Late-Stage Isotopic Exchange of Primary Amines

Stable isotopes such as H-2, C-13, and N-15 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 N-15-primary amines from their naturally occurring N-14-analogues has not yet been disclosed. We report an approach to access N-15-labeled primary amines via late-stage isotopic exchange using a simple benzophenone imine as the N-15 source. By activating alpha-1 and alpha-2 degrees amines to Katritzky pyridinium salts and alpha-3 degrees 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.