Recoverable silica-gel supported binam-prolinamides as organocatalysts for the enantioselective solvent-free intra- and intermolecular aldol reaction

Silica-gel supported binam-derived prolinamides are efficient organocatalysts for the direct intramolecular and intermolecular aldol reaction under solvent-free conditions using conventional magnetic stirring. These organocatalysts in combination with benzoic acid showed similar results to those obtained under similar homogeneous reaction conditions using an organocatalyst of related structure. For the intermolecular process, the aldol products were obtained at room temperature and using only 2 equiv of the ketone with high yields, regio-, diastereo- and enantioselectivities. Under these reaction conditions, also the cross aldol reaction between aldehydes is possible. The recovered catalyst can be reused up to nine times providing similar results. More interestingly, these heterogeneous organocatalysts can be used in the intramolecular aldol reaction allowing the synthesis of the Wieland–Miescher and ketone analogues with up to 92% ee, with its reused being possible up to five times without detrimental on the obtained results.

Microwave-Promoted Copper-Free Sonogashira–Hagihara Couplings of Aryl Imidazolylsulfonates in Water

Aryl imidazol-1-ylsulfonates have been efficiently cross-coupled with aryl-, alkyl-, and silylacetylenes in neat water under copper-free conditions at 110 °C assisted by microwave irradiation. Using 0.5 mol% of an oxime palladacycle as precatalyst, 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (SPhos, 2 mol%) as ligand, hexadecyltrimethylammonium bromide (CTAB) as additive, and triethylamine (TEA) as base, a wide array of disubstituted alkynes has been prepared in good to high yields in only 30 min.

Synthesis of Dihydroisobenzofurans via Palladium-Catalyzed Sequential Alkynylation/Annulation of 2-Bromobenzyl and 2-Chlorobenzyl Alcohols under Microwave Irradiation

The palladium-catalyzed synthesis of dihydroisobenzofurans has been performed by sequential Sonogashira cross-coupling/cyclization reactions between terminal alkynes and 2-(hydroxymethyl)bromo- and chlorobenzenes in methanol as solvent at 130 °C under microwave irradiation. A 4,4′-dichlorobenzophenone oxime-derived chloro-bridged palladacycle is an efficient pre-catalyst to perform this tandem process using 2-dicyclohexylphosphanyl-2′,4′,6′-triisopropylbiphenyl (Xphos) as ancillary ligand and potassium hydroxide as base in the absence of a copper cocatalyst. Under these conditions, functionalized 2-bromo- and 2-chlorobenzaldehydes are also suitable partners in the domino process affording phthalans in good yields. All the reactions can be performed under air and employing reagent-grade chemicals under low loading conditions (1 mol% Pd).

Biscarboxy-Functionalized Imidazole and Palladium as Highly Active Catalytic System in Protic Solvents: Methanol and Water

The coupling reaction between aryl bromides and boron reagents is efficiently catalyzed by an in situ generated palladium complex obtained from palladium(II) acetate (0.1 mol%) and 1,3-bis(carboxymethyl)imidazole (0.2 mol%). The catalytic system is very active in protic solvents, especially in methanol. Biaryl derivatives have been prepared in good isolated yields (up to >99%), and additionally styrene and stilbene derivatives have also been prepared by means of this protocol.

Palladium and Bimetallic Palladium–Nickel Nanoparticles Supported on Multiwalled Carbon Nanotubes: Application to Carbon–Carbon Bond-Forming Reactions in Water

