N-Heterocyclic thiones are common motifs in pharmaceuticals such as methimazole and enzalutamide as well as antifungals such as prothioconazole. A common method for synthesizing imidazole thiones, such as N,N’-dimethylimidazolethione, involves treating 1-methylimidazole with an alkyl halide to generate a disubstituted imidazolium salt. Base addition results in formation of a reactive N-heterocyclic carbene that reacts with elemental sulfur to form the disubstituted thione. However, these conditions do not work for synthesis of acetate- or propionate-substituted imidazole thiones, since base addition leads to deprotonation of the acetate or propionate substituents rather than the imidazole 2H ring hydrogen, preventing sulfur addition. Due to the higher acidity of the side chain alkyl groups compared to the imidazole hydrogen, a non-basic route for sulfur installation is needed. Recent work by Tang et al. (Adv. Synth. Catal. 2018, 360, 4795–4806) reported a similar transformation using sulfite in a single-electron-transfer reaction, activating the S-S bonds of S8 and creating an imidazole carbene leading to imidazole thione formation. The mechanism proposed by the authors requires heterolytic cleavage of a C-Br bond in ethyl bromofluoroacetate that requires at least one of the imidazolium side chains to be ethyl fluoroacetate, considerably limiting the scope of their chemistry. Reasoning that SN2 substitution of the heterocyclic nitrogens must occur faster than the proposed radical mechanisms, we demonstrate installation of acetate and propionate esters on the imidazole nitrogens prior to sulfur addition, thereby expanding the scope of the radical-mediated approach. By eliminating the need for the reactive ethyl bromofluoroacetate and sulfite reagents, and more carefully adjusting the reaction temperatures, we obtain substantially higher purity in a one-pot SN2 imidazole functionalization followed by sulfur installation than reported by Tang et al. We also present electron paramagnetic spectroscopy (EPR) studies that provide key information in elucidating specific radicals present during the reaction.

Radical-induced sulfur addition to di-N-substituted imidazolium rings

ACS Fall 2021

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