Metal-free molecular iodine-catalyzed direct sulfonylation of pyrazolones with sodium sulfinates leading to sulfonated pyrazoles at room temperature

Abstract

A simple and convenient molecular iodine-catalyzed direct sulfonylation of pyrazolones with sodium sulfinates has been developed in the presence of TBHP at room temperature. This methodology can allow for the synthesis of a series of valuable sulfonated pyrazoles in good to excellent yields simply using readily-available starting materials without requiring any metal or cryogenics.

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Pyrazoles are highly valuable structural scaffolds in various pharmaceuticals and biologically active compounds, which exhibit a wide range of bioactivities, such as antifungal,¹ antidepressant,² antitumor,³ antimicrobial,⁴ immunosuppressive,⁵ antiamoebic,⁶ antibacterial⁷ and anticonvulsant activities.⁸ In particular, the introduction of functional groups in a regioselective fashion could dramatically enhance or alter the pharmacophoric profile of pyrazoles.⁹ Sulfone groups represent one of the most important classes of organic functionalities, which are widely found in a number of biologically active molecules, agrochemicals, and materials.¹⁰ Sulfone functionality is often incorporated into some molecular frameworks to enhance the possible activities during the drug design.¹¹ In particular, sulfonated pyrazoles have attracted the increasing synthesis pursuit of chemists due to their important biological activity and pharmacological value.¹² For example, compound I can be used as a potent antiinflammatory agent;^12b compound II is identified as a high-affinity 5-HT6 receptor with improved pharmacokinetic and pharmacological properties;^12c compound III exhibits significant fungicidal activities against Alternaria solani Sorauer, Corynespora cassiicola, and Phytophthora capsici (Fig. 1).^12d

Fig. 1 Biologically active sulfonated pyrazole compounds.

Generally, sulfonated pyrazoles are synthesized through the cyclocondensation of hydrazines with sulfenylated 1,3-dicarbonyl compounds¹³ and the 1,3-dipolar cycloaddition of diazo compounds with acetylenic sulfones.¹⁴ Alternative procedures include a base mediated reaction of diazosulfones with nitroalkenes (eqn (1)),¹⁵ DMAP-promoted 1,3-sulfonyl shift and cyclization of N-propargylic sulfonylhydrazones (eqn (2)),¹⁶ the oxidation of preformed pyrazolones by employing stoichiometric amounts of m-CPBA or H₂O₂ (eqn (3)),¹⁷ and the Fries-rearrangement reaction of 4-bromo(hydrogen)-5-sulfonyloxypyrazoles in the presence of t-BuLi or LDA at −78 °C (eqn (4)).¹⁸ However, most of these reactions suffer from certain limitations, such as extra steps for preparation of active precursors, the need for excess amounts of organometallic reagents, tedious work-up procedures, harsh reaction conditions, and poor substrate scope or low yields. It still remains a highly desirable but challenging task to develop mild, convenient, efficient, and especially, metal-free methods to access sulfonated pyrazoles from simple and readily available materials.

Molecular iodine as an alternative and promising metal-free catalyst has attracted considerable interest in modern synthetic chemistry due to its low cost, ready availability, non-toxicity, and environmentally benign properties.¹⁹ With our continuous interest in the construction of sulfone-containing organic compounds,²⁰ we herein wish to report a new strategy for the facile and highly efficient synthesis of sulfonated pyrazoles through molecular iodine-catalyzed direct sulfonylation of pyrazolones with sodium sulfinates in the presence of TBHP. The present reaction is realized at room temperature to give various sulfonated pyrazoles in good to excellent yields. Moreover, it can avoid the risk of metal contamination, the use of inert gas and cryogenics.

Initially, the reaction of 3-methyl-1-phenyl-1H-pyrazol-5(4H)-one 1a with sodium benzenesulfinate 2a was investigated by using a variety of various iodide-containing reagents (10 mol%) in CH₃CN at room temperature in the presence of TBHP. To our delight, among the various iodide-containing reagents examined, molecular iodine was found to be the most effective one to afford the desired product 3aa in 68% yield (Table 1, entries 1–4). No desired product was detected in the absence of molecular iodine, indicating that iodine was essential to this sulfonylation reaction (Table 1, entry 5). Further investigation of other oxidants showed that TBHP was the best choice (Table 1, entries 6–10). Among a series of solvents screened, DME was the most suitable reaction medium for this transformation (Table 1, entry 11). In contrast, a good yield of 3aa was also obtained when the reaction was performed in THF, 1,4-dioxane, or EtOAc (Table 1, entries 12–14). Only a moderate to low yield of the product was isolated in EtOH, toluene, DCE or H₂O (Table 1, entries 15–18). Notably, the corresponding product 3aa was still obtained in an excellent yield (96%) when the molecular iodine loading was reduced to 2 mol%. The increasing of reaction temperature did not improve obviously the reaction efficiency (Table 1, entries 21 and 22). Consequently, the reaction conditions employed in entry 20 were determined to be the optimal conditions.

