N-Methylation of Self-Immolative Thiocarbamates Provides Insights into the Mechanism of Carbonyl Sulfide Release

C. M. Levinn, J. L. Mancuso, C. H. Hendon, M. M. Pluth
Journal of Organic Chemistry
Volume 86, Issue 8, Page 5443-5451


Hydrogen sulfide (H2S) is an important biomolecule, and selfimmolative thiocarbamates have shown great promise as triggerable H2S donors with suitable analogous control compounds; however, thiocarbamates with electron-deficient payloads are less efficient H2S donors. We report here the synthesis and study of a series of N-methylated esterase-triggered thiocarbamates that block the postulated unproductive deprotonation-based pathway for these compounds. The relative reaction profiles for H2S release across a series of electron-rich and electron-poor N-Me aniline payloads are examined experimentally and computationally. We show that thiocarbamate N-methylation does block some side reactivity and increases the H2S release profiles for electron-poor donors. Additionally, we show that isothiocyanate release is not a competitive pathway, and rather that the reduced efficiency of electron-poor donors is likely due to other side reactions.