Electrochemical/I – Dual-Catalyzed Access to Sulfonated Pyrazoles under External Oxidant-Free Conditions

An electrochemical/I – dual-catalyzed access to sulfonated pyrazoles from pyrazolones and sodium sulfites under external oxidant-free conditions has been developed. This established electrochemical reaction works smoothly under external oxidant-free conditions and has the advantages of good functional group tolerance, easy to gram- scale synthesis, delivering up to 95% yield for 35 examples.

Sulfone groups are very important functional groups, exist in various natural products, bioactive molecules, pharmaceuticals, and functional materials, and can enhance the activity of compounds. 1 According to statistics, in 2021 of the world's top 200 best-selling small-molecule drugs containing sulfone-based drugs accounted for 20, with sales of up to $27.5 billion. 2 The introduction of the sulfone group is one of the frontier research hotspots in the field of organic synthesis and pharmaceuticals. 3 In particular, the development of convenient and efficient strategies for the incorporation of sulfone groups into heterocyclic compounds has attracted widespread interest among organic synthesis practitioners. 4 Pyrazoles, as one of the high-value N-heterocyclic scaffolds, are epitomized in various pharmaceuticals and bioactive molecules, with a variety of biological activities. 5 In particular, site-selective incorporation of sulfone groups can dramatically enhance the pharmacological profile of pyrazoles. 6 For example, pyrazole derivative I 7 incorporated with the sulfone group has important anti-inflammatory activity; compound II 8 is a potential pesticide with excellent larvicidal and herbicidal activity; and compound III 9 is a modulator of cystic fibrosis transmembrane conductance regulator (CFTR), and it is a key component of Trikafta (Scheme 1a). 10 Given this, the development of efficient, convenient, and practical strategies to access sulfonated pyrazole derivatives is of great significance and has been widely concerned. Wei 11 and Wang's 12 groups have successively developed I 2 /TBHP and TBAI/TBPB systems to deliver sulfonated pyrazole from pyrazolones and sodium sulfites. Although these elegant methods have been developed successively, the presence of stoichiometric oxidants is necessary, and the absence of chemical oxidants remains elusive.
Organic electrochemistry is the study of chemical reactions which take place at the interface of an electrode and electrolyte, involving the activation of the substrate by electron transfer. Although a series of important achievements have been made in organic electrochemistry in the last decade, few studies have been carried out in the absence of external electrolytes. 13 Considering the importance of the sulfonated pyrazole frameworks, and together with our growing interest in organic electrochemistry 13i,14 and sulfone-containing compound synthesis, 15 herein we wish to report an external oxidant-free electrochemical method for SYNOPEN2 5 0 9 -9 3 9 6 Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart 2023, 7, 272-276 letter Virtual Collection Electrochemical Organic J. Ma et al.

Letter SynOpen
the sulfonylation of pyrazolones with sodium sulfinates via a radical pathway. The established electrochemical reaction works smoothly under external oxidant-free conditions and has the advantages of excellent functional group tolerance, easy-to-gram-scale synthesis, and avoiding the use of stoichiometric chemical oxidants.
As shown in Table 1, 5-methyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one (1a) and sodium 4-methylbenzenesulfinate (2b) were selected as the temple coupling substrate to optimize the reaction conditions, including electrode material, current, solvent, and halogen anion source under room temperature in an inert atmosphere. By optimizing various reaction parameters, it was found that the desired product 1c could be delivered in 90% yield by performing the reaction with a constant current of 10 mA electrolysis 2 h in an undivided cell employing NH 4 I (30 mol%) was the electrolyte and catalyst (Table 1, entry 1). The control experiment shows that both current and NH 4 I are the key factors of the transformation (Table 1, entries 2 and 3). The yield of desired product 1c decreased slightly when the amount of NH 4 I was reduced to 20 mol% (Table 1, entry 4). Moreover, other iodized salts, such as n-Bu 4 NI, KI, and NaI, were individually examined for their ability to deliver the desired product 1c in yields of 58%, 82%, and 73%, respectively (Table 1, entry 5). However, the yield of the desired product was reduced to 75%, 7% by employing CH 3 CN or H 2 O as the reaction solvent (Table 1, entry 6). To our delight, 1c was delivered with a yield of 83% when the reaction was performed using dichloromethane as the solvent (Table 1, entry 7). Furthermore, the influence of the electrode materials for the electrochemical/Idual-catalyzed sulfonylation of pyrazolones with sodium sulfinates access to sulfonated pyrazoles under external oxidant-free conditions was also investigated. The results show that C (+) | Pt (-) was the best choice (Table 1, entries 8 and 9). Finally, either increasing or decreasing the current of the reaction is detrimental to the yield of the desired product (Table 1, entry 10).

Table 1 Optimization of the Reaction Conditions a
With the standard conditions in the hand, we began to investigate the substrate scope of this external oxidant-free protocol (Table 2). Firstly, the scope of the pyrazole was investigated based on sodium 4-methylbenzenesulfinate (2b). The results showed that both electron-donor and electron-deficient groups on the para site of the pyrazolone benzene ring can give the corresponding products in moderate to good yields under standard conditions (1c-8c).

