English

• 1.   Introduction

  Organic aromatic sulfoxides are significant skeletons in medicinal chemistry and especially in the synthesis of biologically and pharmaceutically compounds, ^[1] such as anti-ulcer omeprazole^[2] and central stimulant modafinil^[3] (Figure 1). They also have other biological activities, including antigout, ^[4a] antidiabetic, ^[4b] anti-inflammatory, ^[4c] antifungal, ^[4d] anti-HIV, ^[4e] antitumor^[4f] and insecticidal activities.^[4g] Furthermore, they have found extensive app-lications in organic chemistry^[5~8] as versatile synthetic intermediates, ligands and catalysts, as well as in industry as producing polymer and photographic processes materials.^[9]

  Figure 1

  

  Figure 1.  Biologically active compounds containing sulfoxide moieties

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  In light of the importance of sulfoxides, development of the procedures for the selective oxidation of sulfides to sulfoxides becomes increasingly challenging and significant in synthetic methodology. Since the firstly reported synthesis of sulfoxides by Maercker in 1865, ^[10] various reagents and oxidizing media have been employed for the conversion of sulfides to sulfoxides. Palmieri and co- workers^[11] reported the oxidation of sulfides into sulfoxides using (n-Bu₄N)(AuCl₄) and nitric acid as catalyst and oxidant. A number of new catalytic strategies involving the activated molecular oxygen have been developed for the oxidation of sulfides using traditional oxidants such as H₂O₂^[12] and t-butylhydroperoxide (TBHP), for example, which catalyzed by tetrazole amides or aluminum tri-tert- butoxide.^[13] Some metal or no-metal catalysts were also applied with other oxidants including hypervalent iodine reagents, ^[14~16] hypervalent metal oxidants, ^[17~20] Schiff bases, ^[21] Oxone, ^[22] ionic liquid^[23] and so on.^[24~26] In addition, new and efficient technologies have been promoted, such as porous solids, ^[27] nanosphere, ^[28] magnetic nanoparticle^[29] and visible light photocatalytic.^[30] Almost all these oxidation systems need catalysts or additives, their selectivity is often limited to the oxidation of sulfides to sulfoxides. Therefore, development of a new and high selective method without catalysts or additives is required (Scheme 1).

  Scheme 1

  

  Scheme 1.  Representative of oxidation of sulfides

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  Using TBHP as an oxidant has the advantages of environmentally benign, cheap and more abundant characteristics. TBHP can be used in the oxidation of a variety of compounds including alcohols, aliphatic methylene, aromatic methylene and other compounds.^[31] Herein, a convenient protocol for the direct selective oxidation of sulfides by TBHP to give the desired products in moderate to excellent yields in the absence of catalyst and additive was reported. Surprisingly, this method can also be applied to the selective oxidation of disulfides to thiosulfonates.

  2.   Results and discussion

  Initially, the thioanisole 1a was chosen as the model substrate for the optimization of reaction conditions in 1, 2-dichloroethane at 80 ℃. The desired product (methylsulfinyl)benzene (2a) was obtained in 50%~95% yields with the increase of TBHP amount (Table 1, Entries 1~3), while the yield of sulfone 3a remained essentially unchanged. However, when TBHP was increased to 10.0 equiv. and reaction time was prolonged to 24 h, sulfone 3a became the main product (Table 1, Entry 4). When H₂O₂ was used as an oxidant, the yield of sulfoxide was decreased, while the yield of byproduct sulfone was increased (Table 1, Entry 5). The reaction did not proceed in the presence of other oxidants such as K₂S₂O₈ and di-t-butyl peroxide (DTBP) (Table 1, Entries 6, 7). The solvents such as CHCl₃, CH₂Cl₂, MeCN, EtOAc and tetrahydrofuran (THF), were also screened for the reaction. Interestingly, a higher yield (98%) of sulfoxide was obtained in CHCl₃ with the shortest time, and almost no sulfone was detected (Table 1, Entry 8). On the contrary, the use of other solvents led to decrease in the yield of 2a, and generation of sulfone. The best result was obtained in the presence of 5.0 equiv. of TBHP using CHCl₃ as solvent. And no better results were gained in further variations in temperature, time and so forth. Therefore, the optimal conditions for this reaction are thioanisole (1.0 mmol), TBHP (5.0 mmol) and CHCl₃ (2 mL) at 60 ℃ for 1.5 h.

