Remote Site-Selective Radical C(sp3)-H Monodeuteration of Amides using D2O

Site-selective incorporation of deuterium into biologically active compounds is of high interest in pharmaceutical industry. We present a mild and environmentally benign metal-free method for the remote selective radical C-H monodeuteration of aliphatic C-H bonds in various amides with inexpensive heavy water (D2O) as the deuterium source. The method uses the easily installed N-allylsulfonyl moiety as an N-radical precursor that generates the remote C-radical via site-selective 1,5- or 1,6-hydrogen atom transfer (HAT). Methyl thioglycolate, that readily exchanges its proton with D2O, serves as the radical deuteration reagent and as a chain-carrier. The highly site-selective monodeuteration has been applied to different types of unactivated sp(3)-C-H bonds and also to the deuteration of C-H bonds next to heteroatoms. The potential utility of this method is further demonstrated by the site-selective incorporation of deuterium into natural product derivatives and drugs.