Difluoromethylation Reactions of Organic Compounds

Abstract

The relevance of the -CF H moiety has attracted considerable attention from organic synthetic and medicinal chemistry communities, because this group can act as a more lipophilic isostere of the carbinol, thiol, hydroxamic acid, or amide groups. Being weakly acidic, the CF H moiety can establish hydrogen-bonding interactions to improve the binding selectivity of biologically active compounds. Therefore, the hydroxyl, amino, and thio substituents of lead structures are routinely replaced by a CF H motif in drug discovery, with great benefits in the pharmacological activity of drugs and drug candidates and agrochemicals. Consequently, the late-stage introduction of CF H is a sought-after strategy in designing bioactive compounds. Secondly, but nonetheless relevant and meaningful, is the study of synthetic pathways to introduce a CF -Y moiety (Y≠H, F) into organic substrates because compounds that contain a CF -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. Although emphasis is made on difluoromethylation strategies to functionalize different families of organic compounds, three main methodological protocols will be presented in this review article for the late-stage introduction of a CF H or CF Y moieties into organic substrates: i) a metal-photoredox catalysis; ii) through transition metal-catalyzed thermal protocols; and iii) from transition-metal-free strategies.

Learning From Vitamin B12‐Mediated Reactions: Cobalt(III)−Carbon‐Assisted Catalytic C−H Difluoroacylation of (Hetero)Arenes through Controlled‐Potential Electrolysis

“…Therefore, the development of novel synthetic methodology for the direct CF 2 group functionalization of arenes, and heteroarenes under mild conditions remains highly desirable. Advances in difluoroalkylation reactions have recently been reviewed by Postigo and co‐workers …”

Photocatalyzed Cyanodifluoromethylation of Alkenes

“…[2] During the past decades,anumber of HCF 2 -based pharmaceuticals and agrochemicals,s uch as eflornithine,d eracoxib,s edaxane, isopyrazam, bixafen, and thiazopir, have been developed. [2] Thei ncorporation of aH CF 2 group into organic molecules has garnered significant attention. [2,3] Because difluoromethylation is the most straightforward strategy for incorporation of HCF 2 into organic molecules,m any difluoromethylation reagents have been developed, [4] such as TMSCF 2 H [5] and XCF 2 H( X= F, Cl, or Br).…”

“…[2] Thei ncorporation of aH CF 2 group into organic molecules has garnered significant attention. [2,3] Because difluoromethylation is the most straightforward strategy for incorporation of HCF 2 into organic molecules,m any difluoromethylation reagents have been developed, [4] such as TMSCF 2 H [5] and XCF 2 H( X= F, Cl, or Br). [6] Simultaneous incorporation of as econd functional group into molecules would allow further transformation;t he second functional group could also have excellent potential for the design of pharmaceuticals and agrochemicals.T herefore,m uch effort has been devoted to development of efficient methods for difluoromethylative difunctionalization of alkenes,i ncluding hydrodifluoromethylation, [7] carbodifluoromethylation, [8] oxydifluoromethylation, [9] and halodifluoromethylation.…”

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“…Eventually, the discovery of practical methods for the introduction of difluoroalkyl groups into target molecules continue to be a challenging topic . Protocols working under metal free conditions and showing wide substrate scope are still highly desirable.…”