An efficient, one-pot and CuCl-catalyzed route to the synthesis of symmetric organic disulfides via domino reactions of thioacetamide and aryl (alkyl) halides

Article abstract of DOI:10.1002/aoc.3074

In this article, a simple, general and novel method for the synthesis of diaryl (dialkyl) disulfides from aryl (alkyl) halides is described. This is a convenient approach that involves the use of commercially available and inexpensive thioacetamide as a sulfur transfer reagent in the domino process for the synthesis of symmetric organic disulfides. Copyright

Full text of DOI:10.1002/aoc.3074

Full Paper
Received: 24 July 2013
Revised: 25 August 2013
Accepted: 29 August 2013
Published online in Wiley Online Library: 24 October 2013
(wileyonlinelibrary.com) DOI 10.1002/aoc.3074
An efficient, one-pot and CuCl-catalyzed route
to the synthesis of symmetric organic
disulfides via domino reactions of
thioacetamide and aryl (alkyl) halides
Mohammad Soleiman-Beigi* and Maryam Hemmati
In this article, a simple, general and novel method for the synthesis of diaryl (dialkyl) disulfides from aryl (alkyl) halides is
described. This is a convenient approach that involves the use of commercially available and inexpensive thioacetamide as
a sulfur transfer reagent in the domino process for the synthesis of symmetric organic disulfides. Copyright © 2013 John Wiley
& Sons, Ltd.
Additional supporting information may be found in the online version of this article at the publisher’s web site.
Keywords: copper-catalyzed; domino reaction; disulfides; thioacetamide; sulfur transfer reagents
conducted in DMF in the presence of copper chloride at different
temperatures. As is evident from Table 1, progress of the reaction
Introduction
Organic disulfides, which belong to an important class of sulfur-
containing compounds, have attracted much attention because
of their various biological, industrial and synthetic applications.[1]
These compounds are typically prepared by oxidative coupling
of thiols to disulfides in the presence of oxidants.[2] However, po-
tential environmental and health risks associated with them, as well
as difficulty in working with thiols, have persuaded organic chem-
ists to develop new methods to overcome these disadvantages.
In this regard, much attention has been directed to the use of sulfur
transfer reagents for the synthesis of organic disulfides from alkyl
and aryl halides through coupling reactions.[3,4] These methods
not only have novelty aspects and provide routes for the synthesis
of disulfides, but also are important from environmental and eco-
nomic perspectives.[5] However, the number of methods available
for the direct synthesis of disulfides from aryl halides is limited.[4]
Recently, we managed to develop a new method for the syn-
thesis of symmetric disulfides from aryl and alkyl halides using
potassium 5-methyl-1,3,4-oxadiazole-2-thiolate reagent.[4b] In ad-
dition, we aimed at introducing another new method for the syn-
thesis of compounds in the presence of a commercially available
and inexpensive reagent. For this purpose, thioacetamide, which
had already been used as a sulfur transfer reagent in the synthe-
sis of symmetric sulfides from alkyl halides,[6] was employed in
this study.
depends strongly on temperature. However, the reaction is ex-
tremely slow at lower temperatures (<50°C); at higher tempera-
tures, diphenyl disulfide was formed as the sole reaction
product, with a yield of 98% at 5 h. Like temperature, solvent also
has significant effects on the reaction yield. For instance, progress
of the reaction was insignificant in toluene, 1,4-dioxane and tetra-
hydrofuran (unlike with DMF).
The model reaction was performed in the presence of some
copper salts such as CuI and Cu2O, whose reaction yields were
90% and 63%, respectively; it was not performed in the absence
of copper.
A series of symmetric diaryl (dialkyl) disulfides were synthe-
sized from related aryl and alkyl halides at 110°C in DMF and in
the presence of CuCl catalyst under atmospheric conditions
(Table 2).
In this procedure, different types of aryl halides (such as chlo-
rides, bromides and iodides) were used; aryl iodides provided
better yields than the others. The gas chromatographic yields
and NMR data show that diaryl (dialkyl) disulfide was often the
only reaction product, although diaryl sulfide was formed in
some cases (Table 2, entries 5, 7 and 10).
