Ausgangspunkte der vorliegenden Arbeit waren stereoselektive Synthesen von Reissert-Verbindungen über chirale N-Acylisochinoliniumsalze. Es galt die Konfiguration der erhaltenen Produkte zu beweisen und deren Synthesepotential zu erforschen. Ein Ziel dieser Arbeit war es, weiterführende Reaktionen für die Synthese von alkaloidanalogen Substanzen zu entwickeln. Es gelang, die Reissert-Reaktion mit Chlorameisensäurementhylester erfolgreich auf andere Heterocyclen als Isochinolin auszudehnen. Die Annahme eine stereoselektiven Verlaufes mußte korrigiert werden. Das Reissert-Produkt konnte mit einer großen Anzahl von Alkylhalogeniden in 1-Position alkyliert werden. Die Cyanogruppe konnte in zwei Verfahren abgewandelt werden. Die Behandlung des Reissert-Produktes und der alkylierten Verbindungen mit Säuren, Halogen und Grignard-Reagenzien führte zu verschiedenen interessanten Cyclisierungen. Es gelang, die Reissert-Reaktion auf elektronenreiche Aromaten und metallorganische Reagenzien als Nucleophile zu erweitern. Es gelang eine asymmetrische C-C-Knüpfung mit Zink-Nucleophilen sowie Grignard-Verbindungen. 4-Bromsubstituierte Mannich-Produkte konnten erfolgreich in einer Suzuki-Kupplung zu 4-arylsubstituierten Isochinolinaddukten umgesetzt werden. Es gelang die Hydrierung der Enamindoppelbindung und die Abspaltung des chiralen Auxiliars auf zwei verschiedenen Wegen. Während Additionsreaktionen an die 1-Position von 2-Menthyloxcarbonylisochinoliniumsalzen im wesentlichen nicht stereoselektiv verliefen, konnte beim Einsatz von geschützten Aminosäurefluoriden als chirale Auxiliare Diastereoselektivitäten bis zu 6:1 erzielt werden. Der Einsatz der elektronenreichen Aromaten als Nucleophile führte zu Mannich-Produkten in guten Ausbeuten. Auch der Einsatz von Grignard-Reagenzien als Nucleophile konnte erfolgreich getestet werden. Hiermit ist die erste stereoselektive Addition von elektronenreichen Aromaten an cyclische Iminiumsalze gelungen. / Starting points of the present work were stereoselective syntheses of Reissert compounds about chiral N-acylisoquinoliniumsalts. It was a matter of proving the configuration of the preserved products and of investigating synthesis potential. A purpose of this work was to develop continuing reactions for the synthesis of alkaloide-analogous substances. One succeeded in expanding the Reissert reaction with menthylchloroformat successfully to other heterocycles than isoquinoline. The acceptance a stereoselective course had to be corrected. The Reissert product could be alkylated with a big number of alkylhalides in 1 position. The Cyanogroup could be modified in two procedures. The treatment of the Reissert product and the alkylated compounds with acids, halogens and Grignard reagents led to different interesting cyclisations. One succeeded in extending the Reissert reaction to electronrich aromatic and heteroaromatic compounds and metal-organic reagents as nucleophiles. An asymmetrical C-C-bondformation with Zink-nucleophiles as well as Grignard compounds succeeded. 4-Bromine-substituted Mannich products could be transformed successfully in a Suzuki coupling to 4-arylsubstituted isoquinolineadducts. The hydrogenation of the enamindoublebond and the splitting off chirale auxiliary on two different ways succeeded. While addition reactions ran to the 1 position of 2-Menthyloxcarbonylisoquinoliniumsalts basically not stereoselectively, could be achieved by the application by protected Aminosäurefluoriden as chirale auxiliaries slide stereo selectivities up to 6:1. The application of the electronrich aromatics as nucleophiles led to Mannich products in good exploiting. Also the application of Grignard reagents as nucleophiles could be tested successfully. Herewith the first stereoselective addition from electronrich aromatics to cyclic iminiumsalts has succeeded.

