New Palladium-Catalysed Intramolecular Coupling Reactions: Nucleophilic Addition toAldehydes and C-H Carbene Insertion

[eng] Although sygma-aryl and sygma-vinylpalladium(II) complexes are commonly used as electrophiles in C—C bond forming reactions, recent research has demonstrated that the same palladium intermediates can also react with carbon-heteroatom multiple bonds in a nucleophilic manner. Continuing with the interest of our group on the palladium-catalysed intramolecular coupling of aryl halides whit carbonyl compounds, we have expanded our previous findings to substrates containing other carbon-heteroatom multiple bonds. In this context, the first objective of the PhD Thesis has been the study of the dual nature of the sygma-arylpalladium(II) species in aldehyde containing compounds. Thus, after some preliminary studies on the ambiphilic character of the sygma-arylpalladium(II) intermediates involved in the palladium-catalysed intramolecular reactions of (2-iodoanilino)-aldehydes, we have described an efficient new methodology for the synthesis of dibenzo[b,e]azepin-11-ones based on the intramolecular acylation of aryl iodides with aldehydes. Continuing whit our interest in these nucleophilic addition processes, we have developed an efficient methodology for the preparation of a small library of tetrahydroisoquinolin-4-ols based on the palladium-catalysed intramolecular nucleophilic addition of a-(2-iodobenzylamino)- aldehydes. Finally, we have expanded the influence of the heteroatom (nitrogen, oxygen, and sulphur) on the course of the palladium-catalysed intramolecular reactions of aryl iodides and aldehydes having heteroatom—containing tethers. Through an extensive experimental-computational (DFT) study we have concluded that the nature of the heteroatom in the tether is not decisive for the outcome of these reactions. Continuing our research for methodologies that help us to increase the synthetic potential of organopalladium chemistry, we decide to investigate the feasibility of the palladium-catalysed intramolecular coupling of aryl halides and diazoderivatives as a methodology for the synthesis of nitrogen heterocycles. So, the second objective was the study of the Pd-catalysed intramolecular coupling of aryl halides with N-tosylhydrazones and sygma-diazoesters in nitrogen containing substrates. We have found that palladium can be used to catalyse the C(sp3)-H insertion of metal carbenoids derived from sygma-diazoesters to form pyrrolidines through intramolecular assembly of C(sp3)-C(sp3) bonds. This reaction is the first example of palladium-catalyzed C(sp3)-C(sp3) bond assembly starting from diazocarbonyl compounds. The coupling reaction can be catalyzed by both Pd(0) and Pd(II), is regioselective, and shows a broad functional group tolerance. [spa] Las especies de tipo sigma-aril y sigma-vinilpaladio(II) actuan generalmente como electrofilos en las reacciones de formacion de enlaces C—C. Durante los ultimos anos se ha demostrado que en ciertos casos estas mismas especies pueden cambiar al caracter electrofilo usual por un caracter nucleofilo y adicionarse a enlaces multiples carbono-heteroatomo. En este sentido, se ha estudiado el caracter ambifilico (electrofilo vs. nucleofilo) de los intermedios de 6-arilpaladio(11) derivados de 2-haloanilinas frente al grupo formilo. Hemos sido capaces de controlar la reactividad (sigma-arilacion vs. acilacion del haluro arilico) de esos intermedios mediante la modificacion de las condiciones de reaccion. Eso ha permitido desarrollar una metodologia eficiente para la sintesis de una pequena libreria de dibenzoazepinas, compuestos importantes desde el punto de vista farmaceutico, mediante la reaccion de acilacion nucleofila intramolecular catalizada por Pd(0). A continuacion hemos centrado nuestro interes en la reaccion de adicion nucleofilica intramolecular de yoduros arilicos a aldehidos catalizada por Pd(0) en sustratos de tipo sigma-(2- iodobenzylamino)-aldehido. Esta reaccion ha permitido la sintesis de diversas tetrahydroisoquinolin-4-oles. Para finalizar el estudio de las reacciones de acoplamiento intramolecular de yoduros arilicos con aldehidos catalizadas por Pd(0) en sustratos de tipo 2-iodoanilino- y sigma-(2- iodobenzylamino)-aldehidos, hemos investigado la influencia que los heteroatomos de nitrogeno, oxigeno y azufre poseen en el curso de la reaccion. El estudio combinado experimental-computacional (DFT) ha permitido concluir que la naturaleza del heteroatomo no juega un papel clave en ese tipo de transformaciones. La segunda parte de esta Tesis Doctoral se ha focalizado en el estudio de las reacciones de acoplamiento catalizadas por paladio entre yoduros de arilo y diazo derivados. El estudio ha permitido el descubrimiento de una nueva metodologia para la sintesis de pirrolidinas basada en la reaccion de insercion de carbenos de paladio derivados de sigma-diazoesteres sobre enlaces C(sp3)—H.