Palladium and bimetallic Pd–Ni nanoparticles (NPs) protected by polyvinylpyrrolidone were prepared by the reduction-by-solvent method and deposited on multiwalled carbon nanotubes (MWCNTs). The catalytic activity of these NPs to carbon–carbon bond-forming reactions was studied by using 0.1 mol % Pd loading, at 120 °C for 1 h and water as a solvent under ligand-free conditions. The Suzuki–Miyaura reaction took place quantitatively for the cross-coupling of 4-bromoanisole with phenylboronic acid, better than those obtained with potassium phenyltrifluoroborate, with Pd50Ni50/MWCNTs as a catalyst and K2CO3 as a base and TBAB as an additive, with good recyclability during 4 cycles with some Ni leaching. The Hiyama reaction of 4-iodoanisole with trimethoxyphenylsilane, under fluoride-free conditions using 50 % aqueous NaOH solution, was performed with Pd/MWCNTs as a catalyst in 83 % yield with low recyclability. For the Mizoroki-Heck reaction 4-iodoanisole and styrene gave the corresponding 4-methoxystilbene quantitatively with Pd50Ni50/MWCNTs using K2CO3 as a base and TBAB as an additive although the recycle failed. In the case of the Sonogashira-Hagihara reaction, Pd/MWCNTs had to be used as a catalyst and pyrrolidine as a base for the coupling of 4-iodoanisole with phenylacetylene under copper-free conditions. The corresponding 4-methoxytolane was quantitatively obtained allowing the recycling of the catalyst during 3 cycles.

A gradient descent algorithm for minimizing amino acid coupling reactions when synthesizing cyclic-peptide libraries

Combinatorial chemistry has become an invaluable tool in medicinal chemistry for the identification of new drug leads. For example, libraries of predetermined sequences and head-to-tail cyclized peptides are routinely synthesized in our laboratory using the IRORI approach. Such libraries are used as molecular toolkits that enable the development of pharmacophores that define activity and specificity at receptor targets. These libraries can be quite large and difficult to handle, due to physical and chemical constraints imposed by their size. Therefore, smaller sub-libraries are often targeted for synthesis. The number of coupling reactions required can be greatly reduced if the peptides having common amino acids are grouped into the same sub-library (batching). This paper describes a schedule optimizer to minimize the number of coupling reactions by rotating and aligning sequences while simultaneously batching. The gradient descent method thereby reduces the number of coupling reactions required for synthesizing cyclic peptide libraries. We show that the algorithm results in a 75% reduction in the number of coupling reactions for a typical cyclic peptide library.

Coupling of Heck and hydrogenation reactions in a continuous compact reactor

A continuous multi-step synthesis of 1,2-diphenylethane was performed sequentially in a structured compact reactor. This process involved a Heck C-C coupling reaction followed by the addition of hydrogen to perform reduction of the intermediate obtained in the first step. Both of the reactions were catalysed by microspherical carbon-supported Pd catalysts. Due to the integration of the micro-heat exchanger, the static mixer and the mesoscale packed-bed reaction channel, the compact reactor was proven to be an intensified tool for promoting the reactions. In comparison with the batch reactor, this flow process in the compact reactor was more efficient as: (i) the reaction time was significantly reduced (ca. 7 min versus several hours), (ii) no additional ligands were used and (iii) the reaction was run at lower operational pressure and temperature. Pd leached in the Heck reaction step was shown to be effectively recovered in the following hydrogenation reaction section and the catalytic activity of the system can be mostly retained by reverse flow operation. © 2009 Elsevier Inc. All rights reserved.

Developing of Germyldesulonylation and Thiodesulfonylation Reactions for the Synthesis of Novel Nucleoside Analogues. Efficient Synthesis of Novel (α-Fluoro)vinyl Sulfides

