Amine-catalyzed preparation of oxygenated derivatives of symmetric trisulfides

Article abstract of DOI:10.1016/j.tetlet.2009.07.104

Bipyridinium tribromide reacts with thiols in the presence of thionyl chloride to yield symmetric trisulfide derivatives (RSS(O)SR) as the major products. Two possible mechanisms are advanced to explain the chemistry.

Full text of DOI:10.1016/j.tetlet.2009.07.104

Tetrahedron Letters 50 (2009) 5987–5989
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Amine-catalyzed preparation of oxygenated derivatives of symmetric trisulfides
Mahbubeh Pourshahbaz a, Mohammad Joshaghani a,b, , Ezzat Rafiee a,b, Jahangir Shahmoradi a,
*
Fereshteh Emami a, Asieh Iranpour a
a Chemistry Department, Faculty of Science, Razi University, Kermanshah, Iran
b Kermanshah Oil Refining Company, Kermanshah, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 11 March 2009
Revised 4 July 2009
Accepted 17 July 2009
Available online 23 July 2009
Bipyridinium tribromide reacts with thiols in the presence of thionyl chloride to yield symmetric trisul-
fide derivatives (RSS(O)SR) as the major products. Two possible mechanisms are advanced to explain the
chemistry.
Ó 2009 Elsevier Ltd. All rights reserved.
Trisulfides are important organic sulfur compounds with signif-
icant industrial and biological importance. These compounds have
been found in many natural sources such as onions and garlic,
brown algae and various animals.1–4 Numerous routes have been
developed for the preparation of trisulfides. The most routine are
the reactions of sulfur dichloride with thiols,5 alkyl halides with so-
dium trisulfide,6 thiols with sulfur,7 etc.8–13 Among trisulfides, tri-
sulfide 2-oxides have been shown to be sources of sulfur monoxide
which is a challenging problem in organic and inorganic chemis-
try.2b,14–16 As a result, there is still a need for the development of
a general and efficient methodology to synthesize trisulfides and
their oxygenated derivatives.
We recently reported that bipyridinium tribromide (BPTB) is a
mild and efficient oxidant in the oxidative coupling of thiols to
the corresponding symmetric disulfides.17 The easy preparation
of the reagent, short reaction times and excellent yields of the
disulfide as the only product without over-oxidation made this re-
agent useful for the preparation of disulfides. The relative higher
reactivity of BPTB compared to that of the well-known alternative,
pyridine hydrobromide perbromide suggested that the unproto-
nated nitrogen may act as a base and remove the acid formed dur-
ing the reaction. Therefore, the oxidative coupling of thiols is
carried out under base-catalyzed conditions. On the other hand,
base-catalyzed preparation of trisulfides from the corresponding
thionyl chloride has been reported to occur in good yields.7 Thus,
we investigated the conversion of thiols into the corresponding
symmetric trisulfide 2-oxides using thionyl chloride in the pres-
ence of BPTB. The effect of sequential addition of BPTB and thionyl
chloride was also investigated (Scheme 1).
A series of aromatic, benzylic, heterocyclic and alkyl thiols were
reacted with thionyl chloride via either route A which proceeds by
way of the corresponding symmetric disulfide intermediate, or
route B (Table 1). Aromatic thiols containing weak electron-donat-
ing groups such as methyl and chloro were converted into the cor-
responding trisulfide 2-oxides in excellent yields and relatively
short reaction times, (Table 1, entries 1–4). The presence of a
strong electron-donating group such as NH2 at the ortho position
decreased the yield dramatically (Table 1, entry 6). Benzyl thiol
was converted into the corresponding symmetric trisulfide 2-oxide
in a similar manner but required a longer reaction time and the
product was obtained in a lower yield (Table 1, entry 5). The two
relatively bulky and inactive heterocyclic thiols, benzothiazole-2-
thiol and 1H-benzimidazole-2-thiol (Table 1, entries 7 and 8) were
converted in lower yields and required longer reaction times. Alkyl
thiols failed to react via route A but were converted into the
corresponding symmetric trisulfide-2-oxides via route B in very
long reaction times (Table 1, entries 9–12). However, addition of
thionyl chloride to the alkyl disulfides yielded the desired
1) BPTB
2) SOCl
2
RSSR
A
O
S
RS
SR
RSH
B
1) SOCl
2
2) BPTB
The results show that trisulfide 2-oxides are obtained as the
major products, probably with other polysulfides as minor side
products, under mild conditions at room temperature.18
-
BPTB:
Br3
N
HN
+
* Corresponding author. Present address: Chemistry Department, Faculty of
Science, Razi University, Kermanshah, Iran. Tel./fax: +98 831 4274559.