  Table 1

  

  Table 1.  Optimization of conditions for oxidation of sulfides to sulfoxides^a

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  Entry	Oxidant (equiv.)	Solvent	Temp./℃	Time/h	Conversion/% of 1a	Yieldb/% of 2a	Yieldb/% of 3a
  1c	TBHP (3.0)	ClCH2CH2Cl	80	6	55	50	0
  2c	TBHP (4.0)	ClCH2CH2Cl	80	6	84	80	0
  3	TBHP (5.0)	ClCH2CH2Cl	80	3	99	95	3
  4	TBHP (10.0)	ClCH2CH2Cl	80	24	98	10	85
  5	H2O2 (5.0)	ClCH2CH2Cl	80	6	98	87	10
  6	K2S2O8 (5.0)	ClCH2CH2Cl	80	6	25	N.R.	N.R.
  7	DTBP (5.0)	ClCH2CH2Cl	80	6	30	N.R.	N.R.
  8	TBHP (5.0)	CHCl3	60	1.5	99	98	Trace
  9d	TBHP (5.0)	CH2Cl2	60	10	98	90	5
  10	TBHP (5.0)	CH3CN	81	24	99	91	4
  11	TBHP (5.0)	EtOAc	77	11	98	90	6
  12	TBHP (5.0)	THF	65	7	42	N.R.	N.R.
  a Reaction conditions: 1a (1 mmol), oxidant, solvent (2.0 mL). b Isolated yields based on 1a. c Reaction was not complete. d Reaction in a sealed tube.

  Under the optimized reaction conditions, the scope of oxidation reaction of 1 with TBHP to 2 was next explored (Table 2). A series of sulfides with different substituents were investigated. Overall, all the substrates could be transformed into the corresponding sulfoxides smoothly in good to excellent yields ranging from 67% to 98%. The substrates with an electron-donating group on the benzene ring reacted faster than those with electron-withdrawing groups (2b, 2c vs 2d, 2e), but they all gave the corresponding products in excellent yields (>95%). Similarly, sulfide with different R² also underwent efficient oxidation to afford the corresponding sulfoxide. When R² was ethyl or benzyl, R² had a little influence on the reaction and the reaction rate. The yield was slightly reduced. However, when R² was phenyl, the reaction rate was greatly reduced, and more oxidants (8 equiv.) were needed in order to obtain high yield of product (2f~2i vs 2j). The difficulty of oxidation could be attributed to the steric hindrance effect and conjugative effect of benzene ring. Conversely, it had the advantage of producing byproduct more difficultly. In addition, reactions of the substrates containing sensitive groups, such as carbon-carbon double bonds, carbon-car- bon triple bonds, aldehyde group and hydroxyl groups, can also proceed (2k~2n). A high yield was still achieved in the cases of allyl sulfides 1k and propinyl sulfides 1l. Although the aldehyde group is unstable in the presence of oxidant, oxidation of 1m provided desired product 2m in a moderate yield of 67% at relatively lower temperature. Product 2n was also generated in good yield, but longer reaction time was necessary due to the steric-hindrance effect of 4-hydroxyphenyl groups. No other byproduct was observed in this reaction.

  Table 2

  

  Table 2.  Substrate scope of sulfides to sulfoxides^a

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  Entry	R1	R2	Time/h	Product	Yieldb/%
  1	H	CH3	1.5	2a	98
  2	4-CH3	CH3	1.5	2b	97
  3	4-OCH3	CH3	1	2c	98
  4	4-Cl	CH3	2	2d	96
  5	4-Br	CH3	2	2e	95
  6	4-CH3	CH2CH3	3	2f	93
  7	4-Cl	CH2CH3	5	2g	92
  8	4-CH3	CH2Ph	3	2h	96
  9	4-Cl	CH2Ph	4	2i	94
  10c	H	Ph	7	2j	95
  11	4-CH3	CH2CH=CH2	0.8	2k	93
  12	4-CH3	CH2C≡CH	6	2l	87
  13d	4-CHO	CH3	4	2m	67
  14e	4-OH	4-HOC6H4	9	2n	85
  a Reaction conditions: 1 (1 mmol), TBHP (5.0 mmol), CHCl3 (2.0 mL), stirred at 60 ℃ unless noted. b Isolated yields based on 1. c 8.0 equiv. TBHP were used. d 50 ℃. e 2 mL CHCl3, 0.5 mL CH3CN.

