Abstract. In this thesis the synthesis of potentially biologically active heterocyclic compounds has been developed through novel catalytic methods involving C-N and C-O bond forming processes. The thesis consists of three main chapters: a) oxidative intramolecular palladium(II)-difunctionalizations of alkenes (Chapter 1); b) iodine species as a powerful tool in oxidative ring closing reaction (Chapter 2); c) intramolecular rhodium(I) allylic addition to afford α-vinyl-substituted heterocycles (Chapter 3). In Chapter 1.1 an aminoarylation process of allylic ureas has been investigated as a tool to construct 4-substituted imidazolidinones. In the presence of aryltin nucleophiles and hydrogen peroxide as an inexpensive and green oxidant, a 5-exo-regioselective procedure has been developed. On the other hand, when the homoallylic urea is used under similar conditions the seven-membered ring is obtained as a consequence of the β-elimination accountable to a Pd(II)/Pd(0) catalytic cycle. In Chapter 1.2 an intramolecular alkoxyacylation is described employing an hypervalent iodine (III) as both the acylating and oxidizing reagent. A regioselective 6-exo-trig Pd(II)-catalysed cyclisation of N-allyl aminophenol and N-allyl aminoethanol affords benzoxazine and morpholine nuclei, respectively. The synthetic utility of this new products is demonstrated through two-step transformations into purine derivatives, which are used for the treatment and prevention of cancer, and into β-aminoacids. In Chapter 2.1 it is reported the development of an intramolecular domino-type Diels Alder reaction initiated by hypervalent iodine reagents. The employment of N-allyl 2-aminophenols as substrates leads to the formation of a tricyclic system in the sole presence of I(III) species. Moreover, the insertion of various nucleophiles on the α-position of the amino group opens up the way to further unexplored functionalizations. The substrate scope is investigated varying both substituents on the aromatic ring, protective groups and nucleophiles, affording the respective products in 23-67% yields. In Chapter 2.2 a metal-free aminoiodination of O-allyl Ts-protected carbamates is described. Thus, by using hydrogen peroxide and potassium iodide in aqueous media, iodomethyl-substituted heterocycles are obtained in good yields and for selected substrates in a diastereoselective way, too. The reaction proceeds through the formation of an iodonium intermediate with the subsequent attack of the nitrogen in anti. In Chapter 3.1 an intramolecular hydroamination of Ts-protected allenyl amines is investigated. The ability of Rh(I) to catalyse a hydroamination process in a complete selective way, mostly modulating the type of ligand employed, is herein shown. Vinyl-substituted benzoxazine and benzoxazepine have been obtained in good yields and excellent enantioselectivity, as it has never been done before, by employing Josiphos J688-1 ligand and PPTS as co-catalyst. In Chapter 3.2 the results regarding the intramolecular hydroalkoxylation of allenyl alcohols are reported. N-allenyl aminoethanol, N-allenyl aminophenol, allenyl alcohols and allenyl phenols are subjects of our research. Despite the substrate diversity, the chiral ferrocelane diphosphine ligand, (R,R) Me-ferrocelane, is proven optimal for the intramolecular OH-addition to allenes. High yields and good enantioselectivity can be reached varying the Brønsted acid, employed as additive in the reaction. In conclusion, oxidative palladium(II)-catalysed alkene difunctionalizations, hypervalent iodine-promoted dearomatizing intramolecular Diels-Alder reaction, oxidative aminoiodinations and intramolecular enantioselective rhodium(I)-catalysed hydroaminations and alkoxylations of allenes are approaches described in this thesis as valuable methods for the construction of medicinally relevant heterocycles.
SYNTHESIS OF NITROGEN-CONTAINING HETEROCYCLIC SYSTEMS OF BIOLOGICAL INTEREST THROUGH DOMINO STRATEGIES / S. Giofre' ; tutor: E. M. Beccalli ; coordinatore: G. Aldini. - Milano : Università degli studi di Milano. Università degli Studi di Milano, 2020 Jan 22. ((32. ciclo, Anno Accademico 2019.
|Titolo:||SYNTHESIS OF NITROGEN-CONTAINING HETEROCYCLIC SYSTEMS OF BIOLOGICAL INTEREST THROUGH DOMINO STRATEGIES|
|Supervisori e coordinatori interni:||ALDINI, GIANCARLO|
|Data di pubblicazione:||22-gen-2020|
|Parole Chiave:||[domino reactions; heterocyclic compounds; amination; alkoxylation; Pd(II) chemistry; Rh(I) chemistry]|
|Settore Scientifico Disciplinare:||Settore CHIM/06 - Chimica Organica|
|Citazione:||SYNTHESIS OF NITROGEN-CONTAINING HETEROCYCLIC SYSTEMS OF BIOLOGICAL INTEREST THROUGH DOMINO STRATEGIES / S. Giofre' ; tutor: E. M. Beccalli ; coordinatore: G. Aldini. - Milano : Università degli studi di Milano. Università degli Studi di Milano, 2020 Jan 22. ((32. ciclo, Anno Accademico 2019.|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.13130/giofre-sabrina_phd2020-01-22|
|Appare nelle tipologie:||Tesi di dottorato|