Synthesis of diaryl disulfides via mild reduction of arylsulfinates with hydrazine monohydrate in DMSO

Article abstract of DOI:10.1080/00397911.2010.535947

Arylsulfinates were reduced with hydrazine monohydrate at room temperature in dimethylsulfoxide (DMSO) to afford diaryl disulfides in good yields. A dramatic solvent effect was observed, and DMSO was found to be the best solvent for the reaction. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397911.2010.535947

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Synthesis of Diaryl Disulfides via
Mild Reduction of Arylsulfinates with
Hydrazine Monohydrate in DMSO
Rui-Heng Zhu a & Xiao-Xin Shi a
a Department of Pharmaceutical Engineering, School of Pharmacy,
East China University of Science and Technology, Shanghai, China
Accepted author version posted online: 07 Oct 2011.Version of
record first published: 22 Dec 2011.
To cite this article: Rui-Heng Zhu & Xiao-Xin Shi (2012): Synthesis of Diaryl Disulfides via Mild
Reduction of Arylsulfinates with Hydrazine Monohydrate in DMSO, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 42:8, 1108-1114
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Synthetic Communications1, 42: 1108–1114, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.535947
SYNTHESIS OF DIARYL DISULFIDES VIA MILD
REDUCTION OF ARYLSULFINATES WITH HYDRAZINE
MONOHYDRATE IN DMSO
Rui-Heng Zhu and Xiao-Xin Shi
Department of Pharmaceutical Engineering, School of Pharmacy,
East China University of Science and Technology, Shanghai, China
GRAPHICAL ABSTRACT
Abstract Arylsulfinates were reduced with hydrazine monohydrate at room temperature in
dimethylsulfoxide (DMSO) to afford diaryl disulfides in good yields. A dramatic solvent
effect was observed, and DMSO was found to be the best solvent for the reaction.
Keywords Arylsulfinate; disulfide; hydrazine monohydrate; reduction
INTRODUCTION
A disulfide bond (S-S bond) is an important functional group that occurs in
natural products[1] and the three-dimensional structures of peptides and proteins.[2]
Disulfides have exhibited many interesting biological activities[3] and have demon-
strated wide applications in various aspects of material science.[4] Therefore, the
synthesis of disulfides has been of considerable interest for chemists.[5]
Disulfides can usually be obtained via oxidation of mercaptans,[5b] but nobody
would be glad to suffer from the notoriously unpleasant smell of mercaptans,
especially in large-scale preparations. This prompted us to investigate other useful
methods for large-scale preparation of disulfides. Herein, we report an efficient, mild,
and general method for the synthesis of diaryl disulfides via the reduction of aryl-
sulfinates with hydrazine monohydrate in dimethylsulfoxides (DMSO).
RESULTS AND DISCUSSION
We first attempted the reaction of methyl benzenesulfinate with hydrazine
monohydrate under various conditions (Table 1). A dramatic solvent effect was
Received August 15, 2010.
Address correspondence to Xiao-Xin Shi, Department of Pharmaceutical Engineering, School of
Pharmacy, East China University of Science and Technology, Shanghai 200237, China. E-mail: xxshi@
ecust.edu.cn
1108

