Late-stage difluoromethylation: concepts, developments and perspective

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.