A regioselective palladium-free protocol for accessing unsymmetrical biaryls through ring transformation of 6-aryl-~-pyrones

A regioselective synthesis of unsymmetrical biaryls with electron withdrawing or donating substituents is described and illustrated by carbanion-induced ring transfonnation of 6-aryl-a-pyrones with methoxyacetone in excellent yield. Our methodology is an alternative to classical organometal-catalyzed aryl-aryl coupling reactions and can be applied to the synthesis of functionally demanding naphthyl biaryls for the development of new ligands for asymetric synthesis

6-[omega-arylalkenyl]-5,6-dihydro-alpha-pyrones from Cryptocarya moschata (Lauraceae)

Eleven 6-[omega-arylalkenyl]-5,6-dihydro-alpha-pyrones, cryptomoscatones D2, E1, E2, E3 and F1 and cryptopyranmoscatones A1, A2, A3, B1, B2 and B4, in addition to goniothalamin and cryptofolione, were isolated from branch and stem bark of Cryotocarya moschata, Lauraceae. Their structures were established by spectroscopic methods. (C) 2000 Elsevier B.V. Ltd. All rights reserved.

Studies toward the construction of substituted piperidine-2-ones and pyridine-2-ones from Baylis-Hillman adducts: Discovery of a facile synthesis of 5-methyl-4-oxo-6-aryl-3-aza-bicyclo[3.1.0]hexane-1-carboxylates

Studies toward the construction of functionalised piperidone derivatives from derivatives of Baylis-Hillman adducts are described. Interestingly the 6-oxo-4-aryl-piperidine-3-carboxylates generated during the study serve as precursor for the facile synthesis of 4-oxo-6-aryl-3-aza-bicyclo[3.1.0]hexane-1-carboxylates

Synthesis of arylated highly congested indans using a domino sequence

A novel and efficient regioselective synthesis of various arylated highly congested 7-aryl-5-methylsulfanylindan-4-carbonitriles (3a-(), methyl 7-aryl-5-methylsulfanylindan-4-carboxylates (lOa-e) and 7-aryl-5-methylsulfanylindan-4-carboxylic acids (lla-e) through base-catalyzed reaction of 6-aryl-4-methylsulfanyl-2-oxo-2H-pyran-3-carbonitriles (la-() and methyl 6-aryl-4-methylsulfanyl-2-oxo-2Hpyran-3-carboxylates (9a-e) by cyclopentanone (2) has been delineated. The synthetic potential of 2-pyranone was explored further to generate mo'iecular diversity using 6-aryl-4-secamino- 2-oxo-2H-pyran-3-carbonitriles (7a-h), 5,6-diaryl-4-methylsulfanyl-2-oxo2H-pyran-3-carbonitriles (Sa,b) and methyl 5,6-diaryl-4- methylsulfanyl-2-oxo-2H-pyran-3-carboxylates (12a,b) as precursors for the ring transformation by cyclopentanone to assess the effects of substituents on the course of the reaction to obtain highly congested indans, 6,7diaryl-5-methylsulfanylindan-4-carbonitriles (6a,b), 7-aryl-5-(piperidin-I-yl)indancarbonitriles (8a-h) and methyl 6,7-4- diaryl-5-methylsulfanylindan-4-carboxylate 13a,b).

An Efficient Multi-component Synthesis of 6-Amino-3-methyl-4-Aryl-2,4- dihydropyrano[2,3-c]Pyrazole-5-carbonitriles

