Imidazole Promoted Highly Efficient Large-Scale Thiol-Free Synthesis of Symmetrical Disulfides in Aqueous Media

Article abstract of DOI:10.1080/10426507.2014.1003643

A highly efficient and environmentally friendly method for the imidazole promoted preparation of symmetrical organic disulfides from Bunte salts is described. This thiol-free procedure produces the desired disulfides even on a large scale by reaction of Bunte salts with imidazole in good to high yields in aqueous media.

Full text of DOI:10.1080/10426507.2014.1003643

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Phosphorus, Sulfur, and Silicon and the Related
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Imidazole Promoted Highly Efficient Large Scale Thiol-
Free Synthesis of Symmetrical Disulfides in Aqueous
Media
Babak Mokhtaria, Ali Reza Kiasata & Javid Monjezia
a Chemistry Department, Faculty of Science, Shahid Chamran University of Ahvaz, Ahvaz
61357-43169, Iran
Accepted author version posted online: 11 Feb 2015.
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To cite this article: Babak Mokhtari, Ali Reza Kiasat & Javid Monjezi (2015): Imidazole Promoted Highly Efficient Large Scale
Thiol-Free Synthesis of Symmetrical Disulfides in Aqueous Media, Phosphorus, Sulfur, and Silicon and the Related Elements,
DOI: 10.1080/10426507.2014.1003643
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IMIDAZOLE PROMOTED HIGHLY EFFICIENT LARGE SCALE THIOL-FREE
SYNTHESIS OF SYMMETRICAL DISULFIDES IN AQUEOUS MEDIA
Babak Mokhtari*, Ali Reza Kiasat and Javid Monjezi
Chemistry Department, Faculty of Science, Shahid Chamran University of Ahvaz,
Ahvaz 61357-43169, Iran
Abstract A highly efficient and environmentally friendly method for the imidazole promoted
preparation of symmetrical organic disulfides from Bunte salts is described. This thiol-free
procedure produces the desired disulfides even on a large scale by reaction of Bunte salts with
imidazole in good to high yields in aqueous media.
Keywords: Bunte salt, thiol-free, imidazole, disulfides
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1. INTRODUCTION
Compounds containing a disulfide (disulfane) functionality are found among many various
natural products, pharmaceuticals and their intermediates.1 For instance, some naturally
occurring disulfides such as ajoene and dysoxysulfone, which are found in garlic, onions and
mahogany trees, have shown promise as antifungal, anticancer, and antithrombotic compounds.2
Furthermore, polysulfide bonds have wide applications as vulcanizing agents for rubbers and
elastomers, giving those materials excellent tensile strength.3 So the formation of the disulfide
bond is an important process from both the synthetic and the biological viewpoint, and a broad
range of reagents and reaction conditions has been developed for this purpose.
In general, there are two widely used strategies for the preparation of symmetrical
disulfides: alkylation of the disulfide dianion and oxidation of mercaptanes.4 In the first general
method, alkyl halides or alkyl sulfonates are used as alkylating agent and various reagents and
conditions used for this transformation include elemental sulfur plus NaOH,5 NaBH4/S8/wet
neutral alumina,6 piperidinium tetrathiotungstate or piperidinium tetrathiomolybdate.7 In the
second approach, the preparation of symmetrical organic disulfides was done via oxidative
coupling of thiols by various oxidants including electrophilic halogen reagents,8 metal ions,9
11
iodine,10 H2O2 organometallic manganese complex,12 Burgess reagent,13 Ceric ammonium
nitrate (CAN),14 Al2O3/KF,15 CsF,16 silica sulfuric acid/NaNO2,17 and electrochemical methods.18
In addition, organic disulfides can also be prepared indirectly starting from Bunte salts19 by
reaction with samarium metal,20 InCl3(cat.)/Sm(0),21 and Sm/I2.22
However the reported methods suffer from disadvantages such as long reaction times, high
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temperature reaction, expensive reagents and tedious work-up. Thus, the introducing convenient
methods which use the green and mild reaction conditions are practically concerned and still in
demand. Herein, and as an extension of our previous studies on introducing new synthetic
methodology in organosulfur chemistry, 5, 6, 23 we wish to report on an environmentally friendly,
simple, scalable, remarkably fast and thiol-free method for the preparation of symmetrical
organic disulfides in aqueous media.
2. RESULTS AND DISCUSSION
The reaction procedure is very simple and includes heating of a mixture of imidazole and
Bunte salts in water at 70 °C for less than 40 minutes (Scheme 1).
To obtain optimized reaction conditions, we selected the conversion of sodium S-benzyl
sulfothioate into the corresponding disulfide at 70 °C as a model reaction and studied the effect
of various parameters in detail. In the first step, the influence of various bases was examined to
evaluate their capabilities. The results are summarized in Table 1. As Table 1 shows, higher
yields and shorter reaction times were observed when imidazole was used. Apparently, imidazole
was the base of choice for the next reactions.