S-adenosyl-L-homocysteine (AdoHcy) hydrolase effects hydrolytic cleavage of AdoHcy to produce both adenosine and L-homocysteine and is a feedback inhibitor of S-adenosyl- L-methionine (SAM). Nucleoside analogues bearing an alkenyl or fluoroalkenyl chain between sulfur and C5' utilizing Negishi coupling reactions were synthesized. Palladium-catalyzed cross-coupling between the 5'-deoxy-5'-(iodomethylene) nucleosides and alkylzinc bromides gives analogues with the alkenyl unit. Palladium-catalyzed selective monoalkylation of 5'-(bromofluoromethylene)-5'-deoxy-adenosine with alkylzinc bromide afford adenosylhomocysteine analogues with a 6'-(fluoro)vinyl motif. The vinylic adenine nucleosides produced time-dependent inactivation of the S-adenosyl-L-homocysteine hydrolases. Stannydesulfonylation reaction is a critical step in the synthesis of E-fluorovinyl cytidine (Tezacitabine) a ribonucleoside reductase inhibitor with a potent anticancer activity. The synthesis involves the removal of the sulfonyl group by a radical-mediated stannyldesulfonylation reaction using tributyltin hydride. In order to eliminate the toxicity of tin, I developed a radical-mediated germyldesulonylation utilizing less toxic germane hydrides. Treatment of the protected (E)-5'-deoxy-5'-[(p-toluenesulfonyl)-methylene]uridine and adenosine derivatives with tributyl- or triphenylgermane hydride effected radical-mediated germyldesulfonylations to give 5'-(tributyl- or triphenylgermyl)methylene-5'-deoxynucleoside derivatives as single (E)-isomers. Analogous treatment of 2'-deoxy-2'-[(phenylsulfonyl)methylene]uridine with Ph3GeH afforded the corresponding vinyl triphenylgermane product. Stereoselective halodegermylation of the (E)-5'-(tributylgermyl)-methylene-5'-deoxy nucleosides with NIS or NBS provided the Wittig-type (E)-5'-deoxy-5'-(halomethylene) nucleosides quantitatively. Radical-mediated thiodesulfonylation of the readily available vinyl and (α-fluoro) vinyl sulfones with aryl thiols in organic or aqueous medium to provide a bench and environmentally friendly protocol to access (α-fluoro)vinyl sulfides were developed. Methylation of the vinyl or (α-fluoro)vinyl phenyl sulfide gave access to the corresponding vinyl or (α-fluoro)vinyl sulfonium salts. These sulfonium ions were tested as possible methyl group donors during reactions with thiols, phenols or amino groups which are commonly present in natural amino acids.

Total synthesis of furospongolide and related furanolipid analogues as potential anti-tumour agents

This thesis details the design, development and execution of innovative methodology in the total synthesis of the terpene-derived marine natural product, furospongolide. It also outlines the synthetic routes used to prepare a novel range of furanolipids derivatives and subsequent evaluation of their potential as antitumour agents. The first chapter is a review of the literature describing efforts undertaken towards the synthesis of biologically active furanosesterterpenoid marine natural products. A brief discussion on the sources and biological activity exhibited by furan natural products is also provided. In addition, a concise account of the role of hypoxia in cancer, and the increasing interest in HIF-1 inhibition as a target for chemotherapeutics is examined. The second chapter discusses the concise synthesis of the marine HIF-1 inhibitor furospongolide, which was achieved in five linear steps from (E,E)-farnesyl acetate. The synthetic strategy features a selective oxidation reaction, a Schlosser sp3-sp3 cross-coupling, a Wittig cross-coupling and an elaborate one-pot selective reduction, lactonisation and isomerization reaction to install the butenolide ring. The structure-activity relationship of furospongolide was also investigated. This involved the design and synthesis of a library of structurally modified analogues sharing the same C1-C13 subunit. This was achieved by exploiting the brevity and high level of convergence of our synthetic route together with the readily amenable structure of our target molecule. Exploiting the Schlosser cross-coupling allowed for replacement of furan with other heterocycles in the preparation of various furanolipid and thiophenolipid derivatives. The employment of reductive amination and Wittig chemistry further added to our novel library of structural derivatives. The third chapter discusses the results obtained from the NCI from biological evaluation From a collection of 28 novel compounds evaluated against the NCI-60 cancer cell array, six drug candidates were successfully selected for further biological evaluation on the basis of antitumour activity. COMPARE analysis revealed a strong correlation between some of our design analogues and the blockbuster anticancer agent tamoxifen, further supporting the potential of furanolipids in the treatment of breast cancer. The fourth chapter, details the full experimental procedures, including spectroscopic and analytical data for all the compounds prepared during this research.

