NBS-promoted sulfenylation of sulfinates with disulfides leading to unsymmetrical or symmetrical thiosulfonates

Article abstract of DOI:10.1002/cjoc.201200028

A highly practical method to access unsymmetrical and symmetrical thiosulfonates in moderate to excellent yields has been developed through NBS-promoted sulfenylation of sulfinates with disulfides. The present process enables the use of two RS in RSSR and shows broad functional group tolerance, which represents an atom-economical and practical procedure for the synthesis of thiosulfonates. A plausible mechanism for the role of NBS as a promoter for the cleavage of disulfides generating N-(organothio)succinimide that then undergos facile sulenylation with sulfinates is proposed. Copyright

Full text of DOI:10.1002/cjoc.201200028

FULL PAPER
DOI: 10.1002/cjoc.201200028
NBS-Promoted Sulfenylation of Sulfinates with Disulfides
Leading to Unsymmetrical or Symmetrical Thiosulfonates
Liang, Gaigaia(梁改改)
Ding, Jinchanga,b(丁金昌)
Liu, Miaochanga(刘妙昌)
Gao, Wenxiaa(高文霞)
Chen, Jiuxi*,a(陈久喜)
Wu, Huayue*,a(吴华悦)
a College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou, Zhejiang 325035, China
b Wenzhou Vocational and Technical College, Wenzhou, Zhejiang 325035, China
A highly practical method to access unsymmetrical and symmetrical thiosulfonates in moderate to excellent
yields has been developed through NBS-promoted sulfenylation of sulfinates with disulfides. The present process
enables the use of two RS in RSSR and shows broad functional group tolerance, which represents an atom-eco-
nomical and practical procedure for the synthesis of thiosulfonates. A plausible mechanism for the role of NBS as a
promoter for the cleavage of disulfides generating N-(organothio)succinimide that then undergos facile sulenylation
with sulfinates is proposed.
Keywords sulfenylation, N-bromosuccinimide (NBS), sulfinate, disulfide, thiosulfonate
with sulfenamides,[10] oxidation of thiosulfinates,[11]
Introduction
spontaneous desulfurization of sulfenic sulfonic thioan-
hydrides[12] and reaction of potassium thiosulfonates
with diaryliodonium salts.[13] Each of the above methods
has its own merit, while some of these methods are
plagued by limitations due to low yields, the use of
toxic and unstable sulfenylating agents, and/or the un-
available starting materials. To overcome these draw-
backs, the development of a highly practical route using
both commercially available materials and metal-free
mild reaction conditions remains a challenging area for
exploration.
As part of a continuing effort in our laboratory to-
ward the development of using disulfide as a reaction
partner[5,14] and new methods,[15] we herein wish to re-
port a new strategy for the synthesis of unsymmetrical
and symmetrical thiosulfonates via sulfenylation of
sulfinates with disulfides in the presence of N-bromo-
succinimide (NBS).
Thiosulfonate derivatives have widespread applica-
tions both in polymer production and in photographic
processes.[1] In addition, these compounds have also
shown a broad spectrum of biological activities such as
antimicrobial and fungicidal agents.[2] Due to their sta-
ble and strong sulfenylating power, thiosulfonates have
also been extensively used as electrophilic sulfenylating
agents in synthetic organic chemistry.[3] Therefore, con-
siderable effort has been made in the development of
efficient strategies for their construction.[4-13] The vast
majority of these transformations are the direct oxida-
tion of disulfides and thiols affording symmetrical thi-
osulfonates.[4,5] However, these methods can not be
suitable for the synthesis of unsymmetrical thiosul-
fonates, which may lead to a mixture of isomeric prod-
ucts[6] with low regioselectivity when R1 and R2 have
similar skeletons (Eq. 1).
