Palladium Catalyzed C–H activation of arylethyl amines and their derivatives: application to the construction of heterocyclic compounds
[eng] 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...
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| Tipo de recurso: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2017 |
| País: | España |
| Institución: | Universidad de Barcelona |
| Repositorio: | Dipòsit Digital de la UB |
| OAI Identifier: | oai:diposit.ub.edu:2445/111616 |
| Acceso en línea: | https://hdl.handle.net/2445/111616 http://hdl.handle.net/10803/403465 |
| Access Level: | acceso abierto |
| Palabra clave: | Compostos heterocíclics Pal·ladi (Element químic) Amines Heterocyclic compounds Palladium |
| Sumario: | [eng] 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. |
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