E-mail address: mjoshaghani@razi.ac.ir (M. Joshaghani).
R= Alkyl, Aryl, Heterocycle
Scheme 1.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.07.104

5988
M. Pourshahbaz et al. / Tetrahedron Letters 50 (2009) 5987–5989
Table 1
Trisulfide-2-oxide formation via routes A and Ba
Entry
R
Procedure A
Procedure B
Refc
15d
15d
Time (min)
15
Yieldb (%)
95
Time (min)
20
Yield (%)
90
1
2
15
15
90
90
20
20
85
85
CH3
Cl
3
4
5
6
7
8
20a
20b
—
15
20
95
85
15
80
80
25
30
85
75
15
75
75
CH2
180
25
25
180
35
35
—
NH2
S
—
N
H
N
—
N
9
10
11
12
13
14
n-C4H9–
120
120
—
—
45
60
75 (10)
70 (15)
—
180
180
360
720
—
80
80
65
75d
—
—
—
—
—
—
—
n-C8H17
–
HOCH2CH2–
HOCH2CH(SH)CH2–
Me
Et
—
85 (10)
80 (10)
—
—
a
Reaction conditions: room temperature, acetonitrile (5 ml), thiol (2 mmol), BPTB (1 mmol) and thionyl chloride (1 mmol).
The figures in parentheses are the yields of the corresponding tetrasulfide-2-oxides.
Known products were characterized based on literature data and the new products were characterized based on spectroscopic data as well as elemental analysis (see
b
c
Supplementary data).
d
Unresolved mixture of products.
(Scheme 1, Procedure A) first resulted in the formation of the cor-
responding disulfide, which was converted into the trisulfide-2-
oxide on addition of SOCl2. The reactions failed to give trisulfide
2-oxides in the absence or in the presence of a low concentration
of thionyl chloride. In these cases, the only products were the cor-
responding disulfides. On the other hand, trisulfide 2-oxides were
formed directly on addition of SOCl2 followed by BPTB (Scheme 1,
Procedure B). In route A, the symmetric trisulfide-2-oxides are
probably produced via a sulfur atom insertion mechanism (Scheme
2).10
Cl
O
R
Cl
S
S
O
S
O
S
+
+
R
R
S
S
S
S
R
R
Cl
Cl
Cl
+
R S Cl
S
Cl
SR
SR
R
RS
O
Cl
S
O
S
O
S
SR
+
R
RS
S Cl
S
S
R
R
Scheme 2.
In route B, a base-catalyzed mechanism may be responsible for
the formation of trisulfide 2-oxides from the corresponding thiols
(Scheme 3). This mechanism is similar to that proposed for the
reaction of inorganic nucleophiles and sulfur19 wherein ‘N’ repre-
sents the unprotonated nitrogen of BPTB. To confirm the base-cat-
alyzed mechanism, similar reactions were carried out in the
trisulfide-2-oxides along with tetrasulfide-2-oxides as side prod-
ucts (Table 1, entries 9, 10, 13 and 14).
Interestingly, the reaction was very sensitive to the sequence of
the addition of thionyl chloride and BPTB. Addition of BPTB

M. Pourshahbaz et al. / Tetrahedron Letters 50 (2009) 5987–5989
5989
1003; (g) Shankar, S.; Chen, Q.; Ganapathy, S.; Singh, K. P.; Srivastava, R. K. Mol.
Cancer Ther. 2008, 7, 2328–2338.
δ
δ
N
H
H
SR
N
+
SR
2. (a) Steudel, R.; Hassenberg, K.; Pickardt, J. Organometallics 1999, 18, 2910–
2911; (b) Grainger, R.; Procopio, A.; Steed, J. W. Org. Lett. 2001, 3, 3565–3568;
(c) Lee, A. H. F.; Chen, J.; Liu, D.; Leung, T. Y. C.; Chan, A. S. C.; Li, T. J. Am. Chem.
Soc. 2002, 124, 13972–13973; (d) Kimura, T.; Sasaki, T.; Yamaki, H.; Suzuki, E.;
Niizuma, S. Eur. J. Org. Chem. 2003, 4902–4908; (e) Ishii, A.; Suzuki, M.;
Yamashita, R. Tetrahedron 2006, 62, 5441–5447; (f) Sato, R.; Ohta, H.;
Yamamoto, T.; Nakajo, S.; Ogawa, S.; Alam, A. Tetrahedron Lett. 2007, 48,
4991–4999; (g) Sato, R.; Fujio, T.; Nakajo, S.; Ogawa, S.; Alam, A. Tetrahedron
Lett. 2007, 48, 3013–3016.
