Synthetic and mechanistic study on the conjugate isothiocyanation of enones with trimethylsilyl isothiocyanate

Alkyl isothiocyanates (R-NCS) have pharmacological applications and provide a synthetic handle to various functional groups including thioureas. There are however few methods to access alkyl isothiocyanates through the creation of the C–N bond. We have developed a simple approach for the conjugate isothiocyanation of enones by trimethylsilyl isothiocyanate (TMSNCS), which proceeds through the 1,4-addition of the weak isothiocyanate nucleophile to activated enones in the absence of external promoters. This method avoids the direct use of highly toxic acids and bases, produces β-isothiocyanato carbonyl products in yields of 87–98% under mild conditions (less than 6 hours at 0 °C), and displays wide functional group tolerance. Density functional theory calculations highlighted competing cationic and anionic mechanisms, where the enone activation by the TMSNCS reagent is accelerated in protic solvents. The selective formation of the isothiocyanate vs. thiocyanate isomers is explained by the thermodynamically-controlled nature of the reaction in which only the conjugate isothiocyanation is exergonic.