Despite a well-developed and growing body of work in copper catalysis, the potential of copper to serve as a photocatalyst remains underexplored. Herein, we describe a photoinduced, copper-catalyzed method for coupling readily available racemic tertiary alkyl chloride electrophiles with amines to generate fully substituted stereocenters with high enantioselectivity. The reaction proceeds at –40 °C under excitation by a blue light-emitting diode and benefits from the use of a single, Earth-abundant transition metal acting as both the photocatalyst and the source of asymmetric induction. An enantioconvergent mechanism transforms the racemic starting material into a single product enantiomer.

Although the alkylation of an amine by an alkyl halide serves as a “textbook example” of a nucleophilic substitution reaction, the selective mono-alkylation of aliphatic amines by unactivated, hindered halides persists as a largely unsolved challenge in organic synthesis. We report herein that primary aliphatic amines can be cleanly mono-alkylated by unactivated secondary alkyl iodides in the presence of visible light and a copper catalyst. The method operates under mild conditions (−10 °C), displays good functional-group compatibility, and employs commercially available catalyst components. A trapping experiment with TEMPO is consistent with C–N bond formation via an alkyl radical in an out-of-cage process.

Copper is an essential metal nutrient for life that often relies on redox cycling between Cu(I) and Cu(II) oxidation states to fulfill its physiological roles, but alterations in cellular redox status can lead to imbalances in copper homeostasis that contribute to cancer and other metalloplasias with metal-dependent disease vulnerabilities. Copper-responsive fluorescent probes offer powerful tools to study labile copper pools, but most of these reagents target Cu(I), with limited methods for monitoring Cu(II) owing to its potent fluorescence quenching properties. Here, we report an activity-based sensing strategy for turn-on, oxidation state-specific detection of Cu(II) through metal-directed acyl imidazole chemistry. Cu(II) binding to a metal and oxidation state-specific receptor that accommodates the harder Lewis acidity of Cu(II) relative to Cu(I) activates the pendant dye for reaction with proximal biological nucleophiles and concomitant metal ion release, thus avoiding fluorescence quenching. Copper-directed acyl imidazole 649 for Cu(II) (CD649.2) provides foundational information on the existence and regulation of labile Cu(II) pools, including identifying divalent metal transporter 1 (DMT1) as a Cu(II) importer, labile Cu(II) increases in response to oxidative stress induced by depleting total glutathione levels, and reciprocal increases in labile Cu(II) accompanied by decreases in labile Cu(I) induced by oncogenic mutations that promote oxidative stress.

HR-MS: m/z 287.9878 ([M+H] + , C10H11INO + calcd. 287.9885). 3-Iodo-1-(4-methoxyphenyl)pyrrolidin-2-one. The title compound was prepared according to Method B from 2,4-dibromobutyryl chloride and p-anisidine. After purification by flash chromatography (30→70% Et2O in hexanes), the title compound was isolated as a white solid in 48% yield over 2 steps.

Metal-catalyzed enantioconvergent cross-coupling reactions of alkylelectrophiles are emerging as apowerful tool in asymmetric synthesis.T od ate,h igh enantioselectivity has been limited to couplings of electrophiles that bear adirecting group or ap roximalp / p orbital. Herein, we demonstrate for the first time that enantioconvergent cross-couplings can be achieved with electrophiles that lack such features;specifically, we establish that achiral nickel catalyst can accomplish Negishi reactions of racemic a-halosilanes with alkylzinc reagents with good enantioselectivity under simple and mild conditions, therebyproviding access to enantioenriched organosilanes,an important class of target molecules.