  Interestingly, this system can also be applied to the selective oxidation of disulfide. Therefore, the oxidation reactions of 1, 2-diphenyldisulfane (4a) with TBHP were discussed. Surprisingly, thiosulfonate (5a) was obtained rather than sulfoxide compounds. Thiosulfonate moiety exists in many compounds with various pharmacological activities including antibacterial sulfamethoxazole, ^[32] antigout probenecid, ^[33] antidiabetic glibenclamide^[34] and the COX-2 inhibitor rofecoxib^[35] (Figure 2). The previously reported methods using TBHP as oxidant need other catalysts or additives.^{[13, 26i]} Therefore, oxidation of different disulfides was investigated under the same conditions for the oxidation of sulfides.

  Figure 2

  

  Figure 2.  Biologically active compounds containing sulfone moieties

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  Further optimization for the reaction conditions is shown in Table 3. With the decreased of TBHP amount, the yield was reduced even the reaction proceeded for longer time. When TBHP was 3 equiv., the raw materials reacted incompletely (Table 3, Entries 1~3). It needed longer reaction time when the temperature decreased to 50 ℃ (Table 3, Entry 4). Ulteriorly, when the temperature dropped to 40 ℃, the corresponding product 5a was formed in trace amounts (Table 3, Entry 5). Increasing the amount of oxidant or prolonging reaction time did not increase the yield any more (Table 3, Entries 6, 7). Therefore, the optimal conditions for this reaction are ascertained as: 1, 2-di-phe- nyldisulfane (1.0 mmol), TBHP (5.0 mmol) and CHCl₃ (2 mL) at 60 ℃.

  Table 3

  

  Table 3.  Optimization of conditions for oxidation of disulfides to thiosulfonates^a

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  Entry	Oxidant (equiv.)	Solvent	Temp./℃	Time/h	Yieldb/%
  1	TBHP (5.0)	CHCl3	60	2	89
  2	TBHP (4.0)	CHCl3	60	7	88
  3c	TBHP (3.0)	CHCl3	60	14	60
  4	TBHP (5.0)	CHCl3	50	6	88
  5	TBHP (5.0)	CHCl3	40	8	Trace
  6	TBHP (5.0)	CHCl3	60	10	85
  7	TBHP (10.0)	CHCl3	60	1.5	88
  a Reaction conditions: 4a (1 mmol), TBHP, CHCl3 (2.0 mL). b Isolated yields based on 4a. c Reaction was not complete.

  With the optimized reaction condition in hand, the scope of oxidation reaction of 4 with TBHP to 5 was next explored (Table 4). Numbers of disulfides with different substituent groups on the benzene ring were investigated. In general, electron-donating groups were more tolerated in this reaction than electron-withdrawing groups (5b, 5c vs 5e, 5f). The mult-substituted products (5d) were obtained in 85% yield possibly because of the steric-hindrance effect. However, the benzyl substrate (4g) provided the corresponding product (5g) in the lowest yield amongst the seven symmetric disulfides. Asymmetric disulfide (4h) was also applied in this system, yielding the desired product (5h) in 18% yield with many byproducts. It demonstrated that the oxidation of asymmetric disulfides has low selectivity.

  Table 4

  

  Table 4.  Substrate scope of disulfides to thiosulfonates^a

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  Entry	R3	R4	Timeb/h	Product	Yieldc/%
  1	Ph	Ph	2	5a	89
  2	4-CH3C6H4	4-CH3C6H4	3	5b	90
  3	4-CH3OC6H4	4-CH3OC6H4	2	5c	90
  4	2, 4-(CH3)2C6H3	2, 4-(CH3)2C6H3	5	5d	85
  5	4-ClC6H4	4-ClC6H4	4	5e	87
  6	4-BrC6H4	4-BrC6H4	5.5	5f	73
  7	Bn	Bn	10	5g	22
  8	4-CH3C6H4	4-BrC6H4	12	5h	18
  a Reaction conditions: 4 (1 mmol), TBHP (5.0 mmol), CHCl3 (2.0 mL), stirred at 60 ℃ unless noted. b Time taken on complete the reaction. c Isolated yields based on 1.

  According to the experiment results and previous reports, ^[36] a plausible mechanism of this reaction is proposed (Scheme 2). Initially, t-butylhydroperoxide generates t-butyl oxygen radical and hydroxyl radical by cracking. Then, t-butyl peroxide radical forms through the reaction of t-butylhydroperoxide with t-butyl oxygen radical. Subsequently, thioanisole radical positive ion forms by the reaction of thioanisole 1a and t-butyl peroxide radical through single electron transfer (SET) process. Finally, t-butyl peroxide radical attacks thioanisole radical positive ion to afford (methylsulfinyl)benzene (2a). For 1, 2-diphe- nyldisulfane (4a), it is oxidized by TBHP to produce sulfoxide compound A, which is then oxidized to form sulfoxide compound B. The intermediate B is rapidly decomposed to form sulfoxide radical intermediate C.^[37] Next, intermediate C attacks compound A to afford thiosulfonate product 5a and sulfur radical D. Moreover, sulfur radical D reacts with compound A to obtain raw material 4a and sulfoxide radical intermediate C, forming a cycle until the termination of the reaction.

