Synthesis of Sulfonyl Halides from Disulfides or Thiols Using Sodium Hypochlorite Pentahydrate (NaOCl·5H₂O) Crystals

Abstract

Synthesis of sulfonyl halides using sodium hypochlorite pentahydrate (NaOCl·5H₂O) crystals was studied in detail, considering the reaction rate and yield of the desired product. NaOCl·5H₂O reacted with disulfides or thiols in acetic acid to produce sulfonyl chlorides. The yields of the desired sulfonyl chlorides were enhanced when the reaction was performed in (trifluoromethyl)benzene under a CO₂ atmosphere. The generation of hypochlorous acid (HOCl) was essential for both reactions. Similarly, sulfonyl bromides were prepared via the reaction of disulfides or thiols with sodium bromide and NaOCl·5H₂O crystals in acetic acid owing to the generation of hypobromous acid (HOBr). However, the reaction could not proceed in (trifluoromethyl)benzene under a CO₂ atmosphere because bromine was produced instead of HOBr.

Introduction

Sulfonyl chlorides are useful reagents in organic synthesis and can be converted into sulfonic esters, sulfonamides, sulfonic anhydrides, sulfonyl hydrazides, and sulfonyl azides. Oxidative chlorination of disulfides or thiols is the most practical method to prepare sulfonyl chlorides.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] Many reactions have been developed using a variety of chlorinating agents, such as chlorine-acetic acid,[1] aqueous chlorine,[2] potassium nitrate-sulfuryl chloride,[3] hydrochloric acid-chlorine,[4] hydrogen peroxide-zirconium tetrachloride,[5] hydrogen peroxide-thionyl chloride,[6] Oxone-thionyl chloride,[7] potassium nitrate-chlorotrimethylsilane,[8] trichlorocyanuric acid-benzyltrimethylammonium chloride,[9] aqueous hydrogen bromide-ammonium nitrate-oxygen,[10] hydrochlorous acid-N-chlorosuccinimide,[11] N-chlorosuccinimide-tetra-n-butylammonium chloride,[12] N-chlorosuccinimide,[13] N-chlorosuccinimide-isopropyl alcohol,[14] and Oxone-potassium chloride.[15]

Recently, sodium hypochlorite pentahydrate (NaOCl·5H₂O) crystals have been employed to prepare sulfonyl chlorides.[16] NaOCl·5H₂O is commercially available and is one of the environmentally benign oxidants[16] [17] [18] because its post-oxidation product is ‘table salt’ (NaCl). The NaOCl·5H₂O crystals have several advantages over the conventional sodium hypochlorite solution (NaOCl concentration up to 13% in aqueous solution). For example, the crystals contain 44% active ingredient (NaOCl) and minimal sodium hydroxide and NaCl. The aqueous solution prepared from NaOCl·5H₂O crystals has a lower pH value (ca. 11) than the conventional NaOCl solution (ca. 13). Moreover, the NaOCl·5H₂O crystals are more stable than the conventional NaOCl solution below 7 °C.

As shown in Scheme [1], NaOCl·5H₂O reacted with disulfides 1 or thiols 2 in acetic acid (AcOH) and produced sulfonyl chlorides 3.[16] Recently, Miyamato and Uchiyama reported that the reaction of NaOCl·5H₂O could proceed in a more cost-effective, scalable, and non-toxic way, that is, under a CO₂ atmosphere instead of in AcOH solution.[19] In this study, a further investigation of this reaction was reported considering solvent effects, using various disulfides or thiols, and the possibility to conduct it under a CO₂ atmosphere. Furthermore, sulfonyl bromides are more reactive than the corresponding sulfonyl chlorides[20] and synthetically valuable because they are reagents for radical bromosulfonylation of alkenes.[21] However, the organic synthesis of sulfonyl bromides was seldom reported.[22] In this study, a new method was also reported to prepare sulfonyl bromides 4 via the reaction of 1 or 2 with NaOCl·5H₂O and sodium bromide (NaBr) in AcOH (Scheme [1]).

Synthesis of Sulfonyl Chlorides

Investigation of Reaction Conditions

The solvent effects were first examined in the reaction of di-p-tolyl disulfide (1a) with NaOCl·5H₂O (Table [1]). The desired product 3a was obtained in a good yield when acetic acid was used as the solvent (Table [1], run 1). The starting material 1a quickly reacted with NaOCl·5H₂O in polar solvents, such as acetic acid, acetonitrile, and t-butyl alcohol, as shown in runs 1–3, respectively, with the reaction time ranging from 1–6 minutes. In contrast, the reaction proceeded very slowly in the less polar solvent. For example, 1a remained unreacted after 16.7 hours in dichloromethane or toluene (runs 4 and 5). After extraction using dichloromethane, 3a was the only product obtained in runs 1–5. If methanol or ethanol was used as the solvent (runs 6 and 7), sulfonyl esters (3′a or 3′′a) were obtained in a low yield as the sole product. In these cases, excessive amounts of NaOCl·5H₂O were required because they were involved in additional reactions with the solvents (MeOH and EtOH).[23] Investigation of the aqueous phase after the synthesis revealed that water-soluble sodium p-toluenesulfonate was produced in runs 2–7.

Table 1 Reaction of 1a with NaOCl·5H₂O in Different Solvents

^a The starting material 3a had completely disappeared, and no other product was obtained.

^b At 30 °C.

^c At room temperature.

^d Some starting material 3a remained.

^e Sodium p-toluenesulfonate was detected as the by-product.

These results suggest that AcOH is crucial to the production of the desired sulfonyl chlorides. The reaction of diphenyl disulfide (1b) with 5 equivalents of NaOCl·5H₂O or the conventional aqueous NaOCl (12% w/w) was investigated, as shown in Table [2].