Initial experiments were performed with 1/1 S-benzyl sulfothioate / imidazole but
subsequent experiments using a 2/1 molar ratio of S-benzyl sulfothioate / imidazole gave nearly
complete formation of dibenzyl disulfide. Using lower amounts lowered the yields and therefore
the 2/1 molar ratio Bunte salt/ imidazole was selected as optimal condition and applied for other
substrates.
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The effect of temperature was also studied and the results showed the best conversion into
disulfide was achieved at 70 °C. Conducting of the model reaction at room temperature lowered
the yield and performing the reaction at reflux condition did not lead to a significant change on
the outcome of the reaction.
After optimizing reaction condition using benzyl sulfothioate, a wide range of structurally
diverse substituted benzyl or alkyl sulfothioates were conducted to this reaction resulting to
formation of corresponding symmetrical organic disulfides in good to excellent yields.
Representative results are summarized in Table 2. As is clear from Table 2, the primary para and
meta-substituted benzylic and benzylic-like Bunte salts (Entries 1–10) were easily converted into
corresponding disulfides in excellent yields. In the case of primary ortho-substituted benzylic
substrates, the yields were lower and the reaction times were longer than with para- and meta-
substituted substrates, respectively (Entries 11, 12). Furthermore, secondary and tertiary Bunte
salts (Entries 13-15) due to relatively pronounced steric hindrance gave lower yields of desired
products as compared with benzylic ones. Finally, aliphatic primary and secondary Bunte salts
produced the corresponding disulfides in moderate yields.
Finally, we examined this method for the large scale preparation of disulfides and the
results for the preparation of benzyl disulfide showed that the method can be easily applied for
large scale preparations of this type of organosulfur compounds.
Mechanistically, we suggest the reaction to take place in two steps as shown in Scheme 2.
Firstly, imidazole reacts with the Bunte salt to form 2. In the second step, the Bunte salt reacts
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with water to form RS and finally, subsequent reaction of RS with 2 produces the
corresponding disulfide. An equimolar instead of only a catalytic amount of imidazole is
required for the neutralization of the generated sulfuric acid.
3. CONCLUSIONS
In this study, we present a new, simple, efficient and clean method for the synthesis of
organic disulfides from Bunte salts with excellent yields by use of imidazole as base in aqueous
solution. This environmentally friendly, “green” route offers several advantages and avoids
hazardous and toxic organic solvents for work-up, high yields, short reaction times, a simple
work-up procedure, and ease of separation as well as the ability to tolerate a wide variety of
substitutions. Further, in our protocol a high yield of the product is achieved in short reaction
time even at large scale.
4. EXPERIMENTAL
4.1 General
All materials were obtained from Merck, Fluka and Aldrich chemical companies and were
used without further purification. The Bunte salts were synthesized from the corresponding
benzyl and alkyl halides following Bunte’s procedure34 for the preparation of S-ethyl sodium
sulfothioate. The reactions were monitored by TLC (silica-gel 60 F254, n-hexane/ethyl acetate).
The melting points were measured by an Electro thermal engineering LTD IA9200 apparatus. IR
1
13
spectra were recorded on a FT-IR Shimadzu-470 spectrometer and the H and C NMR spectra
were obtained using a Bruker Avance DRX 400 MHz spectrometer. Mass spectra were recorded
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on a MS Model: 5973 Network Mass Selective Detector. The products were characterized by
comparison of their spectra and physical data with those reported in the literature.
4.2 General procedure for synthesis of symmetrical disulfides
Imidazole (1mmol, 0.068 g), Bunte salt (2mmol) and water (15ml) were added to a 50 mL
flask fitted with a reflux condenser. The reaction mixture was stirred at 70 °C for 15 - 35 min.
After complete consumption of the Bunte salt as judged by TLC using n-hexane/ethyl acetate
)10/1( as eluent, the crude product was obtained by simple filtration of the mixture. The product
was washed with water to remove the impurities. Highly pure products can be obtained by
recrystallization from water.
4.3 Typical procedure for the large-scale synthesis of dibenzyl disulfide
Imidazole (20 mmol, 1.36 g), S-benzyl sodium sulfothioate (40 mmol, 9.04 g) and water
(100 mL) were added to a 250 mL flask fitted with a condenser. The reaction mixture was heated
at 70 °C for 50 min. After complete consumption of the sodium S-benzyl sulfothioate as judged
by TLC using n-hexane/ethyl acetate )10/1 (as eluent, the crude product was obtained by simple
filtration of the mixture. The product was washed with water to remove the impurities. Highly
pure products can be obtained by recrystallization from water (yield: 89 %).