  Scheme 2

  

  Scheme 2.  A plausible reaction mechanism

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  Several control experiments were designed in order to gain more deep understanding about the reaction mechanism. In the first place, the reaction was performed under nitrogen atmosphere and the yield of product 2a was the same as that obtained under air. This result revealed that oxygen was not involved in oxidation reaction (Eq. 1). Next, using TBHP (5.0~6.0 mol/L in decane) as oxidant, the result was the same as that of TBHP aqueous solution, indicating that the oxygen in the sulfoxide product doesnʼt come from water (Eq. 2). Finally, 2 equiv. of free radical scavenger 2, 2, 6, 6-tetramethyl-1-piperidinyloxy (TEMPO) was introduced, the oxidation reaction was absolutely suppressed, and only 10% yield of product 2a was isolated. Clearly, a radical pathway was involved (Eq. 3).

  (1)

  (2)

  (3)

  3.   Conclusions

  In conclusion, we have developed an efficient method for the selective oxidation of sulfides or disulfides to form sulfoxides or thiosulfonates by TBHP in the absence of catalyst and additive. This transformation proved a broad substrate scope and high efficiency. Furthermore, a plausible free radical mechanism of this reaction is proposed. The control experiments demonstrated that the oxidation performed was carried out through a radical pathway, whereas oxygen and water were not involved in oxidation.

  4.   Experimental section

  4.1   General information

  All reagents were obtained from commercial suppliers and used without further purification, unless otherwise indicated. TLC analysis was performed using pre-coated glass plates. Silica gel for column chromatography was purchased from Qingdao Haiyang Chemical Co., Ltd. Melting points were determined using a Büchi B-540 capillary melting point apparatus. ¹H NMR and ¹³C NMR were recorded with Bruker and Varianinstrument at 600, 500, 400 and 150, 125, 100 MHz, respectively, and TMS was used as internal standard. Mass spectra were measured with a Thermo Finnigan LCQ-Advantage. High resolution mass spectra (HRMS) were measured on a Brukermicr OTOF-Q Ⅱ instrument using ESI techniques. The structures of known compounds were further corroborated by comparing their ¹H NMR, ¹³C NMR and MS data with those of literature.

  4.2   General procedure for the synthesis of 2a

  Thioanisole 1a (1.0 mmol), 70% TBHP (5.0 mmol, 5.0 equiv.), and CHCl₃ (2 mL) were mixed in an 25 mL round bottom flask stirred at 60 ℃ for 1.5 h. After the reaction was completed (monitored by TLC), the reaction mixture was cooled to room temperature, added water (5 mL) and extracted with dichloromethane (5 mL×3). The combined organic layers were dried over Na₂SO₄, then were concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel using hexane/EtOAc (V: V=20: 1) as eluent to give the product 2a, yield 98%.

  (Methylsulfinyl) benzene (2a): 98% yield, yellow oil. ¹H NMR (500 MHz, CDCl₃) δ: 7.64~7.62 (m, 2H), 7.53~7.46 (m, 3H), 2.70 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 145.4, 130.9, 129.2, 123.4, 44.0; ESI-MS m/z: 303 [2M+Na]⁺; HRMS (ESI) calcd for C₅H₅N₂OS [M+H]⁺ 141.0116, found 141.0117.

  (Methylsulfonyl) benzene (3a): 2% yield. White solid, m.p. 84~85 ℃ (Lit.^[38] 85~85 ℃); ¹H NMR (500 MHz, CDCl₃) δ: 7.95~7.93 (m, 2H), 7.67~7.64 (m, 1H), 7.59~7.55 (m, 2H), 3.05 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ: 140.7, 133.8, 129.5, 127.5, 44.6; ESI-MS m/z: 157 [M+ H]⁺.

  Methyl-4-(methylsulfinyl)benzene (2b):^[39] 97% yield. Yellow oil. ¹H NMR (400 MHz, CDCl₃) δ: 7.52 (d, J=8.4 Hz, 2H), 7.31 (d, J=8.4 Hz, 2H), 2.70 (s, 3H), 2.41 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 142.2, 141.3, 129.8, 123.4, 44.0, 21.5; ESI-MS m/z: 331 [2M+Na]⁺.

