Photoredox-Catalyzed Generation of Tertiary Anions from Primary Amines via a Radical Polar Crossover.

A method for the generation of tertiary carbanions via a deaminative radical-polar crossover is reported using redox active imines from α-tertiary primary amines. A variety of benzylic amines and amino esters can be used in this approach, with the latter engaging in a novel "aza-Reformatsky" reaction. Electronic trends correlate the stability of the resulting carbanion with reaction efficiency. The anions can be trapped with different electrophiles including aldehydes, ketones, imines, Michael acceptors, and H2 O/D2 O. Selective anion formation can be achieved in the presence of another equivalent or more acidic C-H bond in both an inter- and intramolecular fashion. Mechanistic studies suggest the intermediacy of a discrete carbanion intermediate.

Late-Stage Isotopic Exchange of Primary Amines.

Stable isotopes such as 2H, 13C, and 15N have important applications in chemistry and drug discovery. Late-stage incorporation of uncommon isotopes via isotopic exchange allows for the direct conversion of complex molecules into their valuable isotopologues without requiring a de novo synthesis. While synthetic methods exist for the conversion of hydrogen and carbon atoms into their less abundant isotopes, a corresponding method for accessing 15N-primary amines from their naturally occurring 14N-analogues has not yet been disclosed. We report an approach to access 15N-labeled primary amines via late-stage isotopic exchange using a simple benzophenone imine as the 15N source. By activating α-1 and α-2° amines to Katritzky pyridinium salts and α-3° amines to redox-active imines, we can engage primary alkyl amines in a deaminative amination. The redox-active imines proceed via a radical-polar crossover mechanism, whereas the Katritzky salts are engaged in copper catalysis via an electron donor-acceptor complex. The method is general for a variety of amines, including multiple drug compounds, and results in complete and selective isotopic labeling.

Dual Nickel/Photoredox-Catalyzed Deaminative Cross-Coupling of Sterically Hindered Primary Amines.

We report a method to activate α-3° amines for deaminative arylation via condensation with an electron-rich aldehyde and merge this reactivity with nickel metallaphotoredox to generate benzylic quaternary centers, a common motif in pharmaceuticals and natural products. The reaction is accelerated by added ammonium salts. Evidence is provided in support of two roles for the additive: inhibition of nickel black formation and acceleration of the overall reaction rate. We demonstrate a robust scope of amine and haloarene coupling partners and show an expedited synthesis of ALK2 inhibitors.