Multi-component reactions are effective in building complex molecules in a single step in a minimum amount of time and with facile isolation procedures; they have high economy1–7 and thus have become a powerful synthetic strategy in recent years.8–10 The multicomponent protocols are even more attractive when carried out in aqueous medium. Water offers several benefits, including control over exothermicity, and the isolation of products can be carried out by single phase separation technique. Pyranopyrazoles are a biologically important class of heterocyclic compounds and in particular dihydropyrano[2,3-c]pyrazoles play an essential role in promoting biological activity and represent an interesting template in medicinal chemistry. Heterocyclic compounds bearing the 4-H pyran unit have received much attention in recent years as they constitute important precursors for promising drugs.11–13 Pyrano[2,3-c]pyrazoles exhibit analgesic,14 anti-cancer,15 anti-microbial and anti-inflammatory16 activity. Furthermore dihydropyrano[2,3-c]pyrazoles show molluscidal activity17,18 and are used in a screening kit for Chk 1 kinase inhibitor activity.19,20 They also find applications as pharmaceutical ingredients and bio-degradable agrochemicals.21–29 Junek and Aigner30 first reported the synthesis of pyrano[2,3-c]pyrazole derivatives from 3-methyl-1-phenylpyrazolin-5-one and tetracyanoethylene in the presence of triethylamine. Subsequently, a number of synthetic approaches such as the use of triethylamine,31 piperazine,32 piperidine,33 N-methylmorpholine in ethanol,34 microwave irradiation,35,36 solvent-free conditions,37–39 cyclodextrins (CDs),40 different bases in water,41 γ -alumina,42 and l-proline43 have been reported for the synthesis of 6-amino-4-alkyl/aryl-3-methyl- 2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitriles. Recently, tetraethylammonium bromide (TEABr) has emerged as mild, water-tolerant, eco-friendly and inexpensive catalyst. To the best of our knowledge, quaternary ammonium salts, more specifically TEABr, have notbeen used as catalysts for the synthesis of pyrano[2,3-c]pyrazoles, and we decided to investigate the application of TEABr as a catalyst for the synthesis of a series of pyrazole-fused pyran derivatives via multi-component reactions

Mono- and heterodimetallic FeII and RuII complexes based on a novel heteroditopic 4′-{bis(phosphanyl)aryl}-2,2′:6′,2″-terpyridine ligand

In the search for a versatile building block that allows the preparation of heteroditopic tpy-pincer bridging ligands, the synthon 14'-[C6H3(CH2Br)(2)-3,5]-2,2':6',2 ''-terpyridine was synthesized. Facile introduction of diphenylphosphanyl groups in this synthon gave the ligand 14'-[C6H3(CH2PPh2)2-3,5]-2,2':6',2"-terpyridine) ([tpyPC(H)Pj). The asymmetric mononuclear complex [Fe(tpy){tpyPC(H)P}](PF6)(2), prepared by selective coordination of [Fe(tpy)Cl-3] to the tpy moiety of [tpyPC(H)P], was used for the synthesis of the heterodimetallic complex [Fe(tpy)(tpyPCP)Ru(tpy)](PFC,)3, which applies the "complex as ligand" approach. Coordination of the ruthenium centre at the PC(H)P-pincer moiety of [Fe(tpy){tpyPC(H)P}](PF6)(2) has been achieved by applying a transcyclometallation procedure. The ground-state electronic properties of both complexes, investigated by cyclic and square-wave voltammetries and UV/Vis spectroscopy, are discussed and compared with those of [Fe(tPY)(2)](PF6)(2) and [Ru(PCP)(tpy)]Cl, which represent the mononuclear components of the heterodinuclear species. An in situ UV/Vis spectroelectrochemical study was performed in order to localize the oxidation and reduction steps and to gain information about the Fe-II-Ru-II communication in the heterodimetallic system [Fe(tpy)(tpyPCP)Ru(tpy)](PF6)(3) mediated by the bridging ligand [tpyPCP]. Both the voltammetric and spectroelectrochemical results point to only very limited electronic interaction between the metal centres in the ground state.

2,3-Divinyl- und 2-Aryl-3-vinylindole als Bausteine zu Carbazolen und Versuche zur photochemischen und Ultraschall-induzierten 1,6-Elektrocyclisierung

Es wurden neue funktionalisierte Carbazole und anellierte Benzo[a]carbazole als potentielle pharmakologische Therapeutika durch 1,6-pi-Elektrocyclisierung auf photo-chemischem, thermischem und sonochemischem Weg synthetisiert und die Synthesemethoden der 1,6-pi-Elektrocyclisierung sowie der 2,3-Divinylindole und der 2-Aryl-3-vinylindole als entsprechende Ausgangsprodukte validiert und evaluiert. Es gelang weder das nach den Woodward-Hoffmann-Regeln erwartete primäre Cyclisierungsprodukt mit Indolochinodimethanstruktur noch die Existenz des in einer photochemischen Abfangreaktion daraus resultierenden Cycloprodukts NMR-spektroskopisch nachzuweisen, um den stereochemischen Verlauf der Cyclisierung vorherzusagen. Ergebnisse der quantenchemischen Berechnungen der Eduktmoleküle (AO-Koeffizienten der MO's, HOMO/LUMO-Energien) sowie der Übergangszustandsgeometrien der Cyclisierungen decken sich mit den experimentellen Daten. Divinyl- und 2-Aryl-3-vinylindole sind als Systeme mit Hexatriensymmetrie aufzufassen, deren Cyclisierungsverhalten sich mit den Woodward-Hoffmann-Regeln beschreiben läßt. Im Vergleich der verschiedenen 1,6-pi-Elektrocyclisierungsmethoden zeigte sich, daß die photochemische Variante eine elegante Synthesemethode darstellt, um funktionalisierte Carbazole und Benzo[a]carbazole mit unterschiedlichen pharmakologischen Aktivitäten unter schonenden Reaktionsbedingungen mit den vergleichbar höchsten Ausbeuten zu erhalten. Demgegenüber lieferten die Ultraschallreaktionen keine nachweisbaren Cyclisierungsprodukte. Die thermische Cyclisierung führte zur Gruppe der 1,2-Dihydrocarbazole. Sie bildeten sich in einer Folgereaktion durch [1,5s]-H-Verschiebung aus dem primär entstandenen Woodward-Hoffmann-Cyclisierungsprodukt. In abschließenden DNA-Bindestudien mit verschiedenen Testsystemen zeigte keine der synthetisierten Testsubstanzen DNA-Bindungsaktivität.