3. (a) Nicolaou, K. C.; Dai, W. M. Angew. Chem., Int. Ed. Engl. 1991, 30, 1387–1416;
(b) Nicolaou, K. C.; Hummel, C. W.; Nakada, M.; Shibayama, K.; Pitsinos, E. N.;
Saimoto, H.; Mizuno, Y.; Baldenius, K. U.; Smith, A. L. J. Am. Chem. Soc. 1993,
115, 7625–7635.
4. (a) Katritzky, A. R.; Zhao, X.; Hitchings, G. J. Synlett 1990, 473–476; (b)
Yasuhara, A.; Fuwa, K. Bull. Chem. Soc. Jpn. 1977, 50, 3029–3032.
5. (a) Derbesy, G.; Harpp, D. N. Tetrahedron Lett. 1994, 35, 5381–5384; (b) Clayton,
J.; Etzler, D. J. Am. Chem. Soc. 1974, 69, 974–975.
6. Organic Chemistry of Bivalent Sulfur; Reid, E. E., Ed.; Chemical Publishing
Company: New York, 1960; Vol. 3, p 387.
Cl
O
Cl
δ
δ
S
N
H
SR
+
RS
S
N
H
S
Cl
Cl
+
O
Cl
Cl
Cl
RS
S
Cl
H
N
N
+
RS
+
O
H
O
SR
Cl
Cl
SR
δ
δ
N
H
SR
S
+
+
S
N
H
RS
+
O
O
O
SR
Cl
7. Vineyard, B. D. J. Org. Chem. 1966, 31, 601–602.
8. Buckman, J. D.; Field, L. J. Org. Chem. 1967, 32, 454–457.
Cl
H
RS
S
SR
N
+
H
S
N
RS
O
9. (a) Williams, C. R.; Britten, J. F.; Harpp, D. N. J. Org. Chem. 1994, 59, 806–812; (b)
Hou, Y.; Abu-Yousef, I. A.; Doung, Y.; Harpp, D. N. Tetrahedron Lett. 2001, 42,
8607–8610; (c) Harpp, D. N.; Granata, A. Tetrahedron Lett. 1976, 17, 3001–3004;
(d) Harpp, D. N.; Ash, D. K.; Back, T. G.; Gleason, J. G.; Orwig, B. A.; Vanhorn, W.
F.; Snyder, J. P. Tetrahedron Lett. 1970, 11, 3551–3554; (e) Harpp, D. N.; Gingras,
M.; Aida, T.; Chan, T. H. Synthesis 1987, 1122–1124; (f) Abu-Yousef, I. A.; Rys, A.
Z.; Harpp, D. N. J. Sulfur Chem. 2007, 28, 251–258; (g) Abu-Yousef, I. A.; Rys, A.
Z.; Harpp, D. N. J. Sulfur Chem. 2006, 27, 15–24; (h) Ryan, M. D.; Abu-Yousef, I.
A.; Rys, A. Z.; Cheer, C. J.; Harpp, D. N. Sulfur Lett. 2003, 26, 29–35; (i) Zysman-
Colman, E.; Harpp, D. N. J. Org. Chem. 2003, 68, 2487–2489.
10. Haoyun, A.; Jenny, Z.; Xiaobo, W.; Xiao, X. Bioorg. Med. Chem. Lett. 2006, 16,
4826–4829.
11. Capozzi, G.; Capperucci, A.; Degl’Innocenti, A.; Duce, D. R.; Menichetti, S.
Tetrahedron Lett. 1989, 30, 2991–2994.
12. Sinha, P.; Kundu, A.; Roy, S.; Prabhakar, S.; Vairamani, M.; Sankar, A. R.;
Kunwar, A. C. Organometallics 2001, 20, 157–162.
13. Banerji, A.; Kalena, G. P. Tetrahedron Lett. 1980, 21, 3003–3004.
14. (a) Harpp, D. N. Phosphorus, Sulfur Silicon 1997, 120/121, 41–59; (b) Tardif, S. L.;
Rys, A. Z.; Abrams, C. B.; Abu-Yousef, I. A.; Leste´-Lasserre, P. B. F.; Schultz, E. K.
V.; Harpp, D. N. Tetrahedron 1997, 53, 12225–12236; (c) Abu-Yousef, I. A.;
Harpp, D. N. J. Org. Chem. 1997, 62, 8366–8371.
15. (a) Schenk, W. A. Angew. Chem., Int. Ed. Engl. 1987, 26, 98–109; (b) Huang, R.;
Guzei, I. A.; Espenson, J. H. Organometallics 1999, 18, 5420–5422; (c) Clennan, E.