Scheme 1 The background of sulfonated pyrazole
Wei's work I 2 / TBHP (1 equiv) TBAI / TBPB (1.5 equiv) Wang's work (c)  J. Ma et al. To prove the scalability of this protocol, a large-scale synthesis of the sulfonated pyrazole 1c was performed. Even the model reaction that was scaled up to 40-fold can get 74% yields, simply by performing the reaction at room temperature in a three-neck flask. Subsequently, the steric hindrance effect has been investigated, and the corresponding products can be obtained in moderate to excellent yields from the meta or ortho site of benzene ring, polysubstituted, or naphthyl pyrazolones under the established conditions (9c-15c). To our delight, the desired products 16c-18c can be delivered smoothly when R 1 and R 2 are converted into methyl, phenyl, or ester groups. In the following stage, sodium sulfinates were systematically examined by employing 1a as the benchmark. Notably, the desired products can be obtained with excellent yields when the different positions of sodium aryl sulfonate have electron-donating or electron-withdrawing groups were carried out under the given conditions (19c-30c). Besides, both aromatic heterocyclic and alkyl sodium sulfite can deliver the desired products in excellent yields under established conditions (31c-34c). Unfortunately, 35c was not observed when 5oxo-1-phenyl-4,5-dihydro-1H-pyrazole-3-carboxylic acid was performed in the present protocol, which may be affected by the carboxyl group.

Letter SynOpen
Intrigued by the outstanding efficacy of the electrochemical/Idual-catalyzed sulfonylation of pyrazolones under external oxidant-free conditions, we became interested in clarifying the mechanism of this transformation. To this end, various control and cyclic voltammetry (CV) experiments were performed based on model reaction. Firstly, only trace amounts of desired product 1c were observed in the presence of 2,2,6,6-tetramethylpiperidin-1-oxyl (TEM-PO), 2,6-di-tert-butyl-4-hydroxytoluene (BHT) or CBr 4 suggesting that the electrochemical/Idual-catalyzed sulfonylation of pyrazolones may proceed via a radical pathway (Scheme 2a). Satisfactorily, this conclusion was further confirmed by the trapped products 1d ( Figure S1). Secondly, intermediate validation experiments demonstrated that A 16 and E 15c should be the intermediate of the transformation (Scheme 2b).
To understand the role of NH 4 I in the present transformation, various stoichiometric experiments were performed as shown in Scheme 2c, suggesting that anodic oxidation Ito I + delivers the product faster than the route of iodine radicals. Finally, the CV experiments were carried out and the results are summarized in Figure 1. The electrochemical behavior of the mixed NH 4 I and 2b demonstrate that the in situ generated iodine radical or I + with 2b has undergone undisguised electron transfer (Figure 1   J. Ma et al. Figure 1 CV experiments with glass carbon as the working electrode, Pt (1.5 × 1.5 cm 2 ) as the counter electrode, Ag/AgCl as the reference electrode in 0.05 M n-Bu 4 NBF 4 , CH 3 CN (10.0 mL), scan rate 50 mV/s, 1b (0.25 mM), NH 4 I (0.25 mM).

Letter SynOpen
Based on these preliminary results mentioned above and the previous reports, 11,12 a plausible mechanistic pathway for electrochemical/Idual-catalyzed sulfonylation of pyrazolones was proposed and is shown in Scheme 3. Initially, iodide anion was anodized to I • (0.66 V vs. Ag/AgCl) and I + (1.11 V vs. Ag/AgCl) catalyst species. 16 Subsequently, the intermediate A can be produced by the reaction of I + with 1a (path A) or via the radical cross-coupling of D and I • (path B). The desired product 1c was generated through the rapid tautomerization of sulfonated pyrazolone B, which was produced from the reaction of sodium sulfonate 2b and intermediate A. Moreover, according to the experimental results, the delivery of product 1c through the radical addition and iodine radical induce dehydrogenation of G cannot be ruled out (path C). The released iodine ions will be oxidized again on the surface of the anode for catalytic cycling, while H + will be reduced on the surface of the cathode to release hydrogen gas as a greener byproduct.

Scheme 3 Postulated reaction pathway
In conclusion, an electrochemical/Idual-catalyzed sulfonylation of pyrazolones with sodium sulfonate access to sulfonated pyrazoles under external oxidant-free conditions have been disclosed. 17 A variety of sulfonated pyrazoles can be effectively synthesized by employing the present protocol. A series of control experiments have confirmed that the established electrochemical conversion undergoes a radical process. Besides, this electrochemicalinduced sulfonylation of pyrazolones strategy can be easily scaled up for synthesis with biologically active sulfonated pyrazoles.

Conflict of Interest
The authors declare no conflict of interest.

Funding Information
This work was supported by the National Natural Science Foundation of China (No. 21902083, 22076097)