, 4H, H2 and H7), 1.76-1.48 (m, 4H, H3 and H6), 1.44-1.26 (m, 2H, H11), 1.19 (t, 3H, J = 7.2 Hz, H10), 0.78 (t, 3H, J = 7.2 Hz, H12). 13 C NMR (CDCl 3 , 75.5 MHz): δ (ppm) = 173.4 (C1), 172.6 (C8), 60.6 (C9), 50.6 (C5), 33.6 (C4), 29.6 (C2 or C7), 28.8 (C2 or C7), 28.6 (C3 or C6), 27.7 (C3 or C6), 26.5 (C11), 14.2 (C10), 7.4 (C12). HRMS (ESI): [M+Na] + C 12 H 21 NO 3 Na : calcd. 250.1413, found 250.1420.