Functionalization of organic substrates with aryl and alkyl palladium derivativesstoichiometric and catalytic studies

Abstract

The targets of this PhD Thesis consisted in the development of new methodologies and strategies for the functionalization of C-H and C-C bonds in either a stoichiometric or catalytic way by using palladium. The isolation of organometallic complexes of palladium(II) and the study of the mechanism involved in the catalytic cycles were also relevant goals of this work. The scientific content is structured in five chapters, in the chronological order they were carried out, and two appendixes. Prior to the discussion of the new results, the Chapter I serves as a general introduction in which the relevance of catalysis and cross-coupling reactions in the field of transition metals is emphasized. Particularly, the use of palladium in organic synthesis is described. Some examples of well-known palladium-mediated coupling reactions, cascade reactions, and remote C-H activations are highlighted. As an extension of the previous studies of our research group in the field of orthometalation of primary amines, Chapter II describes the functionalization of a benzofuran core bearing a tethered primary amine at the 3-position, mediated by palladium. The preparation of new orthopalladated complexes and the study of their further reactivity to get organic benzofuran derivatives are deeply described in this chapter. In addition, the work was completed with the direct catalytic alkenylation of the benzofuran core. In connection with our interest in C-H activation, the Chapter III describes the results dealing with a challenging aim: the design of a palladium-catalyzed cascade reaction. In this case, basic transformations took place sequentially on conveniently selected polyfunctional starting materials such as: a) the oxidative addition of ArX to a Pd(0) complex, b) the intramolecular carbopalladation of an unsaturated species, and c) a remote C-H functionalization step (arylation or alkylation depending on the coupling partner we use). Two different cascade reactions based on the intramolecular Heck arylation of substrates bearing a tethered alkene are described. These cascade reactions proceeded via remote C-H bond activation performed by sigma-alkyl Pd intermediates, arising form the intramolecular carbopalladation of the substrate after an initial oxidative addition. The two distinct reactions that were studied involved the use of arynes and diazocarbonyl compounds as coupling partners, respectively. Both types of reactions led to the formation of interesting spirocyclic molecules. This Chapter includes a thorough study on the reaction pathway operating in these transformations, and for instance, several organometallic intermediates were isolated and conveniently characterized. In Chapter IV a proof-of-concept for the cleavage of non-strained C(sp3)-C(sp3) bonds is described. In this process a palladium-mediated C(sp3)-H activation through a tethered 8-aminoquinoline group was followed by the asynchronous concerted insertion of a carbene into the Pd-C bond, and one unexpected ?-carbon elimination reaction. To our knowledge, this transformation represents a new case of directed C-C bond cleavage, which hopefully could provide inspiration for future catalytic developments. The Chapter V collects the experimental part corresponding to the Chapters II-IV, including the synthetic procedures and the characterization data of the new compounds. Regarding the methodological aspects of this PhD Thesis, a great variety of instrumental techniques have been applied to assess the analysis of the molecular structures and reactivity of the different species that have been studied. Hence, the data obtained from NMR spectroscopy, X-ray diffraction, HRMS spectrometry, elemental analysis and computational calculations, among others, appear along the discussion and experimental section of this work. In the appendixes A and B crystallographic data (including CIF files), and IR, 1H, 13C, 19F and 31P NMR spectra of the prepared organic and organometallic compounds are included. Additionally, this Thesis accomplishes the requirements to get the International Doctorate Certificate according to the doctorate regulations of the University of Murcia, since I spent a three-months research stay at the University of Vienna, working under the supervision of Prof. Vittorio Pace.