O
S
O
S
Experimental
oxidation
R1
(1)
R1
S R2
R1
S
R2
S
S
R2
+
General
O
O
Chemicals and solvents were used as received and
purified by standard techniques if necessary. Melting
points were recorded on a Digital Melting Point Appa-
ratus WRS-1B and are uncorrected. IR spectra were
recorded on an AVATAR 370 FI-Infrared Spectropho-
tometer. NMR spectroscopy was performed on a Bruck
spectrometer operating at 300 MHz or 500 MHz (1H
In general, unsymmetrical thiosulfonates are gener-
ated by the sulfur-sulfur bond formation. One of the
most common approaches is the reaction of sulfinic acid
or its derivatives with sulfenylating reagents.[7-9] An
alternative approach for the synthesis of unsymmetrical
thiosulfonates involves thiosulfonates exchange reaction
*
E-mail: jiuxichen@wzu.edu.cn; huayuewu@wzu.edu.cn
Received January 10, 2012; accepted January 12, 2012; published online XXXX, 2012.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201200028 or from the author.
Chin. J. Chem. 2012, XX, 1—6
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
1

Liang et al.
FULL PAPER
NMR) and 125 MHz (13C NMR). TMS (tetramethylsi-
lane) was used as an internal standard and CDCl3 was
used as the solvent. Mass spectrometric analysis was
performed on a GC-MS spectrometry (SHIMADZU
GC/MS-QP2010 plus). Elemental analysis was deter-
mined on a Carlo-Erba 1108 instrument. All reactions
were conducted using standard Schlenk techniques.
Column chromatography was performed using EM Sil-
ica gel 60 (300—400 mesh).
S-p-Tolyl 4-fluorobenzenesulfonothioate (3ca): m.p.
102—105 ℃; H NMR (CDCl3, 500 MHz) δ: 7.59—
1
7.56 (m, 2H), 7.24—7.23 (m, 2H), 7.16—7.15 (m, 2H),
7.11—7.08 (m, 2H), 2.38 (s, 3H); 13C NMR (CDCl3,
1
125 MHz) δ: 165.47 (d, JC-F＝255.0 Hz, 1C), 142.6,
139.1, 136.5, 130.5, 130.4 (d, 3JC-F＝6.3 Hz, 1C ), 124.2,
2
116.0 (d, JC-F＝22.5 Hz, 1C), 21.5; IR (KBr) ν: 1717,
1581, 1488, 1320, 1223, 1136, 1071, 839, 810, 710, 657
－
＋
1
cm ; MS (EI, 70 eV) m/z (%): 282 (M , 32), 159 (9),
139 (100), 123 (71), 95 (35), 77 (26), 51 (8). Anal. calcd
for C13H11FO2S2: C 55.30, H 3.93; found C 55.38, H
3.87.
General procedure for the synthesis of unsymmetri-
cal thiosulfonates
A mixture of sulfinate 1 (0.8 mmol), disulfide 2 (0.2
mmol) and NBS (0.4 mmol) in CH3CN (3 mL) was
stirred at room temperature for respective time. After
the completion of the reaction, as monitored by TLC
and GC-MS analysis, the reaction mixture was washed
with water and extracted with ethyl acetate. The organic
phase was separated and dried over anhydrous magne-
sium sulfate and filtered. The filtrate was concentrated
and the resulting residue was purified by column chro-
matography on silica gel (300—400 mesh) with petro-
leum ether-EtOAc as eluent to provide the desired un-
symmetrical thiosulfonates.
S-2-Fluorophenyl
4-fluorobenzenesulfonothioate
1
(3cc): m.p. 59—61 ℃; H NMR (CDCl3, 500 MHz) δ:
7.65—7.62 (m, 2H), 7.53—7.49 (m, 2H), 7.22—7.19
(m, 1H), 7.13—7.05 (m, 3H); 13C NMR (CDCl3, 125
1
1
MHz) δ: 165.7 (d, JC-F＝255.7 Hz, 1C), 162.8 (d, JC-F
4
＝252.4 Hz, 1C), 139.4 (d, JC-F＝2.9 Hz, 1C), 139.1,
3
3
134.5 (d, JC-F＝8.3 Hz, 1C), 130.4 (d, JC-F＝9.6 Hz,
4
1C), 125.2 (d, JC-F＝3.9 Hz, 1C), 116.4 (d, 2JC-F＝22.4
Hz, 1C), 116.2 (d, 2JC-F＝22.7 Hz, 1C), 115.0; IR (KBr)
ν: 1708, 1588, 1470, 1330, 1238, 1138, 1075, 1010, 837,
－
＋
1
767, 654 cm ; MS (EI, 70 eV) m/z (%): 286 (M , 55),
159 (86), 143 (100), 127 (56), 95 (89), 83 (53), 57 (11).
