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Cheaper and Easier Method to Synthesize Useful Organic Compounds

The Suzuki-Miyaura reaction is a popular chemical process where a reaction between aryl halides and organic boronic acids results in the formation of “biaryl” compounds. These compounds are major ingredients of numerous chemical and drug products.

This reaction is also known as cross-coupling because a pair of aryl molecules is integrated, or cross-coupled, in this procedure. The organic aromatic molecules—which are produced due to the Suzuki-Miyaura reaction—have numerous applications, for example, in drugs and solvents. Therefore, it is important to identify a way to improve prevalent cross-coupling reactions.

This was the reason why, a research team from Japan, including Junior Associate Professor Yuichiro Mutoh and Professor Shinichi Saito from Tokyo University of Science, wanted to find out whether it is possible to make this reaction more efficient. The study was published in the ACS Catalysts journal.

“Protected” organic boronic acid is an organic boronic acid that has a “masking group.” This acid is often utilized as a precursor for boronic acid employed in the Suzuki-Miyaura reaction. Since the protected boronic acid has a low reactivity, it is not involved in this reaction. Hence, the masking group has to be eliminated to allow the reaction to continue, and this removal of the masking group introduces an additional step in the process.

This mechanism made the researchers wonder that if the masked molecules are directly utilized in the reaction, it may perhaps lead to a relatively cheaper and faster method.

Because the removal of the masking group is necessary to provide the latent boronic acids that engage in subsequent Suzuki-Miyaura reactions, the direct use of the protected boronic acid in a Suzuki-Miyaura reaction would be highly desirable in terms number of steps and atom economy. This would help streamline the synthesis of complex molecules

Shinichi Saito, Professor, Tokyo University of Science

The only difficulty was that so far, no identified method was available to directly apply protected boronic acids without eliminating the masking group first, and hence, the researchers set out to explore ways to achieve this.

The researchers were aware that the process needed a base, a palladium catalyst (a compound or molecule that can accelerate a reaction), and a couple of starting aryl molecules. They went on to check if the reaction occurs with a protected molecule. Initially, they analyzed the impact of numerous bases on the reaction.

The researchers observed that upon using a specific potassium base, known as KOτ-Bu, it led to a high yield of products. This kind of effect was not observed with other kinds of bases.

The team then tested numerous palladium-based catalysts and observed that all catalysts created an analogous yield. This indicated that standard palladium-based catalyst systems can be utilized for the cross-coupling reaction.

The outcome made the researchers conclude that the KOτ-Bu base had an important role to play if protected boronic acid is used directly. Following more than a dozen fruitful Suzuki-Miyaura reactions with high yield for various biaryl compounds, the researchers performed “control” experiments to look for other variables and to get a better understanding of the fundamental mechanisms of the KOτ-Bu base.

The scientists particularly checked if the chemical species existed in the reaction mixture prior to the completion of the reaction. This revealed an intermediate compound involving the boronic acid reagent and the KOτ-Bu base.

Using methods like single-crystal X-ray diffraction analysis and NMR spectroscopy, the researchers validated that the use of KOτ-Bu base is essential to successfully perform these cross-coupling reactions because this base allows the formation of an active borate, which is crucial for the reaction.

The technique discovered in this analysis offers an understanding of the Suzuki-Miyaura reaction and recommended a new method where the essential steps to apply protected boronic acids can be reduced.

The whole procedure to achieve biaryl molecules was performed in just a single pot, which is beneficial in terms of both cost and space.

We developed a way for the reaction to be step- and pot-economic, features that have received considerable attention in recent years. Thus, this study opens up new possibilities for the use of protected boronic acids in various coupling reactions.

Shinichi Saito, Professor, Tokyo University of Science

Due to its innovative findings, the research also featured on the cover of the January 2020 issue of the ACS Catalysis journal.

It is believed that such findings will help in streamlining the production of key complex molecules, such as pharmaceutical drugs, so that an increasing number of people can gain from developments made in the chemical sciences.


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