  Methoxy-4-(methylsulfinyl)benzene (2c): 98% yield. White solid, m.p. 40~42 ℃ (Lit.^[40] 42~45 ℃); ¹H NMR (500 MHz, CDCl₃) δ: 7.56 (d, J=9.0 Hz, 2H), 7.00 (d, J=9.0 Hz, 2H), 3.82 (s, 3H), 2.67 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ: 162.1, 136.6, 125.5, 114.9, 55.6, 44.0; ESI-MS m/z: 171 [M+H]⁺.

  Chloro-4-(methylsulfinyl)benzene (2d): 96% yield. White solid, m.p. 46~48 ℃ (Lit.^[40] 45~47 ℃); ¹H NMR (400 MHz, CDCl₃) δ: 7.58 (d, J=8.4 Hz, 2H), 7.49 (d, J=8.4 Hz, 2H), 2.72 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 144.0, 137.1, 129.5, 124.9, 44.1; ESI-MS m/z: 175 [M+ H]⁺.

  Bromo-4-(methylsulfinyl)benzene (2e): 95% yield. White solid, m.p. 76~81 ℃ (Lit.^[40] 78~79 ℃); ¹H NMR (500 MHz, CDCl₃) δ: 7.66 (d, J=8.5 Hz, 2H), 7.51 (d, J=8.5 Hz, 2H), 2.71 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ: 145.0, 132.7, 125.57, 125.2, 44.1; ESI-MS m/z: 219 [M+H]⁺.

  1-(Ethylsulfinyl)-4-methylbenzene (2f):^[39] 93% yield, yellow oil. ¹H NMR (500 MHz, CDCl₃) δ: 7.47 (d, J=8.5 Hz, 2H), 7.29 (d, J=8.0 Hz, 2H), 2.85 (dq, J=13.5, 7.5 Hz, 1H), 2.75 (dq, J=13.0, 7.5 Hz, 1H), 2.39 (s, 3H), 1.16 (t, J=7.5 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ: 141.5, 140.0, 129.9, 124.3, 50.4, 21.5, 6.1; ESI-MS m/z: 169 [M+H]⁺.

  Chloro-4-(ethylsulfinyl)benzene (2g):^[41] 92% yield, yellow oil. ¹H NMR (500 MHz, CDCl₃) δ: 7.55~7.52 (m, 2H), 7.50~7.48 (m, 2H), 2.89 (dq, J=13.5, 7.5 Hz, 1H), 2.76 (dq, J=13.5, 7.5 Hz, 1H), 1.18 (t, J=7.5 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ: 141.9, 137.2, 129.5, 125.7, 50.4, 5.9; ESI-MS m/z: 189 [M+H]⁺.

  1-(Benzylsulfinyl)-4-methylbenzene (2h): 96% yield. White solid, m.p. 138~140 ℃ (Lit.^[42] 140~142 ℃); ¹H NMR (400 MHz, CDCl₃) δ: 7.26~7.18 (m, 7H), 6.97 (d, J=6.4 Hz, 2H), 4.07 (d, J=12.4 Hz, 1H), 3.95 (d, J=12.4 Hz, 1H), 2.38 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 141.5, 139.5, 130.3, 129.5, 129.3, 128.4, 128.1, 124.4, 63.8, 21.7; ESI-MS m/z: 483 [2M+Na]⁺.

  1-(Benzylsulfinyl)-4-chlorobenzene (2i): 94% yield. White solid, m.p. 130~131 ℃ (Lit.^[42] 131~133 ℃); ¹H NMR (400 MHz, CDCl₃) δ: 7.38~7.34 (m, 2H), 7.28~7.21 (m, 5H), 6.95 (dd, J=7.2, 1.6 Hz, 2H), 4.09 (d, J=12.8 Hz, 1H), 3.97 (d, J=12.4 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃) δ: 141.4, 137.5, 130.5, 129.2, 128.7, 128.7, 128.5, 126.0, 63.6; ESI-MS m/z: 523 [2M+Na]⁺.

  Sulfinyldibenzene (2j): 95% yield. White solid, m.p. 69~70 ℃ (Lit.^[43] 70~71 ℃); ¹H NMR (500 MHz, CDCl₃) δ: 7.65~7.62 (m, 4H), 7.47~7.41 (m, 6H); ¹³C NMR (125 MHz, CDCl₃) δ: 145.7, 131.2, 129.4, 124.9; ESI-MS m/z: 203 [M+H]⁺.

