Palladium Catalyzed C–H activation of arylethyl amines and their derivatives: application to the construction of heterocyclic compounds

Abstract

The development of selective methods for the direct conversion of carbon−hydrogen bonds into carbon-heteroatom and carbon−carbon bonds remains a critical challenge in organic chemistry. An interesting approach to address this issue involves the use of substrates that contain coordinating atoms (or directing groups) that bind to the metal center in a first step, and a further rearrangement allows the C−H bond activation. A variety of palladium, rhodium, ruthenium, iridium, rhenium, and copper and, to a lesser extent, manganese, nickel, iron, and cobalt metal derivatives have been shown to be effective in this process. Palladium complexes are particularly attractive catalysts for such transformations because ligand-directed C−H functionalization at Pd(II) centers can be used to obtain different types of C−Y bonds (Y being carbon, oxygen, nitrogen, sulfur, or halogen). Furthermore, Pd(II) can activate C−H bonds, both at sp2 and sp3 sites, and a wide range of catalytic processes has been described with different nitrogen-based directing groups. These include amides, pyridines, triazoles, pyrroles, imines, oximes, azobenzenes, amines, carboxylic acids, ketones, aldehydes, esters, and hydroxyl derivatives. In contrast, few examples of the use of primary amines as directing groups have been described in spite of the fact that this functional group is ubiquitous in organic structures, probably because the NH2 group is too reactive toward different organic functions and also can easily coordinate too tightly to transition-metal centers. In this thesis, a quite large survey of different processes based on C-H activation of arylethyl amines and their derivatives is reported. In the first part of the work, the reactivity of palladium-activated primary amines with carbonyl surrogates or radical species was tested. The outcomes suggested that the substrates that we employed were not reactive in absence of radicals, while several undesired secondary reactions were observed in the presence of radical species. It was never possible to obtain a satisfactory selective functionalization. In the second part of the thesis, a palladium–catalyzed reaction for the construction of tetrahydroisoquinolines was developed starting from primary amines. The process was based on a tandem palladium-mediated olefination-annulation reaction. An extense search of suitable amines and olefins was performed and the synthesis of several functionalized tetrahydroisoquinolines was achieved thanks to the combination of various α-functionalized arylethyl amines and different olefins. Afterwards, the reactivity of oxidized analogs of phenylethyl amines in C-H activation processes was studied in order to develop catalytic reactions in absence of external oxidants. O-Acyl hydroxylamines allowed the olefination-annulation reaction for the construction of tetrahydroisoquinolines (cited in the previous paragraph) without the need of further oxidizing agents. In some cases, the desired products were obtained in better yields, compared to the original conditions. Unfortunately, the oxidized substrates were not useful to the overcoming of the structural limitations that had been observed in these reactions, nor to the development or improvement of different C-H activation processes. In the fourth part of the work, we tested the use of imines, as an amine surrogate that could be eliminated by hydrolysis at the end of the reaction. As a result, the isolation of a new palladium

complex with three coordinating centers was accomplished and a new palladium-catalyzed reaction for the construction of N-acylated indolines starting directly from primary amines was developed. This transformation was never reported before. Unfortunately, the yields and the scope of the reaction were only moderate. Furthermore, the oxidation of the imine to amide did not agree with the original aim of introducing an easy removable directing group in the structure of the substrates. Finally, the reactivity of aromatic sulphones obtained with our olefination-annulation reaction was launched. Thanks to this research an unusual reaction leading to the elimination of the sulphone and the consequent formation of dihydroisoquinolines was discovered. The functionalization of these products and the finding of the appropriate conditions for a modified Julia reaction (starting from bis(trifluoromethyl)phenyl sulphones, allowed us to prepare several kinds of functionalized or unsaturated tetrahydroisoquinolines that were difficult to prepare by other methodologies.

En la Memoria de Tesis se recoje un amplio estudio de diferentes procesos basados en la activación C-H de ariletil aminas y sus derivados. En la primera parte del trabajo se ensayó la reactividad de aminas primarias activadas por paladio con distintos equivalentes sintéticos de grupos carbonilos o con especies radicalarias. Resultó que los substratos utilizados no eran reactivos en ausencia de radicales, mientras que experimentaban muchas reacciones colaterales en su presencia. En ningún caso se pudo obtener una funcionalización mayoritaria de forma satisfactoria. En la segunda parte de la tesis se trabajó en el desarrollo de una reacción catalizada por paladio para la obtención de tetrahidroisoquinolinas a partir de aminas primarias, basándonos en una potencial reacción de olefinación-ciclación catalizada por paladio. Desarrollamos una vasta exploración de las aminas y de las olefinas utilizables en el proceso y se logró la síntesis de muchas tetrahidroisoquinolinas funcionalizadas gracias a la combinación de diferentes ariletil aminas α-cuaternarias con varias olefinas. Seguidamente se ensayó la reactividad en procesos de activación C-H de análogos oxidados de feniletil aminas con la finalidad de desarrollar procesos catalíticos en ausencia de oxidantes externos. Las O-acilhidroxilaminas permitieron realizar el proceso de olefinación-addición de Michael para la obtención de tetrahidroisoquinolinas (descrita en la precedente parte del trabajo) en ausencia de oxidante, llevando en algunos casos a la síntesis de los productos deseados en mayor rendimiento. Lamentablemente los substratos oxidados no se revelaron adecuados para superar las limitaciones estructurales que se habían observado por esta reacción ni para su utilizo en otros procesos de activación C-H. En la cuarta parte del trabajo se ensayó el uso de iminas, como grupo director equivalente al grupo amino de las ariletil aminas pero que podía ser eliminado posteriormente por hidrólisis. Este estudio llevó al aislamiento de un nuevo complejo de paladio con tres centros de coordinación y al desarrollo de una reacción catalizada por paladio para la construcción de precursores de indolinas a partir de aminas primarias, nunca descrito anteriormente. Desafortunadamente los rendimientos y el campo de aplicabilidad del proceso fueron sólo moderados. Además, la oxidación de las iminas a amidas, que ocurría en el proceso de ciclación, no estaba de acuerdo con la idea inicial de introducir grupos quelantes fáciles de eliminar. Finalmente se estudió la reactividad de modelos de sulfonas aromaticas construidas gracias a la reacción de olefinación-ciclación descrita en el segundo capítulo de la memoria. Fruto de este trabajo se descubrió una reacción inusual de eliminación de la sulfona y la posterior formación de dihidroisoquinolinas. La funcionalización de estos productos y la búsqueda de condiciones adecuadas para una reacción de Julia modificada a partir de bis(trifluorometil)fenil sulfonas permitió la síntesis de varios tipos de tetrahidoisoquinolinas funcionalizadas o insaturadas, difíciles de obtener por otras metodologías.