Iodophor-Catalyzed Disulfenylation of Amino Naphthalenes with Aryl Sulfonyl Hydrazines

An iodophor-catalyzed direct disulfenylation of amino naphthalenes with aryl sulfonyl hydrazines in water was developed. A series of aryl sulfides were obtained in moderate to excellent yields. The advantages of this green protocol were the simple reaction conditions (metal-free, water as the solvent, under air), the odorless and easily available sulfur reagent, the broad substrate scope, and gram-scale synthesis. Moreover, the potential application of aryl sulfides was exemplified by further transformations.


Introduction
As important organosulfides, diaryl sulfides have a wide range of applications in the fields of organic synthesis, medicinal chemistry, and materials science due to their unique biological activities and physical properties [1][2][3][4].Therefore, the development of green and efficient strategies for the synthesis of diaryl sulfides is one of the hot spots in current research [5].In recent years, the synthesis of diaryl sulfides by direct C-H sulfenylation of arenes has received much attention because of the shortening of the reaction steps and the reduction in waste generation [6,7].In particular, the use of water as a safe, cheap, and environmentally friendly solvent makes sulfenylation greener and more economical.Examples of relevant processes include the following: (i) copper-catalyzed three-component reaction of arenes, iodoaromatics (or iodoalkanes), and sulfur [8]; (ii) iodine-mediated C-H sulfenylation of arenes [9][10][11][12]; (iii) cobalt-catalyzed aerobic couplings of C-H and thiols [13]; (iv) potassium persulfate-glucose-mediated sulfenylation of indole and thiophenols [14].In 2015, Kang et al. reported an iodine-mediated thiolation of substituted naphthylamines and aryl sulfonyl hydrazides via direct C-H bond functionalization (Scheme 1a) [15].In 2020, Liu et al. developed the TBAI-promoted sulfenylation of 2-aminonaphthalene and aryl sulfonyl hydrazides in the presence of DPDME (dipropylene glycol dimethyl ether) as a green solvent (Scheme 1b) [16].However, all of the above reactions result in monosubstituted aryl thioethers.Double-substituted aryl sulfides have not been realized as yet.
It is well known that iodophors are now widely used as bactericidal products for surface disinfection, wound treatment, pre-and post-operative care, mouthwashes, gargles, and nasal sprays [17].Studies have shown that iodophor as a highly effective topical disinfectant is not significantly cytotoxic or irritating [18].However, to the best of our knowledge, the use of iodophor as a catalyst for organic synthesis reactions has not been reported.Considering that povidone iodine as a commercially readily available reagent has the advantage of possessing a two-component reagent (iodine and polyvinylpyrrolidone surfactant), this provides a rare opportunity for iodine-catalyzed organic reactions in the aqueous phase.On the basis of our previous research work [19][20][21][22], we herein report the iodophor-catalyzed disulfenylation of naphthylamine with aryl sulfonyl hydrazines; a series of 1,3-bis(arylthio)naphthalene-2-amines and 2,4-bis(arylthio)naphthalene-1-amines were obtained in moderate to excellent yields (Scheme 1c).

Results and Discussion
Initially, 0.3 mmol of 2-aminonaphthalene 1a and 0.6 mmol of phenylsulfonyl hydrazine 2a were chosen for a model reaction to investigate the feasibility of the Sulfite reaction (Table 1).The results showed that the product 1,3-bis(phenylthio)naphthalene-2-amine 3a was successfully obtained in the presence of 7 mL of iodophor at 100 °C for 24 h (Table 1, entry 1).The dosage study of iodophor showed that 2 mL was the most efficient in producing the corresponding product 3a in a 60% yield (entries 2-5).When the ratio of 1a to 2a was 1:3, 2 mL of iodophor was still the most catalytically effective and the desired product was obtained in a 90% yield (entries 6-8).Changes in reaction temperature are detrimental to the reaction (entries 9-11).Shortening the reaction time resulted in a significant decrease in the reaction yield (entries 12).The yield of product 3a declined to 71% when the ratio of 1a to 2a was adjusted to 1:4 (entries 13).Finally, the optimum reaction conditions were determined: 1a (0.3 mmol), 2a (0.9 mmol), and iodophor (2 mL) under air at 100 °C for 24 h.

