The Deuterated “Magic Methyl” Group: A Guide to Site‐Selective Trideuteromethyl Incorporation and Labeling by Using CD₃Reagents

Abstract

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 an important tool for drug optimization and development. This review provides a structured overview, according to trideuteromethylation reagent, of currently established methods for site‐selective trideuteromethylation of carbon atoms. In addition to CD3, the selective introduction of CD2H and CDH2 groups 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.

Recent Developments for the Deuterium and Tritium Labeling of Organic Molecules

“…Because of all these applications, development of methodologies for the synthesis of deuterated and tritiated compounds continued to receive an impressive attention over the years. General reviews, ,− as well as more specific ones dedicated to subareas in the field of deuteration such as hydrogen isotope exchange (HIE), visible-light photocatalytic deuteration reactions, nanocatalyzed HIE, trideuteromethyl incorporation, , reductive deuteration, base metal-catalyzed HIE, HIE catalysis in alkanes, iridium-catalyzed HIE, specific labeling of the α position of heteroatoms, of the C­(sp 2 )-H, as well as of the C­(sp 3 )–H positions have been published in recent years . Similarly, the number of scientific publications dealing with hydrogen isotopes is constantly increasing.…”

Photoredox-Catalyzed Site-Selective Generation of Carbanions from C(sp3)–H Bonds in Amines

“…Accordingly, significant advances have been made in the deuteration/tritiation of organic compounds via metal- and photocatalysis. − A notable example is the deuteration and tritiation of the aromatic C­(sp 2 )–H bond using a homogeneous iron catalyst, reported by the Chirik group . This method shows an orthogonal selectivity to the traditional ortho-directing Crabtree iridium catalyst.…”

Platinum on carbon-catalysed site-selective H–D exchange reaction of allylic alcohols using alkyl amines as a hydrogen source

“…Recently, the development of site-selective deuteration of functional molecules has attracted significant attention. 7 Deuterium-labelled alkenes are beneficial synthetic precursors used to prepare deuterium-labelled functional materials because of their facile chemical transformation. Deuterium-labelled alkenes are generally provided by the partial deuterogenation of alkynes using D 2 gas 8,9 or lithium aluminium deuteride (LiAlD 4 ), 10 although it is difficult to control their reactivity and selectivity.…”