Solvent- and metal-free selective oxidation of thiols to disulfides using I2/DMSO catalytic system

Article abstract of DOI:10.1016/j.tetlet.2017.11.009

We describe herein a simple, fast and inexpensive protocol for the oxidative coupling of thiols employing a stoichiometric amount of DMSO and iodine as the catalyst. Various aromatic disulfides were obtained in good to excellent yields in short reaction times at room temperature, while aliphatic disulfides were achieved in good yields when the reactions were conducted under microwave irradiation.

Full text of DOI:10.1016/j.tetlet.2017.11.009

Accepted Manuscript
Solvent- and metal-free selective oxidation of thiols to disulfides using I2/DMSO
catalytic system
Luana Bettanin, Sumbal Saba, Fábio Z. Galetto, Gustavo A. Mike, Jamal
Rafique, Antonio L. Braga
PII:
S0040-4039(17)31403-X
https://doi.org/10.1016/j.tetlet.2017.11.009
TETL 49452
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
23 September 2017
31 October 2017
5 November 2017
Please cite this article as: Bettanin, L., Saba, S., Galetto, F.Z., Mike, G.A., Rafique, J., Braga, A.L., Solvent- and
metal-free selective oxidation of thiols to disulfides using I2/DMSO catalytic system, Tetrahedron Letters (2017),
doi: https://doi.org/10.1016/j.tetlet.2017.11.009
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Graphical Abstract
To create your abstract, type over the instructions in the template box below.
Fonts or abstract dimensions should not be changed or altered.
Solvent- and metal-free selective oxidation of
thiols to disulfides using I2/DMSO catalytic
system
Leave this area blank for abstract info.
Luana Bettanin, Sumbal Saba, Fábio Z. Galetto, Gustavo A. Mike, Jamal Rafique,* and Antonio L. Braga*

1
Tetrahedron Letters
journal homepage: www.els evier.com
Solvent- and metal-free selective oxidation of thiols to disulfides using I2/DMSO
catalytic system
Luana Bettanin,a Sumbal Saba,a,b Fábio Z. Galetto,a Gustavo A. Mike,a Jamal Rafique,a* and Antonio L.
Bragaa*
a Departamento de Química, Universidade Federal de Santa Catarina, Florianópolis, 88040-900, SC-Brazil. http://labselen.ufsc.com/ Fax: 55 48 3721 6427;
Tel: 55 48 37216427; *E-mail: jamal.chm@gmail.com, braga.antonio@ufsc.br
b Department of Chemistry, Shaheed Benazir Bhutto Women University, Peshawar, 25000, KPK, Pakistan.
ARTICLE INFO
ABSTRACT
Article history:
Received
We describe herein a simple, fast and inexpensive protocol for the oxidative coupling of thiols
employing a stoichiometric amount of DMSO and iodine as the catalyst. Various aromatic
disulfides were obtained in good to excellent yields in short reaction times at room temperature,
while aliphatic disulfides were achieved in good yields when the reactions were conducted under
microwave irradiation.
Received in revised form
Accepted
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Disulfides
Iodine
Solvent-free
Metal-free
Sustainable chemistry
1. Introduction
reaction time (5 h) were required and benzene was used as the
solvent.9
The selective oxidation of thiols to disulfides is an important
process from the synthetic, economic and biochemical points of
view.1,2 Although several methods and oxidizing agents have
been described to accomplish this transformation,3-4 the
development of fast, inexpensive and less harmful protocols is
still of great interest. In addition, selectivity remains a challenge
in many cases, since thiols and disulfides can undergo over-
oxidation leading to the production of sulfonates, sulfoxides and
sulfones, among other compounds.5 Taking this into account,
several transition metals based catalysts have been developed and
successfully applied in this transformation.6 Although they offer
selectivity, their high toxicity and difficulties associated with
separating the catalyst from the final product are common
drawbacks related to the use of metal-containing catalysts, which
hampers their use in several processes.7
In this context, DMSO appears to be an interesting alternative,
since it is an inexpensive and easy-to-handle reagent. Since most
of the oxidizable functional groups are not affected by DMSO, it
should be possible to address the issue of selectivity. The use of
DMSO8 and DMSO/iodine9 in catalytic systems to promote the
oxidation of thiols to disulfides has been previously reported, but
the conditions applied to perform this conversion were harsh in
comparison with our observations. For example, when DMSO
was employed without iodine, an excess of DMSO, long reaction
time (8 h) and high temperatures (80-90 ºC) were necessary to
furnish the desired disulfides.8 On the other hand, when I2 (or HI)
was used as the catalyst, the reactions could be carried out at
room temperature but, again, an excess of DMSO and long
During our investigations on C-S coupling reactions
employing aromatic thiols,10 we observed that the oxidation of
the latter to the corresponding disulfides was completed in a short
reaction time, employing 1.0 equiv. of DMSO and 20 mol% of
iodine. As part of our wider research program aimed at designing
and developing eco-friendly processes,11 including the use of
solvent-free systems, herein we report the molecular iodine
catalyzed oxidation of thiols into symmetrical diorganyl
disulfides. This oxidative transformation was performed at room
temperature under solvent-free conditions.
