Many drugs, including those for depression, schizophrenia, and malaria, would not be safe without a type of organic chemical called an alicyclic compound. These compounds are 3D structures formed when three or more carbon atoms join in a ring via covalent bonds, but the ring is not aromatic.
Aromatic compounds (or arenes) are another class of organic compounds which are 2D structures with reactive properties distinct from those of alicyclic compounds. A well-known example is benzene, the six-carbon ring comprising single and double bonds alternating between carbon atoms.
By dearomatizing arenes, alicyclic compounds can be obtained. In fact, this dearomatization is one of the most powerful ways to obtain alicyclic compounds. But some of the more abundantly available arenes, such as benzene and naphthalene, are very stable, and breaking them down to build alicyclic compounds has been a challenge. With existing methods, large amounts of reagents often give very little product.
“The highly efficient conversion of readily available commercially available arenas into high value-added alicyclic compounds could accelerate drug discovery research by leaps and bounds,” say Assistant Professor Kei Muto and Professor Junichiro Yamaguchi of the University. Waseda, in Japan, who led the discovery of an effective new drug. method. Their study is published in the Royal Society of Chemistry’s Chemical sciences.
In the new process, the bromoarenes are reacted with two other classes of organic compounds, the disazo compounds and the malonates, in the presence of a palladium catalyst (a compound which allows a chemical reaction), under optimal conditions of concentration, temperature and time (determined experimentally in the study). Subsequently, good amounts of the corresponding alicyclic compounds are produced.
âWhat’s really special about this method is that a range of bromoarenes, including benzenoids, azines, and heteroles, can be converted to their alicyclic counterparts,â explains Muto. He also talks about the key parts of an alicyclic molecule that give it complexity and utility – the functional groups attached to cyclic carbons. He says, “The resulting compounds have functional groups at two points in the ring chain, and these can be easily diversified through other reactions to produce a variety of highly functionalized 3D molecules.”
The use of malonates as a reagent is what allows this multifunctionality, distinguishing this new method from existing methods, often very specific in terms of possible products. Because malonates are known to react primarily with palladium-benzyl complexes, the use of a palladium-based catalyst has become the key to the success of this method. The palladium catalyst led to the formation of a benzyl-palladium intermediate which could then react with the malonates, producing the final multifunctional alicyclic products.
Thus, the design of a suitable catalysis process was essential to develop the technique of aromatic to alicyclic transformation. âNext, we would like to design new catalysts to make this reaction more general, that is, compatible with a wider range of arenas,â Yamaguchi explains.
With their plans for the future in place, Muto and Yamaguchi are convinced of the good their team’s work can do in the world: “We believe this organic reaction will help drug discovery research to finally ‘escape the plain’. simpler, 2D aromatics, so to speak, significantly advancing medicinal chemistry. “
Reference: Kato, et al. (2020) Catalytic three-component CC bond forming dearomatization of bromoarenes with malonates and diazo compounds. Chemical sciences. DO I: https://doi.org/10.1039/D0SC02881A
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