Ausgangspunkte der vorliegenden Arbeit waren stereoselektive Synthesen von Reissert-analogen N-Acylaminohydroperoxiden über chirale N-Acylisochinoliniumsalze. Edukte waren Isochinolin(derivaten), Menthylchloroformiat und Wasserstoffperoxid. Es galt die Konfiguration der erhaltenen Produkte zu beweisen und deren Sauerstoffübertragungspotential zu erforschen. Ein zweites Ziel dieser Arbeit war es, von bekannten Diketopiperazinhydroperoxiden ebenfalls das Sauerstoffübertragungspotential zu überprüfen, weil sie die gleiche N-Acylaminohydroperoxidstruktur aufweisen aber bisher wenig untersucht wurden. Es gelang durch NMR-Untersuchungen und Vergleich mit ähnlichen Reaktionen die Annahme eines stereoselektiven Verlaufes zu widerlegen. Weiterhin wurde gezeigt, dass anstelle von Hydroperoxiden Peroxide vorliegen. Es konnte eine in situ Methode entwickelt werden, um mit dem vorgegebenen Substanzen unter Zusatz eines Metallkatalysators wie Vanadium(V)triisopropylat und Titan(IV)tetraisopropylat eine Sauerstoffübertragung auf Methylphenylsulfid zu erzielen. In Abhängigkeit der eingesetzen Isochinolinderivate gelang eine kinetische Racematspaltung, so dass eine stereoselektive Sulfoxidation möglich wurde. Das günstigste Ergebnis betrug 51 % Sulfoxid bei 73 % Enantiomerenüberschuss. Mit einem bekannten Diketopiperazinhydroperoxid konnte Methylphenylsulfid direkt in 62 % Sulfoxid mit 32 % Enantiomerenüberschuss überführt werden. Dies sind die ersten erfolgreichen stereoselektiven Sulfoxidationen mit N-Acylaminohydroperoxiden. / Starting points of the present work were stereoselective syntheses of Reissert analogous N-acylaminohydroperoxides derived from chiral N-acylisochinoliniumsalts. Starting materials were isochinoline (and derivates), menthylchloroformiate and hydrogen peroxide. It was a matter of proving the configuration of the preserved products and of investigating the oxygen transfer potential. The second purpose of this work was to check the oxygen transfer potential of known diketopiperazinehydroperoxides likewise because they show the same N-acylaminohydroperoxide structure, however, up to now they were only examined scarcely. One succeeded by NMR investigations and comparison with similar reactions in disproving the acceptance of a stereoselective course. Furthermore it was shown that there are peroxides instead of hydroperoxides. We developed an in situ method to achieve with the given substances under addition of a metal catalyst like vanadium(V)triisopropylate and titanium(IV)tetraisopropylate an oxygen transfer to methylphenylsulfide. In dependence of the used isochinoline derivates a kinetic resolution was observed, so that a stereoselective sulfoxidation became possible. The most favorable result amounted to 51% sulfoxide with 73% enantiomeric excess. With a known diketopiperazinehydroperoxide methylphenylsulfide could be directly transfered into 62% sulfoxide with 32% enantiomeric excess. These are the first successful stereoselective sulfoxidations with chiral N-acylaminohydroperoxides.

<p>This thesis describes the use of copper and palladium to mediate transformations of carboranes, especially <i>p</i>-carborane.</p><p>1-(1-<i>p</i>-carboranyl)-<i>N</i>-methyl-<i>N</i>-(2-butyl)-3-isoquinolinecarboxamide, a carborane containing analogue of the peripheral benzodiazepine receptor (PBR) ligand PK11195, has been synthesised. A key step in the reaction is the copper (I) mediated coupling of p-carborane with ethyl 1-bromo-isoquinoline-3-carboxylate. </p><p><i>p</i>-Carborane has been arylated on the 2-<i>B</i>-atom in high yields, using the Suzuki–Miyaura reaction. Thus the reaction between 2-I-<i>p</i>-carborane and various arylboronic acids [1-naphthyl-, phenyl-, 4-MeO-C₆H₄-, 3-CH₃CONH-C₆H₄-, 4-NC-C₆H₄-, 3-NO₂-C₆H₄-], gave the corresponding 2-aryl-<i>p</i>-carboranes in DME solution when reacted in the presence of cesium fluoride and the catalytic Pd₂(dba)₃–dppb system. Under the same conditions, the boron-boron bond forming reaction of two <i>p</i>-carboranylboronic esters (2-[(pinacolato)boron]-<i>p</i>-carborane and 2-[(neopentyl glycolato)boron]-p-carborane) was also shown feasible.