Anal. calcd for C12H8F2O2S2: C 50.34, H 2.82; found C
50.29, H 2.88.
S-2-Fluorophenyl benzenesulfonothioate (3ac): m.p.
1
57—59 ℃; H NMR (CDCl3, 500 MHz) δ: 7.63—7.59
(m, 3H), 7.51—7.43 (m, 4H), 7.19—7.16 (m, 1H),
S-3-Nitrophenyl-4-fluorobenzenesulfonothioate (3ce):
m.p. 84—86 ℃; 1H NMR (CDCl3, 500 MHz) δ: 8.37—
8.34 (m, 1H), 8.16 (t, J＝2.0 Hz, 1H), 7.81—7.79 (m,
7.07—7.03 (m, 1H); 13C NMR (CDCl3, 125 MHz) δ:
1
162.9 (d, JC-F＝252.2 Hz, 1C), 143.4, 139.0, 134.3 (d,
3JC-F ＝8.3 Hz, 1C), 133.9, 128.9, 127.4, 125.0 (d,
4JC-F＝4.0 Hz, 1C), 116.4 (d, 2JC-F＝22.5 Hz, 1C), 115.2;
IR (KBr) ν: 1708, 1473, 1327, 1263, 1142, 1077, 753,
J＝7.5 Hz, 1H), 7.64—7.60 (m, 3H), 7.17—7.13 (m,
＝
2H); 13C NMR (CDCl3, 125 MHz) δ: 165.9 (d, JC-F
1
4
257.1 Hz, 1C), 148.4, 142.2, 138.6 (d, JC-F＝3.1 Hz,
－
＋
1
3
716, 683 cm ; MS (EI, 70 eV) m/z (%): 268 (M , 39),
141 (59), 125 (65), 97 (7), 77 (100), 51 (25). Anal. calcd
for C12H9FO2S2: C 53.71, H 3.38; found C 53.65, H
3.43.
1C), 130.8, 130.5 (d, JC-F＝9.7 Hz, 1C), 130.4, 130.0,
2
126.2, 166.2 (d, JC-F＝22.8 Hz, 1C); IR (KBr) ν: 1715,
1581, 1525, 1489, 1348, 1281, 1237, 1140, 1074, 839,
－
＋
1
732, 700, 655 cm ; MS (EI, 70 eV) m/z (%): 313 (M ,
10), 159 (100), 143 (7), 95 (71), 75 (12). Anal. calcd for
C12H8FNO4SS2: C 46.00, H 2.57; found C 45.96, H
2.64.
S-2-Fluorophenyl-4-methylbenzenesulfonothioate
1
(3bc): m.p. 67—69 ℃; H NMR (CDCl3, 500 MHz) δ:
7.51—7.47 (m, 4H), 7.24—7.16 (m, 3H), 7.07—7.04
(m, 1H), 2.43 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ:
S-Benzyl 4-fluorobenzenesulfonothioate (3cf): Oil;
1H NMR (CDCl3, 500 MHz) δ: 7.80—7.78 (m, 2H),
7.23—7.22 (m, 5H), 7.18—7.09 (m, 2H), 4.28 (s, 2H);
1
162.9 (d, JC-F＝252.0 Hz, 1C), 145.0, 140.7, 139.0,
134.2 (d, 3JC-F＝8.3 Hz, 1C), 129.5, 127.5, 125.0, 116.3
2
13C NMR (CDCl3, 125 MHz) δ: 165.3 (d, JC-F＝255.1
1
(d, JC-F＝22.4 Hz, 1C), 115.4; IR (KBr) ν: 1719, 1589,
－
1
3
1473, 1329, 1256, 1140, 1079, 811, 758, 692 cm ; MS
(EI, 70 eV) m/z (%): 282 (M＋, 27), 155 (64), 127 (19),
91 (100), 65 (22). Anal. calcd for C13H11FO2S2: C 55.30,
H 3.93; found C 55.37, H 3.89.