The preparation and characterization of seven-coordinate tin(IV) complexes of the 2,6-diacetylpyridine Schiff bases of S-alkyl/aryl-dithiocarbazates and the X-ray crystal structure of the [Sn(dapsme)I-2] complex (dapsme=doubly deprotonated form of the 2,6

New tin(IV) complexes of empirical formula, Sn(SNNNS)I-2 (SNNNS = anionic form of the 2,6-diacetylpyridine Schiff bases of S-methyl- or S-benzyldithiocarbazate) have been prepared and characterized by a variety of physico-chemical techniques. The structure of Sn(dapsme)I-2 has been determined by single crystal X-ray crystallographic structural analysis. The complex has a seven-coordinate distorted pentagonal-bipyramidal geometry with the Schiff base coordinated to the tin(IV) ion as a dinegatively charged pentadentate chelating agent via the pyridine nitrogen atom, the two azomethine nitrogen atoms and the two thiolate sulfur atoms. The ligand occupies the equatorial plane and the iodo ligands are coordinated to the tin(IV) ion at axial positions. The distortion from an ideal pentagonal bipyramidal geometry is attributed to the restricted bite size of the pentadentate ligands. (C) 2004 Elsevier Ltd. All rights reserved.

Highly efficient palladium-catalyzed Suzuki-Miyaura reactions of potassium aryltrifluoroborates with 5-iodo-1,3-dioxin-4-ones in water: an approach to alpha-aryl-beta-ketoesters

The high efficient palladium-catalyzed Suzuki-Miyaura reactions of potassium aryltrifluoroborates 3 with 5-iodo-1,3-dioxin-4-ones 2a-b in water as only solvent in the presence of n-Bu(4)NOH as base is reported. The respective 5-aryl-1,3-dioxin-4-ones 4a-n were obtained in good to excellent yields. The catalyst system provides high efficiency at low load using electronically diverse coupling partners. The obtained 2,2,6-trimethyl-5-aryl-1,3-dioxin-4-ones were transformed into corresponding alpha-aryl-beta-ketoesters 6 by reaction with an alcohol in the absence of solvent. (C) 2009 Elsevier Ltd. All rights reserved.

Synthesis of 2-Aryl- and 2,5-Diarylfurans and Thiophenes by Suzuki-Miyaura Reactions Using Potassium Trifluoroborate Salts and Heteroaryltellurides

The Suzuki-Miyaura cross-coupling reaction of 2-(butyltellanyl) or 2,5-bis-(butyltellanyl)furans and thiophenes with potassium aryltrifluoroborate salts catalyzed by palladium afforded 2-aryl- or 2,5-diaryl-furans and thiophenes in moderate to good yields.

Síntese de beta-N-acetilglicosaminídeos de arila modificados em C-6 como potenciais agentes antimicrobianos

We report herein the synthesis of aryl beta-N-acetylglucosaminides containing azido, amino and acetamido groups at C-6 as potential antimicrobial agents. It was expected that these compounds could interfere with the biosynthesis and/or biotransformation of N-acetylglucosamine in fungi and bacteria. None of the compounds showed antimicrobial activity against bacteria (Bacillus subtilis, Micrococcus luteus, Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa), filamentous fungus (Aspergillus niger) and yeasts (Saccharomyces cerevisae, Candida albicans and Candida tropicallis), at the concentration of 1 mg/mL in agar diffusion assay.

