Tailored homogeneous catalytic methodologies for the sustainable synthesis of value-added chemicals

Abstract

My research, which has been carried out during my PhD in Chemical Science (XXXI cycle), has as main theme sustainable catalysis. My objective was the development of tailored homogeneous catalytic methodologies for the sustainable synthesis of value added chemicals. In this context, I firstly investigate the activity of an innovative catalytic system composed of palladium and potassium iodide. This winning combination allows a smooth activation of aryl bromides in coupling chemistry and in C-H activation. The above-mentioned catalytic system was applied to the synthesis of isocoumarins. The procedure involves 2-alo benzoates and easy accessible and abundant ketones, catalyzed by a commercially available Palladium source. This method features the α-arylation of the ketone and the intramolecular condensation with the ester group. The use of potassium iodide proved to be essential to boost the selectivity when 2-bromo benzoates were employed. To obtain more insights in the role of KI, we tested 2-iodo benzoates, which were successfully coupled in absence of iodine anions. From a mechanistic point of view, KI can trigger an halogen exchange reaction or promote the in situ formation of highly nucleophilic palladium species able to increase the oxidative addition rate of aryl bromides to Pd(II) complexes. Using 2-iodo benzoates in presence of KI we noticed a remarkable decrease in reaction time (from 24 hours to 8 hours) and, since the so called halogen effect cannot take place, the present result strongly supports that the role of iodide anions is crucial in the coordination of the metal center. The synthetic usefulness of this approach is furthermore demonstrated with the synthesis of Xiridine A, in only two reaction steps. The same combination was successfully employed in the synthesis of tailor-made functionalized dibenzo[b,f]azepine from commercially available starting materials. The presence of iodide anions that acts as competing ligands is crucial to enhance selectivity and reactivity. The synthetic utility of this protocol was further demonstrated with the formal synthesis of Clomipramine®, prepared in three steps from commercial reagents. The reaction mechanism involves sequential ortho C-H activation and double ortho and ipso functionalization of aryl bromides. Since both staring materials can undergo to oxidative addition to the palladium species, competing experiments were proposed in order to ascertain the most probable pathway. An organometallic intermediate was trapped with the fast Suzuki-Miyaura coupling, so we proved that the aryl bromide, and not the o-bromoaniline, starts the catalytic cycle. Then my attention was drawn into useful methodologies, including also the application of new technologies, to achieve sustainable and benign approaches for the synthesis of value-added molecules. From the energetic point of view one of the most accessible and greener source of energy is, beyond any doubt, solar energy. The use of visible light to promote a chemical reaction is highly desirable for an environmentally benign chemistry. In this context I developed an innovative photocatalytic strategies for the oxidation and dearomatization of naphtobenzo azepine derivatives using molecular oxygen as oxidant. We tested different substituents and this methodology proved to tolerate diverse functional groups providing from excellent to good yields. Further studies are ongoing in the laboratory to enlarge the generality of this transformation and to support with experimental evidences the proposed catalytic cycle. During my second year I spent eight months at the Eindhoven University hosted by Prof. Timothy Noël. Taking advantage by the experience of the hosting group, continuous flow processing, I develop a highly practical and efficient continuous-flow platform for homogeneous and gas-liquid Catellani-type reactions. The use of gaseous olefins allows to significantly expand the scope of Catellani-like reactions, providing access to a series of relevant ortho-disubstitued styrenes and vinyl arenes in an atom-efficient fashion. A control experiment was also performed to demonstrate the key role of flow technology to enable efficient gas-liquid transformations. When the same gas-liquid reaction was carried out in batch, uncontrolled and inefficient use of the gaseous olefin and the evaporation of norbornene into the headspace resulted in a lower yield for the desired product (12% batch vs 66% flow) along with the formation of several by-products. Furthermore, the use of flow also allows to readily scaling the reaction conditions (1.26 g of product). Another interesting aspect in terms of sustainability is the attempt to replace metal catalysts with organic ones especially in the synthesis of active pharmaceutical ingredients (API). With this goal in mind I studied the first base-catalyzed intramolecular hydroamidation to highly substituted imidazolidin-2-ones and imidazol-2-ones. Notable features of this methodology include (i) excellent chemo- and regio-selectivity to 5-membered cyclic ureas, (ii) ample substrate scope and high functional group tolerance, (iii) very mild reaction conditions and short reaction times, (iv) key mechanistic insights on the reaction pathways. Further, the feasibility of the one-pot step-economical protocol starting from propargylic amines and isocyanates was demonstrated. I also exploited a complementary approach to the base catalyzed hydroamidation of propargylic ureas. This silver (I) catalytic procedure allows a smooth activation of propargylic ureas bearing an alkylic fragment unreactive under the previously reported methodology and almost completely unexplored in other methodologies. In literature only another example is reported with one similar substrate achieving low yield with high temperature and catalyst loading. The reported approach involves the use of a cheap source of silver (silver nitrate) employing methanol as a benign reaction media. Also in this case the possibility to obtain these compounds with a one-pot reaction was reported.