Hetero-Selective Cross-Linking of Primary and Secondary Alkyl Amines with CS₂ Under Ambient Aerobic Oxidation for...

Umpolung of primary amines via isothiocyanation presents an attractive approach for cross-linking biorelevant molecules through two nucleophilic handles. However, conventional isothiocyanation reactions typically require highly electrophilic reagents or strongly oxidative conditions, rendering them unsuitable for complex molecular systems. Herein, we present a robust and nonchemist-friendly protocol for the isothiocyanation of primary alkyl amines using CS₂ under ambient aerobic oxidation conditions, eliminating the need for additional promoters. These mild conditions not only ensure broad compatibility with endogenous functional groups in biorelevant molecules but also unlock a powerful new capability: selective differentiation between primary and secondary alkyl amines. Notably, the unique suppression of homo-linking for both primary and secondary amines under these conditions enables near-perfect hetero-selectivity in cross-linking two different biorelevant molecules via their abundant amino handles in a one-pot operation, offering a streamlined, thiol-independent, and small-footprint approach to biocompatible conjugation.