Méthodologie pour la synthèse combinatoire d’azapeptides: application à la synthèse d’analogues aza-GHRP-6 en tant que ligands du récepteur CD36

Les azapeptides sont des mimes peptidiques où le carbone alpha d’un ou de plusieurs acides aminés est remplacé par un atome d’azote. Cette modification tend à stabiliser une conformation en repliement beta en raison de la répulsion électronique entre les paires d’électrons libres des atomes d’azote adjacents et de la géométrie plane de l’urée. De plus, le résidu semicarbazide a une meilleure résistance face aux protéases en plus d’être chimiquement plus stable qu’une liaison amide. Bien que les propriétés des azapeptides en fassent des mimes peptidiques intéressants, leurs méthodes de synthèses font appel à la synthèse laborieuse d’hydrazines substituées en solution. Le peptide sécréteur d’hormone de croissance 6 (GHRP-6, His-D-Trp-Ala-Trp-D-Phe-Lys-NH2) est un hexapeptide synthétique qui possède une affinité pour deux récepteurs distincts: les récepteurs GHS-R1a et CD36. Les travaux effectués au cours de mon doctorat qui seront détaillés dans cet ouvrage visent à atteindre deux objectifs: (1) le développement d’analogues du peptide GHRP-6 sélectif à un seul récepteur et (2) la mise au point d’une nouvelle méthodologie pour la synthèse combinatoire d’azapeptides. En réponse au premier objectif, la synthèse parallèle de 49 analogues aza-GHRP-6 a été effectuée et certains candidats sélectifs au récepteur CD36 ont été identifiés. L’étude de leurs propriétés anti-angiogéniques, effectuée par nos collaborateurs, a également permis d’identifier des candidats intéressants pour le traitement potentiel de la dégénérescence maculaire liée à l’âge. Une nouvelle approche pour la synthèse combinatoire d’azapeptides, faisant appel à l’alkylation et la déprotection chimiosélective d’une sous-unité semicarbazone ancrée sur support solide, a ensuite été développée. La portée de cette méthodologie a été augmentée par la découverte de conditions permettant l’arylation régiosélective de cette sous-unité semicarbazone, donnant accès à treize nouveaux dérivés aza-GHRP-6 possédant des résidus aza-arylglycines aux positions D-Trp2 et Trp4. L’élaboration de conditions propices à l’alkylation et la déprotection chimiosélective de la semicarbazone a donné accès à une variété de chaînes latérales sur l’acide aminé « aza » préalablement inaccessibles. Nous avons, entre autres, démontré qu’une chaîne latérale propargyl pouvait être incorporée sur l’acide aminé « aza ». Tenant compte de la réactivité des alcynes, nous avons ensuite élaboré des conditions réactionnelles permettant la formation in situ d’azotures aromatiques, suivie d’une réaction de cycloaddition 1,3-dipolaire sur support solide, dans le but d’obtenir des mimes de tryptophane. Sept analogues du GHRP-6 ont été synthétisés et testés pour affinité au récepteur CD36 par nos collaborateurs. De plus, nous avons effectué une réaction de couplage en solution entre un dipeptide possédant un résidu aza-propargylglycine, du paraformaldehyde et une variété d’amines secondaires (couplage A3) afin d’accéder à des mimes rigides d’aza-lysine. Ces sous-unités ont ensuite été incorporées sur support solide afin de générer sept nouveaux azapeptides avec des dérivés aza-lysine à la position Trp4 du GHRP-6. Enfin, une réaction de cyclisation 5-exo-dig a été développée pour la synthèse de N-amino imidazolin-2-ones en tant que nouveaux mimes peptidiques. Leur fonctionnalisation par une série de groupements benzyliques à la position 4 de l’hétérocycle a été rendue possible grâce à un couplage Sonogashira précédant la réaction de cyclisation. Les propriétés conformationnelles de cette nouvelle famille de composés ont été étudiées par cristallographie aux rayons X et spectroscopie RMN d’un tétrapeptide modèle. L’activité biologique de deux mimes peptidiques, possédant un résidu N-amino-4-méthyl- et 4-benzyl-imidazolin-2-one à la position Trp4 du GHRP-6, a aussi été examinée. L’ensemble de ces travaux devrait contribuer à l’avancement des connaissances au niveau des facteurs structurels et conformationnels requis pour le développement d’azapeptides en tant que ligands du récepteur CD36. De plus, les résultats obtenus devraient encourager davantage l’utilisation d’azapeptides comme peptidomimétiques grâce à leur nouvelle facilité de synthèse et la diversité grandissante au niveau de la chaîne latérale des acides aminés « aza ».