Table 2 Reaction of 1b with NaOCl Using AcOH or BTF as Solvent^a

^a Reaction conditions: 1b (3.0 mmol), NaOCl (15.0 mmol), solvent (33 mL)

^b GC yield using an internal standard.

^c Most of 1b was unreacted.

^d Sodium benzenesulfonate was accompanied as the by-product.

The reaction with the conventional aqueous NaOCl in AcOH exhibited the same result as the reactions with NaOCl·5H₂O crystals (Table [2], runs 1 and 2), and the desired sulfonyl chloride 3b was obtained in 80% yield. Owing to the advantages of the NaOCl·5H₂O crystals described in the introduction, they could be used to replace NaOCl solution to produce sulfonyl chloride. In the presence of 6.75 equivalents of AcOH, 3b was effectively derived from the reaction of NaOCl·5H₂O in (trifluoromethyl)benzene (benzotrifluoride, BTF) (run 3). In contrast, 1b was almost inert in BTF in the absence of AcOH because NaOCl·5H₂O was difficult to dissolve in BTF (run 4).

The reactions were then investigated in BTF without AcOH but in the presence of a phase-transfer catalyst (tetrabutylammonium bromide or tetrabutylammonium hydrogen sulfate) (Table [2], runs 5–7). The reaction was completed within 0.5–1 hour; however, the yield of 3b was less than 50%, and sodium benzenesulfonate was detected as the main by-product. These results suggest that generating hypochlorous acid (HOCl) from NaOCl and AcOH is essential to obtain 3b in a satisfactory yield.

Synthesis of Sulfonyl Chlorides from the Reaction of Various Disulfides or Thiols with NaOCl·5H₂O in Acetic Acid

Table 3 Reaction of Disulfides with NaOCl·5H₂O in AcOH

^a GC yield.

The reactions of several disulfides 1 with NaOCl·5H₂O (6.5 equiv)[24] in acetic acid were investigated, as shown in Table [3]. The reaction was completed immediately, and the desired sulfonyl chlorides were obtained in satisfactory yields in most cases. If the disulfide has a pyridine-moiety (R = 2-pyridyl, 1g), the isolated yield of the desired sulfonyl chloride 3g was very low (17%). Despite the easy reaction between 1g and NaOCl·5H₂O, a considerable proportion of 3g was hydrolyzed to the corresponding sodium sulfonate (sodium 2-pyridinesulfonate) at the workup stage because the pyridine moiety required an alkaline condition for its isolation from the AcOH solution.

Table [4] summarizes the reactions between several thiols 2 and NaOCl·5H₂O in AcOH. Similar to Table [3], the reactions were complete within 1 minute, and the corresponding sulfonyl chlorides 3 were produced in high yields except for 3g. Because 3g had a 2-pyridyl moiety, it was isolated in a low yield (9%).

Table 4 Reaction of Thiols with NaOCl·5H₂O in AcOH

A plausible reaction mechanism is suggested in Scheme [2]. NaOCl reacted with AcOH to form HOCl,[23a] which chlorinated the sulfur atom of disulfide 1. The nucleophilic substitution of the chlorine atom in the sulfonium ion A generated thiosulfinate B. The second reaction of HOCl with B and the successive reaction with water produced an equilibrium mixture of disulfoxide C and thiosulfonate D.

There are two possible reaction routes for the formation of mixture (Paths A and B). In Path A, the third HOCl chlorinated the sulfur atom of C, and water attacked the other sulfur atom of C to produce sulfinic acid E and sulfinyl chloride F. Two more equivalents of HOCl reacted with E and F to form two molecules of sulfonyl chloride 3. In Path B, thiosulfonate D reacted with HOCl and chlorine anion (Cl^–, eliminated from A) to generate sulfanyl chloride G and sulfonyl chloride 3. The fourth HOCl reacted with G to develop sulfinyl chloride F, and the fifth HOCl converted F into sulfonyl chloride 3.

Synthesis of Sulfonyl Chlorides from the Reaction of Disulfides or Thiols with NaOCl·5H₂O under a CO₂ Atmosphere

Recently, Miyamato and Uchiyama reported that the oxidizing agent 1-hydroxy-1,2-benziodoxol-3(1H)-one 1-oxide could be derived from the oxidation of 2-iodobenzoic acid in an aqueous solution of NaOCl under a CO₂ atmosphere.[19]

Table 5 Reaction of 1a with NaOCl·5H₂O in Several Solvents under a CO₂ Atmosphere

^a Sodium p-toluenesulfonate was also produced.

^b Aqueous 13% NaOCl (8 eq.) was used instead of NaOCl·5H₂O.

Inspired by these results, the reaction of 1a and NaOCl·5H₂O (8.0 equiv)[25] under a CO₂ atmosphere (balloon) was investigated using different solvents (Table [5]). When BTF was used, the reaction was completed in 15 minutes and the desired product 3a was obtained. In this case, the reaction time was slightly longer than that in run 1, Table [1] (1 min when AcOH was used) because NaOCl·5H₂O did not dissolve in BTF. However, 3a was isolated in a better yield (94%) than run 1, Table [1] (88%). In CH₂Cl₂ (Table [5], run 2), the desired 3a was also obtained in a satisfactory yield (88%); however, the reaction time was significantly longer (60 min). In acetonitrile (run 3), 1a rapidly reacted with NaOCl·5H₂O, but 3a was obtained in a low yield with sodium p-toluenesulfonate as a by-product. Conventional NaOCl aqueous solution (13%) could also react with 1a in BTF under CO₂ (run 4) with a long reaction time (54 min). The possible reactions under a CO₂ atmosphere were proposed, that is, NaOCl·5H₂O or aqueous NaOCl reacted with CO₂ to form HOCl, which reacted with 1b via the same routes depicted in Scheme [2].

