Since its discovery in 1979, the Suzuki-Miyaura (SM) reaction has become one of the most widely utilised tools for carbon-carbon bond formation. The palladium catalysed coupling of an organoboron and organohalide compounds proceeds through a three-stage mechanism of oxidative addition, transmetalation and reductive elimination. The transmetalation of boronic acids to a palladium(II) complex has been widely studied. However, very little is known about the transmetalation of boronic esters, which are commonly used as an alternative to unstable boronic acids. Whether these species undergo direct transmetalation or prior hydrolysis to the boronic acid under SM conditions remains unknown. This research aimed to elucidate the mechanism of this cross-coupling process. Initial results under typical SM conditions created a biphasic reaction, promoted by the inorganic base and solvent composition, and showed that the boronic esters and corresponding boronic acid couple at the same absolute rate. This is thought to be a consequence of the formation of a biphasic mixture, rendering phase transfer the turnover-limiting step. The conditions were thus adapted to maintain a monophasic system using an organic soluble base, 2-tert-butyl-1,1,3,3-tetramethylguanidine, enabling the focus to be transmetalation as the turnover-limiting step. These new conditions show a significant difference in both reaction rate and induction period when using a boronic ester compared to the corresponding boronic acid. The use of guanidine was also shown to have an interesting effect on the boronic acid/ester species by 19F and 11B NMR. Further studies found the use of guanidine to create a boronate species, with this species being an aryl trihydroxyboronate or the hydroxyl"ate"-complex of the boronic ester, depending on the presence of diol in the system. Formation of a boronate species was found to be crucial for efficient cross-coupling. When testing weaker bases, unable to form a boronate species, poor SM cross-coupling conversion was found using the newly developed phosphine-free guanidine conditions, showing the importance of the boronate species under these conditions. The results suggest that depending on the strength of base used, the pathway of transmetalation pathway can be switched, between the boronate pathway and the oxo-palladium pathway, under the specific conditions developed.

Pseudomonas Aeruginosa est un pathogène opportuniste qui adapte son comportement aux molécules présentes dans son milieu. Il augmente en virulence lorsqu’il détecte des peptides natriurétiques dans son environnement. L’isatine est une molécule qui bloque cet effet. Pour mieux comprendre sur quel récepteur l’isatine agit, la conception d’un biocapteur a été menée. Un biocapteur est un outil alliant un bioélément, réagissant spécifiquement avec une cible biologique, et un support physique permettant la transduction du signal pour le rendre mesurable. Les travaux de thèse suivants décrivent la préparation d’un transducteur polymérique, le copolymère d’oléfines cycliques (COC), par greffage de sels de diazonium en surface. La modification de l’isatine par couplage pallado-catalysé compose la partie principale des travaux de synthèse organique effectués. Les méthodes de couplages peptidiques en surface et techniques d’accroche des isatines modifiées sur les surfaces des transducteurs (or ou COC) sont également décrites dans ce manuscrit. Pour finir, l’évaluation des effets biologiques des isatines modifiées et des biocapteurs conçus a été effectuée sur Pseudomonas Aeruginosa et sur d’autres bactéries. / Pseudomonas Aeruginosa is an opportunistic pathogen which can adapt its behavior to the present molecules in its surrounding. It increases in virulence when it detects natriuretics peptides in its environment. Isatin is a molecule which can block this effect. To determine on which receptor isatin acts on, the conception of a biosensor have been conducted. A biosensor is a tool combining a bioelement, reacting specifically with a biological target, and a physical support allowing the transduction of the signal to make it measurable. The following thesis describes the preparation of a polymeric transducer, the cyclic olefin copolymer (COC), by diazonium salts surface grafting. Isatin modification by palladium-catalysed coupling reaction represents the major part of the organic synthesis carried out. Surface peptide coupling methods and techniques to link the modified isatins to the surfaces of transducers (gold or COC) are also described in this dissertation. To finish, biological effects of the modified isatins and designed biosensors have been evaluated on Pseudomonas Aeruginosa and others bacteria.