Synthèse et étude de nouvelles molécules potentiellement polymérisables pour la fabrication de matériaux électroluminescents : analogues du 1,3,5 benzènetripyrrole, méthyle 3,5-bipyrrolebenzoate et 6,12-diméthyle-1,5-dipyrrolediazocane

Pyrroles are found in various natural products and in the chemical composition of certain drugs because of their interesting biological properties. Lipitor, Tolmetin and Amtolmetin are examples of drugs with 1,2,5-substituted pyrroles in their composition, in which biological activities have been certified. Moreover, pyrroles are used as precursors of semiconductor polymers, oligomers and dendrimers useful for the synthesis of electroluminescent materials used in devices, such as organic light-emitting diodes, field-effect transistors, solar and organic photovoltaic cells. We are interested in conjugated polymers based on pyrrole due to their optical properties, electrochemical and the conductivity produced by electron delocalization along their carbon chains. The overall objective of the work presented in this thesis is the synthesis of new molecules based on pyrrole for studying their electronic and electrochemical properties as well for the synthesis of conjugated polymers. Initially, we performed the synthesis of 1,3,5-tri-(1-alkyl-5-methylpyrrol-2-yl)benzenes, which may serve as precursors for the synthesis of conjugated dendrimers. Their synthesis was made in three steps starting from trimethyl 1,3,5-benzene-tricarboxylate which was converted to 1,3,5-tri-(pent-4-enoyl)benzene using vinylmagnesium bromide in a Grignard reaction catalyzed by copper cyanide. The olefins of 1,3,5-tri-(pent-4-enoyl)benzene were oxidized to produce 1,3,5-tri-(4-oxopentanoyl)benzene using a modified protocol of the Tsuji-Wacker reaction. Subsequent, Paal-Knorr condensation reactions on 1,3,5-tri-(4-oxopentanoyl)benzene with different amines were used to synthesize 1,3,5-tri-(1-alkyl-5-methylpyrrol-2-yl)benzenes with different N-substituents in yields between 44 and 60%. Incomplete reaction of vinylmagnesium bromide with trimethyl 1,3,5-benzenetricarboxylate gave the methyl-3,5-di(pent-4-enoyl)benzoate, which was converted to methyl-3,5-dipyrrolylbenzoate following the reaction of Tsuji- Wacker and Paal-Knorr with yields between 30 and 60%. The photochemical and electrochemical properties of the 1,3,5-tri-(1-alkyl-5-methylpyrrol-2-yl)benzenes and methyl-3,5-dipyrrolylbenzoates were studied in collaboration with the research group of professor William Skene. The results have shown that both types of pyrrole have potential for the synthesis of conjugated polymers and dendrimers used in the manufacture of electroluminescent materials. Following these encouraging results, we performed the synthesis of 6,12-dimethyl-1,5-dipyrrolediazocane. Methyl N-(Boc)-β-alaninate was converted to its corresponding homoallylic ketone, which was oxidized to N-(Boc)aminoheptan-3,6-dione. The Paal-Knorr condensation between N-(Boc)aminoheptan-3,6-dione and aminoheptan-3,6-dione hydrochloride gave 6,12-dimethyl-1,5-dipyrrolediazocane in 17% yield. In sum, we have synthesized and characterized seven new molecules, six of them having photochemical and electrochemical properties interesting for the synthesis of conjugated polymers and dendrimers. The latter offering potential as precursor for the conception of compounds of therapeutic interest.

Synthesis of hyperbranched poly(aryl amine)s via a carbene insertion approach

A novel diazirine functionalised aniline derivative, 3-(3-aminophenyl)-3-methyldiazirine 1, was prepared and employed as an AB(2)-type monomer in the synthesis of hyperbranched polymers; thus providing the first instance in which polyamines have been prepared via carbene insertion polymerisation. Photolysis of the monomer 1 in bulk and in solution resulted in the formation of hyperbranched poly(aryl amine)s with degrees of polymerisation (DP) varying from 9 to 26 as determined by gel permeation chromatography (GPC). In solution, an increase in the initial monomer concentration was generally found to result in a decrease in the molecular weight characteristics of the resulting poly(aryl amine) s. Subsequent thermal treatment of the poly(aryl amine) s caused a further increase in the DP values up to a maximum of 31. Nuclear magnetic resonance (NMR) spectroscopic analysis revealed that the increase in molecular weight upon thermal treatment resulted from hydroamination of styrenic species formed in the initial photopolymerisation or activation of diazirine moieties.