Electron-withdrawing groups, such as F and NO2, increased the
yield of disulfide synthesis from aryl bromides and aryl chlorides
(Table 2, entries 6, 8 and 9); however, the reaction yield was low
in the absence of electron-withdrawing groups (Table 2, entry 7).
In this project, KF/Al2O3 was used as a strong, stable, recyclable
and heterogeneous base, which has a history of use in both cou-
pling reactions[7] and oxidative transformation of thiols to symmet-
ric disulfides.[8] KF/Al2O3 can be prepared easily in the laboratory.[9]
*
Correspondence to: Mohammad Soleiman-Beigi, Department of Chemistry,
Basic of Sciences Faculty, Ilam University, PO Box 69315-516, Ilam, Iran. E-mail:
SoleimanBeigi@yahoo.com
Results and Discussion
To find the optimal reaction conditions, first the reaction be-
tween iodobenzene (2 mmol) and thioacetamide (2 mmol) was
Department of Chemistry, Basic of Sciences Faculty, Ilam University, PO
Box 69315-516, Ilam, Iran
Appl. Organometal. Chem. 2013, 27, 734–736
Copyright © 2013 John Wiley & Sons, Ltd.

Cu-catalyzed; organic disulfides synthesis
Table 1. Optimization of the reaction temperature, and screening of
solvent of reactionsa
CuCl, KF/Al2O3
Solvent, Tmp.
I
CH3
H2N
S
S
S
+
Scheme 1. Chemoselectivity of the studied procedure.
Entry
Solvent
DMF
Temperature (°C)
Yield (%)b
1
2
3
4
5
6
7
8
9
130
110
80
98
98
DMF
DMF
77
DMF
50
50
DMF
25
-
DMSO
THF
110
110
110
110
78
Trace
-
PhCH3
1,4-dioxane
Trace
aGeneral reaction conditions: iodobenzene (2.0mmol), thioacetamide
(2.0 mmol), KF/Al2O3(1.0g, 40% KF by weight), CuCl (0.4mmol), in
solvent (2ml) for 5 h.
bIsolated yield.
Scheme 2. Proposed mechanism for symmetric disulfide synthesis from
aryl (alkyl) halides.
Table 2. CuCl-catalyzed and KF/Al2O3-mediated direct synthesis of
diaryl (dialkyl) disulfides from aryl (alkyl) halides at 110°C for 5 h
CuCl, KF/Al2O3
S
DMF, 110 °C
+
R-S-S-R
R-X
CH3
NH2
Entry
R-X
Yield (%)a
1
PhI
98
67
63
80
40b
29
10b
56
31
80b
70
83
95
Scheme 3. Investigation of oxidation ability of optimized reaction
conditions.
2
p-MeOPh―I
m-MeOPh―I
p-NH2Ph―I
3
4
5
2-Iodothiophene
p-NO2Ph―Br
p-MePh―Br
2,4-F2Ph―Br
2,4-(NO2)2Ph―Cl
1-Iodonaphthalene
PhCH2Cl
6
bis-(4-bromophenyl) disulfide was the main product (71% yield)
and bis-(4-iodophenyl) disulfide was the minor product (10%)
(Scheme 1).
However, in the case of 1-bromo-2,4-difluorobenzene, interest-
ingly, bis-(4-bromo-3-fluorophenyl) disulfide was the major prod-
uct (Table 2, entry 8; 56% yield), while bis-(2,4-difluorophenyl)
disulfide was the minor product (16%).
7
8
9
10
11
12
13
Ph(CH2)2Br
Ph(CH2)3Br
Although the exact reaction mechanism is not understood
completely, thiolate appears to be generated first in the coupling
reaction between thioacetamide and aryl and alkyl halides via an
Ullman-type mechanism.[3c,7b,10] The generated thiolate is then
converted into the corresponding disulfide under reaction condi-
tions (Scheme 2).[8]
aYield of the isolated product.
bA small amount of the corresponding diaryl sulfide derivative
was formed as a by-product (5–12%).
The reaction efficiency of the synthesis of symmetric dialkyl
disulfides was also examined, which was as effective as aryl
halides (Table 2, entries 11–13). Results show that the reaction
yield increased with increasing hydrocarbon chain.