New methods for the asymmetric synthesis of α-alkylated ketones and 1,3-amino alcohols

A large number of optically active drugs and natural products contain α-functionalised ketones or simple derivatives thereof. Furthermore, chiral α-alkylated ketones are useful synthons and have found widespread use in total synthesis. The asymmetric alkylation of ketones represents one of the most powerful and longstanding procedures in organic chemistry. Surprisingly, however, only one effective methodology is available, and this involves the use of chiral auxiliaries. This is discussed in Chapter 1, which also provides a background of other key topics discussed throughout the thesis. Expanding on the existing methodology of chiral auxiliaries, Chapter 2 details the synthesis of a novel chiral auxiliary containing a pyrrolidine ring and its use in the asymmetric preparation of α-alkylated ketones with good enantioselectivity. The synthesis of racemic α-alkylated ketones as reference standards for GC chromatography is also reported in this chapter. Chapter 3 details a new approach to chiral α-alkylated ketones using an intermolecular chirality transfer methodology. This approach employs the use of simple non-chiral dimethylhydrazones and their asymmetric alkylation using the chiral diamine ligands, (+)- and (-)-sparteine. The methodology described represents the first example of an asymmetric alkylation of non-chiral azaenolates. Enantiomeric ratios up to 83 : 17 are observed. Chapter 4 introduces the first aldol-Tishchenko reaction of an imine derivative for the preparation of 1,3-aminoalcohol precursors. 1,3-Aminoalcohols can be synthesised via indirect routes involving various permutations of stepwise construction with asymmetric induction. Our approach offers an alternative highly diastereomeric route to the synthesis of this important moiety utilising N-tert-butanesulfinyl imines in an aldol-Tishchenko-type reaction. Chapter 5 details the experimental procedures for all of the above work. Chapter 6 discusses the results of a separate research project undertaken during this PhD. 2-alkyl-quinolin-4-ones and their N-substituted derivatives have several important biological functions such as the role of Pseudomonas quinolone signal (PQS) in quorum sensing. Herein, we report the synthesis of its biological precursor, 2-heptyl-4-hydroxy-quinoline (HHQ) and possible isosteres of PQS; the C-3 Cl, Br and I analogues. N-Methylation of the iodide was also feasible and the usefulness of this compound showcased in Pd-catalysed cross-coupling reactions, thus allowing access to a diverse set of biologically important molecules.

Studies in asymmetric and heterocyclic synthesis: I. chiral ketones II. Quinolones III. Trifluoromethylated pyrones

This thesis is split into three sections based on three different areas of research. In the first section, investigations into the α-alkylation of ketones using a novel chiral auxiliary is reported. This chiral auxiliary was synthesised containing a pyrrolidine ring in the chiral arm and was applied in the preparation of α-alkylated ketones which were obtained in up to 92% ee and up to 63% yield over two steps. Both 3-pentanone and propiophenone based ketones were used in the investigation with a variety of both alkyl and benzyl based electrophiles. The novel chiral auxiliary was also successful when applied to Michael and aldol reactions. A diamine precursor en route to the chiral auxiliary was also applied as an organocatalyst in a Michael reaction, with the product obtained in excellent enantioselectivity. In the second section, investigations into potential anti-quorum sensing molecules are reported. The bacteria Pseudomonas aeruginosa is an antibiotic-resistant pathogen that demonstrates cooperative behaviours and communicates using small chemical molecules in a process termed quorum sensing. A variety of C-3 analogues of the quorum sensing molecules used by P. aeruginosa were synthesised. Expanding upon previous research within the group, investigations were carried out into alternative protecting group strategies of 2-heptyl-4-(1H)- quinolone with the aim of improving the yields of products of cross-coupling reactions. In the third section, investigations into fluorination and trifluoromethylation of 2-pyrones, pyridones and quinolones is reported. The incorporation of a fluorine atom or a trifluoromethyl group into a molecule is important in pharmaceutical drug discovery programmes as it can lead to increased lipophilicity and bioavailability, however late-stage incorporation is rarely reported. Both direct fluorination and trifluoromethylation were attempted. Eight trifluoromethylated 2-pyrones, five trifluoromethylated 2-pyridones and a trifluoromethylated 2-quinolone were obtained in a late-stage synthesis from their respective iodinated precursors using methyl fluorosulfonyldifluoroacetate as a trifluoromethylating reagent.