Hz, 1C), 141.0, 133.4, 129.7 (d, JC-F＝9.6 Hz, 1C),
129.0, 128.7, 128.0, 166.3 (d, JC-F＝22.8 Hz, 1C); IR
2
(KBr) ν: 1712, 1587, 1490, 1328, 1235, 1138, 1075, 836,
－
＋
1
700, 657 cm ; MS (EI, 70 eV) m/z (%): 282 (M , 0.15),
246 (0.16), 122 (100), 91 (85), 77 (11). Anal. calcd for
C13H11FO2S2: C 55.30, H 3.93; found C 55.37, H 3.86.
S-3-Nitrophenyl 4-methylbenzenesulfonothioate
(3be): m.p. 98—100 ℃; 1H NMR (CDCl3, 500 MHz) δ:
8.34—8.33 (m, 1H), 8.06 (s, 1H), 7.83—7.82 (m, 1H),
7.60 (t, J＝8.0 Hz, 1H), 7.48—7.47 (m, 2H), 7.27—
7.25 (m, 2H), 2.44 (s, 3H); 13C NMR (CDCl3, 125 MHz)
δ: 148.2, 145.7, 142.3, 139.7, 130.9, 130.4, 130.3, 129.7,
127.6, 125.9, 21.7; IR (KBr) ν: 1704, 1596, 1526, 1348,
S-2-Fluorophenyl
4-chlorobenzenesulfonothioate
1
(3dc): m.p. 82—85 ℃; H NMR (CDCl3, 500 MHz) δ:
7.56—7.52 (m, 4H), 7.42—7.41 (m, 2H), 7.23—7.20
(m, 1H), 7.10—7.06 (m, 1H); 13C NMR (CDCl3, 125
1
MHz) δ: 162.8 (d, JC-F＝252.4 Hz, 1C), 141.8, 140.6,
－
1
139.0, 134.5 (d, 3JC-F＝8.3 Hz, 1C), 129.2, 128.9, 125.2
1331, 1142, 1078, 810, 750, 732 cm ; MS (EI, 70 eV)
m/z (%): 309 (M＋, 8), 155 (100), 91 (98), 65 (20). Anal.
calcd for C13H11NO4S2: C 50.47, H 3.58; found C 50.41,
H 3.66.
4
2
(d, JC-F＝4.0 Hz, 1C), 116.5 (d, JC-F＝22.5 Hz, 1C),
114.9; IR (KBr) ν: 1712, 1571, 1473, 1331, 1264, 1144,
－
1
1096, 1077, 1012, 826, 752, 700 cm ; MS (EI, 70 eV)
2
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© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2012, XX, 1—6

NBS-Promoted Sulfenylation of Sulfinates with Disulfides
m/z (%): 304 ([M＋2]＋, 28), 302 (M＋, 66), 254 (14),
175 (100), 143 (23), 111 (98), 83 (62), 57 (12). Anal.
calcd for C12H8ClFO2S2: C 47.60, H 2.66; found C
47.57, H 2.71.
tion of the reaction, as monitored by TLC and GC-MS
analysis, the reaction mixture was washed with water
and extracted with ethyl acetate. The organic phase was
separated and dried over anhydrous magnesium sulfate
and filtered. The filtrate was concentrated and the re-
sulting residue was purified by column chromatography
on silica gel (300 — 400 mesh) with petroleum
ether-EtOAc as eluent to provide the desired symmetri-
cal thiosulfonates.
S-p-Tolyl 4-methylbenzenesulfonothioate (3ba): m.p.
69—70 ℃; 1H NMR (300 MHz, CDCl3) δ: 2.36 (s, 3H),
2.40 (s, 3H), 7.12—7.21 (m, 6H, ArH), 7.44—7.47 (m,
2H, ArH); 13C NMR (125 MHz, CDCl3) δ: 21.3, 21.5,
124.3, 127.4, 129.2, 130.1, 136.3, 140.1, 142.0, 144.4.