Several disulfides 1 were reacted with NaOCl·5H₂O (8 equiv) under a CO₂ atmosphere in the BTF (Table [6]). In all cases, the desired sulfonyl chlorides 3 were obtained as the sole products, and the yields of 3 were better than those presented in Table [3] (reaction with NaOCl·5H₂O in AcOH). In particular, 2-pyridylsulfonyl chloride (3g) was obtained in a satisfactory yield (64%).

Table 6 Reaction of Disulfides with NaOCl·5H₂O in BTF under a CO₂ Atmosphere

Thiols 2 were also good substrates for the reaction with NaOCl·5H₂O in BTF under a CO₂ atmosphere. Despite the slightly longer reaction time (15–77 min), the corresponding sulfonyl chlorides 3 were obtained in better yields (Table [7]) when compared with Table [4] (reaction with NaOCl·5H₂O in AcOH). In particular, 2-pyridylsulfonyl chloride (3g) was obtained in substantially a higher yield (43%) in comparison with the yield of the same reaction that occurred in AcOH (9%).

Under the reaction conditions, most ofNaOCl·5H₂O crystals can not dissolve in BTF. The NaOCl·5H₂O crystals directly react with CO₂ molecule, which dissolves in BTF, to produce HOCl (Scheme [3]). The resulting HOCl reacts with disulfides or thiols under the same mechanism as depicted Scheme [2].

Synthesis of Sulfonyl Bromides

Table 7 Reaction of Rhiols with NaOCl·5H₂O in BTF under a CO₂ Atmosphere

Our study on oxidative chlorination had been extended to the preparation of sulfonyl bromides by adding NaBr to the reaction system. It was expected that hypochlorite (OCl⁻) reacts with the bromine anion (Br⁻) to produce hypobromite (OBr⁻).[26] Based on the hypotheses shown in Scheme [3], disulfides 1 or thiols 2 could react with NaOCl·5H₂O in AcOH in the presence of excess NaBr to produce sulfonyl bromides 4 (Scheme [4]).

First, the synthesis of sulfonyl bromides from disulfides was investigated. NaBr was treated with NaOCl·5H₂O in AcOH for 30 minutes, followed by the reaction with 1a. The corresponding sulfonyl bromide 4a was obtained in an 85% yield. The desired 4a was also obtained in 91% yield when thiol 2a was used as the starting material (Scheme [5]).

Different disulfides or thiols were treated with NaBr and NaOCl·5H₂O in AcOH under the same conditions. As shown in Tables 8 and 9, the desired products were obtained in a reasonable yield in all cases.

Table 8 Synthesis of Sulfonyl Bromides from Disulfides

Table 9 Synthesis of Sulfonyl Bromides from Thiols

Next, the reactions of di-p-tolyl disulfide (1a) and p-methylthiophenol (2a) with NaBr and NaOCl·5H₂O were performed in BTF under a CO₂ atmosphere. Unfortunately, the desired sulfonyl bromide was not obtained. Under the above reaction conditions, 1a was recovered quantitatively, and 2a was converted into 1a (Scheme [6]).

During the reaction, the organic phase of the mixture (upper layer) turned red, suggesting that bromine (Br₂) was produced and dissolved in the BTF. In this case, most of NaOCl·5H₂O and NaBr did not dissolve in BTF, and they directly reacted with CO₂ to produce Br₂, which is soluble in BTF. Since H₂O is insoluble in BTF, HOBr cannot be produced from Br₂.

We confirmed that Br₂ oxidized the thiol 2a to produce 1a in BTF under a CO₂ or N₂ atmosphere.[27] No further oxidation from 1a to sulfonyl bromide was observed (Scheme [7]).

These results suggested that the active species for this reaction is HOBr, which was consistent with the original hypothesis for the conversion of disulfides or thiols to sulfonyl bromide, as depicted in Scheme [3]. In AcOH, NaBr reacted with NaOCl·5H₂O to produce HOBr, which further reacted with disulfides or thiols via a mechanism similar to that shown in Scheme [2]. In contrast, under a CO₂ atmosphere in BTF, Br₂ was produced first and immediately dissolved in the BTF. Since H₂O is hard to dissolve in BTF, the conversion from Br₂ to HOBr could be difficult even in the presence of CO₂ (Scheme [8]).

Conclusion

The crystals of NaOCl·5H₂O reacted with disulfides or thiols in AcOH to produce the corresponding sulfonyl chlorides, and the active species in the reaction was HOCl. This reaction also occurred in BTF under a CO₂ atmosphere with higher yields of sulfonyl chlorides. Sulfonyl bromides were synthesized via the reaction of disulfides or thiols with NaBr and NaOCl·5H₂O in AcOH, and the active species was HOBr. This reaction could not proceed in BTF under a CO₂ atmosphere because disulfide was completely unreacted with NaBr and NaOCl·5H₂O while thiols generated the corresponding disulfides under the reaction conditions.

All reagents were purchased from Nacalai Tesque, FUJIFILM Wako Pure Chemical Corporation, Kanto Kagaku, Kishida Reagents Chemical Co., Tokyo Chemical Industry, or Aldrich, and used without further purification. NaOCl·5H₂O crystals were manufactured by Nippon Light Metal Co., Ltd. For reference, the reagent could be purchased from Wako Pure Chemical Industries, Ltd., Tokyo Chemical Industry Co., Ltd., Junsei Chemical Co., Ltd., TCI America, and TCI Europe for laboratory use. Melting points were measured using a Yanaco micro melting point apparatus (MP-J3) without additional correction. NMR spectra were recorded on a JEOL (JNM-EX400) spectrometer using TMS or the residual solvent peak as the internal standard. Mass spectra were recorded on a Shimadzu GCMS-QP2020 spectrometer. GC analyses were performed on a Shimadzu GC-2014 instrument with flame-ionization detectors, equipped with an NB-1 (0.25 mm × 60 m, df1/40.4 mm) GC column using helium as the carrier gas. The GC yields were determined using 1-chloronaphthalene or decalin as an internal standard.

