Late-stage difluoromethylation: concepts, developments and perspective

This review describes the recent advances made in difluoromethylation processes based on X-CF 2 H bond formation where X is C(sp), C(sp 2 ), C(sp 3 ), 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 CF 2 H to C(sp 2 ) sites both in stoichiometric and catalytic mode. Difluoromethylation of C(sp 2 )-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(sp 3 )-CF 2 H bonds, but cases of stereoselective difluoromethylation are still limited. In this sub-field, an exciting departure is the precise site-selective installation of CF 2 H onto large biomolecules such as proteins. The formation of X-CF 2 H bond where X is oxygen, nitrogen or sulfur is conventionally achieved upon reaction with ClCF 2 H; 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. This review describes the conceptual advances that have led to the multiple difluoromethylation processes making use of well-defined CF 2 H sources.