</p><p><i>p</i>-Carborane has been vinylated on the 2-<i>B</i>-atom in high yields by use of the Heck reaction. The coupling between 2-I-<i>p</i>-carborane and various styrenes [4-H-, 4-C₆H₄-, 4-Cl , 4-Br-, 4-NO₂-, 4-CH3O- and 4 CH₃ ] resulted in the formation of the corresponding<i>trans</i>-β-(2-<i>B</i>-<i>p</i>-carboranyl) styrene in DMF solution when reacted in the presence of silver phosphate and the palladacycle Herrmann´s catalyst. The reaction was shown to proceed at higher rate with electron rich than with electron deficient olefins.</p><p>The feasibility of palladium-catalysed isotopic exchange of an iodinated closo-carborane with a radioisotope of iodine has been studied. 2-I-<i>p</i>-carborane was selected as a model compound. It was shown, that such isotopic exchange is possible and provides a high yield (83 ± 4.2 %) during 40 min long reaction. The reaction conditions were optimised, and it was demonstrated that presence of the tetra n-butylammonium hydrogensulphate is important in order to stabilise catalyst and provide reproducibility of labelling. In this work we have modified the methodology and extended the application to a wider range of iodinated carboranes. By the use of Herrmann’s catalyst in toluene at 100 °C this [¹²⁵I]-iodide labelling could be improved and extended. 2-I-<i>p</i>- 9-I-<i>m</i>-, 9-I-<i>o</i>-, 3-I-<i>o</i>-carborane, 1-phenyl-3-I-<i>o</i>-carborane and 1,2-diphenyl-3-I-<i>o</i>-carborane could be [¹²⁵I]-iodide labelled in high to excellent yields within 5 minutes.This reported palladium catalyzed radio-iodination of the uncharged closo-carboranes might find use in pharmacokinetic studies of carborane derivatives.</p>

This thesis describes the use of copper and palladium to mediate transformations of carboranes, especially p-carborane. 1-(1-p-carboranyl)-N-methyl-N-(2-butyl)-3-isoquinolinecarboxamide, a carborane containing analogue of the peripheral benzodiazepine receptor (PBR) ligand PK11195, has been synthesised. A key step in the reaction is the copper (I) mediated coupling of p-carborane with ethyl 1-bromo-isoquinoline-3-carboxylate. p-Carborane has been arylated on the 2-B-atom in high yields, using the Suzuki–Miyaura reaction. Thus the reaction between 2-I-p-carborane and various arylboronic acids [1-naphthyl-, phenyl-, 4-MeO-C6H4-, 3-CH3CONH-C6H4-, 4-NC-C6H4-, 3-NO2-C6H4-], gave the corresponding 2-aryl-p-carboranes in DME solution when reacted in the presence of cesium fluoride and the catalytic Pd2(dba)3–dppb system. Under the same conditions, the boron-boron bond forming reaction of two p-carboranylboronic esters (2-[(pinacolato)boron]-p-carborane and 2-[(neopentyl glycolato)boron]-p-carborane) was also shown feasible. p-Carborane has been vinylated on the 2-B-atom in high yields by use of the Heck reaction. The coupling between 2-I-p-carborane and various styrenes [4-H-, 4-C6H4-, 4-Cl , 4-Br-, 4-NO2-, 4-CH3O- and 4 CH3 ] resulted in the formation of the correspondingtrans-β-(2-B-p-carboranyl) styrene in DMF solution when reacted in the presence of silver phosphate and the palladacycle Herrmann´s catalyst. The reaction was shown to proceed at higher rate with electron rich than with electron deficient olefins. The feasibility of palladium-catalysed isotopic exchange of an iodinated closo-carborane with a radioisotope of iodine has been studied. 2-I-p-carborane was selected as a model compound. It was shown, that such isotopic exchange is possible and provides a high yield (83 ± 4.2 %) during 40 min long reaction. The reaction conditions were optimised, and it was demonstrated that presence of the tetra n-butylammonium hydrogensulphate is important in order to stabilise catalyst and provide reproducibility of labelling. In this work we have modified the methodology and extended the application to a wider range of iodinated carboranes. By the use of Herrmann’s catalyst in toluene at 100 °C this [125I]-iodide labelling could be improved and extended. 2-I-p- 9-I-m-, 9-I-o-, 3-I-o-carborane, 1-phenyl-3-I-o-carborane and 1,2-diphenyl-3-I-o-carborane could be [125I]-iodide labelled in high to excellent yields within 5 minutes.This reported palladium catalyzed radio-iodination of the uncharged closo-carboranes might find use in pharmacokinetic studies of carborane derivatives.