High chemoselectivity of the reaction is another desirable
feature of this procedure. In the reaction between 1-bromo-4-
iodobenzene and thioacetamide under optimized conditions,
In order to check the oxidative coupling ability of the reaction
conditions, synthesis of diphenyl disulfide from thiophenol was
studied under optimal reaction conditions, in which the yield of
diphenyl disulfide was 93%. Moreover, following an acidic work-
up (10% HCl solution) of the model reaction under optimized
conditions after 2.0 h (middle of the reaction), thiophenol was
isolated and characterized (Scheme 3).
Appl. Organometal. Chem. 2013, 27, 734–736
Copyright © 2013 John Wiley & Sons, Ltd.
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M. Soleiman-Beigi and M. Hemmati
C. Périgaud, A. Pellet, H. J. Vial, S. Peyrottes, J. Med. Chem. 2012,
55, 4619. h) H. L. Fisher, Ind. Eng. Chem. 1950, 42, 1978.
Conclusions
[2] a) A. Christoforou, G. Nicolaou, Y. Elemes, Tetrahedron Lett. 2006, 47,
9211. b) M. A. Zolfigol, Tetrahedron Lett. 2001, 57, 9509. c) R. Leino,
J.-E. Lonnqvist, Tetrahedron Lett. 2004, 45, 8489. d) K. Tanaka, K. Ajiki,
Tetrahedron Lett. 2004, 45, 25. e) R. Hunter, M. Caira, N. Stellenboom,
J. Org. Chem. 2006, 71, 8268. f) A. Akdag, T. Webb, S. D. Worley,
Tetrahedron Lett. 2006, 47, 3509. g) J. K. Vandavasi, W. -P. Hu, C.-Y.
Chen, J.-J. Wang, Tetrahedron 2011, 67, 8895. h) A. Ghorbani-
Choghamarani, M. Nikoorazm, H. Godarziafshar, A. Shokr, H. Almasi,
J. Chem. Sci. 2011, 123, 453. i) R. Hosseinzadeh, M. Tajbakhsh, H.
Khaledi, K. Ghodrati, Monatsh. Chem. 2007, 138, 871. j) C. C. Silveira,
S. R. Mendes, Tetrahedron Lett. 2007, 48, 7469. k) P. J. Chai, Y. S. Li, C.
X. Tan, Chin. Chem. Lett. 2011, 22, 1403. l) G. W. Kabalka, M. S. Reddy,
M.-L. Yao, Tetrahedron Lett. 2009, 50, 7340.
In summary, in this study thioacetamide has been used as an
inexpensive and readily available sulfur transfer reagent in the
presence of KF/Al2O3. This strategy provides a new method for
the direct synthesis of symmetric diaryl and dialkyl disulfides from
aryl (alkyl) halides, which is more economical, comprehensive and
environmentally friendly than previous methods. Other advantages
of this process are the possibility of reusing the recyclable base
KF/Al2O3, ease of performing and controlling the reaction as well
as purification of the product, and avoidance of expensive and/
or dangerous reagents.
[3] a) H. Firouzabadi, N. Iranpoor, M. Abbasi, Tetrahedron Lett. 2010, 51,
508. b) D. W. Emerson, B. L. Bennett, S. M. Steinberg, Synth. Commun.
2005, 35, 631. c) H. Firouzabadi, N. Iranpoor, M. Gholinejad, Adv.
Synth. Catal. 2010, 352, 119. d) B. P. Bandgar, L. S. Uppalla, V. S.
Sadavarte, Tetrahedron Lett. 2001, 42, 6741. e) S. U. Sonavane, M.
Chidambaram, J. Almog, Y. Sasson, Tetrahedron Lett. 2007, 48,
6048. f) J.-X. Wang, L. Gao, D. Huang, Synth. Commun. 2002, 32,
963. g) V. Polshettiwar, M. Nivsarkar, J. Acharya, M. P. Kaushik,
Tetrahedron Lett. 2003, 44, 887. h) P. Dhar, N. Chidambaram, S.
Chandrasekaran, J. Org. Chem. 1992, 57, 1699. i) M. Tajbakhsh,
M. M. Lskouraj, M. S. Mahalli, Monatsh. Chem. 2008, 139, 1453.
[4] a) J. E. Arguello, L. C. Schmidt, A. B. Penenory, Org. Lett. 2003, 5, 4133.
b) M. Soleiman-Beigi, F. Mohammadi, Tetrahedron Lett. 2012,
53, 4028.
