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.