ACKNOWLEDGMENTS
We are grateful to the Shahid Chamran University of Ahvaz for financial support of this
investigation.
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REFERENCES
[1] (a) Oae, S. (Ed.). Organic Sulfur Chemistry: Structure and Mechanism; CRC: Boca Raton,
FL, 1991; (b) Uemura, S. Oxidation of Sulfur, Selenium, and Tellurium; in Comprehensive
Organic Synthesis; B. M. Trost, I. Fleming (Eds.); Pergamon: Oxford, 1991; vol. 7, pp. 757–787;
(c) Cremlyn, R. J. (Ed.). An Introduction to Organosulfur Chemistry; Wiley & Sons: New York,
1996; (d) Solladié, G.; Carmen Carreno, M., in Organosulfur Chemistry: Synthetic Aspects;
Page, P. B. (Ed.) Academic Press: San Diego, 1995.
[2] Kong, G.; Kain, K. C.; Crandall, I.; Langler, R. F. Sulfur Lett. 2003, 26, 149-154.
[3] Ramadas, K.; Srinivasan, N. Synth. Commun. 1995, 25, 227-234.
[4] (a) Shcherbakova, I.; Pozharskii, A. F., in Comprehensive Organic Functional Group
Transformations II, Katritzky, A. R.; Taylor, R.; Ramsden, Ch., Eds.; Pergamon: Oxford, 2004;
Vol. 2, pp 210–233; (b) Bulman Page, P. C.; Wilkes R. D.; Reynolds, D., in Comprehensive
Organic Functional Group Transformations, Katritzky, A. R.; Meth-Cohn, O.; Rees, C. W.,
Eds.; Pergamon: Oxford, 1995; Vol. 2, pp 177–187; (c) Sato, R.; Kimura, T., in Science of
Synthesis, Kambe, N.; Drabowicz, J.; Molander, G. A., Eds.; Thieme: Stuttgart – New York,
2007; Vol. 39, pp 573-588; (d) Witt, D.; Klajn, R.; Barski, P.; Grzybowski, B. A. Curr. Org.
Chem. 2004, 8, 1763-1797; (e) Mandal, B.; Basu, B. Royal Soc. Chem. Adv. 2014, 4, 13854-
13881; (f) Witt, D. Synthesis 2008, 2491-2509.
[5] Kiasat, A. R.; Mokhtari, B.; Savari, A.; Kazemi, F. Phosphorus Sulfur Silicon Relat. Elem.
2008, 183, 178–182.
[6] Kiasat, A. R.; Mokhtari, B.; Kazemi, F.;Yousefi, S.; Javaherian, M. J. Sulfur Chem. 2007, 28,
171–176.
7
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[7] Dhar, P.; Chandrasekaran, S. J. Org. Chem. 1989, 54, 2998-3000.
[8] Ghorbani-Choghamarani, A.; Azadi, G.; Tahmasbi, B.; Hadizadeh-Hafshejani, M.; Abdi, Z.
Phosphorus Sulfur Silicon Relat. Elem. 2014, 189, 433–439.
[9] (a) Chen, H. Y.; Peng, W. T.; Lee,Y. H.; Chang, Y. L.; Chen, Y. J.; Lai, Y. C.; Jheng, N. Y.;
Chen, H. Y. Organometallics 2013, 32, 5514-5522; (b) Nair, V.; Augustine, A. Org. Lett. 2003,
5, 543-544.
[10] Wang, L.; Clive, D. L. Org. Lett. 2011, 13, 1734-1737.
[11] Harusawa, S.; Yoshida, K.; Kojima, C.; Araki, L.; Kurihara, T. Tetrahedron 2004, 60,
11911-11922.
[12] Tan, K. Y. D.; Kee, J. W.; Fan, W. Y. Organometallics 2010, 29, 4459-4463.
[13] Banfield, S. C.; Omori, A. T.; Leisch, H.; Hudlicky, T. J. Org. Chem. 2007, 72, 4989-4992.
[14] Iranpoor, N.; Firouzabadi, H.; Pourali, A. Tetrahedron 2002, 58, 5179-5184.
[15] Lenardao, E. J.; Lara, R. G.; Silva, M. S.; Jacob, R. G.; Perin, G. Tetrahedron Lett. 2007,
48, 7668-7670.
[16] Ruggles, E. L.; Deker, P. B.; Hondal, R. J. Tetrahedron 2009, 65, 1257-1267.
[17] Zolfigol, M. A. Tetrahedron 2001, 57, 9509-9511.
[18] (a) Doa, Q. T.; Elothmania, D.; Le Guillanton, G.; Simonet, J. Tetrahedron Lett.1997, 38,
3383-3384. (b) Gondi, S. R.; Son, D. Y. Biehl, E. R.; Vempati, R. K. Phosphorus Sulfur Silicon
Relat. Elem. 2010, 185, 34–39.