Le développement de plans synthétiques de molécules de complexité variable qui utilise des réactifs aisés d’accès et qui sont économes en atomes et en étapes est constamment au cœur des préoccupations du chimiste organicien pour accroître la diversité moléculaire de façon efficace et éco-responsable. La catalyse par les métaux de transition a permis de faire des progrès considérables dans la construction et la fonctionnalisation combinées d’hétérocycles d’intérêt à valeur ajoutée dans les sciences des produits naturels et les industries pharmaceutiques et phytosanitaires. Le principe synthétique consiste en l’enchaînement de processus standards élémentaires de transformations chimiques en un seul pot au sein de la sphère catalytique métallique. Un axe de progrès contemporain repose en particulier sur l’incorporation de processus de métallation catalytique de liaisons C-CO2H et C-H. Les travaux de thèse s’inscrivent dans ce jeune domaine de recherche initié au cours de la dernière décennie par plusieurs équipes de recherche dont celle de Jieping Zhu de l’école polytechnique fédérale de Lausanne compte parmi les pionnières et les plus actives. Ils ont visé notamment à implémenter consécutivement aux processus standards de carbopalladation intramoléculaire d’ortho-halogéno allénamides de Grigg de construction d’hétérocycles azotés très variés, d’une part des réactions d’allylation directe de la liaison C-H d’hétérocycles et d’énamides et d’autre part d’allylation décarboxylante d’acides propioliques. Après avoir évalué la réactivité des complexes pi-allypalladium conjugués à un atome d’azote dans la réaction, l’allylation directe de la laison C-H d’oxadiazoles et de 1,3-diazoles à fort caractère acide ainsi que des énamides, des séquences originales de construction et d’hétéroarylation combinées pallado-catalysées d’isoquinolinones et d’indoles ont été établies. Un protocole séquencé conduit en un seul pot et basé sur la génération in situ des allénamides, qui ne sont plus isolées, suivie de la réaction de construction et d’hétéroarylation combinées pallado-catalysée a ensuite été mis au point. Il a été exploité pour la préparation d’indoles, 1(2H)-isoquinoléïnones, isoquinoléïnes mais également des hétérocycles de taille supérieure, benzo-(2H)-azépine et benzo-(2H)-azocine intégrant des oxadiazoles et oxa(thia)zoles. Une première étude d’extension du concept synthétique a finalement été ciblée sur la construction et la propargylation combinée de la large gamme d’hétérocycles azotés obtenus précédemment en utilisant les acides propioliques comme partenaire de couplage. / The design of efficient and eco-friendly atom and step-economical synthetic plans of molecules using highly available starting materials is one of major objectives of organic chemist. Transition metal catalysis has allowed a bold step to build and functionalize consecutively, through a one-pot reaction, major nitrogen-containing heterocycles which are broadly present into numerous natural products, pharmaceutics and agrochemicals. The catalysis is based upon tandem inner-sphere elemental chemical transformations and one of major current challenge is to implement catalytic metallation of C-CO2H and C-H bonds. Involved in this young field of research initiated since the past decade from sevaral groups including pioneering and high active Jieping Zhu team of the Polytechnic School of Lausanne, the present study has been directed towards the design of innovative palladium-catalyzed domino Grigg nitrogen-containing heterocycles building through ortho-halogeno allenamides intramolecular carbopalladation process followed by direct C-H allylation of heterocycles and enamides or direct decarboxylative allylation of propiolic acids. After demonstrating the reactivity of nitrogen-conjugated pi-allypalladium complex in direct C-H allylation of acidic heterocycles, first palladium-catalyzed tandem build and heteroarylation of 1(2H)-isoquinoleinone and indole from ortho-halogeno allenamides was first envisaged. Efforts were next directed to the setting up of a one-pot protocol including in situ generation of allenamide followed by palladium-catalyzed domino building and functionalization of heterocycles. It was then hugely evaluated to the preparation of indole, 1(2H)-isoquinoleinones, isoquinolins as well as high-membred ring heterocycles such as benzo-(2H)-azepine and benzo-(2H)-azocine embedding with oxadiazoles and oxa(thia)zoles. An first extended synthetic concept towards the palladium-catalyzed tandem build and propargylation of nitrogen-containing heterocycles using sevral propiolic acids as coupling partners.