The Deuterated “Magic Methyl“ Group - A Guide for Site-selective Trideuteromethyl Incorporation and Labeling using CD3-reagents

In the field of medicinal chemistry the precise installation of a trideuteromethyl group is gaining ever-increasing attention. Site-selective incorporation of the deuterated “magic methyl” group can provide profound pharmacological benefits and can be considered as an important tool for drug optimization and development. This review provides a structured overview, according to the trideuteromethylation reagent, of currently established methods for site-selective trideuteromethylations of carbon atoms. Selective introduction of CD2H and CDH2 groups, in addition to CD3, is also considered. For all methods, the corresponding mechanism and scope are discussed whenever reported. As such, this review can be a starting point for synthetic chemists to further advance trideuteromethylation methodologies. At the same time, this review aims to be a guide for medicinal chemists, offering them the available C-CD3 formation strategies for the preparation of new or modified drugs.