[19] Distler, H. Angew. Chem. Int. Ed. 1967, 6, 544-553.
[20] (a) Wang, L.; Zhang, Y. Tetrahedron 1999, 55, 10695-10712; (b) Wang, L.; Li, P.; Zhou, L.
Tetrahedron Lett. 2002, 43, 8141-8143.
8
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
[21] Li, P.; Wang, L.; Yang, Y.; Sun, X.; Wang, M.; Yan, J. Heteroatom Chem. 2004, 15, 376-
379.
[22] (a) Zheng, H.; Xu, D.; Xu, Z.; Zhang Y. Synlett 2006, 2492–2494; (b) Huang, Y.; Zhang,
Y.; Wang, Y. Synth. Commun. 1997, 27, 1043-1047.
[23] (a) Mokhtari, B.; Azhdari, A.; Azadi, R. J. Sulfur. Chem. 2009, 30, 585–589; (b) Azadi, R.;
Mokhtari, B.; Oghabi, H. Phosphorus Sulfur Silicon Relat. Elem. 2012, 187, 1377–1382; (c)
Mokhtari, B.; Azadi, R.; Rahmani-Nezhad, S. Tetrahedron Lett. 2009, 50, 6588–6589. (d)
Kiasat, A. R.; Kazemi, F.; Fallah, M. Phosphorus Sulfur Silicon Relat. Elem. 2004, 179, 1841-
1844.
[24] Wang; J.-X.; Wang, C.-H.; Cui, W.; Hu Y. Synth. Commun. 1995, 25, 3573-3581
[25] Ramesha, A. R. Chandrasekaran, S. Synth. Commun. 1992, 22, 3277-3284.
[26] Choi, J.; Yoon, N. M. J. Org. Chem. 1995, 60, 3266-3267.
[27] Truce, W. E.; Toren, G. A. J. Am. Chem. Soc. 1954, 76, 695-698.
[28] Iranpoor, N.; Zeynizadeh, B. Synthesis 1999, 49-51.
[29] Misra, A. K.; Agnihotri, G. Synth. Commun. 2004, 34, 1079-1085.
[30] Sengupta, D.; Basu, B. Tetrahedron Lett. 2013, 54, 2277–2281.
[31] Surajit, S.; Chandrasekaran, I. Tetrahedron 1999, 55, 14769-14776
[32] Ohno, A.; Nakamura, K.; Uohama, M.; Oka, S.; Yamabe, T.; Nagata, S. Bull. Chem. Soc.
Jpn. 1975, 48, 3618-3622.
[33] Cochran, J. C.; Friedman, S. R.; Frazier J. P. J. Org. Chem. 1996, 61, 1533–1536.
[34] Bunte, H. Ber. Dt. Chem. Ges. 1874, 7, 646-648.
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H
N
O
S
S
R
R
S
Na+
N
O-
R
S
O
H2O, 70oC
Scheme 1
H
N
1
2
4
-
R
SO3
S
N
R
HN
2-
N S
+
SO3
+
3
2
H
N
3
R
HN
2
-
N S
+
+
RSSR
R
SO3
+ H2SO4
S
H2O
+
+
N
2
1
Scheme 2
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Table 1 Preparation of dibenzyl disulfide using different bases.
O
S
Base
S
Na+
S
O-
S
O
H2O, 70o
C
Entry
Base
Yield (%)
1
2
3
4
5
4-dimethylaminopyridine
1,8-diazabicyclo[5,4,0]undec-7-en
triethylamine
90
86
78
87
98
1,4-diazabicyclo[2,2,2]octane
imidazole
a Isolated Yields. b Products were characterized by comparison of their spectroscopic data (NMR
and IR) and melting points with those reported in the literature
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Table 2 Thiol free synthesis of symmetrical disulfides from Bunte salt
m.p.
(°C)
71-
Yielda,b Time(min)
(%)
Product
Entry
98
96
25
25
1
7224
S
S
76-
2
3
4
O
7829
S
S
O
Cl
Br
57-
90
25
Cl
5924
S
S
oil28
98
25
Br
S
S
12
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110-
96
25
5
NO2
11224
S
S
O2N
68-
94
93
25
20
6
7
O2N
S
7025
S
NO2
88-
S
8926
S
S
S
106-
97
95
25
15
8
9
10827
Br
highly
viscos
oil
O
S
S
O
Br
87-
86
45
10
Cl
8930
S
S
Cl
13
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85-
83
45
11
Br
8724
S
S
Br
oil31
80
75
35
35
12
13
S
S
124-
S
12728
S
S
oil24
151-
15232
75
67
35
35
S
14
15
S
S
153-
55
45
16
15533
S
S
14
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