Difluorination of α-(bromomethyl)styrenes via I(I)/I(II) catalysis: facile access to electrophilic linchpins for drug discovery

Simple alpha-(bromomethyl)styrenes can be processed to a variety of 1,1-difluorinated electrophilic building blocks via I(I)/I(III) catalysis. This inexpensive main group catalysis strategy employs p-TolI as an effective organocatalyst when combined with Selectfluor (R) and simple amine center dot HF complexes. Modulating Bronsted acidity enables simultaneous geminal and vicinal difluorination to occur, thereby providing a platform to generate multiply fluorinated scaffolds for further downstream derivatization. The method facilitates access to a tetrafluorinated API candidate for the treatment of amyotrophic lateral sclerosis. Preliminary validation of an enantioselective process is disclosed to access alpha-phenyl-beta-difluoro-gamma-bromo/chloro esters.

Automated summary

A simple main group catalysis strategy is used to convert alpha-(bromomethyl)styrenes into 1,1-difluorinated electrophilic building blocks, providing a platform for generating multiply fluorinated scaffolds for further derivatization.