Sulfur-containing compounds are crucial for the synthesis of diverse molecules in organic synthesis, the pharmaceutical industry, and materials science [1-9]. In the last few decades, much effort has been devoted to developing new methods for C–S bond construction. Among these approaches, transition-metal catalyzed cross coupling reactions are among the most powerful tools for C–S bond formation [10-18]. However, some of these methods require expensive and air-sensitive metal catalysts, and are not environmentally benign. Therefore, direct sulfenylation reactions under metal free conditions have received increasing interest recently [19-32]. For example, in 2016, an iodine catalyzed regioselective sulfenylation of imidazoheterocycles using dimethyl sulfoxide as both oxidant and solvent was reported by Prabhu et al. [33]. An efficient method using an ionic liquid as solvent was developed by Zhang et al. for the synthesis of 3-sulfenyl imidazo[1, 2-a]pyridines in the presence of Cs₂CO₃ [34]. In 2016, Lu et al. showed that aryl sulfonyl chlorides were good reagents for the sulfenylation of pyrazolones and benzofurans [35]. In 2016, another system consisting of KIO₃ and air was disclosed by Wan et al. for the α-sulfenylation of enaminones and related enamines [36]. Furthermore, Wang et al. reported that the direct arylthiation of substituted anilines was realized in the present of I₂ and di-tert-butyl peroxide [37]. In 2017, Song et al. described an electrolytic C–H thiolation reaction catalyzed by (2, 2, 6, 6- tetramethyl-piperidin-1-yl)oxyl (TEMPO) for the synthesis of benzothiazoles and thiazolopyridines [38]. However, new versatile and practical methods for C–S bond synthesis remain desirable. As part of our continuing efforts toward iodine-catalyzed reactions [39, 40], we now disclose a new strategy for the convenient and highly efficient iodine-catalyzed synthesis of sulfenylated pyrazoles at room temperature.

The reaction of 3-methyl-1-phenyl-1H-pyrazol-5(4H)-one (1a) with disulfide (2a) in the presence of H₂O₂ was chosen as the model reaction to optimize conditions. Initially, various catalysts were screened, with the highest yield (88%) obtained using I₂ as catalyst (Table 1, entry 5). Using N- bromobutanimide (NBS) as the catalyst, desired product 3a was obtained in only 43% yield (Table 1, entry 1). In contrast, N-chlorosuccinimide (NCS), N-iodosuccinimide (NIS), and NH₄I did not successfully catalyze the model reaction (Table 1, entries 2–4). We next investigated the effect of solvent on the model reaction, and found that 1, 4-dioxane was superior to the other solvents. No desired product was generated when water was used as the solvent (Table 1, entry 10), while other solvents, such as DMF, dichloroethane (DCE), 1, 2- dimethoxyethane (DME), and EtOH, generated the corresponding products in (39–67)% yields (Table 1, entries 6–9). Furthermore, when the amount of H₂O₂ was decreased from 2 to 1 equiv., a slightly lower yield of 60% was obtained (Table 1, entry 11).

Having obtained optimized reaction conditions, the scope of this reaction was evaluated for a variety of pyrazoles with different substituted disulfides. As shown in Scheme 1, substituted pyrazoles with either electron-donating or electron- withdrawing groups were well tolerated in this system (3a–3d). Chlorine-substituted pyrazoles reacted with a series of disulfides smoothly, affording the desired product in (75–93)% yields (3e–3k). Furthermore, methyl-substituted pyrazoles afforded the desired products in (77–97)% yields (3d, 3l–3o). For substituted disulfides, the electronic effects of the substituent groups had no significant effect on the catalytic efficiency (3p–3s). To our delight, when 1, 2- di(pyridin-2-yl)disulfane was used, the corresponding products were obtained in moderate to high yields (3t–3v).

To demonstrate the synthetic utility of this transformation, a scaled up experiment (6 mmol) was carried out (Scheme 2). When 3-methyl-1-phenyl-1H-pyrazol-5(4H)-one (1a) and 1, 2- diphenyldisulfane (2a) were tested under the optimized conditions, product (3a) was obtained without a major decrease in yield. Therefore, the present method should be a robust method for the large-scale synthesis of sulfenylated pyrazoles.

To gain insight into the reaction mechanism, control experiments were performed, as shown in Scheme 3. When TEMPO was added to the reaction, the product yield was significantly decreased (Scheme 3(a)). This indicated that a radical intermediate might be involved in the reaction. When the reaction was conducted without I₂, no desired product was detected, indicating the important role of I₂ (Scheme 3(b)). Furthermore, when the reaction of 1a with 2a was performed without H₂O₂ (Scheme 3(c)), the yields of the desired product decreased to 48%. These results demonstrated the importance of I₂ and H₂O₂ in this reaction.

Based on these preliminary experiments and previous reports [19, 41-45], a plausible reaction mechanism was proposed, as shown in Scheme 4. Firstly, homolytic cleavage of the disulfide bond occurs, forming thiyl radicals. The thiyl radicals then react with I₂ to generate electrophilic sulfenyl iodide PhSI. Finally, electrophilic PhSI reacts with pyrazoles to produce the desired product and HI, and I₂ is readily regenerated by the oxidation of HI with H₂O₂.

In conclusion, we have developed an efficient and simple I₂-catalyzed protocol for the synthesis of sulfenylated pyrazoles at room temperature. Under the present reaction conditions, a variety of desired products were obtained in good to excellent yields. Further investigations into the reaction scope and mechanism, and the synthetic applications of these sulfenylated pyrazoles, are now in progress.