Standard Procedure for the Synthesis of Sulfonyl Chlorides 3 from the Reaction of NaOCl·5H₂O with Disulfides 1 in Acetic Acid (Table [3])

To a solution of disulfide 1 (3.0 mmol) in AcOH (11 mL) was added NaOCl·5H₂O (2.47 g, 15.0 mmol). The reaction was monitored by TLC. After the disulfide had disappeared, H₂O (4 mL) and CH₂Cl₂ (15 mL) were added to the reaction mixture to quench the reaction.

In the preliminary communication,[16] the typical procedures to synthesize sulfonyl chlorides from disulfides or thiols used p-TsCl and sat. aq Na₂S₂O₃ to quench the reaction. However, it was found that the sat. aq Na₂S₂O₃ sometimes promoted the decomposition of the products (sulfonyl chlorides). Therefore, H₂O is recommended to quench the reaction.

The organic layer was separated, and the aqueous phase was extracted with CH₂Cl₂ (2 × 15 mL). The combined extracts were dried (anhyd Na₂SO₄) and evaporated to obtain sulfonyl chloride 3. The products were analyzed without further purification.

p-Toluenesulfonyl Chloride (3a)[12]

Yield: 88%; colorless crystals; mp 68 °C (Lit.[4] mp 65–69 °C).

¹H NMR (CDCl₃): δ = 7.93 (2 H, d, J = 8.4 Hz), 7.41 (2 H, d, J = 8.4 Hz), 2.50 (3 H, s).

¹³C NMR (CDCl₃): δ = 146.8, 141.7, 130.2, 127.1, 21.8.

MS: m/z = 192 (M⁺ for ³⁷Cl), 190 (M⁺ for ³⁵Cl).

Benzenesulfonyl Chloride (3b)[16]

Yield: 95%; colorless oil.

¹H NMR (CDCl₃): δ = 8.07–8.04 (2 H, m), 7.80–7.74 (1 H, m), 7.66–7.62 (2 H, m).

¹³C NMR (CDCl₃): δ = 144.3, 135.3, 129.7, 126.9.

MS: m/z = 178 (M⁺ for ³⁷Cl), 176 (M⁺ for ³⁵Cl).

p-Methoxybenzenesulfonyl Chloride (3c)[12]

Yield: 86%; colorless crystals; mp 38 °C (Lit.[4] 39–42 °C)

¹H NMR (CDCl₃): δ = 8.00–7.96 (2 H, m), 7.06–7.04 (2 H, m), 3.93 (3 H, s).

¹³C NMR (CDCl₃): δ = 164.9, 136.1, 129.5, 114.7, 56.0.

MS: m/z = 208 (M⁺ for ³⁷Cl), 206 (M⁺ for ³⁵Cl).

p-Chlorobenzenesulfonyl Chloride (3d)[12]

Yield: 78%; colorless crystals; mp 53 °C (Lit.[^4] mp 50–52 °C)

¹H NMR (CDCl₃): δ = 7.99 (2 H, d, J = 8.4 Hz), 7.60 (2 H, d, J = 8.4 Hz).

¹³C NMR (CDCl₃): δ = 142.6, 142.2, 130.0, 128.4.

MS: m/z = 213 (M⁺ for ³⁷Cl), 211 (M⁺ for ³⁵Cl).

Benzylsulfonyl Chloride (3e)[12]

Yield: 75%; colorless oil.

¹H NMR (CDCl₃): δ = 7.50–7.44 (5 H, m), 4.87 (2 H, s).

¹³C NMR (CDCl₃): δ = 131.4, 130.3, 129.2, 126.1, 70.9.

MS: m/z = 192 (M⁺ for ³⁷Cl), 190 (M⁺ for ³⁵Cl).

Cyclohexanesulfonyl Chloride (3f)[14]

Yield: 94%; colorless oil.

¹H NMR (CDCl₃): δ = 3.55–3.48 (1 H, m), 2.45–2.41 (2 H, m), 2.02–1.98 (2 H, m), 1.81–1.68 (3 H, m), 1.43–1.20 (3 H, m).

¹³C NMR (CDCl₃): δ = 74.9, 27.2, 25.1, 24.7.

MS: m/z = 99 (M⁺ – C₆H₁₁), 83 (M⁺ – SO₂Cl)

Synthesis of 2-Pyridinesulfonyl Chloride (3g)[28] from the Reaction of 1g with NaOCl·5H₂O in Acetic Acid

To a solution of di-2-pyridyl disulfide (1g; 220.9 mg, 1.0 mmol) in AcOH (6 mL) was added NaOCl·5H₂O (1.07 g, 6.5 mmol) and the mixture was stirred at rt for 30 min. An aq solution of 0.1 M NaOH (5 mL) and CH₂Cl₂ (15 mL) were added to the reaction mixture. The organic layer was separated, and the aqueous phase was extracted with dichloromethane (2 × 15 mL). The combined extracts were dried over anhydrous sodium sulfate and evaporated to obtain 2-pyridinesulfonyl chloride 3g (575 mg, 17%) as a pale-yellow oil. The product was analyzed without further purification.

