Development of metal oxide-based organic reaction by fluorescence-based high-throughput screening and study of transition-metal-free borylation

Abstract

Chapter I. Preparation of metal oxide containing Pd and evaluation of their catalytic activity for the organic reaction by fluorescence-based high-throughput screening method Despite the high activity and selectivity of homogenous catalysts, heterogeneous catalyst has been widely used mainly due to the practical advantages including easy separation and reusability of catalyst. Thus, numerous supported noble metal catalysts have been developed for chemical reactions, such as coupling, oxidation, and reduction. In general, the supporting material is one of the most important parts of a catalyst, because it affects many of its properties, such as stability, distribution, and size. Thus, the interaction between noble metal and supporting material plays a crucial role in their catalytic activity. In this study, several kinds of metal oxides containing Pd were prepared by a simple and scalable co-precipitation method and used to develop a greener method for the reduction of nitroarenes and Suzuki-Miyaura cross coupling. The synthesis of highly functionalized aniline derivatives is an important chemical reaction, because these derivatives are key intermediates in the production of valuable chemicals including pharmaceuticals, agrochemicals, dyes, and polymers. Among several methods available for the synthesis of aniline, the catalytic transformation of a nitro group to the corresponding amine group is a widely used method. Although many methods for the reduction of nitroarenes have been developed, there are still needs for the sustainable and green method for the reduction of nitro groups. Thus, an easily accessible and efficient green method for the reduction of nitroarene compounds was developed using prepared metal oxide catalysts. A fluorescence-based high-throughput screening (HTS) method for the reduction of nitroarenes was also developed for the rapid analysis of the reaction conditions. The catalytic activity of the metal oxides and reaction conditions were rapidly screened by the fluorescence-based HTS method, and Pd/CuO showed the highest catalytic activity under mild reaction conditions. After identifying the optimal reaction conditions, various nitroarenes were reduced to the corresponding aniline derivatives by Pd/CuO (0.005 mol% of Pd) under these conditions. Furthermore, the Pd/CuO catalyst was used for the one-pot Suzuki-Miyaura cross-coupling/reduction reaction. A gram-scale reaction (20 mmol) was successfully performed using the present method, and Pd/CuO showed high reusability, without loss of catalytic activity for five cycles. The Suzuki-Miyaura cross-coupling (SM), generally defined as a palladium-catalyzed cross-coupling between organhalides and organoborons, is one of the most powerful tools for carbon-carbon bond formation. In past four decades, numerous catalysts have been developed for the SM reaction, but there are still demands for the new catalyst from an environmentally friendly perspective. For example; low catalyst loading, non-toxic phosphine ligand or ligand-free, eco-friendly solvent, mild temperature, and high reusability. Thus, metal oxides containing Pd catalysts were used to develop a green method for the SM reaction. A fluorescence-based high-throughput screening (HTS) method for the SM reaction was also developed for the rapid analysis of the reaction conditions. After the first screening, four catalysts were selected. And Pd/Fe2O3 was selected as a most active catalyst after the second screening. After identifying the optimal reaction conditions, various biaryl compounds were obtained by Pd/Fe2O3 (0.02 mol% of Pd) under aqueous ethanol at mild temperature without any ligands.

Chapter II. Development of transition-metal-free borylation of aryl bromides Arylboronic acid is a valuable chemical in various research fields, such as organic reaction, molecular self-assembly, sensors, and medical chemistry. The classical method for the preparation of boronic acid involves the use of organomagnesium (RMgX) or organolithium (RLi) reagents with trialkyl borates at low temperatures and this approach has some limitations, including low temperature during the reaction and low functional group tolerance. In recent decades, the transition-metal-free borylation has emerged as a highly useful method for the preparation of organoboron compounds start from various functional groups. However, these borylation reactions are not suitable for the preparation of boronic acid. The typical product of these reactions is boronic ester. Thus, these methods require an additional deprotection step. Furthermore, they generally used atom-wasteful borylating agent, bis(pinacolato)diboron (B2Pin2). Pinacol, which is part of B2Pin2, accounts for most of the total mass of B2Pin2; however, it must be removed from the reaction mixture. Therefore, the development of an easy and atomically efficient borylation method for the direct production of boronic acid is desired. In this study, we developed a simple and atom-economic transition-metal-free borylation reaction of aryl bromides. An atom-economic and commercially available diboron source, bis-boronic acid (BBA), was used, and the borylation reaction was performed using a simple procedure at a mild temperature. Under mild conditions, aryl bromides were converted to arylboronic acids directly without any deprotection steps, and the functional group tolerance was considerably high. The mechanism study suggested that this borylation reaction proceeds via a radical pathway. This simple borylation reaction will be useful for the synthesis of valuable arylboronic acids.