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.