DISULFIDE SYNTHESIS
1109
Table 1. Reaction of methyl benzenesulfinate with hydrazine monohydrate at room temperature in
various solvents
Entry
Solvent
N2H4-H2O (equiv.)
Time (h)
Product
Yield (%)a
1
2
3
4
5
6
7
8
9
DMSO
DMSO
DMSO
DMF
3
5
9
6
1a
1a
1a
1a
1a
1a
1a
1a
1a
98
98
10
5
3
97
15
15
15
15
15
15
89
CH3CN
THF
5
42b
19b
60b
53b
48b
5
MeOH
EtOH
i-PrOH
5
5
5
aIsolated yield.
b35–70% of methyl benzenesulfinate was recovered.
observed, although the reaction was very slow at room temperature in most solvents
such as N,N-dimethylformamide (DMF), acetonitrile, tetrahydrofuran (THF), meth-
anol, ethanol, and isopropanol (Table 1, entries 4–9), it was much faster in DMSO.
The reduction of methyl benzenesulfinate with 3–10 molar equiv of hydrazine mono-
hydrate in DMSO took place smoothly at room temperature to afford disulfide 1a in
nearly quantitative yields (Table 1, entries 1–3). Room temperature was crucial for
good yield of the reaction, because the product disulfide 1a would be overreduced
when warmed to produce some amount of thiophenol as a by-product.[6]
The mild reduction in DMSO can be applied to various arylsulfinates. Twelve
arylsulfinates as indicated in Table 2 were tested. All the tested arylsulfinates could
be reduced with 1.5–10 molar equiv of hydrazine monohydrate at room temperature
in DMSO to furnish diaryl disulfides 1a–1j in good to excellent yields. Bulkiness of
an alkyl group (R group) in a sulfinate obviously decreased the reaction rate (Table 2,
entries 1–3). Electron-deficient arylsulfinates reacted fast and needed less molar
equiv of hydrazine monohydrate (Table 2, entries 5, 7, and 8). In contrast, elec-
tron-rich arylsulfinates reacted much slower and needed more molar equiv of hydra-
zine monohydrate (Table 2, entries 6, 9, 11, and 12). Moreover, it was found that
electron-withdrawing groups on the aryl ring favored the cleavage of disulfides,[6]
and hence large excesses hydrazine monohydrate should be avoided (Table 2, entries
5, 7, and 8) to diminish the formation of thiophenols.
We have also tried reduction of aliphatic sulfinates under the same conditions.
Unfortunately, the reaction of aliphatic sulfinates with hydrazine monohydrate in
DMSO at room temperature was complicated, and the yields of corresponding dia-
lkyl disulfides were less than 10%.
Kobayashi and Yamamoto[7] observed the reduction of sulfinates with anhy-
drous hydrazine to form disulfides during an attempt to prepare sulfinyl hydrazides.
However, only a few examples were included in their report, so the scope and limita-
tions were not clear yet. Moreover, reduction of sulfinates with anhydrous hydrazine
were performed at 60–80 ꢀC in their report, but the warming condition seems to be
favorable for the cleavage of disulfides, especially for electron-deficient disulfides
(Table 2, entries 5, 7, and 8).[6]

1110
R.-H. ZHU AND X.-X. SHI
Table 2. Reduction of various arylsulfinates with hydrazine monohydrate at room temperature in
dimethylsulfoxide
N2H4-H2O
(equiv.)
Time
(h)
Yield
(%)a
Entry
Sulfinate
Disulfide
1
2
3
R ¼ Me
R ¼ Et
3
3
8
9
13
15
1a
1a
1a
98
95
92
R ¼ i-Pr
4
5
5
7
4
96
95
1.5
6
7
8
8
18
1
96
95
87
1.5
1.5
1
9
8
3
10
5
86
95
10
11
12
10
10
22
14
97
98
aIsolated yield.

DISULFIDE SYNTHESIS
1111
CONCLUSION
In conclusion, a very mild reduction of arylsulfinates with hydrazine monohy-
drate at room temperature has been fully studied. The reaction conditions were opti-
mized (Table 1), a dramatic solvent effect was observed, and DMSO was found to be
the most appropriate solvent for the reaction. Diaryl disulfides could be obtained in
good yields from the reduction of various arylsulfinates in DMSO (Table 2).
EXPERIMENTAL
All chemicals were analytically pure and were used as received from commer-
1
cial suppliers. H NMR spectra were acquired on a Bruker AM-500 instruments.
Chemical shifts were given on the d scale as parts per million (ppm) with tetramethyl-
silane (TMS) as the internal standard. Infrared (IR) spectra were recorded on
Nicolet Magna IR-550 instrument. Mass spectra were recorded on a HP5989A
device. Column chromatography was performed on silica gel (Qingdao Ocean
Chemical Corp.).
Typical Procedure for the Reaction of Arylsulfinates with Hydrazine
Monohydrate in Dimethylsulfoxide
Hydrazine monohydrate (6.02 g, 0.12 mol) was added to a solution of methyl
benzenesulfinate (6.25 g, 40.01 mmol) in DMSO (40 mL). The resulting solution
was then stirred at room temperature for 9 h. After the reaction was complete, water
(150 mL) was added, and the aqueous solution was extracted twice with benzene
(2 ꢁ 80 mL). Extracts were combined and dried over anhydrous MgSO4. Removal
of solvent under vacuum gave the crude product, which was purified by flash
chromatography (eluent: EtOAc=hexane ¼ 1:9) through a short silica column to
afford diphenyl disulfide 1a (4.28 g, 19.60 mmol) in 98% yield. Compounds 1b–1j
were obtained from the same procedure in the yields as indicated in Table 2.
1
High-resolution H NMR spectra showed that the purities of all compounds 1a–1j
were greater than 99%.
Characterization Data of Compounds 1a–1j
Compound 1a. Mp 59–60 ꢀC, white crystals. IR (KBr film) 2925, 1947, 1864,
1575, 1475, 1436, 1296, 1072, 1022, 738, 687, 464 cmꢂ1. 1H NMR (CDCl3) d 7.21 (t,
J ¼ 7.5 Hz, 2H), 7.29 (dd, J1 ¼ 7.5 Hz, J2 ¼ 7.8 Hz, 4H), 7.49 (d, J ¼ 7.8 Hz, 4H). 13C
NMR (CDCl3) d 127.8, 128.1, 129.7, 137.6. MS (EI) m=z (%) 218 (Mþ, 100), 185
(15), 154 (14), 140 (3), 109 (36), 77 (2), 65 (7). Anal. calcd. for C12H10S2: C, 66.01;
H, 4.62. Found: C, 66.14; H, 4.55.
Compound 1b. Mp 45–46 ꢀC, white crystals. IR (KBr film) 3020, 2915, 1894,
1
1633, 1488, 1398, 1377, 1182, 1117, 1077, 1014, 802, 480 cmꢂ1. H NMR (CDCl3) d
2.32 (s, 6H), 7.10 (d, J ¼ 8.0 Hz, 4H), 7.38 (d, J ¼ 8.0 Hz, 4H). 13C NMR (CDCl3) d
21.7, 129.2, 130.4, 134.6, 138.0. MS (EI) m=z (%) 246 (Mþ, 100), 213 (4), 182 (7), 123
(48), 91 (3), 77 (5). Anal. calcd. for C14H14S2: C, 68.25; H, 5.73. Found: C, 68.60; H,
5.65.