For the optimization of the reaction, thiophenol 1a was
selected as a model substrate and was evaluated under various
reaction conditions (Table 1). Continuing our above-mentioned
interests, the optimization reactions were conducted under
solvent-free conditions. The reaction in the presence of 3.0 equiv.
of DMSO at room temperature with a reaction time of 5 min
without a catalyst afforded the desired product 2a in trace yields
(Table 1, entry 1). The use of 20 mol% of molecular iodine as a
catalyst demonstrated a considerable improvement and 2a was
obtained in 93% yield (Table 1, entry 2). In the next step, the
quantities of the additive were screened for this transformation
(entries 3-7). On lowering the amount of DMSO in the reaction
from 3.0 to 1.0 equiv., 2a was obtained quantitatively (entries 2-
4) while in the absence of DMSO the reaction afforded a lower
yield of 2a (entries 5).
In the subsequent step, the type of catalyst, catalytic loading
and reaction time were explored for this transformation (entries
6-11). When the reaction was performed in the presence of NaI

2
Tetrahedron
as the catalyst, 2a was obtained in 12% isolated yield (entry 6).
disulfides 2l-n were isolated in low yields, even after longer
reaction times. Notably, 1,2-dithiane-4,5-diol 2o was isolated in
86% yield after only 5 min of reaction.
It was observed that CuI provided a slightly better yield
compared to NaI (entry 6 vs 7); however, molecular iodine
remained the best option. A constant decrease in the yield of 2a
was observed on decreasing the catalytic amount of I2 (entry 2 vs
8-9). Similarly, the reaction time was also screened for this
transformation (entries 4, 10) and an ideal value of 5 min was
obtained.
Table 2 Scope and generality of the reaction using arenes 2a,b
After determining the appropriate catalyst and catalytic
loading, in the next step we screened the type of additive for this
reaction (entry 11-14). Surprisingly, all of the other organic
additives evaluated were completely ineffective, even when the
reaction time was doubled. When water was employed, the
desired product 2a was obtained in 28% yield after 10 min of
reaction.
Entry Product 2
t (min) yield (%)b
1
5
98
77
78
95
80
2
3
4
5
30
15
32
42
Table 1 - Optimization for standard reaction parametersa
Entry Additive (equiv.) Cat. (mol%) t (min) yield (%)b
1
DMSO (3)
DMSO (3)
DMSO (2)
DMSO (1)
-
-
5
traces
6
7
8
5
8
77
80
2
I2 (20)
I2 (20)
I2 (20)
I2 (20)
NaI (20)
CuI(20)
I2 (15)
I2 (10)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
5
93
3
5
Quantitative
4
5
Quantitative
12
5
62
78
5
5
60
12
37
85
76
75
-
6
DMSO (1)
DMSO (1)
DMSO (1)
DMSO (1)
DMSO (1)
CH3CN (1)
Hexane (1)
DMF (1)
H2O
5
9
7
5
8
5
10
11
9
5
8
2
73
82
10
11
12
13
14
2.5
10
10
10
10
-
12
13
14
35
23
50
40
35
68
-
28
a Reaction conditions: 1a (0.5 mmol),
b Isolated yields.
15
5
86
a Reaction conditions: 1 (0.5 mmol), in the presence of I2 (20
mol%) and DMSO (1 equiv.) at r.t.
b Isolated yields.