Catalytic reactions with palladium supported on mesocellular foam : Applications in hydrogenation, isomerization, and C-C bond forming reactions

The major part of this thesis concerns the development of catalytic methodologies based on palladium nanoparticles immobilized on aminopropyl-functionalized siliceous mesocellular foam (Pd0-AmP-MCF). The catalytic activity of the precursor to the nanocatalyst, PdII-AmP-MCF is also covered by this work. In the first part the application of Pd0-AmP-MCF in Suzuki-Miyaura cross-coupling reactions and transfer hydrogenation of alkenes under microwave irradiation is described. Excellent reactivity was observed and a broad range of substrates were tolerated for both transformations. The Pd0-AmP-MCF exhibited high recyclability as well as low metal leaching in both cases. The aim of the second part was to evaluate the catalytic efficiency of the closely related PdII-AmP-MCF for cycloisomerization of various acetylenic acids. The catalyst was able to promote formation of lactones under mild conditions using catalyst loadings of 0.3 - 0.5 mol% at temperatures of up to 50 oC in the presence of Et3N. By adding 1,4-benzoquinone to the reaction, the catalyst could be recycled four times without any observable decrease in the activity. The selective arylation of indoles at the C-2 position using Pd-AmP-MCF and symmetric diaryliodonium salts is presented in the third part. These studies revealed that Pd0-AmP-MCF was more effective than PdII-AmP-MCF for this transformation. Variously substituted indoles as well as diaryliodonium salts were tolerated, giving arylated indoles in high yields within 15 h at 20 - 50 oC in H2O. Only very small amounts of Pd leaching were observed and in this case the catalyst exhibited moderate recyclability. The final part of the thesis describes the selective hydrogenation of the C=C in different α,β-unsaturated systems. The double bond was efficiently hydrogenated in high yields both under batch and continuous-flow conditions. High recyclability and low metal leaching were observed in both cases.

Nucleophilic addition of Nitrones to Electron deficient acetylenes and related studies

Nitrones or azomethine-N-oxides are important precursors for the synthesis of several heterocyclic systems. They belong to the allyl anion type 1,3-dipoles and possess unique structural features which make them extraordinarily useful synthons. They behave as 1,3-dipoles in 1,3-dipolar cycloaddition reactions and as electrophiles in reactions with organometallic reagents. These are the two basic reactions given by nitrones. Nitrones also act as ‘spin traps’ in which they react with short-lived radicals to furnish stable nitroxide radicals which can be detected and identified by electron paramagnetic resonance (EPR) spectroscopy. Recently SmI2 catalysed reductive cross-coupling reactions of nitrones have gained significant interest in which the reactions are initiated by single electron transfer (SET) to nitrones. Apart from these reactions, nitrones are also known to participate in reactions which are initiated by the nucleophilic attack of nitrone-oxygen. In our group, we have also explored the nucleophilic character of nitrones through various reactions. The results obtained enabled us to develop a novel two-step one-pot strategy for quinolines and indoles - the heterocycles renowned for their pharmacological applications, from nitrones and electron deficient acetylenes. Using dibenzoylacetylene and phenylbenzoylacetylene as dipolarophiles, we could introduce a desired functional group at a predetermined position of the quinolines or indoles to be synthesised. In this context, the thesis entitled “NUCLEOPHILIC ADDITION OF NITRONES TO ELECTRON DEFICIENT ACETYLENES AND RELATED STUDIES” portrays our attempt to expand the scope of our x novel synthetic protocol using ester functionalised acetylenes: dimethyl acetylenedicarboxylate (DMAD) and methyl propiolate. The thesis is organised in to five chapters. The first chapter briefly describes the different classes of reactions that nitrone functionality can tolerate. The research problem is defined at the end of this chapter. The second chapter describes the synthesis of different nitrones used for the present study. The optimisation and expansion of scope of the novel strategy towards quinoline synthesis is discussed in the third chapter. The fourth chapter portrays the synthesis of indole-3-carboxylates using the novel strategy. In the fifth chapter, the reaction of N-(2,6-dimethylphenyl) and N-(2,4,6-trimethylphenyl)nitrones are discussed. Here we also discuss the mechanistic reinvestigation of Baldwin’s proposal in the isoxazoline-oxazoline rearrangement. The major outcome of the work is given at the end of the thesis. The structural formulae, schemes, tables and figures are numbered chapter-wise since each chapter of the thesis is organized as an independent unit. All new compounds (except two compounds reported in fourth chapter) are fully characterised on the basis of spectral and analytical data and single crystal X-ray analysis on representative examples. Relevant references are included at the end of individual chapters.

