Chapter 8 - Difluoromethylation of Bioactive Compounds

Abstract

Considerable attention from organic synthetic and medicinal chemistry communities has been paid to the −CF2H moiety, as this group can act as a more lipophilic isostere of the carbinol, thiol, hydroxamic acid, or amide groups. The weakly acidic CF2H moiety can establish hydrogen-bonding interactions to improve the binding affinity of biologically active compounds. To that effect, the hydroxyl, amino, and thio substituents of lead structures are ordinarily replaced by a CF2H group in drug discovery, with ample benefits in the pharmacological activity of drugs. The late-stage design of bioactive compounds with the CF2H moiety is therefore a sought-after strategy. The study of synthetic pathways to introduce a CF2-Y moiety (Y≠H, F) into organic substrates is also relevant and meaningful because compounds that contain a CF2-Y functionality have also found vast applications in medicinal chemistry and in other areas, such as that of fungicides, insecticides, etc., and thus, this functionality deserves special attention. Three main methodological protocols will be presented in this review article for the late-stage introduction of CF2H or CF2Y moieties into organic substrates: (1) a metal photoredox catalysis; (2) through transition metal–catalyzed thermal protocols; and (3) from transition metal–free strategies.