Dipartimento di Chimica e Tecnologie Chimiche

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Synthesis of high value added molecules by catalytic and heterocyclization approaches
(2018-05-11) Mancuso, Raffaella; Critelli, Salvatore; Gabriele, Bartolo
In the present PhD thesis is reported the development of new sustainable catalytic processes for the production of high value added molecules starting from simple and readily available building blocks, under safer and low-intensive energy conditions, by iodocyclization, carbonylation and cycloisomerization reactions in non-conventionl solvents such as Deep Eutectic Solvents (DES) and Ionic Liquids (ILs). Catalytic processes, in which several different units can be assembled in one step in ordered sequence under the promoting action of a suitable catalyst, are destined to play a central role in current synthesis. Of particular importance is the development of novel catalytic processes for the reconversion of CO and CO2 into organic molecules. CO is an inexpensive and readily available C-1 source, and its incorporation into an organic substrate (carbonylation) is now widely recognized as a very important tool in synthesis. Nowadays, carbonylations are at the basis of important industrial technologies for the conversion of easily available feedstocks into useful products of our daily life, and find increasing application in organic synthesis for the production of fine chemicals. CO2 is another very attractive C-1 feedstock for organic synthesis. It is ubiquitously available, low toxic, and abundant. Since the industrial revolution, CO2 has been continuously released in huge amounts in the atmosphere from all combustion processes of organic carbon for the production of energy. Therefore, the efficient reconversion of CO2 (“spent” carbon) into high value added products (“working”-carbon; chemicals, fuels, materials) is one of the current most important strategic goals in chemical research, which will allow to make a step forward toward a more sustainable economy. Non-conventional solvents, such as polyethylene glycols, ionic liquids (ILs), Deep Eutectic Solvents, or supercritical CO2 are less toxic and more eco-friendly than traditional organic solvents. Their use in the processes studied in this thesis allowed an easier separation and purification of the products and, in the case of catalytic reactions, the recycling of the catalyst as well. The direct syntheses of ureas, oxamides, 2-oxazolidinones, and benzoxazolones by oxidative carbonylation of amines, β-amino alcohols, and 2-aminophenols allows obtaining high value added molecules, with a large number of important applications in several fields, starting from very simple building blocks. In chapter two is reported the possibility to carry out these transformations using the PdI2/KI catalytic system in an ionic liquid (IL), such as BmimBF4, as the solvent. The catalyst-solvent system can be recycled several times with only a slight loss of activity, while the product can be easily recovered by crystallization. In the some chapter the reactivity of 2-(2-alkynylphenoxy)anilines under PdI2/KI-catalyzed oxidative carbonylation conditions has been studied. 8-endo-dig cyclization preferentially occurred when the triple bond was terminal, leading to the formation of carbonylated β-lactam derivatives. These novel medium-sized heterocyclic compounds showed anti-tumor activity against both estrogen receptor-positive (MCF-7) and triple negative (MDA-MB-231) breast cancer cell lines. In chapter three is showed that the heterocyclodehydration and iodocyclization of readily available 1-mercapto-3-yn-2-ols has been performed in a deep eutectic solvent (DES), that is, ChCl/Gly, as a non-conventional green solvent. The DES/catalytic system could be easily recycled several times without appreciable loss of activity, after extraction of the thiophene product with hexane or Et2O. In chapter three the first example of a tandem thionation/S-cyclization process leading to benzo[c]thiophene-1(3H)-thione and 1H-isothiochromene-1-thione derivatives, starting from 2-alkynylbenzoic acids, is also reported. Depending on the nature of the substituent at the distal β carbon of the triple bond, either benzothiophenethiones or isothiochromenethiones were obtained selectively, in high to excellent yields. In chapter four a novel methodology to easily access imidazolidin-2-ones from propargylamines, primary amine and CO2 with guanidine bases as catalysts under solvent-free conditions is reported. Bicyclic guanidines, able to catalyze the formation of oxazolidinones from propargylamines and CO2, are presented for the first time as effective organocatalysts for the chemical fixation of CO2 into linear and cyclic ureas.
New palladium catalyzed carbonylation processes for the synthesis of molecules of applicative interest
(2016-02-26) Ziccarelli, Ida; Mancuso, Raffaella; Gabriele, Bartolo
In the present investigation we have developed new palladium-catalyzed carbonylation processes for the synthesis of molecules of applicative interest. In particular, isoindolinone and isobenzofuranimine derivatives have been synthetized starting from 2-alkynylbenzamides by a divergent PdI2-catalyzed multicomponent carbonylative approach, depending on the nature of the external nucleophile and reaction conditions. Thus, oxidative carbonylation of 2- ethynylbenzamides, bearing a terminal triple bond, carried out in the presence of a secondary amine as external nucleophile, selectively led to the formation of 3- [(dialkylcarbamoyl)methylene]isoindolin-1-ones. On the other hand, 3-[(alkoxycarbonyl)methylene]-isobenzofuran-1(3H)imines were selectively obtained when the oxidative carbonylation of 2-alkynylbenzamides, bearing a terminal or an internal triple bond, was carried out in the presence of an alcohol R'OH (such as methanol or ethanol) as the external nucleophile and HC(OR')3 as a dehydrating agent, necessary to avoid substrate hydrolysis. Isoindolinone derivatives were used as starting material to obtain the corresponding spiro-isoindolin isoxazolidines, able to work as inhibitors of the p53-MDM2 interaction: biological test showed that these compounds have antiproliferative activity on cancer cell lines of neuroblastoma, colorectal adenocarcinoma and hepatocarcinoma in the μM range. Isobenzofuranimine derivatives, instead, showed a strong phytotoxic effect on shoot and root systems of Arabidopsis thaliana, a weed which compete with crops for edaphic resources such as water and nutrients. Furo-furanone derivatives have been synthetized by PdI2-catalyzed oxidative carbonylation starting from 4-yn-1,3-diols, substrates bearing themselves nucleophilic groups in a suitable position to give a “double” intramolecular nucleophilic attack so as to obtain functionalized bicyclic molecules. Biological assay showed that these compounds are promising anticancer agents. Finally, part of this PhD was spent at Leibniz Institute for Catalysis in Rostock University in order to develop a new heterogeneous catalyst based on palladium via immobilization and pyrolysis on activated carbon. Palladium supported on N-doped carbon was applied to the alkoxycarbonylation of aryl iodides to benzoates, important feedstocks and key intermediates for pharmaceuticals.
Pdl2 catalyzed oxidative carbonylation of anime derivatives leading to macrolactam, urea, oxamide, oxazolidinone and benzoxazolone derivatives
(2014-12-01) Dnyaneshwar, Shriram Raut; Bartolino, Roberto; Bartolo, Gabriele; Mancuso, Raffaella
Sintesi di derivati benzofuranici e chinolinici mediante eterociclizzazione Pd-0 Cu-Catalizzata
(2006) Mancuso, Raffaella; Gabriele, Bartolo; Salerno, Giuseppe; Sindona, Giovanni

Dipartimento di Chimica e Tecnologie Chimiche - Tesi di Dottorato

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