Table 1 Optimization of the reaction conditions^a

Entry	Catalyst (mol%)	Solvent	Oxidant (1 eq.)	Yield^b (%)
a Reaction conditions: 1a (0.25 mmol), 2a (0.5 mmol), catalyst (2–10 mol%), TBHP (70% in water, 0.25 mmol), solvent (2 mL, fresh distilled), 25–80 °C, 2 h. b Isolated yields based on 1a. c 60 °C. d 80 °C.
1	KI (10 mol%)	CH3CN	TBHP	<10%
2	NaI (10 mol%)	CH3CN	TBHP	<10%
3	TBAI (10 mol%)	CH3CN	TBHP	Trace
4	I2 (10 mol%)	CH3CN	TBHP	68
5	—	CH3CN	TBHP	0
6	I2 (10 mol%)	CH3CN	DTBP	42
7	I2 (10 mol%)	CH3CN	K2S2O8	51
8	I2 (10 mol%)	CH3CN	Na2S2O8	47
9	I2 (10 mol%)	CH3CN	H2O2	44
10	I2 (10 mol%)	CH3CN	O2	37
11	I2 (10 mol%)	DME	TBHP	97
12	I2 (10 mol%)	THF	TBHP	92
13	I2 (10 mol%)	1,4-Dioxane	TBHP	85
14	I2 (10 mol%)	EtOAc	TBHP	77
15	I2 (10 mol%)	EtOH	TBHP	55
16	I2 (10 mol%)	Toluene	TBHP	31
17	I2 (10 mol%)	DCE	TBHP	21
18	I2 (10 mol%)	H2O	TBHP	Trace
19	I2 (5 mol%)	DME	TBHP	95%
20	I 2 (2 mol%)	DME	TBHP	96%
21	I2 (2 mol%)	DME	TBHP	97^c
22	I2 (2 mol%)	DME	TBHP	96^d

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Under the optimized conditions, the scope of this sulfonylation reaction was examined by conducting the reactions of a variety of sodium sulfinates with pyrazolones. As shown in Table 2, various aryl sodium sulfinates bearing electron-donating or withdrawing groups were suitable for this reaction to give the products 3aa–3ag in good to excellent yields. It should be noted that a series of functional groups including methoxyl, fluoro, bromo and aminocarbonyl were tolerated under the optimal reaction conditions, which could be employed in further transformations (3ac–3af). Heteroaryl sulfonates, for example sodium pyridine-3-sulfinate and sodium thiophene-3-sulfinate, proceeded smoothly and afforded the corresponding products in 87% and 66% yields, respectively (3ah and 3ai). Remarkably, alkyl sodium sulfinates such as sodium methanesulfinate, were also proven to be compatible with this reaction and generated the corresponding product 3aj in good yield. Next, the electronic and steric nature of substituents on the 1 and 3 positions of pyrazolone was further investigated. For the 1 position of pyrazolones, various aryl substrates including electron-donating or withdrawing groups were suitable for the reaction to afford the corresponding products (3ba–3ja) in good yields. The alkyl group in the 1 position of pyrazolone performed well in this process to form the desired product 3ka in 60% yield. The electron-withdrawing trifluoromethyl group in the 3 position of the pyrazolone was also tolerated in this reaction, but leading to the desired product in moderate yield (3la).

Table 2 Molecular iodine-catalyzed sulfonylation of pyrazolones with sodium sulfinates^a,b

a Reaction conditions: 1 (0.25 mmol), 2 (0.5 mmol), I₂ (2 mol%), TBHP (0.25 mmol), DME (2 mL), 25 °C, 2–4 h. b Isolated yields based on 1.

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Considering that sulfonyl radical species are easily generated from sodium sulfinates in the presence of an oxidant,²¹ we supposed that the present sulfonylation reaction might undergo a radical process. Nevertheless, when TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy) or BHT (2,6-di-tert-butyl-p-cresol) was added into the model reaction of 1a and 2a, the corresponding product 3aa was still obtained in 92% and 94% yields, respectively (eqn (6)). This result indicated that a radical process should not be involved in the present reaction system. Furthermore, when the reaction of 1a, 2a and 1 equiv. of molecular iodine was performed in the absence of TBHP, the desired product 3aa was obtained in 84% yield (eqn (7)).

Moreover, it is known that sulfonyl iodide would be formed when sulfinate sodium salts reacted with iodine at room temperature.²² Of note is that when the reaction of pyrazolone 1a with sulfonyl iodide 4b^22a,b was performed in DME at room temperature under air, the desired product 3ab was isolated in 60% yield (eqn (8)), suggesting that sulfonyl iodide might be a key intermediate in the present transformation.

Based on the above experimental results and previous reports,^{9c,d,19,22,23} a possible reaction pathway was proposed as shown in Scheme 1. Initially, the tautomerization of pyrazolone 1 would produce enol intermediate 5. Subsequently, the nucleophilic substitution of 5 with sulfonyl iodide 4, which was generated from the reaction of sodium sulfinate 2 and molecular iodine, gave the corresponding sulfonated pyrazolone 6 with the concomitant formation of HI. Finally, the desired product 3 was produced through the rapid tautomerization of 6. The generated HI would be oxidized by TBHP into molecular iodine to accomplish the catalytic cycle.

Scheme 1 Possible reaction pathway.

In summary, a facile and highly efficient method has been successfully developed for the synthesis of sulfonated pyrazoles via molecular iodine-catalyzed direct sulfonylation of pyrazolones with sodium sulfinates under very mild conditions. A series of structurally diverse sulfonated pyrazoles could be effectively obtained from various readily available starting materials simply by using inexpensive molecular iodine as a catalyst. With the desirable simplicity, this protocol may have potential applications in synthetic chemistry, and further studies on the scope, mechanism, and synthetic application of this reaction are under investigation.

This work was supported by the National Natural Science Foundation of China (No. 21302109, 21302110, 21375075, and 21675099), the Natural Science Foundation of Shandong Province (ZR2015JL004), and the Taishan Scholar Foundation of Shandong Province.

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Footnote

† Electronic supplementary information (ESI) available: Experimental details. See DOI: 10.1039/c6qo00403b

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