¹H NMR (CDCl₃): δ = 7.62 (1 H, ddd, J = 8.0, 4.8, 1.2 Hz), 7.99 (1 H, ddd, J = 8.0, 7.6, 2.0 Hz), 8.06 (1 H, dd, J = 8.0, 1.2 Hz), 8.76–8.77 (1 H, dd, J = 4.8, 2.0 Hz).

¹³C NMR (CDCl₃): δ = 159.2, 159.0, 139.4, 129.5, 122.2.

Standard Procedure for the Synthesis of Sulfonyl Chlorides 3 from the Reaction of NaOCl·5H₂O with Thiols 2 in Acetic Acid

To a solution of a thiol 2 (2.0 mmol) in AcOH (11 mL) was added NaOCl·5H₂O (1.32 g, 12.0 mmol) and stirred at rt over 1 min. H₂O (4 mL) and CH₂Cl₂ (20 mL) were then added to the reaction mixture to quench the reaction. The organic layer was separated, and the aqueous phase was extracted with CH₂Cl₂ (20 mL). The combined extracts were dried (anhyd Na₂SO₄) and evaporated to give sulfonyl chloride 3. The product was analyzed without further purification.

Synthesis of 2-Pyridinesulfonyl Chloride (3g) from the Reaction of 2g with NaOCl·5H₂O in Acetic Acid

To a solution of 2-mercaptopyridine (2g; 111.2 mg, 1.0 mmol) in AcOH (6 mL) was added NaOCl·5H₂O (0.82 g, 5 mmol) and the mixture was stirred at rt for 1 min. Aq solution of 0.1 M NaOH (5 mL) and CH₂Cl­₂ (15 mL) were added to the reaction mixture. The organic layer was separated, and the aqueous phase was extracted with CH₂Cl₂ (2 × 15 mL). The combined extracts were dried (anhyd Na₂SO₄) and evaporated to give 2-pyridinesulfonyl chloride 3g (153 mg, 9%) as a pale-yellow oil. The product was analyzed without further purification.

Standard Procedure for the Synthesis of Sulfonyl Chlorides 3 through the Reaction of NaOCl·5H₂O with Disulfides 1 in BTF under a CO₂ Atmosphere (Table [6])

To a solution of disulfide 1 (1 mmol) in BTF (11 mL) was added NaOCl­·5H₂O (1.31 g, 8 mmol) and the mixture was stirred at rt under a CO₂ atmosphere (balloon). The reaction was monitored by TLC. H₂O (15 mL) and EtOAc (15 mL) were added to the reaction mixture after the disulfide had disappeared completely. The organic layer was separated, and the aqueous phase was extracted with EtOAc (2 × 15 mL). The combined extracts were washed with brine (45 mL), dried (anhyd Na₂SO₄) and evaporated to obtain sulfonyl chloride 3. The products were analyzed without further purification.

Standard Procedure for the Synthesis of Sulfonyl Chlorides 3 from the Reaction of NaOCl·5H₂O with Thiols 2 in BTF under a CO₂ Atmosphere (Table [7])

To a solution of thiol 2 (1 mmol) in BTF (11 mL) was added NaOCl·5H₂O (0.82 g, 5 mmol) and the mixture was stirred at rt under a CO₂ atmosphere (balloon). The reaction was monitored by TLC. H₂O (15 mL) and EtOAc (15 mL) were added to the reaction mixture after the thiol had disappeared completely. The organic layer was separated, and the aqueous phase was extracted with EtOAc (2 × 15 mL). The combined extracts were washed with brine (45 mL), dried over anhydrous sodium sulfate, and evaporated to obtain sulfonyl chloride (3). The products were analyzed without further purification.

Standard Procedure for the Synthesis of Sulfonyl Bromides 4 from Disulfides 1 or Thiols 2 (Tables 8 and 9)

To a solution of NaBr (823 mg, 8.0 mmol) in acetic acid (7 mL), NaOCl·5H₂O (1.07 g, 6.5 mmol) was added under stirring, and the resulting mixture was stirred at room temperature for another 30 min. A solution of disulfide (1) or thiol (2) (1.0 mmol) in AcOH (1 mL) was then added to the mixture under stirring. The reaction was monitored by TLC and stirring was continued until the starting material disappeared. H₂O (50 mL) was added to the reaction mixture, which was then extracted with chloroform (3 × 5 mL). The combined extract was dried (anhyd MgSO₄) and evaporated to obtain the corresponding sulfonyl bromide 4. The product was analyzed without further purification.

4-Toluenesulfonyl Bromide (4a)[12]

Yield: 85% (from disulfide), 91% (from thiol); colorless crystals; mp 95 °C (Lit.[22b] mp 95–96 °).

¹H NMR (CDCl₃): δ = 7.89 (2 H, d, J = 8.4 Hz), 7.39 (2 H, d, J = 8.4 Hz), 2.49 (3 H, s).

¹³C NMR (CDCl₃): δ = 146.9, 144.6, 130.1, 126.5, 21.9.

Benzenesulfonyl Bromide (4b)[12]

Yield: quant (from thiol); yellow oil.

¹H NMR (CDCl₃): δ = 8.01 (2 H, d, J = 8.7 Hz), 7.73 (1 H, t, J = 7.3 Hz), 7.62 (2 H, t, J = 16 Hz).

¹³C NMR (CDCl₃): δ = 147.2, 135.2, 129.6, 126.5.

4-Methoxybenzensulfonyl Bromide (4c)[12]

Yield: 62% (from disulfide), quant (from thiol); colorless oil.

¹H NMR (CDCl₃): δ = 7.95 (2 H, d, J = 9.1 Hz), 7.03 (2 H, d, J = 9.1 Hz), 3.93 (3 H, s).

¹³C NMR (CDCl₃): δ = 170.3, 139.2, 129.1, 114.5, 56.0.

