Researchers solve an organic chemistry problem

Scientists have developed a strategy that could boost the development of pyridine-containing drugs and organic functional materials.

In chemicals used in agriculture, as well as in pharmaceuticals and a variety of materials, pyridines are often found as so-called functional units that decisively determine the chemical properties of substances. Pyridines belong to the group of ring-shaped carbon-hydrogen (CH) compounds (“heterocycles”) and contain a nitrogen (N) atom. For chemists, the direct functionalization of the carbon-hydrogen bonds (CH bonds) of pyridines is a simple approach to design and modify complex molecules, including in the final step of the synthetic sequence.

This means that the active ingredients can be chemically changed without having to reconstruct them. Functionalization of pyridine in a certain position relative to the nitrogen atom – in the hard-to-reach “meta-position” – is extremely difficult and rare. A team of researchers led by Professor Armido Studer from the Institute of Organic Chemistry at the University of Münster has developed a new strategy to bring various functional groups into the meta position of pyridines. Their study has just been published in the journal Science.

Chemists use a temporary dearomatization of pyridine: its electronic properties are reversed, producing a stable intermediate product, a dienamine. Thanks to radical and polar chemistry, researchers are able, with great selectivity, to pass a large number of fluorinated alkanes, as well as a series of “electron-poor substituents” (electrophiles), into the meta position. These transformations also include medically and agrochemically relevant functionalities such as trifluoromethyl and halogen groups. “The important thing,” says Dr. Hui Cao, a post-doctoral fellow in the Studer working group, “is that functionalized dienamine intermediates are easily rearomatized into meta-functionalized pyridines under acidic conditions.”

His colleague, Dr. Qiang Cheng, adds: “The high degree of efficiency, the wide range of applications and the metaselectivity of our approach make it possible to functionalize twelve different types of drugs. In addition, the team has developed processes in which drugs can be transformed directly into trifluoromethyl and chlorine derivatives – in so-called one-pot reactions, which involve little effort and take place in a single reaction vessel. For this, chemists use inexpensive and commercially available reagents. “Our study provides an answer to the unsolved problem of pyridine functionalization at the meta position,” says Armido Studer. “We believe this publication will provide a significant boost to the development of pyridine-containing drugs and organic functional materials.”

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Material provided by University of Munster. Note: Content may be edited for style and length.

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