Results and Discussion
Initially, 0.3 mmol of 2-aminonaphthalene 1a and 0.6 mmol of phenylsulfonyl hydrazine 2a were chosen for a model reaction to investigate the feasibility of the Sulfite reaction (Table 1).The results showed that the product 1,3-bis(phenylthio)naphthalene-2-amine 3a was successfully obtained in the presence of 7 mL of iodophor at 100 • C for 24 h (Table 1, entry 1).The dosage study of iodophor showed that 2 mL was the most efficient in producing the corresponding product 3a in a 60% yield (entries 2-5).When the ratio of 1a to 2a was 1:3, 2 mL of iodophor was still the most catalytically effective and the desired product was obtained in a 90% yield (entries 6-8).Changes in reaction temperature are detrimental to the reaction (entries 9-11).Shortening the reaction time resulted in a significant decrease in the reaction yield (entries 12).The yield of product 3a declined to 71% when the ratio of 1a to 2a was adjusted to 1:4 (entries 13).Finally, the optimum reaction conditions were determined: 1a (0.3 mmol), 2a (0.9 mmol), and iodophor (2 mL) under air at 100 • C for 24 h.
Under optimal reaction conditions, we investigated the range of 1,3-bisulfenylation reactions of β-naphthylamine with aryl sulfonyl hydrazides, and the results are summarized in Table 2. Benzenesulfonyl hydrazide substrates with various substituents attached to the 4-position such as methyl, methoxy, tert-butyl, fluoro, chloro, bromo, trifluoromethyl, and trifluoromethoxy were able to react smoothly with 2-naphthylamine, and the 1,3-bisulfenylated products 3a-3h were obtained in moderate yields.The electronic effect of the substituent group seems to have no influence on the reaction.Likewise, the meso-substituted aryl sulfonyl hydrazides showed similar reactivity to afford the products 3i and 3j.It is worth mentioning that substrates with some spatial site resistance such as 2-methyl-, 2-fluoro-, 2,4-dimethyl-, and 2,4-dichloro-substituted benzenesulfonyl hydrazides are also suitable reactants to provide the desired products 3k-3n in good yields.Heterocyclic substrates such as 2-thiophenesulfonyl hydrazide were also successfully converted to 1,3-bis(thiophen-2-ylthio)-2-naphthyl amine product 3o in a 55% yield.6-Bromon-2-naphthyl-amine was used as a substrate to react successfully with phenylsulfonyl hydrazide to give the desired product 3p in a 60% yield.Predictably, the presence of bromine substituent offered the possibility of further conversions of the product 3p.uct was obtained in a 90% yield (entries 6-8).Changes in reaction temperature are detrimental to the reaction (entries 9-11).Shortening the reaction time resulted in a significant decrease in the reaction yield (entries 12).The yield of product 3a declined to 71% when the ratio of 1a to 2a was adjusted to 1:4 (entries 13).Finally, the optimum reaction conditions were determined: 1a (0.3 mmol), 2a (0.9 mmol), and iodophor (2 mL) under air at 100 °C for 24 h.
To demonstrate the utility of this reaction, we performed a scale-up reaction based on optimal conditions (Scheme 2).The reaction of 5 mmol of 2-aminonaphthalene with phenylsulfonyl hydrazine (10 mmol) in the presence of 20 mL of iodophor afforded 1.06 g of 3a product in a 60% yield (Scheme 2a).Subsequently, further derivatization of 3a was explored.Under the condition of acetic acid as a solvent, ferric nitrate hydrate was able to oxidize 3a to the corresponding sulfoxide product 1,3-bis(phenylsulfinyl)-2-naphthyl amine 3aa in 55% yield (Scheme 2b).
In order to determine the innovation of the iodophor catalytic system and the selectivity of sulfinylation, related control experiments were designed and carried out.The controls used the same substrate concentration ratio, iodine dosage, temperature, and reaction time.According to the reaction (Scheme 3), a substituted 1-(phenylthio)-2-naphthyl-amine is mainly formed in the reaction system of iodine, while a disubstituted 1,3-bis(phenylthio)-2-naphthyl-amine is mainly formed in the reaction system of iodophor according to the reaction (Scheme 3).Therefore, it is speculated that iodophor provides a method to generate disulfide products.
on optimal conditions (Scheme 2).The reaction of 5 mmol of 2-aminonaphthalene with phenylsulfonyl hydrazine (10 mmol) in the presence of 20 mL of iodophor afforded 1.06 g of 3a product in a 60% yield (Scheme 2a).Subsequently, further derivatization of 3a was explored.Under the condition of acetic acid as a solvent, ferric nitrate hydrate was able to oxidize 3a to the corresponding sulfoxide product 1,3-bis(phenylsulfinyl)-2-naphthyl amine 3aa in 55% yield (Scheme 2b).In order to determine the innovation of the iodophor catalytic system and the selectivity of sulfinylation, related control experiments were designed and carried out.The controls used the same substrate concentration ratio, iodine dosage, temperature, and reaction time.According to the reaction (Scheme 3), a substituted 1-(phenylthio)-2-naphthyl-amine is mainly formed in the reaction system of iodine, while a disubstituted 1,3bis (phenylthio)-2-naphthyl-amine is mainly formed in the reaction system of iodophor according to the reaction (Scheme 3).Therefore, it is speculated that iodophor provides a method to generate disulfide products.In order to probe the mechanism of this reaction, a series of control experiments were performed (Scheme 4).The reaction of 2-aminonaphthalene with phenylsulfonyl hydrazine occurred equally well without any significant decrease in the yield of the product 3a when the radical trapping agents TEMPO (2,2,6,6-tetramethylpiperidine oxide) or BHT (butylated hydroxytoluene) were added to the system of this reaction (Scheme 4a), which suggests that the disulfenylation reaction should not be a free radical-involved process.When benzenesulfonyl hydrazide was reacted under standard conditions alone, diphenyl disulfide 2aa and S-phenyl benzenesulfonyl thioate 2ab were obtained in 80% and 16% yields, respectively (Scheme 4b), which suggests that 2aa and 2ab may be important intermediates produced during the reaction.In order to prove this conjecture, the feasibility of 2-aminonaphthalene disulfenylation reaction was explored using 2aa and 2ab as sulfur sources, respectively.It was shown that the reaction of 2-aminonaphthalene with 2aa had difficulty proceeding in the absence of iodophor (Scheme 4c), whereas the reaction of 2aminonaphthalene with 2ab was possible under the same conditions, and the presence of iodophor significantly increased the yield of the disulfenylation reaction (Scheme 4d).All these facts demonstrate the important role played by povidone iodine in catalyzing the disulfenylation reaction.In order to probe the mechanism of this reaction, a series of control experiments were performed (Scheme 4).The reaction of 2-aminonaphthalene with phenylsulfonyl hydrazine occurred equally well without any significant decrease in the yield of the product 3a when the radical trapping agents TEMPO (2,2,6,6-tetramethylpiperidine oxide) or BHT (butylated hydroxytoluene) were added to the system of this reaction (Scheme 4a), which suggests that the disulfenylation reaction should not be a free radical-involved process.When benzenesulfonyl hydrazide was reacted under standard conditions alone, diphenyl disulfide 2aa and S-phenyl benzenesulfonyl thioate 2ab were obtained in 80% and 16% yields, respectively (Scheme 4b), which suggests that 2aa and 2ab may be important intermediates produced during the reaction.In order to prove this conjecture, the feasibility of 2-aminonaphthalene disulfenylation reaction was explored using 2aa and 2ab as sulfur sources, respectively.It was shown that the reaction of 2-aminonaphthalene with 2aa had difficulty proceeding in the absence of iodophor (Scheme 4c), whereas the reaction of 2-aminonaphthalene with 2ab was possible under the same conditions, and the presence of iodophor significantly increased the yield of the disulfenylation reaction (Scheme 4d).All these facts demonstrate the important role played by povidone iodine in catalyzing the disulfenylation reaction.