4-Chlorobenzensulfonyl Bromide (4d)[12]

Yield: 73% (from disulfide), 61% (from thiol); colorless crystals; mp 53 °C (Lit.[22c] mp 56 °C).

¹H NMR (CDCl₃): δ = 7.95 (2 H, d, J = 8.4 Hz), 7.59 (2 H, d, J = 8.4 Hz).

¹³C NMR (CDCl₃): δ = 145.3, 142.1, 129.9, 127.9.

Cyclohexanesulfonyl Bromide (4f)[12]

Yield: 93% (from disulfide), quant (from thiol); pale yellow oil.

¹H NMR (CDCl₃): δ = 3.49 (1 H, tt, J = 11.8, 3.4 Hz), 2.42 (2 H, d, J = 12.9 Hz), 1.99 (2 H, d, J = 13.7 Hz), 1.66–1.75 (3 H, m), 1.21–1.45 (3 H, m).

¹³C NMR (CDCl₃): δ = 78.8, 27.6, 25.0, 24.8.

Decanesulfonyl Bromide (4h)[12]

Yield: 79% (from disulfide); pale yellow oil.

¹H NMR (CDCl₃): δ = 3.66 (2 H, t, J = 8.0 Hz), 2.04 (2 H, m), 1.27–1.52 (14 H, m), 0.89 (3 H, t, J = 7.0 Hz).

¹³C NMR (CDCl₃): δ = 69.7, 31.8, 29.4, 29.2, 29.2, 28.9, 27.3, 24.6, 22.6, 14.1.

Conflict of Interest

The authors declare no conflict of interest.

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• 7 Humljan J, Gobec S. Tetrahedon Lett. 2005; 46: 4069
  CrossrefSearch in Google Scholar
• 8a Reddie RN. Synth. Commun. 1987; 17: 1129
  CrossrefSearch in Google Scholar
• 8b Kvaernø L, Werder M, Hauser H, Carreira EM. Org. Lett. 2005; 7: 1145
  CrossrefPubMedSearch in Google Scholar
• 9 Prakash GK. S, Mathew T, Panja C, Olah GA. J. Org. Chem. 2007; 72: 5847
  CrossrefPubMedSearch in Google Scholar
• 10 Veisi H, Sedrpoushan A, Hemmati S, Kordestani D. Phosphorus, Sulfur, Silicon Relat. Elem. 2012; 187, 769
• 11 Veisi H, Ghorbani-Vaghei R, Hemmati S, Mahmoodi J. Synlett 2011; 2315
  Thieme Connect
• 12 Kirihara M, Naito S, Nishimura Y, Ishizuka Y, Iwai T, Takeuchi H, Ogata T, Hanai H, Kinoshita Y, Kishida M, Yamazaki K, Noguchi T, Yamashoji S. Tetrahedron 2014; 70: 2464
  CrossrefSearch in Google Scholar
• 13 Silva-Cuevas C, Perez-Arrieta C, Polindara-García LA, Lujan-Montelongo JA. Tetrahedron Lett. 2017; 58: 2244
  CrossrefSearch in Google Scholar
• 14 Jereb M, Hribernik L. Green Chem. 2017; 19: 2286
  CrossrefSearch in Google Scholar
• 15 Madabhushi S, Jillella R, Sriramoju V, Singh R. Green Chem. 2014; 16: 3125
  CrossrefSearch in Google Scholar
• 16 Okada T, Matsumuro H, Iwai T, Kitagawa S, Yamazaki T, Akiyama K, Asawa T, Sugiyama Y, Kimura Y, Kirihara M. Chem. Lett. 2015; 44: 185
  CrossrefSearch in Google Scholar
• 17a Kirihara M, Okada T, Asawa T, Sugiyama Y, Kimura Y. J. Synth. Org. Chem. Jpn. 2020; 78: 11
  CrossrefSearch in Google Scholar
• 17b Kirihara M, Okada T, Sugiyama Y, Akiyoshi M, Matsunaga T, Kimura Y. Org. Process Res. Dev. 2017; 21: 1925
  CrossrefSearch in Google Scholar
• 17c Kirihara M, Osugi R, Saito K, Adachi K, Yamazaki K, Matsushima R, Kimura Y. J. Org. Chem. 2019; 84: 8330
  CrossrefPubMedSearch in Google Scholar
• 17d Hakuto N, Saito K, Kirihara M, Kotsuchibashi Y. Polym. Chem. 2020; 11: 2469
  CrossrefSearch in Google Scholar
• 17e Kirihara M, Suzuki K, Nakakura K, Saito K, Nakamura R, Tujimoto K, Sakamoto Y, Kikkawa Y, Shimazu H, Kimura Y. J. Fluorine Chem. 2021; 243: 109719
  CrossrefSearch in Google Scholar
• 17f Kirihara M, Adachi K, Sakamoto Y, Tujimoto K, Yamahara S, Matsushima R, Namba Y, Sato K, Kamada T, Kimura Y, Takizawa S. Heterocycles 2021; 103: 699
  CrossrefSearch in Google Scholar

