Nowadays, nearly 25% of all marketed drugs contain fluorine atoms revealing that this particular element plays a pivotal role in modern drug discovery.<br/>Introduction of fluorine moieties in lead compounds habitually enhances the druggability by transforming the physicochemical properties as well as improving both chemical and metabolic stability. Whereas fluorine and trifluoromethyl group have been introduced in a large number of drugs, the difluoromethyl (-CF<sub>2</sub>H) moiety is very rare. In fact, we have identified only seven compounds that have been in clinical studies (for either human or veterinary applications) and two with agricultural applications. More spectacular, of these, only two compounds are direct difluoromethylated heterocycles. Our main hypothesis is that so few compounds have the carbon-carbon bonded difluoromethyl decoration (as compared to direct fluorinations and trifluoromethylations) because the underlying chemistry has not been available to the medicinal chemist.<br/>We have discovered an innate, technically simple procedure for direct C-H difluoromethylation of heteroaromatic compounds using off-the-shelf difluoroacetic acid as the difluoromethylating agent in the presence of silver nitrate and potassium persulfate as the preferred oxidant. The reaction is tunable as bi-difluoromethylated products can be obtained by controlling the reaction temperature and running the reaction under more forceful conditions. Herein, we wish to report our detailed investigations, mechanistical studies and the scope and limitations of this novel reaction as well as unfold and deploy this methodology for preparation of tool compounds for chemical biology and provide access to this hitherto untapped substituent in drug discovery.

Direct difluoromethylation of heterocycles using difluoroacetic acid

256th National Meeting (2018)

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