Materials and Methods
Unless otherwise stated, all reactions were carried out experimentally in Schlenk tubes.Melting points were determined with a fusion meter and no other corrections were made.Materials obtained from commercial suppliers were used directly without further purification.Chromatography was performed using Qingdao Ocean Chemical 200-300 mesh silica gel.Spectra of 1 H NMR, 13 C NMR (in the Supplementary Materials) were recorded on a Bruker Avance III HD 400 MHz spectrometer in CDCl 3 or DMSO-d 6 solution, and chemical shifts (δ) relative to the internal standard tetramethylsilane (TMS) (0 ppm) were reported.High-resolution mass spectrometry (HRMS) was performed on a Thermo Scientific LTQ or a bitrap XL mass spectrometer, Thermo-fisher Q Exactive.

General Procedure for Iodophor-Catalyzed Disulfenylation of Amino Naphthalenes with Aryl Sulfonyl Hydrazines
A mixture of amino naphthalene (0.3 mmol), aryl sulfonyl hydrazine (0.9 mmol), and iodophor (2 mL) was added to a Schlenk tube.The solution was stirred continuously at 100 • C for 24 h.After completion of the reaction, the mixture was saturated with NaCl (10 mL) and extracted with CH 2 Cl 2 (10 mL × 3).The combined CH 2 Cl 2 extracts were dried with anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure.The crude residue was purified by fast column chromatography on silica gel by using PE (petroleum ether)/EA (ethyl acetate) as eluents.

