Reactions of Nitrile Imines with Thiohydantoin Derivatives: Unexpected Chemoselectivity of the 1,3-Dipolar Cycloaddition: Preferential Addition of C=C rather than C=S Bonds

Nitrile imines are highly reactive 1,3-dipoles that have
found
extensive application in [3 + 2]-cycloaddition reactions, offering
an efficient approach to introducing pyrazoline and pyrazole motifs
into biologically active compounds. In this study, we explore the
reactivity of nitrile imines using thiohydantoin derivatives as dipolarophiles,
which feature both carbon–carbon and carbon–sulfur bonds
suitable for cycloaddition. Typically, carbon–sulfur (C=S)
bonds are considered “super dipolarophiles” in nitrile
imine cycloaddition reactions. However, we observed an unexpected
chemoselectivity in the reaction between nitrile imines and 5-methylidene-2-thiohydantoin,
where the reaction surprisingly favored the carbon–carbon (C=C)
bond over the expected carbon–sulfur (C=S) bond. Our findings
demonstrate that the electronic effects of substituents play a crucial
role in determining the reactivity and selectivity of nitrile imines.
Specifically, electron-withdrawing groups enhance the reactivity and
favor cycloaddition at C=S bonds in thiohydantoins, whereas electron-donating
groups or halogens facilitate cycloaddition at C=C bonds. To gain
a deeper understanding of the reaction mechanisms and chemoselectivity,
we performed density functional theory (DFT) calculations. This work
provides a detailed understanding of the factors influencing 1,3-dipolar
cycloaddition reactions of nitrile imines, highlighting how electronic
effects influence their behavior.