Abstract
This review describes the recent advances made in difluoromethylation processes based on X-CF2H bond formation where X is C(sp), C(sp2), C(sp3), O, N or S, a field of research that has benefited from the invention of multiple difluoromethylation reagents. The last decade has witnessed an upsurge of metal-based methods that can transfer CF2H to C(sp2) sites both in stoichiometric and catalytic mode. Difluoromethylation of C(sp2)-H bond has also been accomplished through Minisci-type radical chemistry, a strategy best applied to heteroaromatics. Examples of electrophilic, nucleophilic, radical and cross-coupling methods have appeared to construct C(sp3)-CF2H bonds, but cases of stereoselective difluoromethylation are still limited. In this sub-field, an exciting departure is the precise site-selective installation of CF2H onto large biomolecules such as proteins. The formation of X-CF2H bond where X is oxygen, nitrogen or sulfur is conventionally achieved upon reaction with ClCF2H; more recently, numerous protocols have achieved X-H insertion with novel non-ozone depleting difluorocarbene reagents. All together, these advances have streamlined access to molecules of pharmaceutical relevance, and generated interest for process chemistry.
Highlights
Introduction a Chemistry ResearchLaboratory, Department of Chemistry, Oxford University, OX1 3TA Oxford, UK
This review focuses on X–CF2H bond disconnection, which relies on the availability of difluorocarbene reagents
Efforts to facilitate the construction of C(sp2)–CF2H bonds have largely focused on cross-coupling and free radical methods
Summary
N-Heteroaromatic scaffolds such as imidazoles and benzimidazoles, are prevalent structural motifs in medicinal chemistry.[186]. In 2018, Jana and co-workers disclosed alternative conditions for the difluoromethylation of N-tosyl protected anilines (Scheme 54C).[198] Using an aqueous solution of LiOH in DMF to generate difluorocarbene from BrCF2CO2Et at room temperature, a broad range of N-difluoromethylated products were accessible. In 2015, Shen et al extended the use of [(NHC)Ag(CF2H)] complex to successfully difluoromethylate various aryldiazonium salts at nitrogen (Scheme 54D).[51] The reaction afforded difluoromethyl diazene compounds in good to excellent yields. Good functional group tolerance was observed and reactions with aryldiazonium salts bearing electron-donating or electron-withdrawing groups all resulted in high yields. This N-difluoromethylation is unique because it does not proceed through a difluorocarbene mechanism.
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