1112
R.-H. ZHU AND X.-X. SHI
Compound 1c. Mp 70–71 ꢀC, white crystals. IR (KBr film) 3078, 1896, 1645,
1
1568, 1471, 1429, 1386, 1112, 1093, 1010, 816, 741, 491 cmꢂ1. H NMR (CDCl3) d
7.27 (d, J ¼ 8.5 Hz, 4H), 7.40 (d, J ¼ 8.5 Hz, 4H). 13C NMR (CDCl3) d 129.9,
130.2, 134.3, 135.8. MS (EI) m=z (%) 290 (Mþ þ 4, 15), 288 (Mþ þ 2, 68), 286
(Mþ, 100), 222 (7), 145 (29), 143 (82), 108 (29). Anal. calcd. for C12H8Cl2S2: C,
50.18; H, 2.81. Found: C, 49.87; H, 2.60.
Compound 1d. Mp 88–89 ꢀC, white crystals. IR (KBr film) 2964, 2902, 1905,
1590, 1486, 1397, 1266, 1114, 1010, 828, 556 cmꢂ1. 1H NMR (CDCl3) d 1.29 (s, 18H),
7.32 (d, J ¼ 8.4 Hz, 4H), 7.44 (d, J ¼ 8.4 Hz, 4H). 13C NMR (CDCl3) d 31.9, 35.2,
126.8, 128.4, 134.7, 151.1. MS (EI) m=z (%) 332 (Mþ þ 2, 6), 331 (Mþ þ 1, 13),
330 (Mþ, 62), 315 (100), 286 (6), 165 (4), 150 (18), 122 (6), 91 (3). Anal. calcd. for
C20H26S2: C, 72.67; H, 7.93. Found: C, 72.71; H, 7.84.
Compound 1e. Mp 81–82 ꢀC, white crystals. IR (KBr film) 3050, 2975, 1565,
1
1446, 1417, 1375, 1241, 1140, 1091, 1031, 855, 808, 578 cmꢂ1. H NMR (CDCl3) d
7.16 (dd, J1 ¼ 8.5 Hz, J2 ¼ 2.3 Hz, 2H), 7.30 (d, J ¼ 8.5 Hz, 2H), 7.52 (d, J ¼ 2.3 Hz,
2H). 13C NMR (CDCl3) d 127.5, 128.9, 130.8, 131.4, 134.6, 136.5. MS (EI) m=z
(%) 360 (Mþ þ 4, 11), 358 (Mþ þ 2, 45), 356 (Mþ, 100), 354 (Mþ ꢂ 2, 70), 288
(19), 286 (29), 179 (36), 177 (56), 144 (20), 142 (56), 107 (8). Anal. calcd. for
C12H6Cl4S2: C, 40.47; H, 1.70. Found: C, 40.42; H, 1.73.
Compound 1f. Mp 111–112 ꢀC, white crystals. IR (KBr film) 2923, 1635,
1
1557, 1436, 1401, 1365, 1239, 1084, 1011, 798, 762 cmꢂ1. H NMR (CDCl3) d 7.23
(dd, J1 ¼ 8.4 Hz, J2 ¼ 2.1 Hz, 2H), 7.40 (d, J ¼ 8.4 Hz, 2H), 7.64 (d, J ¼ 2.1 Hz,
2H). 13C NMR (CDCl3) d 120.6, 123.1, 130.5, 132.1, 134.9, 138.8. MS (EI) m=z
(%) 538 (Mþ þ 4, 20), 536 (Mþ þ 2, 68), 534 (Mþ, 100), 532 (Mþ ꢂ 2, 65), 530
(Mþ ꢂ 4, 16), 376 (21), 374 (40), 372 (19), 295 (12), 267 (19), 188 (37), 186 (35),
107 (12). Anal. calcd. for C12H6Br4S2: C, 26.99; H, 1.13. Found: C, 27.35; H, 1.18.
Compound 1g. Mp 181–182 ꢀC, white crystals. IR (KBr film) 3304, 2950,