Gram Synthesis Procedure for 3a
A mixture of β-amino naphthalene (5 mmol), phenylsulfonyl hydrazine (10 mmol), and iodophor (20 mL) was added to a Schlenk tube.The solution was stirred continuously at 100 • C for 48 h.After completion of the reaction, the mixture was saturated with NaCl (20 mL) and extracted with CH 2 Cl 2 (20 mL × 3).The combined CH 2 Cl 2 extracts were dried with anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure.The crude residue was purified by fast column chromatography on silica gel by using PE/EA as eluents (3a, 60% yield, 1.06 g).

Synthesis Procedure of 3aa
To a 10 mL reaction tube, we added 3a (0.2 mmol), acetic acid (1 mL), ferric nitrate nonahydrate (0.5 equiv.), and iodophor (2 mL).The solution was stirred at 50 • C for 1 h.When the reaction was complete, it was neutralized with saturated sodium bicarbonate solution and extracted with ethyl acetate (20 mL).The solvent was removed under reduced pressure and the crude product was purified by fast chromatography on silica gel (PE/EA) to afford the final product 1,3-bis(phenylsulfinyl)-2-naphthyl-amine 3aa in a 55% yield.

Scheme 3 .
Scheme 3. Control experiment of catalytic system.

Scheme 3 .
Scheme 3. Control experiment of catalytic system.

Scheme 4 .Scheme 5 .
Scheme 4. The control experiments.[a] Reactions in the presence of radical trapping reagents.[b] The reactivity of 2a alone.[c] The reactivity of 2aa without iodophor.[d] The reactivity of 2ab without iodophor.Based on the above investigation and analysis, a plausible mechanism is outlined in Scheme 5.The reaction is initiated by benzenesulfonyl hydrazine, which can be transformed by I2 to form the intermediate 2aa and 2ab.Next, the sulfenylation of naphthylamine is mainly achieved through the following two routes: (1) Phenyl hypoiodothioite formed by the reaction of 2aa with I2 undergoes an electrophilic addition reaction with βnaphthylamine to give intermediate I.This intermediate loses HI to provide intermediate II.Subsequently, intermediate II repeats the above reaction process to obtain product 3a (Path 1).(2) The intermediate 2ab as an electrophile reacts with 1a to form III. The generated benzenesulfinic acid can be converted into 2ab in the presence of I2.Finally, the intermediate II reacts with the generated 2ab to obtain the product 3a (Path 2).

Scheme 4 .
Scheme 4. The control experiments.[a] Reactions in the presence of radical trapping reagents.[b] The reactivity of 2a alone.[c] The reactivity of 2aa without iodophor.[d] The reactivity of 2ab without iodophor.Based on the above investigation and analysis, a plausible mechanism is outlined in Scheme 5.The reaction is initiated by benzenesulfonyl hydrazine, which can be transformed by I 2 to form the intermediate 2aa and 2ab.Next, the sulfenylation of naphthylamine is mainly achieved through the following two routes: (1) Phenyl hypoiodothioite formed by the reaction of 2aa with I 2 undergoes an electrophilic addition reaction with β-naphthylamine to give intermediate I.This intermediate loses HI to provide intermediate II.Subsequently, intermediate II repeats the above reaction process to obtain product 3a (Path 1).(2) The intermediate 2ab as an electrophile reacts with 1a to form III. The generated benzenesulfinic acid can be converted into 2ab in the presence of I 2 .Finally, the intermediate II reacts with the generated 2ab to obtain the product 3a (Path 2).

Scheme 4 .Scheme 5 .
Scheme 4. The control experiments.[a] Reactions in the presence of radical trapping reagents.[b] The reactivity of 2a alone.[c] The reactivity of 2aa without iodophor.[d] The reactivity of 2ab without iodophor.Based on the above investigation and analysis, a plausible mechanism is outlined in Scheme 5.The reaction is initiated by benzenesulfonyl hydrazine, which can be transformed by I2 to form the intermediate 2aa and 2ab.Next, the sulfenylation of naphthylamine is mainly achieved through the following two routes: (1) Phenyl hypoiodothioite formed by the reaction of 2aa with I2 undergoes an electrophilic addition reaction with βnaphthylamine to give intermediate I.This intermediate loses HI to provide intermediate II.Subsequently, intermediate II repeats the above reaction process to obtain product 3a (Path 1).(2) The intermediate 2ab as an electrophile reacts with 1a to form III. The generated benzenesulfinic acid can be converted into 2ab in the presence of I2.Finally, the intermediate II reacts with the generated 2ab to obtain the product 3a (Path 2).

Table 1 .
Optimization of the reaction conditions a .

Table 1 .
Optimization of the reaction conditions a .

Table 1 .
Optimization of the reaction conditions a .