Final Report Summary - AMINATION (SYNTHESIS OF AMINES FROM ALCOHOLS BY METAL-CATALYZED REACTIONS) The project presented in this Marie Curie Action (Intra-European Fellowship, PIEF-GA-2012-328500) was mainly focused on developing new and efficient synthetic methods for biologically relevant chemical structures. More specifically, a variety of amines (compounds in which one or more hydrogen atoms in ammonia have been replaced by an organic functional group) is of significant importance for the bulk- and fine-chemical industry as building blocks for polymers and dyes, but also for the synthesis of pharmaceuticals, agrochemicals or food additives. In addition, many heterocyclic structures can be prepared from the corresponding amines, and they can be found in numerous bioactive compounds such as vitamins, hormones, alkaloids, neurotransmisors, or natural toxics.Despite nowadays many methods for their synthesis are well-known, the development of improved methods for the synthesis of amines and their derivatives continues to be a highly challenging and active area of research. In this project we propose to study the so called “hydrogen autotransfer” or “borrowing-hydrogen” process, a very advantageous methodology for this purpose because water is formed as the only by-product, the high reactivity of carbonyl compounds is used, easily accessible alcohols are employed as reagents, and it is not necessary to use expensive and waste-generating activation agents. However, there are still some limitations in this transformation which need to be solved, as well as it should be applied to the synthesis of more complex and biologically relevant compounds. Under these precedents, the aim of this project was the development of an efficient and versatile methodology for the synthesis of amines and their heterocyclic derivatives from alcohols by metal-catalyzed reactions. As specific objectives of this proposal we decided to study a varied range of substrates and the applicability of the methodology towards biologically active compounds, discovery of new catalysts (based majorly in ruthenium and iron complexes), identify the operating mechanism, and design chiral catalytic systems for performing enantioselective aminations.The first part of the postdoctoral stay was focused on the investigation of new strategies to carry out the synthesis of indoles, a highly relevant heterocycle present in many natural products because it binds to many receptors with high affinity. Thus, we developed two different ruthenium-based catalytic systems to perform their synthesis from easily available substrates such as anilines and epoxides. The use of atom-efficient sequential procedures and non-sensitive additives in catalytic amounts, as well as the formation of water and hydrogen as only by-products, makes the protocol convenient and easy to use. Our results demonstrate that this methodology is valuable for the synthesis of heteroarenes through metal-catalyzed reactions.Once studied the synthesis of this relevant structural moiety, we proposed to access other important heterocycle such as butyrolactones through sequential formation of two different bonds using hydrogen autotransfer. This unit is usually taking part of more complexes frameworks, especially polycyclic ring systems, which display broad biological activities. This relevance makes it very attractive for the discovery of novel potential drugs, so new synthetic procedures are of special interest. In this way, we were able to perform the synthesis of a variety of lactones in good yields by application of a specific ruthenium catalyst (Ru-MACHO-BH), generating for the first time a C-C and a C-O bond using a dehydrogenation-hydrogenation sequence. The regioselectivity as well as the high atom-economy of this process are remarkable features.In line with this direction, we also were interested in the synthesis of oxazolidinones, a chemical structure present in several antimicrobials and antibacterials, and a very useful reagent in asymmetric synthesis as a chiral auxiliary (Evan’s oxazolidinones). In this case, ureas and vicinal diols were used as building blocks to sequentially construct two different C-O and C-N bonds through nucleophilic substitution and amination reactions. In addition to the high chemo- and regioselectivity shown by this environmentally benign ruthenium-catalyzed protocol, we here also developed an asymmetric version which is related to one of the general objectives established in the proposal.After studies on ruthenium-catalyzed hydrogen autotransfer processes to access relevant heterocycles such as indoles, butyrolactones and oxazolidinones, we decided to analyse the reactivity of more green and environmentally friendly iron-complexes in related transformations. Hence, we reported the synthesis of industrially relevant lactones and lactams from corresponding 1,n-diols and 1,n-amino alcohols using a dehydrogenative methodology. An iron(II) pincer catalyst (Fe-MACHO-BH) was used in this atom-efficient process, for which hydrogen is formed as only stoichiometric side product. The ability to access heterocycles of different sizes makes this protocol especially versatile, in which two consecutive oxidation reactions are performed without requiring an external oxidant.Following with iron-catalyzed processes, the synthesis of cyclic carbonates was developed from diols and urea as CO source by using the simple iron(II) bromide as catalyst. Although several methods are well-known for the synthesis of such compounds, a general and systematic study using easily available and benign substrates and catalysts was still required. The versatility is also here a remarkable feature since the application of ruthenium or iron catalysts to the reaction of urea with diols, allowed obtaining the respective oxazolidinones and cyclic carbonates in a selective manner. As final part of this research period, and after the discovery of new ruthenium and iron-catalyzed protocols for the synthesis of important chemical structures, we decided to expand our knowledge by exploring new synthetic methods. In this sense, photocatalytic methods are currently very relevant due to the numerous benefits associated. For this reason, and with the intention of conduct research in the future, we summarized in a highlight paper the recent developments in the area of asymmetric carbon-carbon bond formation using combined photoredox and coupling reactions. These reactions open new avenues for asymmetric catalysis whereby light is used as green energy source.In order to resume the research activities, we can conclude that most of the objectives and technical goals initially proposed were successfully achieved. The developed protocols provided new and sustainable methods for the synthesis of biologically relevant compounds. They might potentially present a high impact on the scientific community since they can be used as synthetic alternative, as well as inspiration for the discovery of new catalytic processes.This experience provided the fellow a deep understanding for relevant research, and thus enabling him to carry out future high quality research projects independently. In addition to his previous experience, he has extended his training by developing new catalytic processes and using new techniques in one of the Europe’s leading institute. Summed to the general skills valuable in the fellow’s future career, this research period provided the following specific training: promotion of scientific independence, as well as teamwork, teaching and managerial skills; personal development from different working/cultural environments; practice of oral and written presentations; creation of personal and host communication networks; introduction to new practical and analytical techniques and instrumentation. This postdoctoral stay funded by the European Comission has given to the fellow the opportunity to conduct research in different areas providing an excellent portfolio of experiences with which to embark on a future scientific career.On the other hand, during this period the fellow had the opportunity to divulge his scientific activities for the general public in order to sensitize about the relevant work that have the chemical laboratories in society and more specifically those related to the pharmaceutical industry. The following dissemination activities were carried out during this research period: several publications in prestigious international journals, participation in relevant symposiums, seminars in his origin Spanish university, supervision of students which allowed transferring the previously acquired knowledge, and other general activities focused to the general public.Finally, it is important to mention that during the course of this research period, no major problems were detected in terms of project management. Fortunately everything worked perfectly and the different departments of the Leibniz Institute for Catalysis, where the research stay took place, have been commissioned to carry out their functions successfully. We can state that implementation of the project proceeded satisfactorily, with unique and expected problems associated exclusively with the research itself (very common issue in the field of Chemistry), because the management have not had associated any unusual problem. Related documents final1-graphical-summary-of-work-achievements-pief-ga-2012-328500-.pdf