Coupling of magnetic, strain and electric polarization fields in the structure of multiferroic material

The comprehensive study on the coupling of magnetism, electrical polarization and the crystalline lattice with the off-stoichiometric effects in self-doped multiferroic hexagonal h-LuMnxO3±δ (0.92≤x≤1.12) ceramic oxides was carried out for the PhD work. There is a complex coupling of the three ferroic degrees. The cancelation of the magnetic moments of ions in the antiferromagnetic order, electric polarization with specific vortex/antivortex topology and lattice properties have pushed researchers to find out ways to disclose the underlying physics and chemistry of magneto-electric and magneto-elastic couplings of h-RMnO3 multiferroic materials. In this research work, self-doping of Lu-sites or Mn-sites of h-LuMnxO3±δ ceramics prepared via solid state route was done to pave a way for deeper understanding of the antiferromagnetic transition, the weak ferromagnetism often reported in the same crystalline lattices and the ferroelectric properties coupled to the imposed lattice changes. Accordingly to the aim of the PhD thesis, the objectives set for the sintering study in the first chapter on experimental results were two. First, study of sintering off-stoichiometric samples within conditions reported in the bibliography and also extracted from the phase diagrams of the LuMnxO3±δ, with a multiple firings ending with a last high temperature step at 1300ºC for 24 hours. Second, explore longer annealing times of up to 240 hours at the fixed temperature of 1300 ºC in a search for improving the properties of the solid solution under study. All series of LuMnxO3±δ ceramics for each annealing time were characterized to tentatively build a framework enabling comparison of measured properties with results of others available in literature. XRD and Rietveld refinement of data give the evolution the lattice parameters as a function to x. Shrinkage of the lattice parameters with increasing x values was observed, the stability limit of the solid solution being determined by analysis of lattice parameters. The evolution of grain size and presence of secondary phases have been investigated by means of TEM, SEM, EDS and EBSD techniques. The dependencies of grain growth and regression of secondary phases on composition x and time were further characterized. Magnetic susceptibility of samples and magnetic irreversibility were extensively examined in the present work. The dependency of magnetic susceptibility, Neel ordering transition and important magnetic parameters are determined and compared to observation in other multiferroics in the following chapter of the thesis. As a tool of high sensitivity to detect minor traces of the secondary phase hausmannite, magnetic measurements are suggested for cross-checking of phase diagrams. Difficulty of previous studies on interpreting the magnetic anomaly below 43 K in h-RMnO3 oxides was discussed and assigned to the Mn3O4 phase, with supported of the electron microscopy. Magneto-electric coupling where AFM ordering is coupled to dielectric polarization is investigated as a function of x and of sintering condition via frequency and temperature dependent complex dielectric constant measurements in the final chapter of the thesis. Within the limits of solid solubility, the crystalline lattice of off-stoichiometric ceramics was shown to preserve the magneto-electric coupling at TN. It represents the first research work on magneto-electric coupling modified by vacancy doping to author’s knowledge. Studied lattices would reveal distortions at the atomic scale imposed by local changes of x dependent on sintering conditions which were widely inspected by using TEM/STEM methods, complemented with EDS and EELS spectroscopy all together to provide comprehensive information on cross coupling of distortions, inhomogeneity and electronic structure assembled and discussed in a specific chapter. Internal interfaces inside crystalline grains were examined. Qualitative explanations of the measured magnetic and ferroelectric properties were established in relation to observed nanoscale features of h-LuMnxO3±δ ceramics. Ferroelectric domains and topological defects are displayed both in TEM and AFM/PFM images, the later technique being used to look at size, distribution and switching of ferroelectric domains influenced by vacancy doping at the micron scale bridging to complementary TEM studies on the atomic structure of ferroelectric domains. In support to experimental study, DFT simulations using Wien2K code have been carried out in order to interpret the results of EELS spectra of O K-edge and to obtain information on the cation hybridization to oxygen ions. The L3,2 edges of Mn is used to access the oxidation state of the Mn ions inside crystalline grains. In addition, rehybridization driven ferroelectricity is also evaluated by comparing the partial density of states of the orbitals of all ions of the samples, also the polarization was calculated and correlated to the off-stoichiometric effect.