L.; Stensaas, K. L. Org. Prep. Proced. Int. 1998, 30, 551–600; (d) Field, L.;
Lacefield, W. B. J. Org. Chem. 1966, 31, 3555–3561.
16. (a) Ghosh, T.; Bartlett, P. D. J. Am. Chem. Soc. 1988, 110, 7499–7506; (b) Watson,
W. H.; Krawiec, M.; Ghosh, T.; Bartlett, P. D. Acta Crystallogr. 1992, C48, 2092–
2094; (c) Kimura, T.; Hanzawa, M.; Horn, E.; Kawai, Y.; Ogawa, S.; Sato, R.
Tetrahedron Lett. 1997, 38, 1607–1610.
17. Joshaghani, M.; Khosropour, A. R.; Jafari, H.; Mohammadpoor-Baltork, I.
Phosphorus, Sulfur Silicon 2005, 180, 117–123.
Scheme 3.
presence of triethylamine instead of BPTB, albeit in longer reaction
times. Similar results obtained confirm that BPTB may act as a base
in these reactions.
The reactions are pH sensitive and were carried out in solutions
of different pH. The best results were obtained in alkali media at a
þ
pH of about 9–10 using NH3/NH4 buffer.
The trisulfide 2-oxide products were isolated and characterized
by FTIR and 1H NMR spectroscopy and elemental analysis (see Sup-
plementary data).18 The presence of a relatively sharp band at
about 1090–1130 cmꢀ1 was attributed to the S@O stretching fre-
quency. The 1H NMR spectra were very similar to the correspond-
ing disulfide albeit with a greater shift into the downfield region
due to the presence of the relatively strong electron-withdrawing
S@O group.
In conclusion, the high selectivity along with very short reaction
times, simple work-up, ease of handling and significant stability of
the BPTB reagent are advantages of this system.
Acknowledgements
18. General procedures for the preparation of trisulfide-2-oxides: Procedure A: To a
stirred solution of a thiol (2 mmol) in acetonitrile (5 ml) was added BPTB (0.4 g,
1 mmol). A pale yellow solid precipitated. Thionyl chloride (1 mmol) was
added gradually and the pH of the solution was maintained at 9.5 using NH3/
The authors thank the Razi University Research Council and
Kermanshah Oil Refining Company for support of this work.
þ
NH4 buffer. The mixture was stirred and the progress of the reaction was
Supplementary data
monitored by TLC (n-heptane–EtOAc, 3:1). After the time according to Table 1,
a pale yellow solid formed which was extracted with ether (3 ꢁ 10 ml). The
organic layers were combined and dried over anhydrous MgSO4. The solvent
was evaporated and the crude product was recrystallized from (n-heptane–
EtOAc, 3:1) to afford the pure trisulfide 2-oxide product. For characterization
see Supplementary data.Procedure B: A similar procedure to that described
above was used for the synthesis of the trisulfide 2-oxide involving gradual
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.07.104.
References and notes
addition of BPTB (1 mmol) to
a stirred solution of a thiol (2 mmol) in
acetonitrile (5 ml) and thionyl chloride (1 mmol).
1. (a) Block, E. Angew. Chem, Int. Ed. Engl. 1992, 31, 1135–1178; (b) Wijaya, C. H.;
Nishimura, H.; Tanaka, T.; Mizutani, J. J. Food Sci. 1991, 56, 72–75; (c) An, H.;
Zhu, J.; Wang, X.; Xu, X. Bioorg. Med. Chem. Lett. 2006, 16, 4826–4829; (d)
Powolny, A. A.; Singh, S. V. Cancer Lett. 2008, 269, 305–314; (e) Gu, L.; Li, L.;
Chen, Z.; Pan, H.; Jiang, H.; Zeng, S.; Xu, X.; An, H. J. Chromatogr., B 2008, 868,
77–82; (f) Lei, Y. P.; Chen, H. W.; Sheen, L. Y.; Lii, C. K. J. Nutr. 2008, 138, 996–
19. (a) Inorganic polymers; Stone, F. G. A., Graham, A. G., Eds.; Academic Press Inc:
New York, 1962; p 149; (b) Vineyard, B. D. J. Org. Chem. 1967, 32, 3833–3836.
20. (a) Steudel, R.; Luger, P.; Bradaczek, H. Chem. Ber. 1977, 110, 3553–3560;
(b) Steudel, R.; Schenk, P. W.; Bilal, J. Z. Anorg. Allg. Chem. 1967, 353, 250–
258.