Scripps Research chemists have developed a new and controllable method for making benzocyclobutenes (BCBs) that has been a long-standing issue in the field of pharmaceutical chemistry. BCBs are highly valued as building blocks for drug molecules but have been notoriously challenging to access. In a paper published in Science, the researchers described their new method that uses designer ligand molecules with palladium-atom catalysts to break pairs of adjacent methylene-type C-H bonds in relatively cheap and abundant carboxylic acids. This process allows for BCBs to be made with unprecedented ease through a formal [2+2] cycloaddition.

Regioselectivity Achieved

The limitations of the various methods for synthesizing BCBs include an inability to control the order in which individual reactions occur, resulting in a mix of products that are hard to separate. The new method developed by the Scripps Research chemists for the first time enables this control, a property called regioselectivity. By employing bidentate amide-pyridone ligands bearing palladium catalysts to activate the C-H bonds of two adjacent methylene units in a carboxylic acid, the chemists were able to accomplish this. In the presence of a dihaloheteroarene, two C–H bonds and two aryl–halogen bonds come together to form a bicyclic BCB scaffold.

Wide Range of Applications

The new method has a wide range of applications and can be used with a variety of cyclic and acyclic aliphatic acids to generate diverse BCBs and hetero-BCBs, which can be very useful in drug molecules. The researchers demonstrated the new method with relatively simple syntheses of several BCBs found in traditional medicines and in experimental and approved drug molecules. The ability to make direct use of abundant and structurally varied acyclic and cyclic acids as substrates, without pre-functionalization, expands chemists’ access to diverse BCB scaffolds.

Overall, the new method developed by the Scripps Research chemists has solved a long-standing problem in the field of pharmaceutical chemistry, making the synthesis of BCBs easier and more controllable. The ability to achieve regioselectivity with this method is a significant breakthrough and has wide-ranging applications for drug molecules and other advanced materials.


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