Sintese de derivados 3 - substituídos de coumarinas

Este trabalho descreve a síntese de novos derivados de coumarinas 3-substituídas por grupos arilo, etenilarilo e etenil-organometálicos, através de novas metodologias via reacções de Heck e de metátese (Grubbs), com controlo da regioquímica e com significativos rendimentos reaccionais. A aplicação destas metodologias permitiu a síntese dos derivados, 3-fenilcoumarina (131), 3-(4-bromofenil)coumarina, (132), 3-(4-iodofenil)­coumarina (134), 3-(4-nitrofenil)coumarina (136), 3-(4-etilfenil)coumarina (133), 4-(coumarin-3-il)benzaldeído (135), 3-(4-metoxifenil)coumarina (137), (E)-3-acrilato-[4-(coumarin-3-il)fenil] de metilo (138), 6,7-metileno­dioxi-[3-(E)-2'-feniletenil]coumarina (145), 6,7-dimetoxi-[-(E)-2'-fenil­etenil]coumarina (146), 6,7-dimetoxi-[3-(E)-2'-(6'-nitrofenil)etenil]coumarina (147), 4-[2-(E)-(6,7-dimetoxicoumarin-3-il)etenil]benzaldeído (148) e 6,7-dimetoxi-[3-(E)-2'-ferroceniletenil]coumarina (149), dos quais os últimos nove, são compostos novos, identificados e caracterizados pela primeira vez. A deslocalização do sistema de electrões  conjugados, induzida pelos diversos substituintes das coumarinas, foi igualmente avaliada através da espectroscopia de UV/Vis. De referir que parte deste trabalho foi publicado como: "New Methodology for the Synthesis of 3-Substituted Coumarins via Pd-Catalyzed Site-Se/ective Cross-Coupling Reactions”, Sérgio Martins, Paula S. Branco, María C. de la Torre, Miguel A. Sierra e António Pereira, Synlett, 2010 (https://www.thieme-connect.com/ejournals/abstract/ synlett/doi/1 O.1 OS5/s-0030-1259014). ABSTRACT: This work describes the synthesis of new 3-aryl, ethenylaryl and ethenyl-organometallics coumarin derivatives, using a new methodology via Heck and metathesis (Grubbs) reactions, with regiochemistry control and significant reaction yields. The application of these methodologies allowed the synthesis of derivatives, 3-phenylcoumarin (131), 3-(4-bromophenyl)coumarin (132), 3-(4-iodophenyl)coumarin (134), 3-(4-nitrophenyl)coumarin (136), 3-(4-ethylphenyl)coumarin {133), 4-(coumarin-3-yl)benzaldehyde {135), 3-(4-methoxiphenyl)coumarin (137), (E)-ethyl 3-[4(coumarin-3-yl)phenyl]­acrylate (138), 6,7-methylenedioxy-[3-(E)-2'-phenylethenyl]coumarin (145), 6,7-dimethoxy-[-(E)-2'-phenylethenyl]coumarin (146), 6,7-dimethoxy-[3-(E)­-2'-(6'-nitrophenyl)ethenyl]coumarin (147), 4-[2-(E)-(6,7-dimethoxy­coumarin-3-yl)ethenyl]benzaldehyde {148) e 6,7-dimethoxy-[3-(E)-2'-(ferro­ cene)ethenyl]coumarin (149), the last nine of these are new compounds, identified and characterized for the first time. The delocalization of conjugated -electron system, induced by different substituents of coumarins, was also assessed by spectroscopy UV/Vis. Part of this work was published at: "New Methodology for the Synthesis of 3-Substituted Coumarins via Pd-Catalyzed Site-Selective Cross-Coupling Reactions", Sérgio Martins, Paula S. Branco, María C. de la Torre, Miguel A. Sierra e António Pereira, Synlett, 2010 (https://www.thieme­connect.com/ejournaIs/abstract/synlett/doi/1O.1 055/s-0030-1259014).