Synthetic reactions using NaOCl·5H₂O recently developed by other groups:
• 18a Miller SA, Bisset KA, Leadbeater NE, Eddya NA. Eur. J. Org. Chem. 2019; 1413
  Crossref
• 18b Porcheddu A, Delogu F, De Luca LD, Fattuoni C, Colacino E. Beilstein J. Org. Chem. 2019; 15: 1786
  CrossrefPubMedSearch in Google Scholar
• 18c Uyanik M, Nishioka K, Kondo R, Ishihara K. Nat. Chem. 2020; 12: 353
  CrossrefPubMedSearch in Google Scholar
• 18d Zhu Y, Wang J, Wu D, Yu W. Asian J. Org. Chem. 2020; 9: 1650
  CrossrefSearch in Google Scholar
• 18e Matsuki S, Kayano H, Takada J, Kono H, Fujisawa S, Saito T, Isogai A. ACS Sustain. Chem. Eng. 2020; 8: 17800
  CrossrefSearch in Google Scholar
• 18f Umeda T, Minakata S. RSC Adv. 2021; 11: 22120
  CrossrefPubMedSearch in Google Scholar
• 19 Miyamoto K, Okada T, Toyama T, Imamura S, Uchiyama M. Heterocycles 2021; 103: 694
  CrossrefSearch in Google Scholar
• 20 Ahluwalia VK, Parashar RK. Organic Reaction Mechanisms, 2nd ed. Alpha Science International Ltd; Oxford: 2005: 4
  Search in Google Scholar
• 21 Toth JE, Collins EA. e-EROS Encyclopedia of Reagents for Organic Synthesis, p-toluenesulfonyl bromide 2004;
  Crossref
• 22a Lukashevich VO. Dokl. Akad. Nauk SSSR 1955; 103: 627
  Search in Google Scholar
• 22b Poshkus AC, Herweh JE, Magnotta FA. J. Org. Chem. 1963; 28: 2766
  CrossrefSearch in Google Scholar
• 22c Litvinenko LM, Dadali VA, Savelova VA, Krichevtsova TI. Zh. Obshch. Khim. 1964; 34: 3730
  Search in Google Scholar
• 22d Prinsen AJ, Cerfontain H. Recl. Trav. Chim. Pays-Bas 1965; 84: 24
  CrossrefSearch in Google Scholar
• 22e Whitmore FC, Thurman N. J. Am. Chem. Soc. 1923; 45: 1068
  CrossrefSearch in Google Scholar
• 23a Ogata Y, Kimura M. J. Synth. Org. Chem. Jpn. 1979; 37: 58
  CrossrefSearch in Google Scholar
• 23b Lee GA, Freedman HH. Tetrahedron Lett. 1976; 17: 1641
  CrossrefSearch in Google Scholar
• 23c Bright ZR, Luyeye CR, Morton AS, Sedenko M, Landolt RG, Bronzi MJ, Bohovic KM, Gonser MW, Lapainis TE, Hendrickson WH. J. Org. Chem. 2005; 70: 684
  CrossrefPubMedSearch in Google Scholar
• 24 Although the desired 3a was obtained in high yields from the reaction of 1a with 5.0 equiv of NaOCl·5H₂O in acetic acid, a small amount of the corresponding thiosulfonate was accompanied. Over 6.5 equiv of NaOCl·H₂O were required to obtain 3a in a pure form.
• 25 Although the desired 3a was obtained in high yields from the reaction of 1a with 5.0 or 6.5 equiv of NaOCl·5H₂O in BTF under CO₂ atmosphere, small amounts of the starting material 1a and/or the corresponding thiosulfonate were accompanied (Scheme 9). In order to obtain 3a in a pure form, over 8 equiv of NaOCl·5H₂O were required.
• 26 Harrelson L, Howarth J, Mesrobian C, Shaver T. Official Proceeding - 72nd International Water Conference 2011; 638
• 27 Br₂ has been known as the reagent for preparation of disulfides from thiols: Ali, M. H.; McDermott, M. Tetrahedron Lett. 2002, 43, 6271; and references cited therein
• 28 Maslankiewicz A, Marciniec K, Pawlowski M, Zajdel P. Heterocycles 2007; 71: 1975
  CrossrefSearch in Google Scholar

Corresponding Author

Publication History

Received: 18 March 2022

Accepted after revision: 12 April 2022

Accepted Manuscript online:
12 April 2022

Article published online:
31 May 2022

© 2022. Thieme. All rights reserved

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

• References

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  Thieme Connect
• 7 Humljan J, Gobec S. Tetrahedon Lett. 2005; 46: 4069
  CrossrefSearch in Google Scholar
• 8a Reddie RN. Synth. Commun. 1987; 17: 1129
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• 8b Kvaernø L, Werder M, Hauser H, Carreira EM. Org. Lett. 2005; 7: 1145
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• 9 Prakash GK. S, Mathew T, Panja C, Olah GA. J. Org. Chem. 2007; 72: 5847
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• 10 Veisi H, Sedrpoushan A, Hemmati S, Kordestani D. Phosphorus, Sulfur, Silicon Relat. Elem. 2012; 187, 769
• 11 Veisi H, Ghorbani-Vaghei R, Hemmati S, Mahmoodi J. Synlett 2011; 2315
  Thieme Connect
• 12 Kirihara M, Naito S, Nishimura Y, Ishizuka Y, Iwai T, Takeuchi H, Ogata T, Hanai H, Kinoshita Y, Kishida M, Yamazaki K, Noguchi T, Yamashoji S. Tetrahedron 2014; 70: 2464
  CrossrefSearch in Google Scholar
• 13 Silva-Cuevas C, Perez-Arrieta C, Polindara-García LA, Lujan-Montelongo JA. Tetrahedron Lett. 2017; 58: 2244
  CrossrefSearch in Google Scholar
• 14 Jereb M, Hribernik L. Green Chem. 2017; 19: 2286
  CrossrefSearch in Google Scholar
• 15 Madabhushi S, Jillella R, Sriramoju V, Singh R. Green Chem. 2014; 16: 3125
  CrossrefSearch in Google Scholar
• 16 Okada T, Matsumuro H, Iwai T, Kitagawa S, Yamazaki T, Akiyama K, Asawa T, Sugiyama Y, Kimura Y, Kirihara M. Chem. Lett. 2015; 44: 185
  CrossrefSearch in Google Scholar
• 17a Kirihara M, Okada T, Asawa T, Sugiyama Y, Kimura Y. J. Synth. Org. Chem. Jpn. 2020; 78: 11
  CrossrefSearch in Google Scholar
• 17b Kirihara M, Okada T, Sugiyama Y, Akiyoshi M, Matsunaga T, Kimura Y. Org. Process Res. Dev. 2017; 21: 1925
  CrossrefSearch in Google Scholar
• 17c Kirihara M, Osugi R, Saito K, Adachi K, Yamazaki K, Matsushima R, Kimura Y. J. Org. Chem. 2019; 84: 8330
  CrossrefPubMedSearch in Google Scholar
• 17d Hakuto N, Saito K, Kirihara M, Kotsuchibashi Y. Polym. Chem. 2020; 11: 2469
  CrossrefSearch in Google Scholar
• 17e Kirihara M, Suzuki K, Nakakura K, Saito K, Nakamura R, Tujimoto K, Sakamoto Y, Kikkawa Y, Shimazu H, Kimura Y. J. Fluorine Chem. 2021; 243: 109719
  CrossrefSearch in Google Scholar
• 17f Kirihara M, Adachi K, Sakamoto Y, Tujimoto K, Yamahara S, Matsushima R, Namba Y, Sato K, Kamada T, Kimura Y, Takizawa S. Heterocycles 2021; 103: 699
  CrossrefSearch in Google Scholar