S-3-Nitrophenyl-4-chlorobenzenesulfonothioate (3de):
1
m.p. 103—105 ℃; H NMR (CDCl3, 500 MHz) δ:
8.37—8.35 (m, 1H), 8.18 (s, 1H), 7.80—7.79 (m, 1H),
7.61 (t, J＝8.0 Hz, 1H), 7.55—7.53 (m, 2H), 7.46—
7.44 (m, 2H); 13C NMR (CDCl3, 125 MHz) δ: 148.4,
142.2, 141.2, 141.1, 130.9, 130.5, 129.9, 129.5, 128.9,
126.2; IR (KBr) ν: 1705, 1526, 1393, 1349, 1221, 1148,
－
1
1091, 1075, 1010, 870, 753, 732, 702, 671 cm ; MS
(EI, 70 eV) m/z (%): 331 ([M＋2]＋, 3), 329 (M＋, 10),
175 (100), 155 (7), 111 (73), 106 (17), 75 (20). Anal.
calcd for C12H8ClNO4S2: C 43.70, H 2.45; found C
43.77, H 2.52.
Results and Discussion
S-(2-Fluorophenyl) 4-bromobenzenesulfonothioate
1
Initially, retrosynthetic analysis of the unsymmetri-
cal thiosulfonates is illustrated in Scheme 1. We as-
sumed that unsymmetrical thiosulfonates could be gen-
erated by the reaction of a salt of sulfinic acid with an
equivalent reagent of electrophilic RS＋ . It is well-
known that sulfenyl halides are very toxic and unstable
sulfenylating reagents. These activated N-(organothio)-
succinimide (A) is most commonly used as electrophilic
sulfenylating reagents[16] since Groebel’s seminal work
fifty years ago.[17] In this paper, we decided to uncover
the effect of NBS in the sulfenylation reaction of sulfi-
nates with disulfides.
(3ec): m.p. 89—91 ℃; H NMR (CDCl3, 300 MHz) δ:
7.60—7.47 (m, 6H), 7.24—7.18 (m, 1H), 7.11—7.05
(m, 1H); 13C NMR (CDCl3, 125 MHz) δ: 162.8 (d,
1JC-F＝252.3 Hz, 1C), 142.5, 139.0, 134.5 (d, 3JC-F＝8.3
4
Hz, 1C), 132.2, 129.2, 128.9, 125.2 (d, JC-F＝4.0 Hz,
2
1C), 116.5 (d, JC-F＝22.5 Hz, 1C ), 114.9; IR (KBr) ν:
1707, 1530, 1457; 1339, 1313, 1265, 1118, 1094, 1060,
－
1
873, 800, 742, 727, 661 cm ; MS (EI, 70 eV) m/z (%):
348 ([M＋2]＋, 38), 346 (M＋, 37), 221 (84), 219 (85),
205 (55), 203 (57), 157 (81), 155 (81), 127 (85), 108
(35), 83 (100), 50 (29). Anal. calcd for C12H8BrFO2S2:
C 41.51, H 2.32; found C 41.59, H 2.26.
S-(3-Nitrophenyl)
4-bromobenzenesulfonothioate
Scheme 1 Retrosynthetic analysis
1
(3ee): m.p. 113—115 ℃; H NMR (CDCl3, 300 MHz)
δ: 8.38—8.34 (m, 1H), 8.19—8.18 (m, 1H), 7.81—7.78
(m, 1H), 7.64—7.59 (m, 3H), 7.48—7.44 (m, 2H); 13C
NMR (CDCl3, 125 MHz) δ: 148.4, 142.1, 141.7, 132.6,
130.9, 130.5, 129.9, 129.8, 128.9, 126.2; IR (KBr) ν:
1706, 1566, 1521, 1457, 1387, 1331, 1218, 1140, 1094,
1064, 1007, 892, 827, 808, 735, 697, 669 cm ; MS (EI,
70 eV) m/z (%): 375 ([M＋2]＋, 12), 373 (M＋, 12), 221
(98), 219 (100), 157 (73), 155 (78), 108 (31), 76 (29),
69 (19). Anal. calcd for C12H8BrNO4S2: C 38.51, H 2.15;
found C 38.58, H 2.23.
