Copper(I)-Mediated Site-Selective Tertiary δ–κ-C(sp3)–H Bond Chlorination of Ketones and Carboxylic Esters and Amides by Dichloramine-T

A synthetic method to prepare δ–κ-chloroketones, -esters and -amides that relies on the copper(I)-mediated chlorination at the unactivated tertiary δ–κ-C(sp³)–H bond of ketones, and carboxylic esters and amides by dichloramine-T is presented. By exploiting the ability of the <i>N</i>-chloramide to act as both the hydrogen atom transfer (HAT) and chlorination reagent, the reactions were shown to be site-selective with halogenation only occurring at the unactivated tertiary carbon center situated four to ten C–C bond distances away from the carbonyl functional group in the substrate. The site-selectivity of the chlorination protocol was further exemplified by the installing of the C–Cl bond at the distal position of one example containing two tertiary carbon centers and the late-stage functionalization of two drug molecules.