  1-(Allylsulfinyl)-4-methylbenzene (2k):^[44] 93% yield, yellow oil. ¹H NMR (500 MHz, CDCl₃) δ: 7.47 (d, J=8.0 Hz, 2H), 7.29 (d, J=8.5 Hz, 2H), 5.66~5.58 (m, 1H), 5.32~5.29 (m, 1H), 5.17 (dq, J=17.0, 1.5 Hz, 1H), 3.55~3.46 (m, 2H), 2.40 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ: 141.6, 139.8, 129.8, 125.5, 124.4, 123.8, 61.0, 21.5; ESI-MS m/z: 383 [2M+Na]⁺.

  Methyl-4-(prop-2-yn-1-ylsulfinyl)benzene (2l):^[45] 87% yield, yellow oil. ¹H NMR (500 MHz, CDCl₃) δ: 7.58 (d, J=8.0 Hz, 2H), 7.31 (d, J=8.0 Hz, 2H), 3.60 (qd, J=16.0, 2.7 Hz, 1H), 2.40 (s, 3H), 2.32 (t, J=3.0 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃) δ: 142.4, 139.7, 129.9, 124.6, 76.4, 73.0, 47.9, 21.6; ESI-MS m/z: 179 [M+H]⁺.

  4-(Methylsulfinyl)benzaldehyde (2m): 67% yield. White solid, m.p. 83~84 ℃ (Lit.^[46] 85~86 ℃); ¹H NMR (500 MHz, CDCl₃) δ: 10.05 (s, 1H), 8.01 (d, J=8.0 Hz, 2H), 7.79 (d, J=8.0 Hz, 2H), 2.76 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ: 191.2, 152.5, 138.2, 130.5, 124.2, 43.8; ESI-MS m/z: 169 [M+H]⁺.

  4, 4'-Sulfinyldiphenol (2n): 85% yield. White solid, m.p. 190~192 ℃ (Lit.^[43] 193~194 ℃); ¹H NMR (500 MHz, DMSO-d₆) δ: 10.08 (s, 1H), 7.42 (d, J=8.5 Hz, 2H), 6.87 (d, J=8.5 Hz, 2H); ¹³C NMR (125 MHz, DMSO-d₆) δ: 159.9, 135.5, 126.5, 116.1; ESI-MS m/z: 235 [M+H]⁺.

  4.3   General procedure for the synthesis of 5a

  1, 2-Diphenyldisulfane (4a) (1.0 mmol), 70% TBHP (5.0 mmol, 5.0 equiv.), and CHCl₃ (2 mL) were mixed in an 25 mL round bottom flask stirred at 60 ℃ for 3.5 h. After the reaction was completed (monitored by TLC), the reaction mixture was cooled to room temperature, added water (5 mL) and extracted with dichloromethane (5 mL×3). The combined organic layers were dried over Na₂SO₄, then were concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel using hexane/EtOAc (V: V=20: 1) as eluent to give the product 5a, 89% yield.

  S-Phenyl benzenesulfonothioate (5a): 89% yield. White solid, m.p. 36~37 ℃ (Lit.^[47] 37~39 ℃); ¹H NMR (500 MHz, CDCl₃) δ: 7.59~7.54 (m, 3H), 7.49~7.29 (m, 7H); ¹³C NMR (100 MHz, CDCl₃) δ: 142.9, 136.5, 133.6, 131.4, 129.4, 128.8, 127.8, 127.5; HRMS(ESI) calcd for C₁₂H₁₀- NaO₂S₂ [M+Na]⁺ 273.0014, found 273.0014.

  S-p-Tolyl 4-methylbenzenesulfonothioate (5b): 90% yield. White solid, m.p. 70~72 ℃ (Lit.^[47] 74~75 ℃); ¹H NMR (500 MHz, CDCl₃) δ: 7.46 (d, J=8.0 Hz, 2H), 7.27~7.21 (m, 4H), 7.15 (d, J=8.0 Hz, 2H), 2.44 (s, 3H), 2.39 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ: 144.7, 142.2, 140.6, 136.6, 130.3, 129.5, 127.7, 124.7, 21.7, 21.6; ESI-MS m/z: 279 [M+H]⁺.