[5] a) R. A. Sheldon, in Green Chemistry and Catalysis (Eds: I. Arends,
U. Hanefeld), Wiley-VCH, Weinheim, 2007, p. 1. b) I. T. Horváth, P. T.
Anastas, Chem. Rev. 2007, 107, 2167. c) L. F. Tietze, in Domino
Reactions in Organic Synthesis (Eds: G. Brasche, K. Gericke), Wiley-VCH,
Weinheim, 2006, p. 470.
[6] a) E. Hammerschmidt, W. Bieber, F. Vogtle, Chem. Ber. 1978, 111,
2445. b) H. Singh, C. S. Gandhi, Synth. Commun. 1979, 9, 569. c) H.
Singh, S. Singh, A. S. Cheema, J. Indian Chem. Soc. 1976, 43, 682.
[7] a) G. W. Kabalka, L. Wang, V. Namboodiri, R. M. Pagni, Tetrahedron
Lett. 2000, 41, 5151. b) B. E. Blass, Tetrahedron 2002, 58, 9301, and
references therein.
Experimental
General Procedure, Synthesis of Diaryl (Dialkyl) Disulfides
from Aryl (Alkyl) Halides and Thioacetamide
2 mmol aryl (alkyl) halide, 2 mmol thioacetamide and 0.4 mmol
CuCl were added to a flask containing 2 ml DMF and 1.0 g KF
(40% by weight)/Al2O3. The reaction continued at 110°C under
atmospheric conditions until completion (5 h). The reaction prog-
ress was controlled by thin-layer chromatography. The reaction
mixture was then filtered. The filtrate was evaporated under
vacuum, CH2Cl2 (20 ml) was added and the mixture was washed
with H2O (2 × 15 ml). The organic layer was dried over anhydrous
Na2SO4. The solvent was evaporated to give the crude diaryl
(dialkyl) disulfide, which was purified by plate chromatography
(silica gel, n-hexane–ethyl acetate, 20:1). (See supporting informa-
1
tion for H-, 13C-, and 19F-NMR of the products).
Acknowledgment
[8] E. J. Lenardo, R. G. Lara, M. S. Silva, R. G. Jacob, G. Perin, Tetrahedron
Lett. 2007, 48, 7668.
[9] a) V. K. Yadav, K. G. Babu, M. Mittal, Tetrahedron 2001, 57, 7047. b) B.
Movassagh, M. Soleiman-Beigi, M. Nazari, Chem. Lett. 2008, 37, 22. c)
S.-X. Wang, J.-T. Li, W.-Z. Yang, T.-S. Li, Ultrasonics Sonochem. 2002,
9, 159.
Financial support from Ilam University Research Council is grate-
fully acknowledged.
References
[10] a) J. K. Kochi, Organomethalic Mechanisms and Catalysis,
Academic Press, New York, 1978; b) E. Sperotto, G. P. M. von Klink,
G. von Koten, J. G. de Vries, Dalton Trans. 2010, 39, 10338, and
references therein.
[1] a) S. Oae, Organic Sulfur Chemistry: Structure and Mechanism, CRC
Press, Boca Raton, FL, 1991. b) R. J. Cremlyn, An Introduction To
Organosulfur Chemistry, Wiley, New York, 1996. c) P. Metzner, A.
Thuillier, in Sulfur Reagents in Organic Synthesis (Eds: A. R. Katritzky,
O. Meth Cohn, C. W. Rees), Academic Press: San Diego, 1994. d) T.
Kondo, T. Mitsudo, Chem. Rev. 2000, 100, 3205. e) N. Taniguchi,
J. Org. Chem. 2007, 72, 1241. f) Y. Kishi, S. Nakatsuga, T. Fukuyama,
M. Havel, J. Am. Chem. Soc. 1973, 95, 6493. g) S. A. Caldarelli, M.
Hamel, J. F. Duckert, M. Ouattara, M. Calas, M. Maynadier, S. Wein,
Supporting Information
Additional supporting information may be found in the online
version of this article at the publisher’s web site.
wileyonlinelibrary.com/journal/aoc
Copyright © 2013 John Wiley & Sons, Ltd.
Appl. Organometal. Chem. 2013, 27, 734–736