RSX
(X = Cl, Br, I)
RS+
O
O
RSSR
+
O
N SR
+ NBS
Ar
S
SR
－
1
O
O
S
A
Ar
ONa
First, the reaction between sodium benzenesulfinate
(1a) and p-tolyl disulfide (2a) was chosen as a model
reaction to screen the optimal reaction conditions and
the results are listed in Table 1. Our investigation began
with an attempt to carry the model reaction in the ab-
sence of NBS, but no target product was detected (Table
1, Entry 1). Next, the solvent effect was tested in the
presence of NBS. Among all the solvents screened, low
yield of the target product 3aa was detected in the pres-
ence of a series of solvents, such as CH2Cl2, toluene,
DMSO, DMF, 1,4-dioxane, CH3CH2OH, H2O and
PEG-400 (Table 1, Entries 2—9). However, we were
delighted to find that the yield could be improved to
59% or 63% when the combination of NBS and or THF
CH3CN was employed at room temperature, respec-
tively (Table 1, Entries 10, 11). Encouraged by these
promising results, we further adjusted reaction parame-
ters including reaction temperature, molar ratio of
sulfinate to disulfide and the amount of NBS loading
S-2-Fluorophenyl methanesulfonothioate (3ec): Oil;
1H NMR (CDCl3, 500 MHz) δ: 7.74—7.71 (m, 1H),
7.60—7.55 (m, 1H), 7.31—7.23 (m, 2H), 3.29 (s, 3H);
1
13C NMR (CDCl3, 125 MHz) δ: 162.4 (d, JC-F＝250.1
3
Hz, 1C), 139.1, 134.5 (d, JC-F＝8.2 Hz, 1C), 125.5 (d,
3JC-F＝7.5 Hz, 1C), 116.6 (d, 2JC-F＝22.5 Hz, 1C), 115.4,
49.2; IR (KBr) ν: 1707, 1590, 1473, 1442, 1324, 1263,
－
1
1221, 1134, 1066, 950, 824, 760, 741, 678 cm ; MS
(EI, 70 eV) m/z (%): 206 (M＋, 45), 143 (76), 127 (100),
83 (77), 57 (15). Anal. calcd for C7H7FO2S2: C 40.76, H
3.42; found C 40.69, H 3.47.
General procedure for the synthesis of symmetrical
thiosulfonates
A mixture of sulfinate 1 (0.8 mmol), disulfide 2 (0.2
mmol), and NBS (0.6 mmol) in CH3CN (3 mL) was
stirred at room temperature for 15 h. After the comple-
Chin. J. Chem. 2012, XX, 1—6
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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3

Liang et al.
FULL PAPER
(Table 1, Entries 12—19). After a series of trial experi-
ments, we found that the reaction could be conducted
successfully to afford 74% yield of the desired product
3aa in the presence of 2 equiv. of NBS (Table 1, Entry
13). The yield was decreased to some extent when the
reaction was carried out at the elevated temperature
(Table 1, Entries 15, 16). We were pleased to discover
that the yield of 3aa was improved to 93% by changing
the ratio of 1a and 2a (Table 1, Entry 18).
ners for the sulfenylation reaction, affording the corre-
sponding products in 70%—95 % yields (Table 2, En-
tries 6—8, 13, 14, 18, 23 and 24).
Table 2 NBS-promoted synthesis of unsymmetrical thiosul-
fonatesa
O
S
O
S
NBS
CH3CN, 25 oC
6—15 h
S R2
R1
R2SSR2
+
ONa
R1
O
3
1
2
Table 1 Selected results of screening for optimal conditionsa
Entry
R1
R2
Product Yield/%
O
NBS
solvent
1
2
3
4
5
6
7
8
9
C6H5 (1a)
C6H5 (1a)
C6H5 (1a)
C6H5 (1a)
C6H5 (1a)
C6H5 (1a)
C6H5 (1a)
C6H5 (1a)
p-MeC6H4 (2a)
3aa
3ab
3ac
3ad
3ae
3af
3ag
3ah
3bb
3bc
3bd
3be
3bf
3bh
3ca
3cc
3ce
3cf
93
91
PhSO2Na +
Me
S
S
S
Me
2
p-FC6H4 (2b)
o-FC6H4 (2c)
p-ClC6H4 (2d)
m-NO2C6H4 (2e)
PhCH2 (2f)
i-Bu (2g)
O
1a
2a
3aa
89
Entry NBS/equiv.