Synthetic reactions using NaOCl·5H₂O recently developed by other groups:
• 18a Miller SA, Bisset KA, Leadbeater NE, Eddya NA. Eur. J. Org. Chem. 2019; 1413
  Crossref
• 18b Porcheddu A, Delogu F, De Luca LD, Fattuoni C, Colacino E. Beilstein J. Org. Chem. 2019; 15: 1786
  CrossrefPubMedSearch in Google Scholar
• 18c Uyanik M, Nishioka K, Kondo R, Ishihara K. Nat. Chem. 2020; 12: 353
  CrossrefPubMedSearch in Google Scholar
• 18d Zhu Y, Wang J, Wu D, Yu W. Asian J. Org. Chem. 2020; 9: 1650
  CrossrefSearch in Google Scholar
• 18e Matsuki S, Kayano H, Takada J, Kono H, Fujisawa S, Saito T, Isogai A. ACS Sustain. Chem. Eng. 2020; 8: 17800
  CrossrefSearch in Google Scholar
• 18f Umeda T, Minakata S. RSC Adv. 2021; 11: 22120
  CrossrefPubMedSearch in Google Scholar
• 19 Miyamoto K, Okada T, Toyama T, Imamura S, Uchiyama M. Heterocycles 2021; 103: 694
  CrossrefSearch in Google Scholar
• 20 Ahluwalia VK, Parashar RK. Organic Reaction Mechanisms, 2nd ed. Alpha Science International Ltd; Oxford: 2005: 4
  Search in Google Scholar
• 21 Toth JE, Collins EA. e-EROS Encyclopedia of Reagents for Organic Synthesis, p-toluenesulfonyl bromide 2004;
  Crossref
• 22a Lukashevich VO. Dokl. Akad. Nauk SSSR 1955; 103: 627
  Search in Google Scholar
• 22b Poshkus AC, Herweh JE, Magnotta FA. J. Org. Chem. 1963; 28: 2766
  CrossrefSearch in Google Scholar
• 22c Litvinenko LM, Dadali VA, Savelova VA, Krichevtsova TI. Zh. Obshch. Khim. 1964; 34: 3730
  Search in Google Scholar
• 22d Prinsen AJ, Cerfontain H. Recl. Trav. Chim. Pays-Bas 1965; 84: 24
  CrossrefSearch in Google Scholar
• 22e Whitmore FC, Thurman N. J. Am. Chem. Soc. 1923; 45: 1068
  CrossrefSearch in Google Scholar
• 23a Ogata Y, Kimura M. J. Synth. Org. Chem. Jpn. 1979; 37: 58
  CrossrefSearch in Google Scholar
• 23b Lee GA, Freedman HH. Tetrahedron Lett. 1976; 17: 1641
  CrossrefSearch in Google Scholar
• 23c Bright ZR, Luyeye CR, Morton AS, Sedenko M, Landolt RG, Bronzi MJ, Bohovic KM, Gonser MW, Lapainis TE, Hendrickson WH. J. Org. Chem. 2005; 70: 684
  CrossrefPubMedSearch in Google Scholar
• 24 Although the desired 3a was obtained in high yields from the reaction of 1a with 5.0 equiv of NaOCl·5H₂O in acetic acid, a small amount of the corresponding thiosulfonate was accompanied. Over 6.5 equiv of NaOCl·H₂O were required to obtain 3a in a pure form.
• 25 Although the desired 3a was obtained in high yields from the reaction of 1a with 5.0 or 6.5 equiv of NaOCl·5H₂O in BTF under CO₂ atmosphere, small amounts of the starting material 1a and/or the corresponding thiosulfonate were accompanied (Scheme 9). In order to obtain 3a in a pure form, over 8 equiv of NaOCl·5H₂O were required.
• 26 Harrelson L, Howarth J, Mesrobian C, Shaver T. Official Proceeding - 72nd International Water Conference 2011; 638
• 27 Br₂ has been known as the reagent for preparation of disulfides from thiols: Ali, M. H.; McDermott, M. Tetrahedron Lett. 2002, 43, 6271; and references cited therein
• 28 Maslankiewicz A, Marciniec K, Pawlowski M, Zajdel P. Heterocycles 2007; 71: 1975
  CrossrefSearch in Google Scholar