A new method for the synthesis of pharmaceutically relevant fluorinated phenanthridines

Phenanthridines are heterocyclic compounds composed of two six-membered benzene rings fused to six nitrogen-containing rings. It is found in many naturally occurring compounds known for its anticancer and antitumor properties. Because of their medicinal potential, there is great interest in the synthesis of phenanthridine derivatives in laboratories. A promising synthetic route involves the addition of isonitrile to form imidoyl radical intermediates, which then cycle to form phenanthridine. However, the exact mechanism of deposition of isonitrile is not well understood.

Recently, a group of researchers, led by Assistant Professor Shigekazu Ito from the Tokyo Institute of Technology (Tokyo Tech), investigated the use of aryl-substituted difluoromethylborates in the production of difluoromethylated phenanthridines. Their study, published in Journal of Organic Chemistryexamines the rate of synthesis of fluorinated phenanthridines from aryl-substituted difluoromethylborates and describes the mechanism of action leading to isonitrile addition.

Considering the importance of difluoromethylated phenanthridines in the discovery of drugs, it is important to develop new and improved methods for the production of 6-(difluoromethyl)phenanthridines, especially using isonitrile insertion.”

Dr. Shigekazu Ito, Assistant Professor, Tokyo Institute of Technology

The researchers synthesized 6-(difluoromethyl)phenanthridines by initiating the formation of the highly reactive difluoromethyl radical.^•CF₂H) through the oxidation of aryl-substituted difluoromethylborates. This served as a starting point for isonitrile synthesis and cyclization processes within the isonitrile group.

After looking at different oxygen conditions, the researchers identified a combination of silver oxide (Ag₂O) and potassium peroxodisulfate (K₂S₂Oh₈) as excellent initiators for isonitrile substitution in 2-isocyano-1,1′-biphenyls. They saw that K₂S₂Oh₈ oxidize Ag₂O, which, in turn, produces aryl-substituted difluoromethylborates, which lead to the generation of ^•CF₂H very much. It combines with the isonitrile group, forming an imidoyl radical, which undergoes intramolecular cyclization, ultimately leading to the formation of 6-(difluoromethyl)phenanthridine.

These researchers investigated different aryl groups in aryl-substituted difluoromethylborates to improve the yield of 6-(difluoromethyl)phenanthridine. Among the tested aryl groups, p-diethylamino-phenyl-substituted borate was stable and produced the corresponding phenanthridine in a satisfactory yield of 53%.

In addition, the researchers used a technique called “transverse-field muon spin rotation” to confirm the reaction and the presence of the short-lived imidoyl radical. They directed the charge of positive muons (particles similar to protons but nine times lighter) to the isonitrile group and observed changes in their spins. The accompanying electrons, called muoniums, are added to the carbon atom of the isonitrile unit, forming an intermediate that later initiates the cyclization process. This observation provided conclusive evidence for the existence of the unknown midoyl radical.

In the future, the group hopes to explore different ways to generate difluoromethyl radicals to facilitate the production of difluoromethylated phenanthridines. “Besides chemical oxidation, it may be possible to use photocatalytic and electrochemical methods to produce difluoromethyl radicals from difluoromethylborates,” says Dr. This.

In conclusion, this study presents a promising method for the production of 6-(difluoromethyl)phenanthridines, an achievement that has great potential for drug development.