Solvent
CH3CN
CH2Cl2
Toluene
DMSO
DMF
Temp./℃ Yieldb/%
87
1
2
—
1
25
25
25
25
25
25
25
25
25
25
25
25
25
25
50
80
25
25
NRc
86
27
90
3
1
38
80
4
1
37
Me (2h)
68
p-MeC6H4 (1b) p-FC6H4 (2b)
81b
79b
71b
91b
94b
73
88b
78b
90b
87b
78b
84b
81b
89b
95b
70
75b
69b
75b
63b
90b
76b
75b
61b
5
1
26
6
1
1,4-Dioxane
EtOH
27
10 p-MeC6H4 (1b) o-FC6H4 (2c)
11 p-MeC6H4 (1b) p-ClC6H4 (2d)
12 p-MeC6H4 (1b) m-NO2C6H4 (2e)
13 p-MeC6H4 (1b) PhCH2 (2f)
14 p-MeC6H4 (1b) Me (2h)
7
1
39
8
1
H2O
Trace
16
9
1
PEG-400
THF
10
11
12
13
14
15
16
17
18
1
59
1
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
63
15 p-FC6H4 (1c)
16 p-FC6H4 (1c)
17 p-FC6H4 (1c)
18 p-FC6H4 (1c)
p-MeC6H4 (2a)
o-FC6H4 (2c)
m-NO2C6H4 (2e)
PhCH2 (2f)
0.5
2
30
74
3
70
2
51
19 p-ClC6H4 (1d) p-MeC6H4 (2a)
20 p-ClC6H4 (1d) p-FC6H4 (2b)
21 p-ClC6H4 (1d) o-FC6H4 (2c)
22 p-ClC6H4 (1d) m-NO2C6H4 (2e)
23 p-ClC6H4 (1d) PhCH2 (2f)
24 p-ClC6H4 (1d) Me (2h)
3da
3db
3dc
3de
3df
3dh
3di
3ea
3ec
3ed
3ee
3fa
3fc
2
61
2
82d
93e
2
a
All reactions were run with 1a (0.4 mmol), 2a (0.2 mmol), and
NBS (loading amount based on 2a) in solvent (3 mL) for 6 h.
b Isolated yield. c NR＝No Reaction. d Compounds 1a (0.6 mmol)
25 p-ClC6H4 (1d) C6H5 (2i)
e
and 2a (0.2 mmol). Compounds 1a (0.8 mmol) and 2a (0.2
26 p-BrC6H4 (1e) p-MeC6H4 (2a)
27 p-BrC6H4 (1e) o-FC6H4 (2c)
28 p-BrC6H4 (1e) p-ClC6H4 (2d)
29 p-BrC6H4 (1e) m-NO2C6H4 (2e)
mmol).
Having the optimized reaction conditions in hand,
we decided to explore the scope and generality of sulf-
enylation using various sulfinates and disulfides.
30 CH3 (1f)
31 CH3 (1f)
32 CH3 (1f)
p-MeC6H4 (2a)
o-FC6H4 (2c)
p-ClC6H4 (2d)
As shown in Table 2, a series of aromatic disulfides
bearing either electron-donating or electron-with-
drawing groups on the aromatic ring were investigated.
The substitution groups on the aromatic ring associated
with disulfides had little effect on the yields. For exam-
ple, both of electron-rich disulfides, such as p-tolyl
disulfide (2a) and electron-deficient disulfides such as
p-fluorophenyl disulfide (2b) and m-nitrophenyl disul-
fide (2e) gave high yields under optimal conditions (Ta-
ble 2, Entries 1—5). It is worth noting that aliphatic
disulfides, such as benzyl disulfide (2f), iso-butyl disul-
fide (2g) and methyl disulfide (2h) were still good part-
3fd
a
All reactions were run with sulfinate 1 (0.8 mmol), disulfide 2
(0.2 mmol), NBS (0.4 mmol), and CH3CN (3 mL) at 25 ℃ for 6
h. Isolated yield. b For 15 h.
On the other hand, other sulfinates 1b—1f and 1i
were also investigated. Aromatic sulfinates bearing
various functional groups, such as methyl, fluoro, chloro,
and bromo groups, were tolerated in this procedure,
achieving the desired products in impressive yields (Ta-
4
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© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2012, XX, 1—6

NBS-Promoted Sulfenylation of Sulfinates with Disulfides
ble 2, Entries 8—32). However, the relatively low
yields of the desired products were obtained when ali-
phatic sulfinate, such as sodium methylsulfinate (1f)
was used as substrate (Table 2, Entries 30—32).
reaction of sodium p-tolylsulfinate (1b) with N-(phenyl-
thio)succinimide under our standard conditions. As we
expected, the desired product 3bg was obtained in good
yield.