1
1651, 1597, 1539, 1493, 1397, 1321, 1267, 1022, 970, 816, 742, 503 cmꢂ1. H NMR
(DMSO-d6) d 2.04 (s, 6H), 7.43 (d, J ¼ 8.5 Hz, 4H), 7.59 (d, J ¼ 8.5 Hz, 4H), 10.08
(s, 2H). 13C NMR (DMSO-d6) d 24.0, 119.7, 129.4, 130.1, 139.5, 168.5. MS (EI)
m=z (%) 332 (Mþ, 100), 290 (3), 167 (14), 166 (13), 125 (18), 124 (61), 80 (4). Anal.
calcd. for C16H16N2O2S2: C, 57.81; H, 4.85; N, 8.43. Found: C, 57.96; H, 4.62; N, 8.12.
Compound 1h. Mp 189ꢂ190 ꢀC, white crystals. IR (KBr film) 3284, 2935,
1
1664, 1575, 1518, 1378, 1300, 1050, 805 cmꢂ1. H NMR (DMSO-d6) d 2.08 (s, 6H),
7.47 (dd, J1 ¼ 8.6 Hz, J2 ¼ 2.0 Hz, 2H), 7.62 (d, J ¼ 2.0 Hz, 2H), 7.77 (d, J ¼ 8.6 Hz,
2H), 9.57 (s, 2H). 13C NMR (DMSO-d6) d 23.3, 126.5, 126.7, 127.1, 128.5, 132.5,
134.9, 168.7. MS (EI) m=z (%) 402 (Mþ þ 1, 34), 400 (Mþ ꢂ 1, 47), 365 (4), 360 (8),
358 (10), 201 (9), 200 (8), 160 (33), 158 (100), 124 (11), 43 (8). Anal. calcd. for
C16H14Cl2N2O2S2: C, 47.88; H, 3.52; N, 6.98. Found: C, 48.24; H, 3.31; N, 6.64.
Compound 1i. Mp 43–44 ꢀC, white crystals. IR (KBr film) 2937, 2835, 2044,
1
1878, 1590, 1491, 1289, 1247, 1172, 1031, 825, 636, 625 cmꢂ1. H NMR (CDCl3) d
3.79 (s, 6H), 6.83 (d, J ¼ 8.8 Hz, 4H), 7.40 (d, J ¼ 8.8 Hz, 4H). 13C NMR (CDCl3)
d 56.0, 115.2, 129.1, 133.3, 160.5. HRMS m=z calcd. for C14H14O2S2 (Mþ)
278.0435. Found: 278.0434.

DISULFIDE SYNTHESIS
1113
Compound 1j. Mp 69–70 ꢀC, white crystals. IR (KBr film) 2999, 2938, 2832,
2045, 1596, 1582, 1483, 1463, 1434, 1269, 1215, 1180, 1052, 1019, 866, 798 cmꢂ1. 1H
NMR (CDCl3) d 3.69 (s, 6H), 3.84 (s, 6H), 6.69 (dd, J1 ¼ 8.8 Hz, J2 ¼ 2.9 Hz, 2H),
6.77 (d, J ¼ 8.8 Hz, 2H), 7.16 (d, J ¼ 2.9 Hz, 2H). 13C NMR (CDCl3) d 56.3, 57.1,
112.3, 113.0, 114.1, 126.2, 151.4, 154.9. HRMS m=z calcd. for C16H18O4S2 (Mþ)
338.0647. Found 338.0649.
ACKNOWLEDGMENTS
We thank the National Natural Science Foundation of China (No. 20972048)
and the Shanghai Educational Development Foundation (Dawn Program No.
03SG27) for financial support of this work.
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