After ascertaining the best conditions (Table 1, entry 4), we
evaluated the generality and scope of this transformation and the
reaction demonstrated wide substrate scope in terms of the thiols
1 under the optimized conditions (Table 2).
Considering the low yields obtained for aliphatic disulfides
(2l-n), we decided to perform the reaction under microwave
irradiation, at 23oC with 100 W of power for 10 min (Scheme 1).
In all cases, better reaction yields were obtained for the
corresponding disulfides, demonstrating that in the case of
aliphatic disulfides the use of microwave irradiation improves the
product yield.
In case of structurally different organic moieties with electron-
withdrawing (Cl, Br, CF3, NO2 etc.), electron-donating (Me,
OMe, NH2, etc.) and bulky groups (t-butyl) groups, the reaction
was performed with success. In general, steric and electronic
effects (EWG and EDG) of the substituents attached at the aryl
ring of 1 afforded the desired products 2a-k in good yields. It
should be noted that thiophenols with EDG at the para position
required longer times compared to the respective EWG. We were
also delighted to find that benzylthiol afforded the desired
product 2k with 82 % yield after only 2 min of reaction.
The success in the iodine-catalyzed synthesis of symmetrical
diaryl disulfides prompted us to extend this method to the
preparation of dialkyl disulfides (2l-o). In general, aliphatic thiols
were not found to be efficient substrates, since the respective
Scheme 1. MW-assisted synthesis of disulfides 2l-n.

3
It can be observed in Figure 1 that, in most cases, the end of
the reaction could be visually identified. Initially, the brownish-
red solution of DMSO/I2 turns light yellow after the addition of
thiophenol 1a. The solution then returns to a brownish-red after 5
min of reaction, indicating the total consumption of thiol and re-
generation of molecular iodine in the reaction medium.
Scheme 3. Investigation of the reaction mechanism.
Figure 1. Visual color changes in the reaction medium during the
oxidation of thiophenol (at 10 mmole scale): (a) 20 mol% of
iodine in 10 mmol of DMSO (1 molar equiv); (b) addition of 10
mmol of PhSH in the reaction medium; and (c) after 5 min of
stirring at r.t.
Based on these results and on previous reports,10,11a,e
a
plausible mechanism for the transformation is proposed in
Scheme 4. An electrophilic species A (PhSI) is most likely
generated when the thiophenol 1a undergoes reaction with the
catalyst (I2) along with the generation of HI. Subsequently,
another molecule of 1a attacks the intermediate A, forming the
desired product B with the simultaneous formation of another
molecule HI. In the next step, HI reacts with DMSO affording a
protonated sulfur species C* (detected by HPLC-MS, ESI-S38A).
This intermediate is quickly converted to D* (detected by HPLC-
MS, ESI-S38B), which on reaction with another HI molecule
forms the iodine-dimethyl sulfide adduct E with the formation of
water.12 Lastly, the iodide species E eliminates dimethyl
sulfide10b,11a with the regeneration of the catalyst (I2), completing
the catalytic cycle.
The importance of symmetrical diorganyl disulfides in organic
reactions is well established, as they are widely used as substrates
and sulfenylating agents.1,2,11a-e Therefore, we further investigated
the synthetic utility of this new protocol by scaling-up the
reaction to 10 mmol and 100 mmol (Scheme 2). Thiophenol 1a
was selected as the reagent to be tested under optimized
conditions, affording 2a with 78% isolated yields at scale up to
100 mmol. Thus, this procedure could be used as a robust method
for the synthesis on the gram scale of symmetrical diorganyl
disulfides.
Scheme 2. Results for the reaction on multigram scale.
To propose a plausible mechanism for this reaction, some
control experiments were carried out (Scheme 3). It was found
that the presence of 3.0 equiv. of TEMPO and hydroquinone as
radical inhibitor did not inhibited the reaction, and 2a was
obtained in 86% and 93% yields, respectively (Scheme 2-I),
which excluded the possibility of
a
radical pathway.
Scheme 4. Proposed mechanism for the reaction.
Subsequently, performing the reaction under an inert atmosphere
led to a slight decrease in efficacy (Scheme 3-II), while an
oxygen atmosphere did not show any effect (Scheme 3-III).
