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

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.