Chapter 1: Metal carbenoids in organic synthesis The chapter describes the phenomena of metal carbenoid insertion reactions in two parts: Part A, and Part B. The study of N-tosylhydrazones as diazo precursor was commenced by Jose Barluenga in 2007,1 which demonstrated an in-situ generation of diazo species and trapping of that with low valent palladium catalyst (Scheme 1). Later, this palladium-carbenoid assumption was supported by few reports. Some of these discoveries were by D. F. Taber in 1986 followed by van Vranken in 1999 & 2001.2 These studies of palladium carbenes were supplemented by several groups in subsequent years. The consequent developments with N-tosylhydrazones as diazo source were very fruitful and produced exceptional chemical transformations in recent years. Though the precursor is also vastly customary for other metals such as Cu, Ni, Rh and Co, the primary focus has been given to Pd catalysis due to its wide utility and applicability. 1) Barluenga, J.; Moriel, P.; Valdes, C.; Aznar, F. Angew. Chem., Int. Ed. 2007, 46, 5587. 2) (a) Taber, D. F.; Amedio, J. C., Jr.; Sherrill, R. G. J. Org. Chem. 1986, 51, 3382. (b) Hoye, T. R.; Dinsmore, C. J.; Johnson, D. S.; Korkowski, P. F. J. Org. Chem. 1990, 55, 4518. (c) Greenman, K. L.; Carter, D. S.; Van Vranken, D. L Tetrahedron 2001, 57, 5219. 3) Palladium catalysed coupling of tosylhydrazones with aryl and heteroaryl halides in the absence of external ligands: synthesis of substituted olefins, Ojha, D. P.; Prabhu, K. R. J. Org. Chem., 2013, 78, 12136. Modes of reactivity of a metal-carbene Scheme 1 Cascade carbene migratory insertion process Part A: Ligand-free coupling of tosylhydrazones with aryl & heteroaryl halides In this part, Palladium catalysed cross-coupling reaction of hydrazones with aryl halides in absence of an external ligand is reported. The versatility of this coupling reaction has been demonstrated by showcasing the selectivity of coupling reaction in presence of hydroxyl and amine functional groups. This method allows synthesizing a variety of heterocyclic compounds, which are otherwise difficult to access from traditional methods. Application of the present methodology is validated in tandem reaction of ketones to the corresponding substituted olefins in a single pot experiment. Few examples are illustrated below in Scheme 2.3 Scheme 2: Scope of aryl halide coupling with tosylhydrazones Part B: Pd-catalysed Synthesis of Highly Branched Dienes The regioselective formation of highly branched dienes is a challenging task. Design and exploration of alternative working models to achieve such a regioselectivity to accomplish highly branched dienes is considered to be a historical advancement of Heck reaction to construct branched dienes. On the basis of the utility of carbene transfer reactions, in the reaction of hydrazones with Pd(II) under oxidative conditions, we envisioned obtaining a Pd-bis-carbene complex with α-hydrogens, which can lead to branched dienes. Herein, we report a novel Pd catalyzed selective coupling reaction of hydrazones in presence of tert-BuOLi and benzoquinone oxidant to form corresponding branched dienes (Scheme 3).4 The utility of the Pd catalyst for cross-coupling reactions for synthesizing branched conjugated dienes are rare. The reaction is very versatile and compatible with a variety of functional groups and is useful in synthesizing heterocyclic molecules. We anticipate that this Pd-catalyzed cross-coupling reaction will open new avenues for synthesizing useful compounds. 4) Pd-catalyzed cross-coupling reactions of hydrazones: regioselective synthesis of highly branched dienes, Ojha, D. P.; Prabhu, K. R. J. Org. Chem., 2012, 77, 11027. 5) Furrow, M. E.; Myers, A. G. J. Am. Chem. Soc. 2004, 126, 5436. 6) Taber, D. F.; Guo, P.; Guo, N. J. Am. Chem. Soc. 2010, 132, 11179. Scheme 3: diene synthesis via bis-carbene insertion process Chapter 2: Tosylhydrazones: Role in modern day organic synthesis In recent days, hydrazone based reactions are focused on the donor-acceptor ability of the hydrazones or the in-situ generated diazo species (Scheme 4). This commenced with the Myers’s report in 2004,5 which simplifies the Barton vinyl halide preparation with a remarkable revision on synthesis of alkyl-silyl-hydrazones and its applications. Improved methods of using tosylhydrazones were demonstrated by Aggarwal in successive years. Cycloadditions were implemented by Douglass F. Taber. 6 This study was enriched in a quite fascinating way by several groups such as Jose Barluenga, with many reductive coupling reactions and 1, 3-dipolar reactions. Thomson, in a very interesting report shows the traceless petasis reaction with hydrazones and also worked in many other prospects such as three component reactions and the acid catalysed [3+3] sigmatropic reactions of hydrazones. 7 Wang has also impressed with very attractive transformations in the past decade. 8 7) Thomson, R. J. et al. Nat. Chem. 2009, 1, 494. 8) Xiao, Q.; Zhang, Y.; Wang, J. Acc. Chem. Res. 2012, 46, 236. 