These results indicate that the presence of oxygen is not crucial
but can contribute to obtaining high yields. Compound 2a was
obtained in 87% yield when the standard reaction was performed
in the presence of 1 equiv. of H2O2 (Scheme 3-IV), indicating
that in this system DMSO acts as an oxidant. Based on our
previous research,10,11a,e with the use of HI as a catalyst instead of
iodine (Scheme 3-V) 3a can be isolated with 96% yield,
indicating that HI is probably one of the intermediates of this
transformation.
In summary, we have developed a selective and efficient
procedure for the oxidative dimerization of thiols catalyzed by
iodine, using a stoichiometric amount of DMSO as a mild
oxidant. This protocol afforded the desired products in good to
excellent yields under solvent- and metal-free conditions and can
be applied under both conventional and microwave heating
conditions. Most importantly, this procedure offers significant
improvements, including operational simplicity,
a greener
procedure and low cost, and thus represents an interesting
alternative to the existing methodologies.

4
Tetrahedron
and Patai. S. Syntheses of Sulphones, Sulphoxides and Cyclic
Sulphides, John Wiley & Sons: Chichester, 1995. (c) Martin, C.;
Sandrinelli, F.; Perrio, C.; Perrio, S.; Lasne, M.-C. J. Org. Chem.
2006, 71, 210-214.
Acknowledgments
We gratefully acknowledge CAPES, CNPq, CERSusChem
GSK/FAPESP (grant 2014/50249-8), INCT-Catálise and
FAPESC-Pronex for financial support. L.B. (doctoral fellow)
thanks CNPq for the fellowships.
6. (a) Das, P.; Ray, S.; Bhaumik, A.; Banerjee, B.; Mukhopadhayay,
C. RSC Adv. 2015, 5, 6323-6331; (b) Khan, M. F.; J. Sorenson, J.
R. J. Inorg. Biochem. 1991, 41, 221-234. (c) Cecconi, I.; Scaloni,
A.; Rastelli, G.; Moroni, M.; Vilardo, P. G.; Costantino, L.;
Cappiello, M.; Garland, M. D.; Carper, D.; Petrash, J. M.; Del
Corso, A.; Mura, U. J. Biol. Chem. 2002, 277, 42017-42027; (d)
Choi, J.; Yoon, N. M. J. Org. Chem. 1995, 60, 3266-3267; (e)
Joseph, J. K.; Jain, S. L.; Sain, B. Ind. Eng. Chem. Res. 2010, 49,
6674-6677; (f) Chauan, S. M. S.; Kumar, A.; Srinivas, K. A.
Chem. Commun. 2003, 2348–2349; (g) Dhakshinamoorthy, A.;
Alvaro, M.; Garcia, H. Chem. Commun. 2010, 46, 6476-6478. (h)
Dutta, P. K.; Majumder, A.; Dutta, S.; Dhar, B. B.; Munshi, P.;
Sen, S. Tetrahedron Lett. 2017, 58, 527-530.
Supplementary Material
Supplementary data associated with this article can be found,
in the online version, at http://
References and notes
7. (a) Sun, C.-L.; Shi, Z.-J. Chem. Rev. 2014, 114, 9219–9280; (b)
Roscales, S.; Csákÿ, A. G. Chem. Soc. Rev. 2014, 43, 8215-8225;
(c) Bhunia, A.; Yetra, S. R.; Biju, A. T. Chem. Soc. Rev. 2012, 41,
3140-3152.
8. (a) Arterburn, J. B.; Perry, M. C.; Nelson, S. L.; Dible, B. R.;
Holguin, M. S. J. Am. Chem. Soc. 1997, 119, 9309-9310. (b) Sanz,
R.; Aguado, R.; Pedrosa, M. R; Arnáiz, F. J. Synthesis 2002, 7,
856-858.
1. (a) Patai, S. and Rappoport, Z. The Chemistry of Sulphur-
Containing Functional Groups, John Wiley & Sons: Chichester,
1993; (b) Patai. The Chemistry of the Thiol Group, John & Sons:
London, 1974. (b) Cremlyn. R. J. An Introduction to Organosulfur
Chemistry, Wiley & Sons: New York, 1996. (c) P. C. Jocelyn.
Biochemistry of the Thiol Group, American Press: NewYork,
1992.
2. Some recent examples:(a) Laudadio, G.; Straathof, N. J. W.;
Lanting, M. D.; Knoops, B.; Hessel, V.; Noël, T. Green Chem.