  S-(4-Methoxyphenyl) 4-methoxybenzenesulfonothioate (5c): 90% yield. White solid, m.p. 84~86 ℃ (Lit.^[47] 88~90 ℃); ¹H NMR (500 MHz, CDCl₃) δ: 7.50 (d, J=9.0 Hz, 2H), 7.27 (d, J=9.0 Hz, 2H), 6.88 (d, J=9.0 Hz, 2H), 6.85 (d, J=9.0 Hz, 2H), 3.87 (s, 3H), 3.84 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ: 163.7, 162.3, 138.5, 135.0, 130.0, 119.0, 115.0, 114.0, 55.8, 55.6; ESI-MS m/z: 311 [M+H]⁺.

  S-(2, 4-Dimethylphenyl) 2, 4-dimethylbenzenesulfono- thioate (5d): 85% yield. Yellow solid, m.p. 59~61 ℃; ¹H NMR (500 MHz, CDCl₃) δ: 7.30 (d, J=8.0 Hz, 1H), 7.11 (d, J=8.0 Hz, 2H), 7.02 (s, 1H), 6.94~6.89 (m, 2H), 2.64 (s, 3H), 2.37 (s, 3H), 2.31 (s, 3H), 2.12 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ: 144.7, 144.0, 142.4, 138.7, 138.4, 137.7, 133.6, 131.8, 130.3, 127.7, 126.6, 124.0, 21.5, 21.5, 20.6, 20.5; IR (KBr) ν: 1590, 1488, 1323, 1180, 1142 cm^-1; HRMS(ESI) calcd for C₁₆H₁₈NaO₂S₂ [M+Na]⁺ 329.0640, found 329.0656.

  S-(4-Chlorophenyl) 4-chlorobenzenesulfonothioate (5e): 87% yield. White solid, m.p. 131~134 ℃ (Lit.^[47] 135~136 ℃); ¹H NMR (500 MHz, CDCl₃) δ: 7.53~7.50 (m, 2H), 7.44~7.41 (m, 2H), 7.36~7.34 (m, 2H), 7.32~7.30 (m, 2H); ¹³C NMR (125 MHz, CDCl₃) δ: 141.4, 140.7, 138.7, 137.8, 130.1, 129.4, 129.1, 126.2; HRMS(ESI) calcd for C₁₂H₈Cl₂NaO₂S₂ [M+Na]⁺ 340.9235, found 340.9222.

  S-(4-Bromophenyl) 4-bromobenzenesulfonothioate (5f): 73% yield. White solid, m.p. 148~152 ℃ (Lit.^[47] 148~149 ℃); ¹H NMR (500 MHz, CDCl₃) δ: 7.61~7.58 (m, 2H), 7.53~7.50 (m, 2H), 7.45~7.42 (m, 2H), 7.25~7.22 (m, 2H); ¹³C NMR (125 MHz, CDCl₃) δ: 142.0, 138.0, 133.1, 132.4, 129.3, 129.1, 127.2, 126.8; ESI-MS m/z: 219.

  S-Benzyl phenylmethanesulfonothioate (5g): 22% yield. White solid, m.p. 105~108 ℃ (Lit.^[48] 106~108 ℃); ¹H NMR (400 MHz, CDCl₃) δ: 7.41~7.33 (m, 6H), 7.32~7.27 (m, 4H), 4.22 (s, 2H), 4.04 (s, 2H); ¹³C NMR (100 MHz, CDCl₃) δ: 135.0, 131.5, 129.5, 129.1, 128.9, 128.5, 127.9, 69.2, 41.1.

  S-(4-Bromophenyl) 4-methylbenzenesulfonothioate (5h): 18% yield. White solid, m.p. 103~106 ℃ (Lit.^[49] 107 ℃); ¹H NMR (400 MHz, CDCl₃) δ: 7.61~7.56 (m, 3H), 7.43 (t, J=8.0 Hz, 3H), 7.17 (d, J=8.0 Hz, 2H), 2.39 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 138.0, 136.6, 133.1, 132.5, 132.2, 130.6, 129.2, 129.1, 21.6; HRMS(ESI) calcd for C₁₃H₁₁BrNaO₂S₂ [M+Na]⁺ 364.9276, found 364.9259.

  Supporting Information   ¹H NMR and ¹³C NMR spectra copies of the products 2a~2n, 3a and 5a~5h. The Supporting Information is available free of charge via the Internet at http://sioc-journal.cn/.