Next, we explored the synthesis of symmetrical thi-
osulfonates under our standard conditions (Scheme 2).
Initial studies were concentrated on reactions between
sodium p-tolylsulfinate (1b) and p-tolyl disulfide (2a). It
was observed that S-p-tolyl 4-methylbenzenesulfono-
thioate (3ba) was isolated in 58% yield. However, we
further adjusted reaction parameters and found that the
yield of 3ba was improved to 94% in the presence of 3
equiv. of NBS. As shown in Scheme 2, other symmetri-
cal thiosulfonates 3ai, 3cb and 3dd were also obtained
in good to excellent yields.
Scheme 3
O
NBS
+
Me
SO2Na
O
N SPh
CH3CN, 25 oC, 15 h
84% yield
1b
O
Me
S
S
O
3bg
Scheme 2 Synthesis of symmetrical thiosulfonates. Reaction
conditions: sulfinate 1 (0.8 mmol), disulfide 2 (0.2 mmol), NBS
(0.6 mmol) and CH3CN (3 mL), 25 ℃, 15 h. Isolated yields were
given in parenthesis
We therefore propose a plausible formation mecha-
nism of thiosulfonate derivatives based on the results
above and relevant reports in the literature[16] (Scheme
4). First, the role of NBS as a promoter for the cleavage
of disulfides 2 affords the reactive N-(organothio)suc-
cinimide (A) and sulfenyl halides (B). Next, N-(organo-
thio)succinimide (A) undergoes facile sulfenylation
with sulfinates 1, achieving the desired product thiosul-
fonate derivatives 3 along with succinimide salt (C).
The succinimide salt (C) can also be converted into the
N-(organothio)succinimide (A) by reacting with sulf-
enyl halides (B). As a result, the present process enables
the use of two RS in RSSR, which represents an
atom-economical procedure for the synthesis of thio-
sulfonates.
O
O
NBS
R1
R2SSR2
S
S R2
+
S
CH3CN, 25 oC, 15 h
R1 = R2
R1
ONa
O
3
1
2
O
O
Me
S
S
Me
F
S
S
F
O
O
3ba (94%)
3cb (87%)
O
O
S
S
Cl
S
S
Cl
O
O
3ai (97%)
3dd (92%)
Scheme 4 Plausible mechanism
C
In order to further confirm the structure of the prod-
uct, the X-ray diffraction analysis was carried out. The
crystal structure of compound 3ba as a representative
example is shown in Figure 1.[18]
O
O
+ R2SSR2
+
R2SBr
N
Br
N
SR2
2
B
O
O
A
O
S
..
O-
R1
1
O
N-
O
O
C
R1
S
S R2
O
3
Figure 1 The single-crystal X-ray structure of 3ba.
To elucidate the mechanism of this sulfenylation re-
action, the following control experiment was performed
under our standard conditions (Scheme 3). According to
relevant reports in the literature[16] and our recent re-
port,[14] we initially thought that N-(phenylthio)suc-
cinimid is a key intermediates, which play an important
role in this transformation. Therefore, we carried out the
Conclusions
In summary, we have developed a general NBS-
promoted sulfenylation of sulfinates with disulfides
leading to thiosulfonates. This technique also avoids the
formation of 1 equiv. of RS waste that occurs when us-
Chin. J. Chem. 2012, XX, 1—6
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
5

Liang et al.
FULL PAPER
918.
ing a disulfide as the electrophilic sulfur source. The
present protocol can be suitable for the preparation of
not only unsymmetrical thiosulfonates but also symmet-
rical ones, which provides a better and practical alterna-
tive to the existing procedures. Efforts to explore the
detailed mechanism and further applications of the pre-
sent system in other transformations using disulfide as a
reaction partner are ongoing in our group.
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4135.
This work was supported by the National Natural
Science Foundation of China (Nos. 21102105 and
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© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2012, XX, 1—6