2017, 19, 4061-4066.; (b) Chauvin, J.-P. R.; Pratt, D. A. Angew.
Chem. Int. Ed. 2017, 56, 6255-6259; (c) Hinman, J. G.; Eller, J.
R.; Lin, W. L.; Li, J.; Li, J.; Murphy, C. J. J. Am. Chem. Soc.
2017, 139, 9851–9854. (d) Lutkus, L. V.; Irving, H. E.; Davies, K.
S.; Hill, J. E.; Lohman, J. E.; Eskew, M. W.; Detty, M. R.;
McCormick, T. M. Organometallics 2017, 36, 2588–259; (e)
Spicer, C. D.; Davis, B. G. Nat. Commun. 2014, 5, 474.
3. (a) Ranke, J.; Stolte, S.; Störmann, J. Jastorf. B. Chem Rev. 2007,
107, 2183-2206; (b) Paul, S.; Islam, S. M. RSC Adv. 2016, 6,
95753-95759. (c) Singh, D.; Galetto, F. Z.; Soares, L. C.;
Rodrigues, O. E. D.; Braga, A. L. Eur. J. Org. Chem. 2010, 2661-
2665.
9. Aida, T.; Akasaka, T.; Furukawa, N.; Oae, S. Bull. Chem. Soc.
Jpn.1976, 49, 1441-1442.
10. (a) Saba, S.; Rafique, J.; Braga, A. L. Adv. Synth. Catal. 2015,
357, 1446-1452; (b) Rafique, J.; Saba, S.; Rosário, A. R.; Braga,
A. L. Chem. Eur. J. 2016, 22, 11854-11862;
11. (a) Saba, S.; Rafique, J.; Braga, A. L., Catal. Sci. Tech. 2016, 6,
3087-3098; (b) Rafique, J.; Saba, S. Schneider, A. R.; Franco, M.
S.; Silva, S. M.; Braga, A. L. ACS Omega, 2017, 2, 2280-2290; (c)
Rafique, J.; Saba, S.; Rosário, A. R.; Zeni, G.; Braga, A. L. RSC
Adv. 2014, 4, 51648-51652; (d) Saba, S.; Botteselle, G. V.; Godoi,
M.; Frizon, T. E. A.; Galetto, F. Z.; Rafique, J.; Braga, A. L.
Molecules 2017, 22, 1367; (e) Silva, L. T.; Azeredo, J. B.; Saba,
S.; Rafique, J.; Bortoluzzi, A. J.; Braga, A. L. Eur. J. Org. Chem.
2017, 4740-4748; (f) Rocha, M. S. T.; Rafique, J.; Saba, S.;
Azeredo, J. B.; Back, D.; Godoi, M.; Braga, A. L. Synth. Commun.
2017, 47, 291-298.
4. (a) Shaabani, A.; Tavasoli-Rad, F.; Lee, D. E. Synth. Commun.
2005, 34, 571-580. (b) Hashemi, M. M.; Rahimi, A.; Jaberi-
Karimi, Z. Lett. Org. Chem. 2005, 2, 485-488. (c) Banfield, S.;
Omori, A. T.; Leisch, H.; Hudlicky. T. J. J. Org. Chem. 2007, 72,
4989-4992. (d) Mlostoń, G.; Capperucci, A.; Tanini, D.; Hamera-
Fałdyga, R.; Heimgartner, H. Eur. J. Org Chem. 2017, DOI:
10.1002/ejoc.201701066.
12. (a) Tamres, M.; Bhat, S. N. J. Am. Chem. Soc. 1972, 94, 2577-
2582; (b) Lo, S. J.; Tamres, M. Can. J. Chem. 1983, 61, 1933-
1940.
Click here to remove instruction text...
5. (a) Trost, B. M. and Fleming. I. Comprehensive Organic
Synthesis: Selectivity, Strategy and Efficiency in Modern Organic
Chemistry, Pergamon Press: New York, 1991. (b) Rappoport, Z.
Highlights
•
Facile access to diorganyl disulfides from thiols.
Selective oxidation of thiols to disulfides using
I2/DMSO catalytic oxidant system
•
•
•
Oxidation of thiophenol to diphenyl disulfide in
up to 100 mmol scale
A greener procedure for the preparation of
disulfides using conventional as well as
microwave irradiations