  
  
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• 

  Figure 1  Biologically active compounds containing sulfoxide moieties

  下载: 全尺寸图片 幻灯片
  

  Scheme 1  Representative of oxidation of sulfides

  下载: 全尺寸图片 幻灯片
  

  Figure 2  Biologically active compounds containing sulfone moieties

  下载: 全尺寸图片 幻灯片
  

  Scheme 2  A plausible reaction mechanism

  下载: 全尺寸图片 幻灯片

  Table 1.  Optimization of conditions for oxidation of sulfides to sulfoxides^a

  Entry	Oxidant (equiv.)	Solvent	Temp./℃	Time/h	Conversion/% of 1a	Yieldb/% of 2a	Yieldb/% of 3a
  1c	TBHP (3.0)	ClCH2CH2Cl	80	6	55	50	0
  2c	TBHP (4.0)	ClCH2CH2Cl	80	6	84	80	0
  3	TBHP (5.0)	ClCH2CH2Cl	80	3	99	95	3
  4	TBHP (10.0)	ClCH2CH2Cl	80	24	98	10	85
  5	H2O2 (5.0)	ClCH2CH2Cl	80	6	98	87	10
  6	K2S2O8 (5.0)	ClCH2CH2Cl	80	6	25	N.R.	N.R.
  7	DTBP (5.0)	ClCH2CH2Cl	80	6	30	N.R.	N.R.
  8	TBHP (5.0)	CHCl3	60	1.5	99	98	Trace
  9d	TBHP (5.0)	CH2Cl2	60	10	98	90	5
  10	TBHP (5.0)	CH3CN	81	24	99	91	4
  11	TBHP (5.0)	EtOAc	77	11	98	90	6
  12	TBHP (5.0)	THF	65	7	42	N.R.	N.R.
  a Reaction conditions: 1a (1 mmol), oxidant, solvent (2.0 mL). b Isolated yields based on 1a. c Reaction was not complete. d Reaction in a sealed tube.

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  Table 2.  Substrate scope of sulfides to sulfoxides^a

  Entry	R1	R2	Time/h	Product	Yieldb/%
  1	H	CH3	1.5	2a	98
  2	4-CH3	CH3	1.5	2b	97
  3	4-OCH3	CH3	1	2c	98
  4	4-Cl	CH3	2	2d	96
  5	4-Br	CH3	2	2e	95
  6	4-CH3	CH2CH3	3	2f	93
  7	4-Cl	CH2CH3	5	2g	92
  8	4-CH3	CH2Ph	3	2h	96
  9	4-Cl	CH2Ph	4	2i	94
  10c	H	Ph	7	2j	95
  11	4-CH3	CH2CH=CH2	0.8	2k	93
  12	4-CH3	CH2C≡CH	6	2l	87
  13d	4-CHO	CH3	4	2m	67
  14e	4-OH	4-HOC6H4	9	2n	85
  a Reaction conditions: 1 (1 mmol), TBHP (5.0 mmol), CHCl3 (2.0 mL), stirred at 60 ℃ unless noted. b Isolated yields based on 1. c 8.0 equiv. TBHP were used. d 50 ℃. e 2 mL CHCl3, 0.5 mL CH3CN.

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  Table 3.  Optimization of conditions for oxidation of disulfides to thiosulfonates^a

  Entry	Oxidant (equiv.)	Solvent	Temp./℃	Time/h	Yieldb/%
  1	TBHP (5.0)	CHCl3	60	2	89
  2	TBHP (4.0)	CHCl3	60	7	88
  3c	TBHP (3.0)	CHCl3	60	14	60
  4	TBHP (5.0)	CHCl3	50	6	88
  5	TBHP (5.0)	CHCl3	40	8	Trace
  6	TBHP (5.0)	CHCl3	60	10	85
  7	TBHP (10.0)	CHCl3	60	1.5	88
  a Reaction conditions: 4a (1 mmol), TBHP, CHCl3 (2.0 mL). b Isolated yields based on 4a. c Reaction was not complete.

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  Table 4.  Substrate scope of disulfides to thiosulfonates^a

  Entry	R3	R4	Timeb/h	Product	Yieldc/%
  1	Ph	Ph	2	5a	89
  2	4-CH3C6H4	4-CH3C6H4	3	5b	90
  3	4-CH3OC6H4	4-CH3OC6H4	2	5c	90
  4	2, 4-(CH3)2C6H3	2, 4-(CH3)2C6H3	5	5d	85
  5	4-ClC6H4	4-ClC6H4	4	5e	87
  6	4-BrC6H4	4-BrC6H4	5.5	5f	73
  7	Bn	Bn	10	5g	22
  8	4-CH3C6H4	4-BrC6H4	12	5h	18
  a Reaction conditions: 4 (1 mmol), TBHP (5.0 mmol), CHCl3 (2.0 mL), stirred at 60 ℃ unless noted. b Time taken on complete the reaction. c Isolated yields based on 1.

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