9) Regioselective Synthesis of vinyl halides, vinyl sulfones, and alkynes: A tandem intermolecular nucleophilic and electrophilic vinylation of tosylhydrazones, Ojha, D. P.; Prabhu, K. R. Org. Lett. 2015, 17, 18. Scheme 4: Trapping diazo species in intermolecular fashion Part A: Synthesis of vinyl halides Trapping diazo species in an intermolecular fashion by attack of two independent ions (a cation followed by an anion) in tandem at the carbene center is unprecedented. As part of our efforts on the utility of tosylhydrazones, herein we report a novel approach of using ambiphilic diazo species to perform a tandem attack of a nucleophile followed by an electrophile in an intermolecular fashion for synthesizing various types of vinyl halides. A few representative examples are shown in Scheme 5.9 Scheme5: Synthesis if vinyl halides Part B: Synthesis of vinyl sulfones Vinyl sulfones are potential synthetic targets due to their presence in biologically and pharmaceutically important molecules ranging from small natural metabolites to proteins, and have found widespread applications in biological research as covalent protease inhibitors. Vinyl sulfones represent one of the important sulfur containing functional groups in organic chemistry, which are generally synthesized through elimination reactions, oxidation of vinyl sulfides or witting reactions using multistep sequence. Following this technique, we were able to synthesize a variety of vinyl sulfones with rich mechanistic features in a single step. A few such examples are documented in Scheme 6.9 Scheme 6: synthesis of vinyl sulfones Part C: Synthesis of alkynes The functional group conversion to achieve alkyne frameworks are generally a difficult transformation. There are very few limited and tedious processes are available in literature, mainly containing multi-step procedures. Additionally these reactions are require harsh conditions. Considering all these factors, there is a need for developing methods to synthesize alkynes from common functional groups under mild reactions conditions. In a similar way, to introduce different halogens at the same carbon, we expected the eliminations of the leaving groups in tandem formed alkynes. After extensive screening studies, it was pleasing to find that the reaction of tosylhydrazones with NCS−BTEAC, NBS−TBAB, or NIS−TBAI combination in presence of K2CO3 in dioxane as solvent at 110 °C can furnish corresponding acetylene derivatives in good yields. Few examples are shown in Scheme 7.9 Scheme 7: Trapping diazo species in intermolecular fashion Chapter 3: Pd catalysed hydroboration This chapter shows a hydroboration study of terminal alkynes in a highly regioselective manner (Scheme 8). Organoboron derivatives have become essential intermediates in organic and medicinal chemistry. Pioneering contributions are made by Brown and Akira Suzuki, who both instigated the development of new synthetic tools for the introduction of boron atoms onto organic molecules. 10 10) (a) Barbeyron, R.; Benedetti, E.; Cossy, J.; Vasseur, J.-J.; Arseniyadis, S.; Smietana, M. Tetrahedron 2014, 70, 8431. (b) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457. 11) Pd-Catalysed regioselective borylation of alkynes: A ligand controlled synthesis of α- and β vinyl boronates (manuscript submitted). Scheme 8: possibility of site selectivity in hydroboration Part A: Pd-catalysed regioselective borylation of alkynes: A ligand controlled synthesis of α and β – vinyl boronates The metal catalyzed borylations of alkynes proceeds in a two-step process. Initially M-Bpin species undergo an addition onto the alkynes to generate organometallic species followed by quenching of the organometallic species with electrophiles. The addition M-Bpin species is regioselective governed by the steric and electronics factors of both metal complex as well as alkyne substituents. In this direction, a palladium catalysed α-selective borylation was achieved for terminal alkynes. A broad range of substrates were successfully borylated under optimized reaction conditions with very high selectivity. Interestingly, the selectivity was reversed to terminal site by using a NHC ligand. A few examples are shown in Scheme 9.11 Scheme 9: α & β-vinyl boronates Chapter 4: Pd/borane unit: Behavior towards isomerization vs reduction of alkenes This study presents a unique behaviour of palladium-boronate unit responsible for olefin chain walking and olefin reduction reactions (Scheme 10). The catalytic system stands efficient against both functionalized and unfunctionalized olefin isomerization as well as reductions. This study has been presented in two parts. Scheme 10: isomerization vs reduction Part A: Pd/ boronates or borane unit as efficient catalytic systems for olefin chain walk This study presents the behaviour of palladium-boronate unit responsible for olefin chain walking. The catalytic system is efficient for both functionalized and unfunctionalized olefin isomerizations (Scheme 11). Cycloisomerization of transient conjugated alkenes to synthesize heterocycles are prominent applications of this technique. The system describes a concept of olefin activation by coordination with Pd-borane complex, this complex assists in a facile [1,3]-hydride shift. This technique allows us to facilitate an isomerization in functionalized as well as unfunctionalized olefinic systems. Considering the substrates scope, the catalytic cycle tolerates various sensitive functional groups and shows good selectivity. In the following Scheme 11 few examples are depicted.12 12) Palladium/boron catalytic unit for olefin chain-walk (manuscript under preparation). Scheme 11: chain-walking of olefins. Part B: Palladium catalysed boronate promoted alkene reduction in water In this work, water has been employed as a source of hydrogen. The reduction of alkenes was achieved using Pd catalyst in presence of bis(pinacolato)diboron and H2O. In this aspect, the utility of water as hydrogen equivalent is the pertinent as well as beneficial with many advantages. Few representative examples are shown in Scheme 12.13 13) Pd-Catalysed homogeneous hydrogenation of olefins by using water as hydrogen source (manuscript under preparation). Scheme 12: synthesis of alkenes reduced products.