Fluorinated bioisosteres have found a broad application in modern drug design. In particular, a fluoroalkene moiety can efficiently mimic an amide bond due to a similarity in the electronic and steric parameters, thus increasing the hydrolytic stability, lipophilicity, and permeability through membranes. As a result, by using such bioisosteric replacement, one could substantially improve the efficiency of biologically active compounds known to date. Among the methods for the preparation of fluoroalkenes and compounds containing a 2-fluoroallyl fragment, one of the most convenient is ring opening in fluoro-substituted cyclopropanes. However, its synthetic application has been limited for a long time due to the difficulty of controlling the regio- and stereoselectivity of nucleophile addition to 2-fluoroallyl-cationic structures, which are key intermediates in these processes.
In the Laboratory of Chemistry of Diazo Compounds of the ZIOC RAS, new stable 2-fluoroallyl electrophiles (2-fluoroallyl)pyridinium tetrafluoroborates were synthesized by the opening of gem-bromofluorocyclopropanes. Palladium-catalyzed reactions of these salts with amines, malonates, and boronic acids open the way to a wide range of functionalized compounds with a fluoroallyl moiety. All developed transformations proceed with high regio- and stereoselectivity.
Angelina Yu. Bobrova, Maxim A. Novikov, and Yury V. Tomilov (2-Fluoroallyl)pyridinium tetrafluoroborates: novel fluorinated electrophiles for Pd-catalyzed allylic substitution Org. Biomol. Chem., 2021, 19, 4678-4684. DOI: 10.1039/D1OB00567G.